Neoreviews 3.11

DOI: 10.1542/neo.12-3-e127 2011;12;e127-e129 NeoReviews

Tonse N.K. Raju Sideshows

Historical Perspectives: Perinatal Profiles: Martin Couney and Newborn Infant

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The Underpinnings ofNeonatal/Perinatal Medicine

Author Disclosure

Dr Raju has disclosed no financial

relationships relevant to this article.

This commentary does not contain a

discussion of an unapproved/

investigative use of a commercial

product/device.

Perinatal Profiles: Martin Couney andNewborn Infant SideshowsTonse N.K. Raju, MD*

IntroductionAmong the many interesting, if bi-zarre, chapters in neonatal history,the one that ranks on top is the storyof preterm baby sideshows, whichwere organized by Dr Martin Couney(Fig 1), starting in 1896 and con-tinuing for 40 years. This articletraces the origins and growth of thebaby shows, with a perspective ontheir effect on contemporary neo-natal practice and a reflection on theboundaries between propaganda, pub-licity, public education, and service.

The SettingAt the time of the French Revolu-tion, the infant death rate in Francewas well over 50%. Alarmed by thiscrisis, the Revolutionary Council en-

acted a decree in 1789 proclaimingthat the working-class parents “havea right to the nation’s succors at alltimes,” (1) heralding reforms towardmaking the country an idealistic wel-fare state. France also began collect-ing national vital statistics, becomingone of the first countries to do so.

Despite these efforts, due to contin-ued high infant mortality and declin-ing birthrates, negative populationgrowth continued through much ofthe 19th century. This led to an unex-pected consequence of shortages ofmen enlisting into the army. As Francewas engaged in several battles withPrussia and other neighbors, a thin-ning army was highly worrisome. Aseries of measures were taken to im-prove maternal and neonatal care andto reduce child mortality, (2)(3) andyoung parents were urged to upholdtheir patriotism and bear “more chil-dren to man the future armies.” Whatan irony that such noble intentionsas saving babies had to be motivatedby the brutal needs for manning thearmies!

The Birth of the Incubatorand Neonatal IntensiveCare UnitsAccording to a popular story, Steph-ane Tarnier, a highly respected Frenchobstetrician, was so inspired by the op-timal warmth inside the chicken farm-ing section of the Paris zoo that heasked Odile Martin, the engineer, todevelop “incubators,” or “couveuses,”for use in the hospitals. The first cou-veuse was installed in the Paris Mater-nity Hospital in 1880 and more fol-lowed. These well-ventilated, 1-cubicmeter, double-walled metal boxeswere heated using a thermo-syphonmethod and could hold two preterm

*Medical Officer/Program Scientist, Pregnancy andPerinatology Branch, CDBPM, Eunice KennedyShriver National Institute of Child Health andHuman Development, National Institutes of Health,Bethesda, MD.

Figure 1. Presumed photograph of theyoung Martin Couney from the Pan-American Exhibition in Buffalo, NewYork, 1901.

historical perspectives

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babies. Tarnier’s students, Pierre Bu-din and Alfred Auvard, made furtherimprovements to preterm baby care bykeeping them in a geographically spec-ified area within the hospital, separatefrom the maternity wards. These werethe first preterm baby wards, whichlater came to be known as neonatalintensive care units throughout theworld.

Enter Dr CouneyThere is some controversy abouthow and why Dr Martin Couney,supposedly a student of Budin, tookpreterm babies into his show in Ber-lin in 1896. (2)(3)(4)(5) Perhaps oneof Couney’s mentors wished to ex-hibit the new incubators to drama-tize modern discoveries that weresaving lives. As he prepared for theBerlin Exposition of 1896, Couneyobtained six incubators, probablyfrom the French innovator Alex-ander Lion. The initial intent was toexhibit only the incubators, but per-haps to add a little drama, Couneymanaged to bring six preterm infantsfrom Rudolph Virchow’s maternityunit in Berlin and exhibited theminside the incubators during the Ex-position. He coined a catchy phrasefor the show, kinderbrutanstalt, or“child hatchery,” igniting the imagi-nation of a public already thirsty forsensational scientific breakthroughs.

Couney’s Berlin baby show wasan unqualified hit. It was more pop-ular than the Congo Village andTyrolean Yodelers, with daily news-paper articles praising the modernmarvel of incubator technology.Buoyed by the success, Couney orga-nized a similar show at Great Brit-ain’s Victorian Era Exhibition in1897. The subsequent year, he sailedthe Atlantic and organized the firstUnited States incubator show at the1898 Omaha Trans-Mississippi Ex-position. He settled in New York and

began annual preterm baby exhibitsat New York’s Coney Island Board-walk that lasted for 40 years. (6)

During summer months, Couneytook his baby shows to state fairs, trav-eling circuses, and science and recre-ational expositions all over the UnitedStates. They were large hits in SanFrancisco, Chicago, St. Louis, Buffalo,and Minneapolis. Charging a dime ora quarter for entrance, on some daysCouney earned $1,500. He claimedthat 6,500 of the 8,000 babies hecared for in these exhibits survived.The last of the baby shows washeld during the 1939 to 1940 seasonin Atlantic City. A commemorativebronze plaque has been placed on thewall next to the entrance to the Holi-day Inn Hotel, where Couney exhibitswere held. (4) Couney, who made agreat deal of money, died impover-ished on March 1, 1950. (6)

Besides the baby shows, Couneyheld annual reunions for the survi-vors from his baby shows, sendingtheir families typewritten invitations(Fig. 2). The “graduates” received adiploma signed by Couney and a sil-ver cup with the infant’s name in-scribed on it. Many survivors fromthose baby shows, who are now intheir seventies and eighties, have comeforward. (6) Two of those born in1933 were featured in a documentaryby the Public Broadcasting Service,aired in the summer of 2009 as part ofits History Detectives series. (7)

Reaction of theScientific EstablishmentJust as the popular media praisedCouney for his baby shows, initial re-action from scientific journals was pos-itive. (8) Lancet even recommendedthat large “incubator stations” similarto “fire stations,” be started for parentsto borrow incubators, hence addingthe phrase incubator stations as partof the medical lexicon that was sy-nonymous with neonatal intensive

care units. The popular media in theUnited States also praised Couney. (6)The New Yorker called him “a patronof the preemies.” (9) However, therewere criticisms. In a later editorial ti-tled “The Danger of Making a PublicShow of Incubators for Babies,” theLancet editors lamented “copy catshows” and warned against exhibitingbabies next to the “. . . leopard cages. . . marionettes . . . [and] . . . catch-penny monstrosity.” (10)

The reaction from the contempo-rary medical profession is harder tounderstand or explain. Very few aca-demicians openly criticized Couneyfor “exhibiting” preterm infants asif they were commodities. I suspectthat they were secretly happy that atleast they could refer the pretermbabies in their care to Couney. Sucheminent pediatricians as Julius Hessof Chicago regularly sent babies tohis care, tacitly acknowledging hisexpertise. In Couney’s visitor’s book,Hess wrote a note thanking him forhis scientific leadership and callinghim “my great teacher.” (6)

A PerspectiveMany questions should be askedabout the Couney shows and theirrelevance to pediatrics. Some claimthat Couney was the “first neonatol-ogist,” but he was not. In fact, thephrase “neonatology” or “neonatol-ogist” did not exist in Couney’s time.They were coined by Dr AlexanderSchaffer in 1960. (11)

Couney had had no license to prac-tice medicine in the state of New Yorkor anywhere else in the United States.Although he looked after many pre-term babies who might have otherwisedied early, he generally looked after agroup of healthy, growing pretermbabies, avoiding the very sick and thevery small.

His success was nevertheless note-worthy. His strict attention to clean-liness, temperature control, and a


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regimented feeding schedule usinghuman milk from wet nurses allowedhim to achieve high survival rateswithout the aid of ventilators, oxy-gen, or antibiotics. In this regard,health care elsewhere during his timewas no better than what he couldoffer. Therefore, there is credenceto his claim that he was a “pioneer,”who popularized newborn care and

educated the public that not all pre-term babies were destined to die.

The story of Couney’s baby showsprovides an eerie echo of the sensation-alism sought today in popularizing“spectacular medical breakthroughs.”The news media’s desire for obtainingstories of medical marvels and the pub-lic’s curiosity about rare phenomenarecall the preterm baby shows. The

shows are also symbolic of the diffi-culty in preserving a delicate balancebetween information, public educa-tion and awareness, and sensational-ism. Traveling baby shows were similarto traveling moon rock exhibits thatexploited the popularity of man’s land-ing on the moon and helped increasethe National Aeronautics and SpaceAdministration’s annual budgets. Inthis regard, the impact of Couney andhis shows on the growth of neonatalmedicine has not been evaluated. Thepublic clearly saw that with Couney’scare, even the most severely preterminfants had a chance for survival. How-ever, did such appreciation translateinto supporting academic pediatriciansin their pursuit of pediatric research?The answer remains unknown.

References1. Spaulding M, Welch P. Dry nursing. In:Nurturing Yesterday’s Child. A Portrayal ofthe Drake Collection of Pediatric History.Philadelphia, PA: BC Decker; 1991:69–1102. Baker JP. The incubator controversy: pe-diatricians and the origins of premature in-fant technology in the United States,1890–1910. Pediatrics. 1991;87:654–6623. Baker JP. The Machine in the Nursery:Incubator Technology and the Origins ofNewborn Intensive Care. Baltimore, MD:Johns Hopkins University Press; 19964. Silverman WA. Incubator-baby sideshows. Pediatrics. 1979;64:127–1415. Butterfield LJ, Baker JP, Ballowitz L, et alfor the AAP Perinatal Section Ad Hoc Com-mittee on Perinatal History. Martin Couney’sstory revisited. Pediatrics. 1997;100:159–1606. Dr. Martin Arthur Couney (1860?–1950).Neonatology on the Web. 2010. Accessed De-cember 2010 at: http://www.neonatology.org/pinups/couney.html7. Episode 609. History Detectives. PublicBroadcasting Service, Oregon PBS Station,20098. The Victorian era exhibition at Earl’sCourt [editorial]. Lancet. 1897;2:1619. Liebling AJ. Profiles: a patron of the pre-emies. The New Yorker. June 3, 1939:20–2410. The danger of making a public show ofincubators for babies [editorial]. Lancet.1898;1:39011. Schaffer AJ. Diseases of the Newborn.Philadelphia, PA: Saunders; 1960

Figure 2. Invitation letter dated July 19, 1934, for the reunion of the incubator babysideshow from Dr Couney to the mother of an infant who was an incubator sideshowsurvivor. Reproduced with permission of Oregon Public Broadcasting.





Tonse N.K. Raju Sideshows

Historical Perspectives: Perinatal Profiles: Martin Couney and Newborn Infant

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Charlotte Clock and Leonardo Pereira Strip of the Month: March 2011







Strip of the Month: March 2011Charlotte Clock, MD,*

Leonardo Pereira, MD,

MCR*

Author Disclosure

Drs Clock and Pereira

have disclosed no

financial relationships

relevant to this

article. This

commentary does not

contain a discussion

of an unapproved/

investigative use of a

commercial

product/device.

Electronic Fetal Monitoring Case Review SeriesElectronic fetal monitoring (EFM) is a popular technology used to establish fetal well-being. Despite its widespread use, terminology used to describe patterns seen on themonitor has not been consistent until recently. In 1997, the National Institute of ChildHealth and Human Development (NICHD) Research Planning Workshop publishedguidelines for interpretation of fetal tracings. This publication was the culmination of2 years of work by a panel of experts in the field of fetal monitoring and was endorsed in2005 by both the American College of Obstetricians and Gynecologists (ACOG) and theAssociation of Women’s Health, Obstetric and Neonatal Nurses (AWHONN). In 2008,ACOG, NICHD, and the Society for Maternal-Fetal Medicine reviewed and updated thedefinitions for fetal heart rate patterns, interpretation ,and research recommendations.Following is a summary of the terminology definitions and assumptions found in the 2008NICHD workshop report. Normal values for arterial umbilical cord gas values andindications of acidosis are defined in Table 1.

Assumptions from the NICHD Workshop

● Definitions are developed for visual interpretation, assuming that both the fetal heart rate(FHR) and uterine activity recordings are of adequate quality

● Definitions apply to tracings generated by internal or external monitoring devices● Periodic patterns are differentiated based on waveform, abrupt or gradual (eg, late

decelerations have a gradual onset and variable decelerations have an abrupt onset)● Long- and short-term variability are evaluated visually as a unit● Gestational age of the fetus is considered when evaluating patterns● Components of fetal heart rate FHR do not occur alone and generally evolve over time

DefinitionsBaseline Fetal Heart Rate

● Approximate mean FHR rounded to increments of 5 beats/min in a 10-minute segmentof tracing, excluding accelerations and decelerations, periods of marked variability, andsegments of baseline that differ by �25 beats/min

● In the 10-minute segment, the minimum baseline duration must be at least 2 minutes(not necessarily contiguous) or the baseline for that segment is indeterminate

● Bradycardia is a baseline of �110 beats/min; tachycardia is a baseline of �160 beats/min

● Sinusoidal baseline has a smooth sine wave-like undulating pattern, with waves havingregular frequency and amplitude

Baseline Variability

● Fluctuations in the baseline FHR of two cycles per minute or greater, fluctuations areirregular in amplitude and frequency, fluctuations are visually quantitated as the ampli-tude of the peak to trough in beats per minute

● Classification of variability:Absent: Amplitude range is undetectableMinimal: Amplitude range is greater than undetectable to 5 beats/minModerate: Amplitude range is 6 to 25 beats/minMarked: Amplitude range is �25 beats/min

*Assistant Professor, Division of Maternal-Fetal Medicine, Oregon Health & Sciences University, Portland, Ore.

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Accelerations

● Abrupt increase in FHR above the most recently deter-mined baseline

● Onset to peak of acceleration is �30 seconds, acme is�15 beats/min above the most recently determinedbaseline and lasts �15 seconds but �2 minutes

● Before 32 weeks’ gestation, accelerations are definedby an acme �10 beats/min above the most recentlydetermined baseline for �10 seconds

● Prolonged acceleration lasts �2 minutes but �10 min-utes

Late Decelerations

● Gradual decrease in FHR (onset to nadir �30 seconds)below the most recently determined baseline, withnadir occurring after the peak of uterine contractions

● Considered a periodic pattern because it occurs withuterine contractions

Early Decelerations

● Gradual decrease in FHR (onset to nadir �30 seconds)below the most recently determined baseline, withnadir occurring coincident with uterine contraction

● Also considered a periodic pattern

Variable Decelerations

● Abrupt decrease in FHR (onset to nadir �30 seconds)● Decrease is �15 beats/min below the most recently

determined baseline lasting �15 seconds but �2 minutes● May be episodic (occurs without a contraction) or

periodic

Prolonged Decelerations

● Decrease in the FHR �15 beats/min below the mostrecently determined baseline lasting �2 minutes but�10 minutes from onset to return to baseline

Decelerations are tentatively called recurrent if they oc-cur with �50% of uterine contractions in a 20-minuteperiod.

Decelerations occurring with �50% of uterine contrac-tions in a 20-minute segment are intermittent.

Sinusoidal Fetal Heart Rate Pattern

● Visually apparent, smooth sine wavelike undulatingpattern in the baseline with a cycle frequency of 3 to5/minute that persists for �20 minutes.

Uterine Contractions

● Quantified as the number of contractions in a 10-minute window, averaged over 30 minutes.

Normal: �5 contractions in 10 minutesTachysystole: �5 contractions in 10 minutes

InterpretationA three-tier Fetal Heart Rate Interpretation system hasbeen recommended as follows:

● Category I FHR tracings: Normal, strongly predictiveof normal fetal acid-base status and require routinecare. These tracings include all of the following:

�Baseline rate: 110 to 160 beats/min�Baseline FHR variability: Moderate�Late or variable decelerations: Absent�Early decelerations: Present or absent�Accelerations: Present or absent

● Category II FHR tracings: Indeterminate, require evalu-ation and continued surveillance and reevaluation. Exam-ples of these tracings include any of the following:

�Bradycardia not accompanied by absent variability�Tachycardia�Minimal or marked baseline variability�Absent variability without recurrent decelerations�Absence of induced accelerations after fetal stimula-

tion

Table 1. Arterial Umbilical Cord Gas ValuespH Pco2 (mm Hg) Po2 (mm Hg) Base Excess

Normal* >7.20 <60 >20 <�10(7.15 to 7.38) (35 to 70) (�2.0 to �9.0)

Respiratory Acidosis <7.20 >60 Variable <�10Metabolic Acidosis <7.20 <60 Variable >�10Mixed Acidosis <7.20 >60 Variable >�10

*Normal ranges from Obstet Gynecol Clin North Am. 1999;26:695

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�Recurrent variable decelerations with minimal ormoderate variability

�Prolonged decelerations�Recurrent late decelerations with moderate variability�Variable decelerations with other characteristics, such as

slow return to baseline● Category III FHR tracings: Abnormal, predictive of

abnormal fetal acid-base status and require promptintervention. These tracings include:

�Absent variability with any of the following:y Recurrent late decelerationsy Recurrent variable decelerationsy Bradycardia

�Sinusoidal pattern

Data from Macones GA, Hankins GDV, Spong CY,Hauth J, Moore T. The 2008 National Institute of ChildHealth and Human Development workshop report onelectronic fetal monitoring. Obstet Gynecocol. 2008;112:661–666 and American College of Obstetricians andGynecologists. Intrapartum fetal heart rate monitoring:nomenclature, interpretation, and general managementprinciples. ACOG Practice Bulletin No. 106. Washing-ton, DC: American College of Obstetricians and Gyne-cologists; 2009.

We encourage readers to examine each strip in thecase presentation and make a personal interpretation ofthe findings before advancing to the expert interpreta-tion provided.

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Case PresentationHistory

A 27-year-old primigravida at 36–1/7 weeks gestationpresents to labor and delivery for induction of labor. Herpregnancy is complicated by elevated maternal serumalpha-fetoprotein (AFP) (2.45 MoM), chronic hepatitisB, intrauterine growth restriction, oligohydramnios, andnow preeclampsia. Anatomy ultrasonography scan ap-peared normal, with no evidence of a neural tube defect.Due to her unexplained elevated AFP value and itsassociation with growth restriction, she underwent in-terval fetal growth ultrasonography imaging. (1) Shehas been followed by the family practice service butnow is transferred to the obstetric service due to hersevere preterm preeclampsia. She denies any head-ache, visual changes, nausea, or right upper quadranttenderness. Of note on her prenatal laboratory testsare an elevated 1-hour glucose tolerance test result of

181 mg/dL (10.0 mmol/L), with a normal 3-hourglucose tolerance test result. Her hepatitis B surfaceantigen is positive, core antibody is positive, and hepatitisBE antigen is negative.

On physical examination, her blood pressure is 151/92 mm Hg and she has 625 mg of protein in a 24-hoururine collection. Her most recent ultrasonographic scandemonstrated growth restriction, with an estimated fetalweight less than the 10th percentile for gestational age.The elevated blood pressures, proteinuria, and fetalgrowth restriction lead to the diagnosis of severe pre-eclampsia. (2) The woman is afebrile, and other exami-nation findings are within normal parameters. Her cervixis 2 cm long, 1 cm dilated, and �2 station. Laboratoryevaluation reveals an elevated creatinine of 1.16 mg/dL(102.5 �mol/L) and a hematocrit of 37% (0.37). Allother values are normal. An FHR tracing is obtained onadmission (Fig. 1).

Figure 1. EFM Strip #1.

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Findings on EFM Strip #1 are:

● Variability: Moderate● Baseline Rate: 130 beats/min● Episodic Pattern: Accelerations● Periodic Pattern: None noted● Uterine Contractions: None observed● Interpretation: Category I tracing● Differential Diagnosis: Normal tracing, with fetal well-

being indicated by moderate variability and accelerations

● Action: No intervention required. Labor should beinduced due to severe preeclampsia.

Case ProgressionThe decision is made to proceed with induction of laborusing a transcervical Foley bulb. Thirteen hours later, theFoley bulb is expelled. Cervical examination shows 4 cmlong, 80% dilated, and �2 station. Oxytocin is startedand titrated to an active contraction pattern. The fetaltracing is shown in Figure 2.



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● Variability: Moderate● Baseline Rate: 130 beats/min● Episodic Pattern: Acceleration● Periodic Pattern: Intermittent variable decelerations● Uterine Contractions: Irregular, but not well docu-

mented● Interpretation: Category II● Differential Diagnosis: Possible variable deceleration

due to intermittent umbilical cord compression● Action: Overall, the tracing is reassuring due to mod-

erate variability, but better documentation of con-tractions could be helpful. An intrauterine pressure

catheter could improve the quality of contraction mon-itoring and can be placed because there are no contra-indications. It is important have accurate informationto evaluate the fetal status before continuing withinduction of labor.

Due to the patient’s chronic hepatitis B status and reas-suring tracing, the decision is made to avoid early ruptureof membranes. The external monitors are adjusted in anattempt to monitor her contractions better. The induc-tion continues with oxytocin. One hour later, the physi-cian is called to the patient’s room to view the fetaltracing (Fig. 3).



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● Variability: Moderate● Baseline Rate: 140 beats/min● Episodic Pattern: None● Periodic Pattern: Recurrent variable decelerations● Uterine Contractions: Occurring every 2 minutes, last-

ing 40 seconds● Interpretation: Category II, with recurrent variable

decelerations and periods of moderate variability● Differential Diagnosis: Intermittent umbilical cord

compression, cord prolapse, or uteroplacental insuffi-ciency could explain the fetal heart rate tracing

● Action: The moderate variability is reassuring, al-though the cause for the variable decelerations should

be considered. Sterile vaginal examination should beperformed to evaluate dilation and to check for cordprolapse. Maternal position changes, administration ofoxygen, and decrease or discontinuation of oxytocinshould be considered.

Cervical examination revealed 5 cm long, 80% dilated,and �2 station, with no palpable cord. Induction iscontinued with intermittent resolution of the variabledecelerations, but 30 minutes later, the variable decel-erations return. The decision is made to rupturemembranes artificially and place an intrauterine pres-sure catheter. The fetal heart tracing is shown inFigure 4.



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● Variability: Minimal to moderate● Baseline Rate: 160 beats/min● Episodic Pattern: Unable to determine● Periodic Pattern: Recurrent variable decelerations● Uterine Contractions: Occurring every 2 minutes● Interpretation: Category II● Differential Diagnosis: Unchanged● Action: Resuscitative measures should be undertaken,

including administration of intravenous fluids and ox-ygen, position changes, and decrease or discontinua-tion of oxytocin. The fetal status should be monitoredvery closely because the recurrent variable decelera-tions reflect fetal hypoxia and acidosis can develop.

The physicians remain at the patient’s bedside tomonitor the fetal status as resuscitative measures areperformed. The variable decelerations continue. An-other fetal heart tracing is obtained (Fig. 5).



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● Variability: Moderate● Baseline Rate: Unable to determine● Episodic Pattern: None● Periodic Pattern: Recurrent variable decelerations fol-

lowed by bradycardia● Uterine Contractions: Difficult to determine● Interpretation: Category III● Differential Diagnosis: Maternal hypotension, abrup-

tion, cord compression with or without prolapse, uter-ine rupture, and vasa previa

● Action: Immediate delivery is indicated because ofconcern for fetal acidosis due to the recurrent variabledecelerations and bradycardia. Oxytocin should be dis-continued, maternal position should be changed, ma-ternal oxygen should be continued, fluid should be

administered, and the patient should be re-examinedfor evidence of cord prolapse.

Cord prolapse is discovered on re-examination. The fetalhead is elevated by the examiner, terbutaline is administeredfor uterine relaxation, and the decision is made to proceedwith cesarean delivery. Fourteen minutes later, a primarycesarean delivery is performed under general anesthesia.

OutcomeA viable female infant is delivered by cesarean section. Sheweighs 3 lb 15 oz and has Apgar scores of 7 at 1 minute and8 at 5 minutes. The arterial blood gas results are consistentwith respiratory acidosis (Table 2). The baby receives tactilestimulation only and is taken to the neonatal intensive careunit for observation due to low birthweight. She receives


Table 2. Arterial Umbilical Cord Gas ValuespH PCO2 (mm Hg) PO2 (mm Hg) Base Excess

Normal* >7.20 <60 >20 <�10(7.15 to 7.38) (35 to 70) (�2.0 to �9.0)

Respiratory Acidosis <7.20 >60 Variable <�10Metabolic Acidosis <7.20 <60 Variable >�10Mixed Acidosis <7.20 >60 Variable >�10Patient 6.99 100 12 �7.4

*Normal ranges from Obstet Gynecol Clin North Am. 1999;26:695

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hepatitis B immune globulin and hepatitis B vaccination.She is discharged to the mother-baby unit after 24 hoursand goes home with her mother.

Umbilical cord prolapse is an obstetric emergencythat occurs in 0.2% of all deliveries. The average cervicaldilation is 5.8 cm when cord prolapse occurs, but it canhappen at any dilation. Risk factors include fetal malpre-sentation, prematurity, premature rupture of mem-branes, polyhydramnios, and obstetric maneuvers. (3)Cord prolapse usually presents with either a severe, pro-longed bradycardia or moderate/severe variable deceler-ations in a previously normal tracing. (4) Once diag-nosed, it is important to try to decompress the pressureon the umbilical cord by elevating the fetal head out ofthe pelvis or through retrograde filling of the bladder.Emergent cesarean delivery is indicated if this option isavailable. Fetal morbidity and mortality from umbilical

cord prolapse has decreased significantly due to the avail-ability of emergent cesarean delivery and improved carein the neonatal intensive care unit. (5)

References1. Waller DK, Lustig LS, Cunningham GS, Golbus MS, Hook EBN.Second-trimester maternal serum alpha-fetoprotein levels and the riskof subsequent fetal death. N Engl J Med. 1991;325:6–102. American College of Obstetricians and Gynecologists (ACOG).Diagnosis and management of preeclampsia and eclampsia. ACOGPractice Bulletin No. 33, January 2002. Obstet Gynecol. 2002;99:159–1673. Koonings PP, Paul RH, Campbell K. Umbilical cord prolapsed.A contemporary look. J Reprod Med. 1990;35:690–6924. Usta IM, Mercer BM, Sibai BM. Current obstetrical practiceand umbilical cord prolapse. Am J Perinatol. 1999;16:479–4845. Panter KR, Hannah ME. Umbilical cord prolapsed: so far sogood? Lancet. 1996;347:74

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Charlotte Clock and Leonardo Pereira Strip of the Month: March 2011













Maureen E. Sims Legal Briefs: Consequences of Ineffective Breastfeeding







Author Disclosure

Dr Sims has disclosed that she has

been compensated for reviewing

records and providing testimony in

some of the cases highlighted in

Legal Briefs. This commentary does

not contain a discussion of an

unapproved/investigative use of a

commercial product/device.

Consequences of IneffectiveBreastfeedingMaureen E. Sims, MD*

Poor Feeding in a NewbornA 3,260-g, 38 weeks’ gestation,appropriate-for-gestational age maleinfant is delivered to a mother whosepregnancy was complicated by gesta-tional diabetes for which she tookglyburide. Group B streptococcalcervical culture was negative. Oxyto-cin was started because of ineffectivelabor. A cesarean section was per-formed because the fetus became in-tolerant of labor. Apgar scores were8 and 9 at 1 and 5 minutes, respec-tively. The physical examinationyielded normal results, and the babywas sent to room-in with his mother.

During the first 24 hours afterbirth, the infant’s glucose was mea-sured by point-of-care strip fivetimes, with results ranging from45 to 66 mg/dL (2.5 to 3.7 mmol/L). The mother repeatedly com-plained to the nurses that the infantwas sleepy at the breast and not nurs-ing. A lactation specialist workedwith the mother, but the baby stilldid not nurse. The mother requestedformula, and the infant took fourfeedings of 35 to 66 mL during thisfirst 24-hour period. The infantvoided one time but did not stool.His weight loss at approximately24 hours was 7.8%. This weight losswas neither brought to the physi-cian’s attention nor addressed by thephysician on morning rounds.

During the next 24-hour period,the infant continued to be sleepy atthe breast and did not latch, accord-ing to the mother. The nurses wrotein their notes the duration of timethat the baby was “placed at thebreast,” but other details such as

latching and audible swallow wereabsent. The mother fed the infantformula twice (40 mL and 60 mL)during this period. He voided threetimes but did not stool.

At 52 hours of age, the infant hadlost 10.4% of his weight since birth.The nurse informed the mother ofthis weight loss. The mother at-tempted feeding, but the baby tookonly 15 mL of formula from the bot-tle. The mother stated in her deposi-tion that she neither understood whythe nurse told her nor the signifi-cance of the weight loss. The physicianwas not notified of the weight loss.The plaintiff expert pointed out thatthe weight loss was excessive. A weightloss of 7% in the first 72 hours is con-sidered excessive, (1) and this infantlost more than 10% at 52 hours. Thebaby needed an overall assessment.Why was he feeding poorly? Was hesick? Was it a transitional problemwhere he was not able to nurse yet butcould bottle-feed? What were thechances of dehydration and hypogly-cemia? This thought process was notentertained. Infants of diabeticmothers (IDM) are known to havetransitional immature sucking pat-terns. (2) Also, it is more challeng-ing for an infant to obtain milkfrom the breast than the bottle, andan IDM may find nursing initiallytoo challenging. The treating pedia-trician said that a 10% weight losswas acceptable in the first 48 hoursafter birth and that 15% total weightloss was typical and normal. The de-fense experts stated that because thestomach capacity of babies is small,they should not be expected to con-sume much. They also pointed outthat because this was an IDM, he was*Professor of Pediatrics, UCLA, Los Angeles, CA.

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born with more fluid than the aver-age neonate and, therefore, entitledto lose more weight. The plaintiff ex-pert disagreed, stating that IDMs ac-tually have a 10% lower water con-tent (65%) compared with neonatesof nondiabetic mothers (75%). (3)

The plaintiff expert pointed outthat 70% of glyburide crosses the pla-centa and would be expected to havea longer half-life than 10 hours anda longer duration than the 16 to24 hours seen in adults because of thereduced renal clearance typical ofneonates. (4)(5) Furthermore, gly-buride has a diuretic effect, whichcould account for the urine outputduring the first 2 postnatal days inthe face of the excessive weight loss.Also, fetal exposure to glyburide po-tentially could be responsible forlowering the neonate’s glucose con-centration after birth because of re-duced medication clearance. The de-fense stated that the baby did notneed to feed much because of the al-ternate fuel available to neonates.The plaintiff countered that alter-nate fuel sources were limited in theIDM compared with the non-IDM,term healthy neonate. (6) The mech-anisms that stimulate glycogenolysis,gluconeogenesis, and lipolysis in-volve the surge of glucagons and epi-nephrine concentrations at the timeof delivery. However, these surges areblunted or absent in the IDM. Thehepatic glycogen begins to be storedat about 27 weeks in the fetus, but inthe IDM, high insulin concentra-tions in utero inhibit gluconeogene-sis. In the term, healthy non-IDM,the stored glycogen protects a neonatefrom hypoglycemia, but the IDM doesnot have this safeguard.

The infant did not take additionalformula. The nurses repeatedly em-phasized to the mother that sheneeded to breastfeed. The motherrequested more assistance withbreastfeeding because she was frus-

trated that her baby would only takeone to two sucks at the breast andthen become either sleepy or cryvigorously for a brief period. At53 hours of age, he would not drinkany formula. According to themother, the baby developed “funnybreathing.”

At 60 hours of age, the phleboto-mist drew a bilirubin sample via aheel stick. The mother noted that herbaby did not cry with the stick, andshe questioned the individual abouther baby not crying. At that point,the phlebotomist noticed that thebaby was not breathing and hadturned blue and called the nurse. Shecame into the room, picked up thebaby, ran down the hall with thebaby in her arms, and arrived in thenormal nursery, where she began ad-ministering blow-by oxygen to him.About 10 minutes later, the satura-tion was 85% and point-of-care glu-cose measured 15 mg/dL (0.83mmol/L). An arterial blood gas onroom air was drawn (20 minutes afterthe baby developed apnea) in thenormal nursery and yielded the fol-lowing results: pH�7.17, PCO2�72 mm Hg, PO2�87 mm Hg, basedeficit��4.5 mEq/L. Five minuteslater, the infant was brought to theneonatal intensive care unit (NICU),where several studies were under-taken, including measurement ofcortisol, growth hormone, ketones,insulin, glucose, and electrolytes aswell as blood culture and a completeblood count. The plaintiff expertssaid that much valuable time waslost running down a hallway, takingthe baby to two different locations,drawing specimens for a large num-ber of studies, and not immediatelyobtaining a bedside glucose mea-surement and responding to it withstat intravenous (IV) line place-ment and infusion of 2 mL/kg 10%glucose.

After the specimens were ob-

tained, 6 mL of 10% glucose wasordered, but 5 minutes later, the or-der was cancelled. It was unclear ifthe infant actually received any IVglucose at this point. Subsequently,another order was written for 3 mLof 25% glucose. This was adminis-tered 1 hour after the glucose of15 mg/dL (0.83 mmol/L) was dis-covered. A repeat glucose measure-ment in the NICU was 18 mg/dL(1.0 mmol/L). Seizures began min-utes later. Two blood samples forglucose were sent to the laboratoryafter the 25% glucose infusion, andthe results were 32 mg/dL (1.8mmol/L) 2 hours after the bolus,and 7 mg/dL (0.39 mmol/L)3 hours after the bolus. A mainte-nance IV infusion of 10% glucose wasstarted. The plaintiff expert was crit-ical of the 25% glucose because thehigher concentration is not only scle-rosing in a peripheral vein butcauses rebound hypoglycemia, whichit did. An IV infusion with glucoseshould have been started immedi-ately after a stat 10% glucose bolusand a central line placed if theglucose concentrations could not bestabilized with 10% or 12.5% contin-uous glucose infusion. The hypoglyce-mia was profound and unnecessar-ily prolonged by the long delay ininstituting glucose therapy. The de-fense expert countered with a com-ment that baseline studies were valu-able to have, a few more minuteswere acceptable, the 25% glucose wasacceptable, and the managementwas within standards.

The laboratory values were: whiteblood cell count�14.5�103/�L (14.5�109/L), hematocrit�46% (0.46),platelet count�252�103/�L (252�109/L), serum sodium�148 mEq/L(148 mmol/L), potassium�6.3 mEq/L (6.3 mmol/L), blood and urineketones�negative, ammonia�86 �g/dL (61.4 �mol/L), and insulin��1 �U/mL (6.9 pmol/L); cortisol,

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lactate, bilirubin, albumin, and the restof the electrolytes were within normallimits. The plaintiff expert pointed outthat the high sodium value under-scored the fact that the baby was be-coming dehydrated from lack of inputand perhaps from a diuretic effect ofthe glyburide. The defense said the so-dium was within normal limits.

Magnetic resonance imaging(MRI) performed at 8 days of agerevealed large areas of infarctions in-volving the dorsum of the brain, pri-marily the bioccipital regions and pa-rietal lobes. Both the plaintiff anddefense experts agreed that the occip-ital damage observed on the MRIwas classic for a hypoglycemic insult.(7) Magnetic resonance angiographydid not show any vessel abnormality.

On follow-up at 4 years of age,the child has spastic cerebral palsy,uncontrollable seizures, profounddevelopmental delays, and corticalblindness.

The plaintiff experts believed thenurses and physicians had violatedthe standard of care: 1) the nurses fornot directing their attention towardthe poorly feeding baby, not notify-ing the physician about the poorfeeding and the weight loss, and fortheir delay in instituting glucosetherapy; 2) the physicians and nursepractitioner for not being attentive tothe mothers’ concerns about herbaby not feeding, the significance ofthe excessive weight loss, and theslow response in administering glu-cose. The defense experts maintainedthat the hypoglycemia was due to anunknown metabolic condition andthat the performance of the nursesand physicians met the standard ofcare.

To establish causation, the plain-tiff must prove that the negligence

was a substantial factor in causingharm, although the negligence neednot be the only cause. In this case,although both sides agreed that hy-poglycemia caused the brain damage,the cause of the hypoglycemia wasin dispute. The plaintiff contendedthat the hypoglycemia was due tolack of nutrition support for whichthe IDM could not adequately com-pensate for the reasons listed previ-ously. The defense maintained thatthe infant must have been sufferingfrom an unknown, unnamed meta-bolic disorder.

The case was arbitrated and theruling was in favor of the plaintiff.The plaintiff was awarded $9.6 mil-lion.

DiscussionAlthough we enthusiastically em-brace the value of breastfeeding,nurses and physicians must not sub-stitute the value of common senseand good clinical judgment in theprocess. An equal amount of fervorto understand why a baby is not feed-ing and to protect that infant duringtransition is far more important thanthe promotion of breastfeeding at allcost. Is it a problem of milk not com-ing in? Is it a problem with the moth-er’s nipples? Is it a minor transitionalissue with the baby? Is it a seriousmedical problem? In this case, whatwas initially a minor transitional issuewith the baby eventually escalatedand became compounded. The babygave many signals that he needed tobe addressed. He was high risk byvirtue of his mother having diabetesand being treated with glyburide.He did not tolerate labor. He neverlatched to the mother’s breast. Themother repeatedly complained thathe was not nursing. He lost exces-

sive weight. He stopped taking bot-tle feedings. He developed “funnybreathing.” All of these warningsigns were ignored. Ignoring thesigns of an infant who cannot yetbreastfeed is dangerous and can havea potentially devastating outcome. Inthis case, the baby developed hypo-glycemia, which was a substantialcausative factor in brain injury.

References1. American Academy of Pediatrics. Policystatement. Breast-feeding and the use of hu-man milk. Pediatrics. 2005;115:496–5062. Bromiker R, Rachamim A, HammermanC. Immature sucking patterns in infants ofmothers with diabetes. J Pediatr. 2006;149:640–6433. Fee BS, Weil WB. Body composition ofinfants of diabetic mothers by direct analy-sis. Ann N Y Acad Sci. 1963;110:869–8974. Dailey TL, Coustan DR Diabetes inpregnancy. NeoReviews. 2010;11:619–6265. Hebert MF, Ma X, Naraharisetti SB. Arewe optimizing gestational diabetes treat-ment with glyburide? The pharmacologicbasis for better clinical practice. Clin Phar-macol Ther. 2009;85:607–6146. Ogata ES. Problems of the infant ofthe diabetic mother. NeoReviews. 2010;11:627–6317. Tam EWY, Widjaja E, Blaser SI. Oc-cipital lobe injury and cortical visual out-comes after neonatal hypoglycemia. Pediat-rics. 2008;122:507–512

American Board of PediatricsNeonatal-Perinatal MedicineContent Specifications• Know the effects

on the fetus and/ornewborn infant ofmaternal diabetes 2mellitus (includinggestational diabetes) and theirmanagement.

• Recognize the clinical and laboratoryfeatures of neonatal hypoglycemia.

• Recognize the approach to therapy andprevention of neonatal hypoglycemia.

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Maureen E. Sims Legal Briefs: Consequences of Ineffective Breastfeeding













Christian Castillo, Chinyere Onyearugbulem and Shefali Khanna Age

Index of Suspicion in the Nursery • Case: Swelling Over the Scalp at 8 Days of







The reader is encouraged to writepossible diagnoses for each casebefore turning to the discussion.We invite readers to contributecase presentations and discussions.Please inquire first by contactingDr. Philip at [email protected].

Author Disclosure

Drs Castillo and Khanna and Ms

Onyearugbulem have disclosed no

financial relationships relevant to

this case. This commentary does not

contain a discussion of an

unapproved/investigative use of a

commercial product/device.

Case: Swelling Over the Scalp at 8 Days of AgeCase PresentationA term appropriate-for-gestationalage male infant who was born byvacuum-assisted vaginal delivery to a31-year-old G1P0 woman presentsto the emergency department at8 days of age after his mother noted aswelling on his scalp. The mother’sprenatal laboratory results, includinggroup B Streptococcus status, werenegative. Delivery was complicatedby prolonged rupture of membranesgreater than 24 hours and develop-ment of preeclampsia. The neonatehad an uneventful nursery course andwas discharged after 72 hours.

At 6 days after birth, the mothernoted swelling of the scalp in theoccipital area that spontaneously re-solved, but another similar lesion de-veloped in the right parietal region,progressively increasing in size. Themother reports normal urine outputand bowel movements and deniesany fever, irritability, lethargy, de-creased oral intake, or feeding diffi-culties. She states that the child hasbeen exclusively breastfeeding sincebirth. On physical examination, theinfant is afebrile, vital signs are stable,

and the only pertinent finding is a1.5�1.5-cm edematous and ery-thematous lesion over the rightparieto-occipital area that is oozingyellowish material and a 0.5-cm le-sion at the level of the lambdoid su-ture that has a crusted scab. The babyis admitted to the inpatient unit forfurther management with parenteralantibiotics and to rule out sepsis.

On admission to the inpatientunit, the complete blood count iswithin normal limits, and blood, ce-rebrospinal fluid (CSF), and scalpwound cultures are sent. A completereview of the maternal obstetricsrecords reveals application of neona-tal scalp spiral electrodes at the samesites as the lesions. The patient isstarted on empiric intravenous anti-biotics. Both blood and CSF culturesreturn with no growth, but the scalpwound culture grows Staphylococcusepidermidis. The patient has an un-eventful hospital course, remains afe-brile and hemodynamically stablethroughout admission, and is dis-charged after 7 days without theneed for oral antibiotics.

index of suspicion in the nursery



Case DiscussionThe Diagnosis

Neonatal scalp abscess due to inutero spiral electrode monitoringwas diagnosed. Neonatal scalp ab-scesses are rare findings that shouldbe strongly suspected in the neonatewho presents in the first week afterbirth with an enlarging, induratedlesion that progressively becomessuppurative, fluctuant, and tenderwith surrounding erythema. Themean age at presentation has beenreported to be 4.5 days. (1) Thissuspicion can be verified with confir-mation via a complete neonatal birthhistory that an invasive monitoringscalp electrode was applied at thesite of the abscess. Cranial imagingstudies can be used to support thediagnosis further as well as rule outcomplications. However, during thehospital stay, this infant remainedafebrile, vital signs remained stable,and the neurologic examination find-ings remained normal. Because ofthis, no cranial imaging examinationswere performed.

The TreatmentDue to the potentially fatal compli-cations that can develop from neo-natal scalp abscess, including menin-gitis, sepsis, and osteomyelitis, thepatient was admitted for close moni-toring and received intravenous anti-biotic therapy for 7 days. The anti-microbial choice is guided by theorganisms that exist in the cervico-vaginal flora and by culture sensitiv-ity. For adequate coverage, cephalo-sporin and clindamycin therapy orbeta lactam/beta-lactamase inhibitorcombination are the most commonantibiotics of choice, with therapyadjusted when meningitis is sus-pected. (2) The scalp abscess of thisneonate gradually improved, as didthe surrounding erythematous re-gion. There was no associated puru-

lent drainage after admission, so anincision and drainage was not at-tempted. By the time of dischargeon the 15th day after birth, the ab-scess had decreased to approximately0.6�0.6 cm, and the infant was dis-charged in stable condition.

The ConditionAbscesses, which are commonly asso-ciated with immunodeficiency, arerare in neonates; scalp abscesses areeven more uncommon in the neo-natal period. However, there havebeen several reports of fetal scalp ab-scesses that occurred as a result ofintrauterine fetal scalp monitoringelectrodes used during obstetricmanagement. (3)(4)(5)

The incidence of neonatal scalpabscess due to fetal scalp monitor-ing has been reported as 0.1% to5.4%. (6) The most common orga-nisms involved are vaginal in originand include a mixture of aerobessuch as groups A, B, and D strepto-cocci; Escherichia coli; Klebsiella;both coagulase-negative (Staphylo-coccus epidermidis) and coagulase-positive Staphylococcus (S aureus);and anaerobes such as Bacteroidesfragilis, Peptostreptococcus, and Pro-pionibacterium acnes. Polymicrobialinfections are present in 61% of cases;single organisms are recovered in39% of cases. (1) The predisposingrisk factors associated with scalp ab-scess following intrauterine fetal scalpmonitoring include duration of moni-toring, prolonged rupture of mem-branes, endometritis, and maternaldiabetes. The postulated mechanismof infection involves the insertionof the electrode contaminated withvaginal flora into the subcutaneoustissue of the fetal scalp, which allowsthe electrode to act as a nidus thatadmits entrance of vaginal flora intothe subcutaneous tissue. Althoughmost neonates have a localized, self-limiting course, some can develop

potentially dangerous sequelae suchas meningitis, osteomyelitis, bactere-mia, and death. As a result, all neo-nates who have scalp abscesses re-quire admission for sepsis evaluation,meningitis evaluation, and empirictreatment with intravenous anti-biotics.

Neonatal scalp abscesses mustalso be differentiated from cephalo-hematomas, a more common pre-sentation that does not have theserious complications associated withscalp abscesses. Unlike cephalohema-tomas, which usually present on thefirst day after birth, neonatal scalpabscesses present more commonlyon the fourth day and have signsof infection such as tenderness, sup-purative drainage, and erythema. (6)Other conditions in the differentialdiagnosis are subcutaneous fat ne-crosis (SFN), subgaleal hematoma,caput succedaneum, herpes simplexvirus (HSV) infection, and pustularmelanosis. Caput succedaneum is asoft, nonfluctuant, nonerythematousswelling of the scalp present at birththat has undefined borders andcrosses suture lines. Intrapartum orpostnatal neonatal HSV infection oc-curs more commonly 5 days afterdelivery and is characterized by pa-thognomonic vesicular exanthem orby more serious complications suchas encephalitis or multiorgan failure.Subgaleal hematoma usually occursduring the first hour after birth andpresents with diffuse scalp swellingthat pits on pressure, with the fatalcomplication of hypovolemic shock.Of note, SFN lesions typically de-velop on the back, shoulders, cheeks,and thighs and affect term or post-term infants. They are characterizedby one or more well-defined, non-suppurative, erythematous or viola-ceous mobile, subcutaneous masses,often with taut overlying skin. (7)

Apart from a complete sepsis eval-uation, diagnostic evaluation of a




neonatal scalp abscess involves cra-nial imaging to screen for intracranialextension, particularly in the pres-ence of signs and symptoms suchas lethargy or persistent fever. (2)Treatment and management involvesincision and drainage of the abscess,as necessary, with concomitant intra-venous antibiotic administration.

Lessons for the ClinicianAlthough neonatal scalp abscessesare commonly benign, they can havefatal complications. To prevent thedevelopment of serious complica-tions from a disease that is usuallyself-limiting, all swellings over thescalp in neonates require a thoroughinvestigation of the birth historyand physical examination to con-sider the possibility of neonatal scalpabscesses. Most importantly, all neo-natal scalp abscesses warrant hos-

pitalization to receive a completesepsis evaluation, including CSFanalysis and blood culture, with in-travenous antibiotic therapy. (Chris-tian Castillo, MD, PGY III, Depart-ment of Pediatrics, Lincoln Hospital,Bronx, NY; Chinyere Onyearug-bulem, MS IV, St. George’s Univer-sity; Shefali Khanna, MD, Chief ofService, Department of Pediatrics,Lincoln Hospital, Bronx, NY)

References1. Brooks I, Frazier EH. Microbiology ofscalp abscess in newborns. Pediatr Infect DisJ. 1992;11:766–7682. Weiner E, McIntosh M, Joseph M,Maraqa N, Davis P. Neonatal scalp abscess:Is it a benign disease? J Emerg Med. Oct2009. Epub ahead of print3. Cordero L, Anderson CW, Zuspan FP.Scalp abscess: a benign and infrequent com-plication of fetal monitoring. Am J ObstetGynecology. 1983;146:126–1304. Koot RW, Reedijk B, Tan WF, DeSonnaville-De Roy Van Zuide. Neonatalbrain abscess: complication of fetal monitor-ing. Obstet Gynecol. 1999;93:8575. McGregor JA, McFarren T. Neonatalcranial osteomyelitis: a complication of fetalmonitoring. Obstet Gynecol. 1989;73:490–4926. Beier KH, Heegaard W, Rusnak RA.Acute neonatal scalp abscess and E. coli bac-teremia in the ED. Am J Emerg Med. 1999;17:241–2437. Norton K, Som P, Shugar J, RothchildM, Popper L. Subcutaneous fat necrosis ofthe newborn: CT findings of head and neckinvolvement. AJNR. 1997;18:545–550

American Board of PediatricsNeonatal-Perinatal MedicineContent Specification• Know how to

recognize anddifferentiatecomplications ofsoft tissue injury toan infant’s scalp, likecaput and subgaleal bleed.





Christian Castillo, Chinyere Onyearugbulem and Shefali Khanna Age

Index of Suspicion in the Nursery • Case: Swelling Over the Scalp at 8 Days of













Anna Maria Hibbs Pharmacology Review: Pharmacotherapy for Gastroesophageal Reflux Disease







Author Disclosure

Dr Hibbs has disclosed no financial

relationships relevant to this article.

This commentary does contain a

discussion of an unapproved/

investigative use of a commercial

product/device.

Pharmacotherapy forGastroesophageal Reflux DiseaseAnna Maria Hibbs, MD, MSCE*

AbstractThe common pharmacologic strategies used to treat gastroesophagealreflux disease (GERD) in the neonatal intensive care unit (NICU) includesuppression of gastric acid with histamine-2 (H2) receptor antagonists andproton pump inhibitors (PPIs) and stimulation of gastrointestinal motilitywith dopamine receptor antagonists or motilin receptor agonists. Thesemedications are primarily metabolized by hepatic cytochrome P450 (CYP)enzymes. Although frequently used, none of these drugs has strongevidence for efficacy in decreasing the complications of reflux in preterminfants or term neonates. In addition, a few well-conducted, masked,randomized studies that have accounted for maturational changes in theirdesign have raised concerns about the safety of these medications ininfants.

Objectives After completing this article, readers should be able to:

1. Describe the mechanism of action of drugs commonly used to treat GERDin the NICU.

2. Describe the evidence for the efficacy of the medications commonly used totreat GERD in the NICU.

3. List the adverse events that have been reported for infants treated withthese medications.

4. List the theoretical risks of these medications that have not been fullyevaluated in preterm infants or term neonates.

IntroductionMedications for GERD are amongthe most commonly prescribeddrugs in the NICU. (1)(2)(3) In theUnited States, pharmacotherapy forGERD primarily consists of proki-netics and drugs to decrease stomachacidity (Table), but the use of thesemedications and clinicians’ beliefsabout their safety and effectivenessvaries extensively. (2)(3)(4)

Any discussion of pharmacother-apy for GERD must touch on thedisease definition and the problems

inherent in its diagnosis in preterminfants, although this topic has beencovered in greater depth elsewhere.(5)(6)(7)(8)(9)(10)(11)(12) GERDis defined as gastroesophageal reflux(GER) that causes complications; in-fants who are “happy spitters” with-out complications from their GERshould not be treated. (7)(8) How-ever, associations between GER(D)and its putative complications in pre-term infants, including apnea andlung disease, are questionable. Theappropriate diagnostic modalities fordiagnosing GERD in the term orpreterm neonate in the NICU arealso controversial, and evaluation

*Department of Pediatrics, Case Western ReserveUniversity and Rainbow Babies & Children’sHospitals, Cleveland, OH.

Abbreviations

CYP: cytochrome P450FDA: United States Food and

Drug AdministrationGER: gastroesophageal refluxGERD: gastroesophageal reflux

diseaseH2: histamine-2NICU: neonatal intensive care unitPPI: proton pump inhibitorVLBW: very low birthweight

pharmacology review



may include upper gastrointestinalradiographic series to assess for ana-tomic abnormalities; esophageal pHor impedance measurements of acidand nonacid reflux, respectively; ornuclear medicine scintigraphy stud-ies to assess gastric emptying and as-piration further.

For the purposes of this review ofpharmacotherapy for GERD, thepresumption is that that the physi-cian is attempting to treat a patientfor whom the diagnosis is reasonablycertain, but it must be rememberedthat medication failures at the bed-side or in research trials may resultfrom either a failure of the medica-tion to achieve its intended action orfrom the erroneous application ofdrugs to symptoms not caused byGERD. Conversely, apparent suc-cesses may result from a true drugeffect or from the natural resolutionof symptoms with maturation. Fi-nally, because the goal of therapy isto treat GERD, not physiologicGER, the gold standard for gaugingtherapeutic success must be improve-ment in symptoms or complications,not simply improvement in physio-logic measures.

Drugs That Increase Gastric pHH2 receptor antagonists and PPIsdecrease gastric acidity, thereby de-creasing the acidity of esophagealrefluxate. This is believed to de-crease esophageal mucosal damageand its associated discomfort. Pro-posed complications of reflux inNICU patients, such as food refusal,lung disease, failure to thrive, andpharyngeal or vocal cord edema,theoretically could stem from theeffect of acid on the esophagus orairway. Some have argued that due toeither a limited capacity to produceacid or to frequent buffering of gas-tric contents by milk feedings, infantsmay experience less acidic GER(D)than older patients. Studies simulta-neously monitoring acid and non-acid GER in infants have shownthat acid GER predominates pre-prandially and nonacid GER pre-dominates postprandially. (13)(14)Although most GER events in in-fants are nonacid, (13)(14) studiesof infants referred for suspicion ofGERD indicate that at least somepreterm infants can experience sig-nificant acid GER, as measured byan esophageal pH of less than 4 formore than 10% of the time. (15) How-

ever, it is not clear whether acidityis the mechanism by which refluxcauses complications in infants. (8)

Both H2 receptor antagonists andPPIs share some potential safety con-cerns. Gastric acidity may play a rolein host immune defense. H2 receptorantagonists have been associatedwith an increased risk of necrotizingenterocolitis, (16) although it is notclear if this is a causal relationship.One small study showed that gastricacidification decreased the incidenceof necrotizing enterocolitis. (17) An-other study of 86 neonates showedthat infants treated with ranitidinehad significantly higher rates of gas-tric colonization with bacteria oryeast, although an increase in infec-tion was not seen. (18) In a largerobservational study, ranitidine wasassociated with increased late-onsetsepsis in NICU patients, althoughconfounding by indication or sever-ity of illness cannot completely beexcluded as the cause of this apparentassociation. (19) In older patients, anassociation between acid suppressionand lower respiratory tract infections,including ventilator-associated pneu-monia, has been proposed but re-mains controversial. (20)(21)(22)(23)

Table. Medications Commonly Used to Treat Gastroesophageal RefluxDisease in Infants in the United States

Drug Class Examples Mechanism of Action

RobustEvidence forEffectivenessin Infants

SafetyConcerns

Gastric AcidSuppression

Histamine-2 receptorantagonists

Ranitidine,cimetidine,famotidine

Decrease basal and meal-inducedacid production by gastricparietal cells

No Yes

Proton pumpinhibitors

Omeprazole,lansoprazole,pantoprazole

Irreversibly block the gastric H�/K�

adenosine triphosphataseresponsible for secreting H� intothe gastric lumen

No Yes

Prokinetics Metoclopramide Metoclopramide Dopamine receptor (D2 subtype)antagonist

No Yes

Erythromycin Erythromycin Motilin receptor agonist No Yes

pharmacology review



(24)(25)(26)(27)(28) Furthermore,increasing gastric pH theoreticallycan have nutritional consequences.Acid reduction may decrease calciumabsorption via decreased ionizationof calcium in the stomach.

Both H2 receptor antagonists andPPIs are metabolized by the CYPenzymatic systems in the liver. Po-tential drug interactions may existwith drugs metabolized by thesepathways. (29)

H2 Receptor AntagonistsThis class of drugs includes raniti-dine, cimetidine, and famotidine.They are antagonists of the H2 recep-tor in acid-producing gastric parietalcells. Parietal cells produce a baselineamount of hydrochloride when theyare not stimulated by histamine. H2

receptor antagonists decrease this pro-duction below physiologic basal secre-tion rates and decrease meal-associatedacid production. In addition, othersubstances that stimulate acid produc-tion, such as acetylcholine and gastrin,have a reduced effect on parietal cellswhen H2 receptors are blocked.

Few randomized clinical trials ofH2 receptor antagonists have assessedtheir impact on the symptoms ofGERD in the general infant popula-tion or in NICU patients. In one smalldouble-blind study, infants ages 1.3 to10.5 months were randomized to ahigher or lower dose of famotidine,followed by a placebo-controlled with-drawal. (30) Infants receiving bothdoses had improved emesis frequencycompared with placebo. Infants receiv-ing the higher dose also had decreasedcrying time and volume of emesis.However, famotidine seemed to causeagitation and a head-rubbing behaviorthat was attributed to headache, andthe authors concluded that furtherstudy was warranted.

In another randomized trial ofH2 receptor antagonists, very low-birthweight (VLBW) infants wererandomized to cimetidine or pla-cebo, with the hypothesis that cime-tidine could decrease CYP-mediatedoxidative injury in the lung. (31) Al-though this study was not targetingtreatment of GERD, it is one of thefew studies in which VLBW infantswere randomized to an H2 receptorantagonist early in life. The study wasstopped by the data safety monitor-ing committee for increased deathand intraventricular hemorrhage in thetreatment group. The mechanism ofthese apparent adverse effects is un-known and, indeed, could have oc-curred by chance or could be specificto cimetidine and not generalizable toother H2 receptor antagonists.

Finally, in a small crossover trialof combined ranitidine and metoclo-pramide therapy in preterm infantswho had bradycardia attributed toGERD, Wheatley and Kennedy (32)found that infants receiving therapyexperienced significantly more bra-dycardic events than those receivingplacebo. This is a biologically plausiblefinding because histamine receptorsare present in the heart, and ranitidine,particularly intravenously administered,has been associated with bradyarrhyth-mias. (33)(34)(35)(36)(37)(38)(39)Of course, the lack of effect in thisstudy also could have been due to mis-identification of bradycardia as a symp-tom of GERD. Even if reflux causescardiorespiratory events in some in-fants periodically, most cardiorespira-tory events in preterm infants are nottemporally related to GER, so brady-cardia is likely to have poor specificityfor the identification of GERD, andtreatment of GERD is unlikely to af-fect most cardiorespiratory events.(40) Notably, this crossover study ofranitidine and metoclopramide, whichappropriately accounted for matura-tional changes, also demonstrated a

significant decrease in bradycardicevents over a 2-week period, under-scoring the need for trials targetingmaturationally related variables, suchas GER, apnea, and bradycardia, toaccount for the effect of time in theirstudy design.

Cimetidine is an inhibitor ofCYP3A and may cause potentiallydangerous increases in the concentra-tions of drugs that are metabolized bythese enzymes, including theophyl-line, benzodiazepines, beta-blockers,and phenytoin. (29) Ranitidine mayinteract with some of these drugs to alesser degree. In addition, ranitidinecan rarely cause leukopenia, neutro-penia, or thrombocytopenia, which isusually reversible.

Proton Pump InhibitorsPPIs are more powerful blockersof gastric acid secretion than H2

receptor antagonists. PPIs irrevers-ibly block the gastric hydrogen/potassium adenosine triphosphatasethat is responsible for secreting hy-drogen ions into the gastric lumen.Examples of PPIs include omepra-zole, lansoprazole, dexlansoprazole,esomeprazole, pantoprazole, andrabeprazole. No PPIs are currentlylabeled for use in infants youngerthan 1 year of age. However, PPI usein infants increased exponentiallybetween 1999 and 2004, with thehighest prescription rates in infantsyounger than 4 months of age. (41)Lansoprazole and omeprazole arethe most commonly prescribed PPIsfor infants.

Although PPIs have been shownto decrease gastric acidity in infantsin physiologic studies, there is a pau-city of masked randomized studies ininfants that account for maturationalchanges in reflux symptoms. Oren-stein and associates (42) randomizedoutpatient infants who had failed a

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run-in period of nonpharmacologicmanagement to lansoprazole or pla-cebo. There was no difference in effi-cacy between the groups, with slightlymore than 50% of the infants in eachgroup experiencing symptomatic im-provement. However, there was asignificant increase in serious adverseevents in the lansoprazole group;among these adverse events, a nonsig-nificant increase in lower respiratorytract infections was seen.

The United States Food and DrugAdministration (FDA) recently re-leased a class labeling change for PPIs,based on findings that adults receiv-ing high doses or prolonged coursesof PPIs may experience more frac-tures. (43)(44) The impact of acidsuppression by PPIs or H2 receptorantagonists on bone health in healthyneonates or preterm infants whohave osteopenia of prematurity is un-known. The off-label use of PPIs ininfants and the possibility of adverseeffect on bones are currently beingtracked by the FDA. (45) VitaminB12 absorption is also dependent ongastric acidity, but the impact of gas-tric acid suppression on B12 status ininfants is also unknown.

Acid suppression has been asso-ciated with Clostridium difficileinfection in some adults, with PPIsseeming to have a higher risk thanH2 receptor antagonists. (46)(47)The relationship between PPI useand pathogenic or colonizing C dif-ficile in infants has not been re-ported.

In older patients, there is someconcern that omeprazole may increasephenytoin and warfarin concentra-tions. (29) Lansoprazole, omepra-zole, and pantoprazole are metabo-lized by CYP2C19, which is absentin approximately 3% of whites and20% of Asians, but it is unclear if thishas any clinical significance. (29)

Drugs That Improve MotilityDrugs that promote gastrointestinalmotility are believed to decrease GERby increasing gastric emptying, there-by limiting the amount of liquid avail-able to reflux into the esophagus. Pro-kinetics may also improve esophagealmotility and lower esophageal sphinc-ter tone.

The primary motility agents cur-rently available in the United Statesare metoclopramide and erythromycin.Cisapride was removed from the mar-ket due to the risk of serious cardiacarrhythmias and QT prolongation.(48) Domperidone is used in somecountries but is not approved in theUnited States due to concerns aboutarrhythmia, and recent studies haveshown that oral domperidone can in-crease the QT interval in neonates.(49)

MetoclopramideMetoclopramide is an antagonist ofthe dopamine D2 receptor subtype.The Cochrane systematic review ofGERD therapies in children foundboth therapeutic benefit and in-creased adverse effects with metoclo-pramide treatment, although mostof the improvements were in physio-logic measures of GER and notGERD symptoms. (50) A systematicreview of metoclopramide therapyfor GERD in infants found insuffi-cient evidence for either efficacy orsafety in this population. (51) Pub-lished after these reviews, the previ-ously described placebo-controlledcrossover study by Wheatley andKennedy (32) of combined therapywith ranitidine and metoclopramidefound an increase in bradycardia inthe treatment group, although thisfinding is not necessarily attributableto metoclopramide.

Metoclopramide crosses the blood-brain barrier and acts on central do-pamine receptors, which allows forneurologic adverse effects. Reported

complications of metoclopramide ininfants include irritability, drowsiness,oculogyric crisis, dystonic reaction,apnea, and emesis. (51) In 2009, theFDA issued a black-box warningabout the risk of tardive dyskinesiawith prolonged or high-dose meto-clopramide exposure. (52) Tardivedyskinesia consists of involuntarybody movements that may persistafter the drug is stopped; it has noknown treatment. Whether neonatesor preterm infants are at greater orlesser risk of tardive dyskinesia thanolder patients has not been estab-lished. Metoclopramide can be usedto induce lactation in mothers by in-creasing prolactin concentrations as aresult of central dopaminergic antag-onism, and it has also been reportedto cause lactation and gynecomastiain neonates. (53)(54)

Metoclopramide may prolong theduration of neuromuscular blockadeduring surgery by depressing cho-linesterase activity. (55) Many of thedrug interactions reported with met-oclopramide involve drugs that acton the same receptor, such as anti-psychotics and antiemetics, which arerarely used in the NICU. (29)

ErythromycinErythromycin is an analog of thegastrointestinal hormone motilin,normally produced by duodenal andjejunal enterochromaffin cells, and ithas a high affinity for the motilinreceptor. (56)(57)(58) It promotesgastrointestinal migrating motor com-plexes. When used to promote motil-ity, it is typically provided in doseslower than those used for antimicro-bial effect, but a standard promotilitydose has not been established in neo-nates or preterm infants. Infantswhose gestational age is greater than32 weeks may be better able to re-spond to stimulation of the motilinreceptor. (59)(60)

Most studies of erythromycin as a

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prokinetic in preterm infants have fo-cused on improving feeding intoler-ance and not specifically on treatingGERD. (59)(60) In a masked, ran-domized trial of erythromycin topromote feeding tolerance in 24 pre-term infants that measured GER as asecondary endpoint, erythromycindid not decrease the time to attainfull enteral feedings, and there wereno changes in GER, as measured byesophageal pH probe. (61) GERDsymptoms were not addressed in thisstudy. In a review of 10 studies usingerythromycin as a prokinetic to pro-mote feeding tolerance, Ng (62) con-cluded that erythromycin could pro-mote the establishment of enteralfeeding and was not associated withany adverse events but cautioned thatbecause long-term adverse eventshad not been fully studied, erythro-mycin should be reserved for infantswho had severe dysmotility.

In antimicrobial doses, erythro-mycin may promote pyloric stenosis.It is unknown whether a similar effectwould be seen with the lower dosesand longer duration of therapy likelyto be used to increase motility, al-though pyloric stenosis has not beenreported in most of the current trialsin preterm infants. (62)

Like cimetidine, erythromycin isan inhibitor of CYP3A. Erythromy-cin may increase serum concentrationsof theophylline, digoxin, some benzo-diazepines, sildenafil, phenytoin, andwarfarin. (63) Erythromycin has beenimplicated in arrhythmias and QT pro-longation when coadministered withcisapride, but it also has a direct pro-arrhythmic effect by itself. Erythromy-cin blocks the rapidly activating com-ponent of the cardiac delayed rectifierpotassium current, thereby prolongingrepolarization in a manner similar tosome antiarrhythmic drugs. (64) Thisaction may prolong the QT intervaland predispose the patient to torsadesde pointes. Reports in older patients

indicated that the risk of sudden deathmay be increased when erythromycinis used with other CYP3A inhibitors,such as cimetidine, methadone, andsome protease inhibitors. (64)

ConclusionNone of the medications commonlyused to treat GERD in the NICU hasbeen demonstrated to be safe and ef-fective. Few rigorously conductedrandomized trials account for matura-tional changes in infants and evenfewer focus on clinical symptoms inneonates or preterm infants. Many ofthe masked, randomized trials in in-fants have found evidence for harm.Therefore, the potential adverse effectsof pharmacologic management ofGERD in the NICU should only berisked for infants experiencing severecomplications that have been rigor-ously linked to reflux and that have notimproved with a trial of nonpharmaco-logic measures and expectant manage-ment. Therapy should be discontinuedpromptly if there is no improvement inthe infant’s status. For infants who doimprove with pharmacotherapy, a planshould be made to assess them offGERD drugs within a few weeks tomonths because maturational changesmay either have been responsible forthe initial improvement or may renderdrug therapy unnecessary in the nearfuture. Finally, under the principle ofprimum non nocere, avoidance of ex-posure to medications that have docu-mented risk and little evidence for effi-cacy should be the preferred approachto a NICU patient who has suspectedGERD.

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management ofgastroesophagealreflux in neonates.

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14. Slocum C, Arko M, Di Fiore J, MartinRJ, Hibbs AM. Apnea, bradycardia and de-saturation in preterm infants before and af-ter feeding. J Perinatol. 2009;29:209–21215. Di Fiore JM, Arko M, Whitehouse M,Kimball A, Martin RJ. Apnea is not prolongedby acid gastroesophageal reflux in preterminfants. Pediatrics. 2005;116:1059–106316. Guillet R, Stoll BJ, Cotten CM, et al.Association of H2-blocker therapy andhigher incidence of necrotizing enterocolitisin very low birth weight infants. Pediatrics.2006;117:e137–e14217. Carrion V, Egan EA. Prevention ofneonatal necrotizing enterocolitis. J PediatrGastroenterol Nutr. 1990;11:317–32318. Cothran DS, Borowitz SM, SutphenJL, Dudley SM, Donowitz LG. Alterationof normal gastric flora in neonates receivingranitidine. J Perinatol. 1997;17:383–38819. Bianconi S, Gudavalli M, Sutija VG,Lopez AL, Barillas-Arias L, Ron N. Raniti-dine and late-onset sepsis in the neonatalintensive care unit. J Perinat Med. 2007;35:147–15020. Apte NM, Karnad DR, Medhekar TP,Tilve GH, Morye S, Bhave GG. Gastriccolonization and pneumonia in intubatedcritically ill patients receiving stress ulcerprophylaxis: a randomized, controlled trial.Crit Care Med. 1992;20:590–59321. Yildizdas D, Yapicioglu H, Yilmaz HL.Occurrence of ventilator-associated pneu-monia in mechanically ventilated pediatricintensive care patients during stress ulcerprophylaxis with sucralfate, ranitidine, andomeprazole. J Crit Care. 2002;17:240–24522. Miano TA, Reichert MG, Houle TT,MacGregor DA, Kincaid EH, Bowton DL.Nosocomial pneumonia risk and stress ulcerprophylaxis: a comparison of pantoprazolevs ranitidine in cardiothoracic surgery pa-tients. Chest. 2009;136:440–44723. Sharma H, Singh D, Pooni P, MohanU. A study of profile of ventilator-associatedpneumonia in children in Punjab. J TropPediatr. 2009;55:393–39524. Tablan OC, Anderson LJ, Besser R,Bridges C, Hajjeh R. Guidelines for pre-venting health-care–associated pneumonia,2003: recommendations of CDC and theHealthcare Infection Control Practices Ad-visory Committee. MMWR Recomm Rep.2004;53(RR-3):1–3625. Beaulieu M, Williamson D, Sirois C,Lachaine J. Do proton-pump inhibitors in-crease the risk for nosocomial pneumonia ina medical intensive care unit? J Crit Care.2008;23:513–51826. Kobashi Y, Matsushima T. Clinicalanalysis of patients requiring long-term me-

chanical ventilation of over three months:ventilator-associated pneumonia as a pri-mary complication. Intern Med. 2003;42:25–3227. Cook D, Guyatt G, Marshall J, et al.A comparison of sucralfate and ranitidine forthe prevention of upper gastrointestinalbleeding in patients requiring mechanicalventilation. Canadian Critical Care TrialsGroup. N Engl J Med. 1998;338:791–79728. Canani RB, Cirillo P, Roggero P, et al.Therapy with gastric acidity inhibitors in-creases the risk of acute gastroenteritis andcommunity-acquired pneumonia in chil-dren. Pediatrics. 2006;117:e817–e82029. Flockhart DA, Desta Z, Mahal SK. Se-lection of drugs to treat gastro-oesophagealreflux disease: the role of drug interactions.Clin Pharmacokinet. 2000;39:295–30930. Orenstein SR, Shalaby TM, DevandrySN, et al. Famotidine for infant gastro-oesophageal reflux: a multi-centre, random-ized, placebo-controlled, withdrawal trial. Al-iment Pharmacol Ther. 2003;17:1097–110731. Cotton RB, Hazinski TA, Morrow JD,et al. Cimetidine does not prevent lung in-jury in newborn premature infants. PediatrRes. 2006;59:795–80032. Wheatley E, Kennedy KA. Cross-overtrial of treatment for bradycardia attributedto gastroesophageal reflux in preterm in-fants. J Pediatr. 2009;155:516–52133. Hu WH, Wang KY, Hwang DS, TingCT, Wu TC. Histamine 2 receptor blocker-ranitidine and sinus node dysfunction. Zhong-hua Yi Xue Za Zhi (Taipei). 1997;60:1–534. Alliet P, Devos E. Ranitidine-inducedbradycardia in a neonate–secondary to con-genital long QT interval syndrome? EurJ Pediatr. 1994;153:78135. Hinrichsen H, Halabi A, Kirch W.Clinical aspects of cardiovascular effects ofH2-receptor antagonists. J Clin Pharmacol.1995;35:107–11636. Nahum E, Reish O, Naor N, Merlob P.Ranitidine-induced bradycardia in a neo-nate—a first report. Eur J Pediatr. 1993;152:933–93437. Ooie T, Saikawa T, Hara M, Ono H,Seike M, Sakata T. H2-blocker modulatesheart rate variability. Heart Vessels. 1999;14:137–14238. Tanner LA, Arrowsmith JB. Bradycar-dia and H2 antagonists. Ann Intern Med.1988;109:434–43539. Yang J, Russell DA, Bourdeau JE. Casereport: ranitidine-induced bradycardia in apatient with dextrocardia. Am J Med Sci.1996;312:133–13540. Di Fiore J, Arko M, Herynk B, MartinR, Hibbs AM. Characterization of cardio-

respiratory events following gastroesopha-geal reflux in preterm infants. J Perinatol.2010;30:683–68741. Barron JJ, Tan H, Spalding J, BakstAW, Singer J. Proton pump inhibitor utili-zation patterns in infants. J Pediatr Gastro-enterol Nutr. 2007;45:421–42742. Orenstein SR, Hassall E, Furmaga-Jablonska W, Atkinson S, Raanan M. Multi-center, double-blind, randomized, placebo-controlled trial assessing the efficacy andsafety of proton pump inhibitor lansopra-zole in infants with symptoms of gastro-esophageal reflux disease. J Pediatr. 2009;154:514–520. e443. United States Food and Drug Admin-istration. Proton Pump Inhibitors (PPI):Class Labeling Change. 2010. Accessed De-cember 2010at:http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm213321.htm44. United States Food and Drug Admin-istration. Possible Increased Risk of Bone Fre-actures With Certain Antacid Drugs. 2010.Accessed December 2010 at: http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm213240.htm45. Taylor AM; Pediatric Advisory Commit-tee Meeting. United States Food and DrugAdministration. Pediatric Focused Safety Re-view: Proton Pump Inhibitors: Esomeprazole,Lansoprazole, Omeprazole, Rabeprazole. 2010.Accessed December 2010 at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/UCM216303.pdf46. Howell MD, Novack V, Grgurich P,et al. Iatrogenic gastric acid suppression andthe risk of nosocomial Clostridium difficileinfection. Arch Intern Med. 2010;170:784–79047. Linsky A, Gupta K, Lawler EV, FondaJR, Hermos JA. Proton pump inhibitorsand risk for recurrent Clostridium difficileinfection. Arch Intern Med. 2010;170:772–77848. United States Food and Drug Adminis-tration. Propulsid (cisapride). 2000. AccessedDecember 2010 at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm173074.htm49. Djeddi D, Kongolo G, Lefaix C, Mou-nard J, Leke A. Effect of domperidone onQT interval in neonates. J Pediatr. 2008;153:663–66650. Craig WR, Hanlon-Dearman A, Sin-clair C, Taback S, Moffatt M. Metoclopra-mide, thickened feedings, and positioningfor gastro-oesophageal reflux in children

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under two years. Cochrane Database SystRev. 2004;4:CD00350251. Hibbs AM, Lorch SA. Metoclopramidefor the treatment of gastroesophageal re-flux disease in infants: a systematic review.Pediatrics. 2006;118:746–75252. United States Food and Drug Ad-ministration. Metoclopramide-containingDrugs. 2009. Accessed December 2010 at:http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm106942.htm53. Madani S, Tolia V. Gynecomastia withmetoclopramide use in pediatric patients.J Clin Gastroenterol. 1997;24:79–8154. Paturi B, Ryan RM, Michienzi KA,Lakshminrusimha S. Galactorrhea with meto-clopramide use in the neonatal unit. J Peri-natol. 2009;29:391–39255. Feldman S, Karalliedde L. Drug inter-

actions with neuromuscular blockers. DrugSaf. 1996;15:261–27356. Itoh Z, Nakaya M, Suzuki T, Arai H,Wakabayashi K. Erythromycin mimics exog-enous motilin in gastrointestinal contractileactivity in the dog. Am J Physiol. 1984;247:G688–G69457. Itoh Z, Suzuki T, Nakaya M, InoueM, Mitsuhashi S. Gastrointestinal motor-stimulating activity of macrolide antibioticsand analysis of their side effects on the ca-nine gut. Antimicrob Agents Chemother.1984;26:863–86958. Feighner SD, Tan CP, McKee KK,et al. Receptor for motilin identified inthe human gastrointestinal system. Science.1999;284:2184–218859. Ng E, Shah VS. Erythromycin for theprevention and treatment of feeding intol-erance in preterm infants. Cochrane Data-base Syst Rev. 2008;3:CD001815

60. Patole S, Rao S, Doherty D. Erythro-mycin as a prokinetic agent in preterm neo-nates: a systematic review. Arch Dis ChildFetal Neonatal Ed. 2005;90:F301–F30661. Ng SC, Gomez JM, Rajadurai VS, SawSM, Quak SH. Establishing enteral feedingin preterm infants with feeding intolerance:a randomized controlled study of low-doseerythromycin. J Pediatr Gastroenterol Nutr.2003;37:554–55862. Ng PC. Use of oral erythromycin forthe treatment of gastrointestinal dysmotilityin preterm infants. Neonatology. 2009;95:97–10463. Rubinstein E. Comparative safety ofthe different macrolides. Int J AntimicrobAgents. 2001;18(suppl 1):S71–S7664. Simko J, Csilek A, Karaszi J, Lorincz I.Proarrhythmic potential of antimicrobialagents. Infection. 2008;36:194–206

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NeoReviews Quiz

16. Histamine-2 receptor antagonists decrease gastric acidity, thereby reducing the acidity of esophagealrefluxate in gastroesophageal reflux disease. Although a causal relationship has not been established,decreasing gastric acidity raises potential safety concerns in neonates. Of the following, the most likelypotential safety concern associated with histamine-2 receptor antagonist use in neonates is:

A. Early-onset sepsis.B. Necrotizing enterocolitis.C. Ventilator-associated pneumonia.D. Vitamin B12 deficiency.E. Vocal cord edema.

17. Proton pump inhibitors (PPIs) irreversibly block the gastric hydrogen/potassium adenosine triphosphatasethat is responsible for secreting hydrogen ions into the gastric lumen. Although not currently labeled foruse in infants younger than 1 year of age, PPI use in infants has increased exponentially in recent years.Of the following, the most commonly prescribed PPI for infants is:

A. Dexlansoprazole.B. Esomeprazole.C. Omeprazole.D. Pantoprazole.E. Rabeprazole.

18. Metoclopramide is an antagonist of the dopamine D2 receptor subtype. It is believed to decreasegastroesophageal reflux by increasing gastric emptying, thereby limiting the amount of liquid available forreflux, and by promoting esophageal motility as well as lower esophageal sphincter tone. Of the following,the most reported complication of metoclopramide in infants is:

A. Calcium deficiency.B. Cardiac arrhythmia from QT prolongation.C. Clostridium difficile sepsis.D. Diffuse osteopenia.E. Neuromuscular dystonia.

19. Erythromycin is an analog of the gastrointestinal hormone motilin, normally produced by duodenal andjejunal enterochromaffin cells. It enhances gastrointestinal motility by promoting migratory motorcomplexes. Of the following, the most reported complication of erythromycin used in antimicrobial dosesin infants is:

A. Cardiac arrhythmia from QT prolongation.B. Gynecomastia and lactation.C. Hypertrophic pyloric stenosis.D. Sensorineural hearing loss.E. Sepsis from resistant microbes.

pharmacology review




Anna Maria Hibbs Pharmacology Review: Pharmacotherapy for Gastroesophageal Reflux Disease













Carissa Cheng and Sandra Juul Iron Balance in the Neonate







Iron Balance in the NeonateCarissa Cheng, RD,*

Sandra Juul, MD, PhD†

Author Disclosure

Ms Cheng and Dr Juul

have disclosed no

financial relationships

relevant to this

article. This

commentary does not


of an unapproved/


commercial product/

device.

AbstractIron is essential for growth and development, and deficiency during gestation andinfancy may have lifelong effects. Iron is necessary for oxygen transport, cellularrespiration, myelination, neurotransmitter production, and cell proliferation. Irondeficiency may decrease hippocampal growth and alter oxidative metabolism, neuro-transmitter concentrations, and fatty acid and myelination profiles throughout thebrain. Excellent articles and reviews have been published on the effect of iron oncognitive development. This review highlights more recent findings, focusing on therole of iron in brain development during gestation and early life, and discussesimplications for practice in the neonatal intensive care unit.


1. Name sites of iron absorption and regulation.2. List the consequences of iron deficiency and excess for the neonate.3. Choose an appropriate tool for iron assessment.4. Discuss practical challenges to providing iron to neonates.5. List iron intake recommendations for preterm infants.

BackgroundIron status of the neonate is a balance between iron accretion during gestation, ironutilization and loss, and iron acquired postnatally, either through enteral or parenteralroutes (Fig. 1). Thus, maternal and fetal conditions as well as postnatal experiences affectneonatal iron status. Iron is a transition metal that readily converts between the ferrous(�2) and ferric (�3) oxidation states. In biochemical systems, iron is often found in thecatalytic site of enzymes, where it facilitates redox reactions. Its redox properties provideprotein function but can also be dangerous because inappropriate oxidation may causecellular damage. Free iron in a biologic system can convert between oxidation states,generating free radicals. Polyunsaturated fatty acids, which are found in cell membranes,are especially susceptible to damage by free radicals. To protect the organism, iron is

sequestered by proteins throughout absorption, transport,storage, and as it performs its physiologic functions. (1)

Among other functions, iron is essential for developmentof the nervous system. Myelination, neurotransmission, den-dritogenesis, and neurometabolism are dependent on iron.(2)(3)(4) Iron deficiency during the late fetal and the earlyinfant periods may result in decreased cellular respiration inthe hippocampus and frontal cortex, abnormal neurotrans-mitter concentrations, and alterations in fatty acid and my-elination profiles. (2) Iron deficiency in infancy may have alasting impact on cognitive, socioemotional, and motorfunctions. (4) The effects of iron deficiency on brain struc-ture and function are interrelated; neuronal developmentaffects behavior that, in turn, affects brain development. (4)

*Nutritional Sciences Program, University of Washington, Seattle, WA.†Department of Pediatrics, Division of Neonatology, University of Washington, Seattle, WA.

Abbreviations

DMT1: divalent metal transporter-1DcytB: duodenal cytochrome BEpo: erythropoietinHCP-1: heme carrier protein 1IRE/IRP: iron response element/iron regulatory proteinMCV: mean cell volumesTfR: soluble transferrin receptorTIBC: total iron binding capacityZnPP/H: zinc protoporphyrin-to-heme ratio

Article nutrition



Thus, having the appropriate amount of iron is essentialbecause both deficiency and excess can be harmful.

Absorption, Transport, and Storage of Iron inInfants

AbsorptionThe uptake of iron by the enterocyte is an importantregulatory step in body iron content. Iron can be ab-sorbed into the enterocyte as heme iron or nonheme iron(both ferrous and ferric forms). Heme iron is soluble inthe duodenum and is absorbed as an intact metallo-protein via heme carrier protein 1 (HCP-1) (Fig. 2A).Ferrous iron is then released from heme via heme oxy-genase. (5) Unbound iron is absorbed into the entero-cyte in the ferrous or ferric form. In the duodenum,nonheme iron is converted to the ferrous (II) form byascorbic acid and duodenal cytochrome B (DcytB) onthe surface of the brush border (Fig. 2B). (6) Ferrousiron then binds to divalent metal transporter-1(DMT1) and is transferred into the enterocyte. (5) Ex-pression of DcytB and DMT1 are regulated by the ironcontent of the enterocyte (6) and transcription factorssensitive to hypoxia and intracellular iron concentration.(7) Ferric iron (III) binds chelators in the small intestineand is absorbed via a �3 integrin and mobilferrin pathway(Fig. 2C). (8) After entry into the enterocyte, ferric ironis reduced by paraferritin and binds mobilferrin. Ferrousiron from all three entry pathways is released into theintracellular iron pool and used for cellular metabolism,stored as ferritin, or transferred out of the enterocyte(Fig. 2D). (6) Iron is released by ferroportin at thebasolateral membrane, where it is oxidized by hephaestinand binds to transferrin for transport (Fig. 2E).

Iron release from the enterocyte into the bloodstreamis a tightly regulated process. When the body is iron-replete, hepcidin binds ferroportin at the basolateralsurface of the enterocyte, inducing internalization and

degradation of the protein (Fig. 2F). This blocks ironrelease, and iron is incorporated into ferritin in the en-terocyte, which is lost when the cells are sloughed. Hep-cidin expression is increased in response to iron overloadand inflammation and is reduced in response to increasederythropoiesis, hypoxia, and iron deficiency. (5) Hep-cidin production is also reduced during pregnancy, al-lowing for increased maternal iron absorption. (6) Inmurine models, hepcidin regulation has been demon-strated by inflammatory cytokines, bone morphogeneticprotein signaling, and toll-like receptors. (9) A recentstudy in mice has demonstrated that H-ferritin, as well ashepcidin, is required for regulation of intestinal ironefflux. (10)

TransportFerric iron is transported through the bloodstreambound primarily to transferrin, a protein that has twoiron-binding sites. (1) Some iron is also found associatedwith albumin or small molecules. In the bloodstream,transferrin is typically one third saturated with iron.Binding of free iron by proteins not only protects thebody from damage by free radicals but also sequestersfree iron from bacteria, which use host iron for reproduc-tion. (5)

Tissue UptakeFor iron uptake in most tissues, transferrin binds totransferrin receptors on the surface of the cell, and thetransferrin receptor–transferrin complex is endocytosed.Protons are pumped into the endosome, lowering thepH and releasing iron from the transferrin. The free ironis released into the cell for use, and the transferrin isreleased back into the bloodstream. The number oftransferrin receptors expressed on the cell surface is reg-ulated by intracellular iron concentrations. In a low-ironstate, expression of the transferrin receptor is increasedand expression of ferritin is reduced. Conversely, whenthe intracellular iron concentration is high, expression ofthe transferrin receptor is reduced while expression offerritin is increased. (5)

StorageApproximately 75% of somatic iron is contained in he-moglobin, 15% in storage sites (liver, bone marrow, andspleen), and 10% in regulatory proteins. Iron is efficientlyrecycled from senescent red blood cells. Erythrocytes arephagocytosed by macrophages in the spleen, where theyare lysed and the protein is degraded. The released ironcan either be stored in the macrophage or sent back intocirculation bound to plasma transferrin. (5) Ferroportin

Figure 1. Iron balance in the neonate is a balance betweeniron input from prenatal placental transfer; enteral andparenteral iron intake; and transfusions and iron loss viaphlebotomy, gastrointestinal loss, and iron use for growth.

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is a transmembrane protein that transports iron from theinside to the outside of a cell. It is found on the surface ofcells that store or transport iron, including enterocytes,hepatocytes, and macrophages in the reticuloendothelialsystem. Ferritin, a 24-subunit hollow protein sphere, isthe primary iron storage protein. Ferritin concentrationis regulated by intracellular iron content via the ironresponse element/iron regulatory protein (IRE/IRP)system. When iron content is low, the IRP binds theIRE on ferritin mRNA and blocks translation. For releasefrom ferritin, iron is reduced to the ferrous form and exitsthrough pores in the ferritin protein. On the cell surface,

iron is reoxidized by ceruloplasmin for transport. (11)Iron loss is not regulated by the human body and occursprimarily by sloughing of iron-containing enterocytes orvia blood loss in menstruating females.

Special Considerations for InfantsRegulatory mechanisms present in adults may not befully developed in infants. In mice, ferroportin andDMT1 are not expressed on the enterocyte surface untillate infancy, indicating that the structure for iron regula-tion continues to develop postnatally. This is also true inrats. Expression of DMT1 and ferroportin is not upregu-

Figure 2. Iron transport through the enterocyte. A. Heme iron is absorbed as an intact metalloprotein via heme carrier protein 1(HCP-1). Ferrous iron is released from heme via heme oxygenase. B. Nonheme iron is converted to the ferrous form by ascorbic acidand duodenal cytochrome B (DcytB) on the surface of the brush border. Ferrous iron then binds to divalent metal transporter-1(DMT1) and is transferred into the enterocyte. C. Ferric iron binds chelators in the small intestine and is absorbed via a �3 integrinand mobilferrin pathway. After entry into the enterocyte, ferric iron is reduced by paraferritin and binds mobilferrin. D. Ferrous ironfrom all three entry pathways is released into the intracellular iron pool and used for cellular metabolism, stored as ferritin, ortransferred out of the enterocyte. E. Iron is released by ferroportin at the basolateral membrane, where it is oxidized by hephaestinand binds to transferrin for transport. F. When the body is iron-replete, hepcidin binds ferroportin (IREG1) at the basolateral surfaceof the enterocyte, inducing internalization and degradation of the protein.

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lated in iron-deficient rat pups by 10 days of age butincreases by 20 days. In humans, a randomized, con-trolled trial found that at 6 months of age, iron absorp-tion was not different between iron-sufficient and-deficient infants, but at 9 months of age, unsupple-mented infants increased iron absorption. (12) This sug-gests that before 6 months of age, infants are unable tomodulate iron absorption in response to iron status.

Consequences of Iron Deficiency and ExcessEffects of Maternal and Perinatal IronDeficiency: Cell Culture and Animal Models

Approximately 80% of iron transfer to the fetus occursduring the third trimester of pregnancy. In rats, whenmaternal iron stores are inadequate, expression of pla-cental transferrin receptor and IRE-regulated DMT1increase to augment iron transfer to the fetus. An in vitromodel of placental iron deficiency shows similar results,with increased iron transfer from the apical to basolateralside of BeWo cells, a commercially available human pla-cental cell line. (13) These mechanisms may mitigate thefetal effects of maternal iron deficiency, but severe ma-ternal iron deficiency may affect fetal neurodevelopmentirreversibly.

Structural changes in iron-deficient rodents includereduced myelin content, (14) shortened hippocampaldendritic arbors, (15) and reduction of proteins neces-sary for myelin compaction. (16) The degree of neuronalmyelination of rat pups from mothers fed iron-deficientand iron-supplemented diets during pregnancy and lac-tation were compared. The iron-deficient rat pups hadreduced brain and spinal cord myelination comparedwith iron-replete pups. (14) Similar results have beenshown in iron-deficient mice. (16) Maternal iron defi-ciency is associated with reduced brain iron concentra-tions, altered dopamine metabolism, and changes inmyelin fatty acid composition. (17) Decreased neuronalmetabolic activity has also been observed in iron-deficient rats. Cytochrome c oxidase activity is reducedin the hippocampus, dentate gyrus, piriform cortex, me-dial dorsal thalamic nucleus, and the cingulate cortex ofiron-deficient rats, indicating that areas of the braininvolved in memory processing are selectively affected byiron deficiency. (18) Iron-deficient rats also have reducedoligodendrocyte metabolic activity, as measured by ac-tivity of 2�,3�-cyclic nucleotide 3�-phosphohydrolase,lower concentrations of myelin basic protein, alterationsin fatty acid composition of hindbrain phospholipids,and reduced cytochrome oxidase activity compared withiron-sufficient rats. Iron deficiency during gestation andearly postnatal life both show these results. (19)

Behavioral changes also occur. These include poorerlearning capacity (20) and spatial navigation (21) andincreased hesitancy (21) and anxiety. (22) These changesmay be irreversible because reversal of iron deficiencyafter weaning did not improve deficits in sensorimotorfunction, increased hesitancy to explore, and spatiallearning. (21)

Effects of Maternal Iron Deficiency:Human Data

The consequences of iron deficiency on the human fetusare less well characterized because ethically sound, ran-domized, controlled trials in this population are difficultto design. However, some information on the effects ofiron deficiency can be gleaned from developing countrieswhere iron deficiency during pregnancy is common.Evidence is also available from the literature on ironsupplementation during pregnancy.

Because the placenta adapts to increased iron transferto the fetus in the presence of maternal iron deficiency,the fetus is relatively protected until severe maternaldeficiency develops. At birth, most studies have shownminimal differences in iron status (cord blood hemoglo-bin, serum iron, serum ferritin, and total iron-bindingcapacity [TIBC]) between iron-supplemented and non-supplemented mothers, although serum ferritin tends tobe higher in infants born to nonanemic mothers. (23)Follow-up evaluation suggests that maternal iron supple-mentation may protect the infant from developing irondeficiency anemia. Infants born with low ferritin storestend to continue to have lower iron stores than age- andweight-matched controls at 9 to 12 months of age. (24)

Neonatal and Infant Iron DeficiencyIron deficiency in infancy appears to affect socioemo-tional, cognitive, and motor function negatively. Iron-deficient infants are less engaged with their environmentand are more shy, hesitant, solemn, and difficult tosoothe. (25) They demonstrate slower auditory neuraltransmission speed, (26) poorer recognition memory,(27) and slower motor function. The severity of irondeficiency affects the degree of socioemotional behav-ioral differences. Socioemotional behavior was assessedamong 77 infants ages 9 to 10 months who receivediron supplementation for 3 months. Linear effects of ironstatus were found for shyness, orientation-engagement,soothability, positive affect, and latency to engagementwith examiner. (25)

Iron deficiency in infancy has been associated withlong-termnegativeoutcomes.Theseincludealteredsleep-wake cycles at preschool age, (28) reduced learning

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capacity and positive task orientation in elementary-agechildren, (29) behavioral problems in adolescence, (30)and deficits in executive function and recognition mem-ory in young adulthood. (31)

The effect of iron supplementation was evaluated in ablinded study of 77 term breastfed infants randomized toeither 7.5 mg/day of elemental iron or placebo from 1 to6 months of age. Iron supplementation resulted in sig-nificantly higher visual acuity and psychomotor develop-ment index at 13 months of age, suggesting there may besome benefit to supplementation in breastfed infants.(32) It has been questioned whether iron supplementa-tion in breastfed infants might increase the risk of infec-tion. A systematic review in 2002 found no evidence ofincreased infection in children receiving iron supplemen-tation, although the risk of diarrhea was increased. Thir-teen of the 28 studies in this review were conducted ininfants, and a variety of iron supplementation methods,including parenteral iron, enteral iron, or iron-fortifiedformula, were included. (33) The American Academy ofPediatrics recommends that exclusively breastfed infantsreceive 1 mg/kg per day of iron at 4 months of age. (34)

Iron Deficiency in Preterm InfantsPreterm infants are at increased risk for long-term con-sequences of iron deficiency because they are born beforethe bulk of placental iron transfer. The human braintriples in weight as it develops between 24 and 44 weekspostconception. Areas of significant development in-clude the visual and auditory cortexes, capability forreceptive language and executive function, and the neu-ronal basis for learning. Because neuronal developmentrequires iron, these processes are vulnerable to iron defi-ciency in the preterm infant. (2)

Tsunenobu and associates (35) examined the correla-tion between umbilical cord ferritin values and perfor-mance on mental and psychomotor tests at 5 years of age.Children whose serum ferritin concentrations were in thelowest quartile at birth performed the worst. In thesample, 13% of the children (n�278) were born pretermand 22% were small for gestational age. The percentageof low birthweight was highest in the lowest quartile ofserum ferritin values. This study highlights the possibilitythat inadequate iron accretion during gestation may havelong-term developmental effects.

Steinmacher and colleagues (36) evaluated the neu-rodevelopment of a cohort of 5-year-old children whoweighed less than 1,301 g at birth and had been random-ized to early (as soon as enteral feedings reached100 mL/kg per day) or late (61 days of age) ironsupplementation. The follow-up study showed a trend

toward better neurodevelopmental outcome in the chil-dren who received early iron supplementation, but it wasunderpowered.

Consequences of Iron Excess: Neonates andInfants

Like iron deficiency, iron excess can have adverse effects.Iron is a pro-oxidant and may damage lipids, polysaccha-rides, DNA, and proteins through free radical formation.(1) Iron is more likely to cause peroxidation of poly-unsaturated fatty acids when adequate antioxidants, es-pecially vitamin E, are not available. (37) Because ofthese effects, concern has been raised that providingroutine iron supplementation to iron-sufficient infantsmight negatively affect long-term development, al-though this was not borne out in a study supplementingiron-sufficient infants age 6 to 18 months who werefollowed until 10 years of age. (38)

Consequences of Iron Excess: Preterm InfantsProviding excess iron might be particularly harmful topreterm infants, who are at increased risk for oxidativeinjury for several reasons, including immature antioxi-dant defense systems. (39) Neonates tend to have lowTIBC; high saturation of circulating transferrin; and lowconcentrations of ceruloplasmin, unbound transferrin,and albumin, all of which bind free iron. (40) Althoughno direct link has been shown between iron excess anddisease in preterm infants, concerns have been raisedabout the potential for iron to cause increased oxidativestress, which may contribute to complications of pre-maturity such as retinopathy of prematurity (41) orbronchopulmonary dysplasia. (42) Short-term studiesindicate that iron does not induce oxidative stress, asmeasured by isoprostanes and antioxidant status, whenprovided to stable, growing low-birthweight infants atdoses ranging from 2 to 12 mg/kg per day or at atwice-daily dose of 9 mg per day. (43)(44)

Risks associated with repeated blood transfusionshave primarily been studied in patients who have thalas-semia major. Treatment for this autosomal recessive dis-order includes frequent transfusion, which is associatedwith increased accumulation of hepatic iron, cardiaccomplications, increased incidence and severity of infec-tions, altered immune function, and endocrinopathies(eg, diabetes, hypothyroidism). (39) These term infantsdiffer from preterm infants requiring multiple transfu-sions because the requirement for transfusions in preterminfants is largely due to phlebotomy losses. (45) The riskor benefit of restrictive versus liberal transfusion guide-lines is still not known. (46)(47) An increased risk of

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apnea and severe brain hemorrhage or periventricularleukomalacia was reported in one single-center trial, (47)but this risk was not corroborated in a larger multicenter,randomized, controlled trial. (46) The long-term neuro-development measured 18 to 21 months after transfu-sion with restrictive or liberal guidelines showed nodifference. (48)

Assessment of Iron StatusAssessing Iron Status in Adults

Traditional measures of iron status include hematocritand hemoglobin, red cell indices, serum ferritin, serumiron, and TIBC. Each test identifies iron availability at adifferent point in iron metabolism. The clinician’s choiceof test(s) for iron status is driven by the question beingasked, coexisting factors that may affect the laboratorytest, and the sensitivity and specificity of the test.

Hemoglobin and hematocrit are the least sensitivemeasures of iron deficiency. (49) Iron deficiency anemiais microcytic and hypochromic. Low mean cell volume(MCV) is consistent with iron deficiency but may alsoreflect dysfunction of hemoglobin synthesis. (50) Serumferritin reflects iron stores. Low serum ferritin is specificfor iron deficiency. (51) However, ferritin is an acute-phase protein and may increase during infection, mask-ing low stores. Serum iron concentration identifies ad-vanced iron deficiency but has low sensitivity. It isaffected by iron intake and time of day, (49) is elevated inerythropoietic dysfunction, and decreased during infec-tion or inflammation. (50) The TIBC primarily reflectsthe amount of available unbound transferrin and is ele-vated in iron deficiency. Historically, TIBC was standardfor measuring iron status, but it has been largely replacedby serum ferritin. Synthesis of the soluble transferrinreceptor (sTfR) is increased when intracellular iron isinsufficient. Increased sTfR is observed in iron deficiencyor when erythropoiesis elevates cellular iron needs. This testis specific for iron deficiency in patients who are suspectedto have nutritional iron deficiency or anemia of chronicdisease, but it is affected by hematologic disorders. (49)

Assessing Iron Status in InfantsThe tests used to assess iron status are affected by hema-tologic changes after birth. Thus, standard referenceranges must be interpreted with caution when evaluatingthe iron status of preterm and even term infants in thefirst 6 months after birth. In a group of term 9- to12-month-old infants who had iron deficiency defined bysTfR greater than 2.45 mg/L, the sensitivity of hemo-globin (67%) was lower than that of serum ferritin (83%)and MCV (86%), while the specificity of hemoglobin was

higher than the other tests. This indicates that serumferritin and MCV may be better screening tests for irondeficiency than hemoglobin assessment. (52)

Serum ferritin may be affected by length of gestation,sex, maternal iron status, maternal-fetal nutrient exchange,(51) hypoxemia, reduced placental perfusion in utero, (53)and inflammation. (49) The effect of inflammation is espe-cially important in preterm infants, who have reduced ironstores and are at increased risk for infection.

sTfR exhibits developmental changes in the first 2postnatal years, but sTfR and the ratio of sTfR to serumferritin may be better markers than ferritin alone fordetection of iron deficiency. (54)

Hemoglobin concentrations change during gestationand the first few postnatal months. Hemoglobin risesfrom 11 to 12 g/dL (110 to 120 g/L) at 22 to 24 weeksto 13 to 14 g/dL (130 to 140 g/L) at term. As eryth-ropoiesis slows after birth (due to reduced erythropoietin[Epo] production in response to increased oxygenation),the hemoglobin concentration drops, then rises again by6 months as erythropoiesis increases again. The drop inhemoglobin concentration after birth is greater in pre-term than term infants. By 4 to 8 weeks after birth, theaverage hemoglobin concentration of a preterm infant(�1,500 g birthweight) is 8 g/dL (80 g/L).

Difficulties in Assessing Infant Iron Status andAnemia of Prematurity

The gestational-appropriate development and hemato-poietic changes that take place after birth includechanges in hemoglobin concentration and red cell size.Iatrogenic changes also occur in preterm infants.

The anemia of prematurity is a hypoproliferative, nor-mochromic, normocytic anemia characterized by re-duced production of Epo. (55) The decrease in Epoproduction is caused by the transition from a hypoxicintrauterine environment to the relatively hyperoxicextrauterine environment. In addition, fetal Epo is pro-duced by the liver, which is relatively insensitive tohypoxia, whereas by term gestation, Epo is primarilyproduced by the kidney, which is more responsive tohypoxia. Additional contributors to anemia in the pre-term infant include phlebotomy losses, the shortened redblood cell life span, iron deficiency, and inflammation.(45) At what point this anemia becomes pathologic andthe appropriate clinical response to such a developmentis an area of ongoing research. Approximately 85% ofextremely low-birthweight infants are transfused withadult red blood cells, further complicating the ability toassess iron status because circulating blood reflects boththe baby’s and the transfused adult cells.

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New Possibilities for Assessment of Iron Statusof Infants

One candidate test for detection of iron-deficient eryth-ropoiesis is the zinc protoporphyrin-to-heme ratio(ZnPP/H). ZnPP/H measures the amount of zinc rel-ative to iron incorporated into the protoporphyrin ringduring heme synthesis. Figure 3 depicts the balancebetween the ZnPP molecule and heme. Because thebody prioritizes iron for hematopoiesis, ZnPP/H is asensitive indicator of iron deficiency. The only knowncause of increased formation of zinc protoporphyrin isincreased iron-deficient erythropoiesis. As a result, thistest is specific for iron-deficient erythropoiesis (not nec-essarily iron deficiency) of any cause. (49) A densitygradient can be used to separate denser, mature erythro-cytes from their lighter, immature counterparts. Measur-ing the ZnPP/H on this top fraction may further in-crease the sensitivity of this test to identify conditionsassociated with impaired erythrocyte iron delivery. (56)The sensitivity and specificity of ZnPP/H in preterm andterm infants, especially in special conditions such as nu-tritional inadequacy or zinc deficiency, have not beenclearly determined. A normal range for ZnPP/H ofpreterm infants has been proposed, (57) but the samplesize was small.

Prevention and Treatment of Iron Deficiencyin the Preterm InfantPreterm birth increases the risk for iron deficiency. Cel-lular immaturities and reduced iron delivery may nega-

tively affect the iron status of the preterm infant. Type offeeding (formula, human milk, soy-based formula, or useof fortifier) also affects iron delivery.

The intestinal epithelium develops rapidly after birth,stimulated by growth factors in amniotic fluid, co-lostrum, and human milk. (58) Similarly, other tissues inthe preterm infant are not fully developed. Althoughthese do not have direct influence on iron absorption,they may affect iron utilization in the preterm infant.

Iron Supplementation: EnteralThe optimal timing and dosage of iron supplementa-tion for the preterm infant has been extensively studied.The American Academy of Pediatrics recently issuednew iron recommendations, indicating that breastfed,iron-sufficient term infants typically have iron stores atbirth that last until 4 months of age, when either iron-containing complementary foods or an iron supplementshould be introduced. (34) Preterm infants are born withless total iron stores and have significant iatrogenic bloodloss, necessitating earlier supplementation.

Low-birthweight infants who begin iron supplemen-tation (2 mg/kg per day) at 2 weeks of age have betteriron status at 3 to 6 months of age than infants who onlyreceive iron before 6 months if they develop iron defi-ciency. (59) Two studies (60)(61) have tested whetherearly iron supplementation in very low-birthweight in-fants (early iron started at 14 days of age or when theinfant was tolerating 100 mL/kg per day enteral feed-ings; late iron started at 61 days of age) improved serumferritin at 2 months. Neither study showed a difference inserum ferritin at 2 months of age, but blood transfusionsand iron deficiency were reduced in one study. (60) Thesecond study (61) was underpowered. (62) Arnon andassociates (37) reported improved iron status of preterminfants at 4 and 8 weeks when iron supplementationbegan at 2 weeks rather than 4 weeks of age. No negativeeffects of early supplementation were reported. Thesestudies indicate that early supplementation may be neu-tral at worst and helpful at best.

Human milk is the best choice for term infants, buthuman milk alone does not provide adequate nutrientsfor the growing preterm infant. Iron absorption is af-fected by protein composition. Iron absorption fromhuman milk, whey- or casein-based cow milk formulas,and soy formulas has been compared. Iron is best ab-sorbed from human milk and is more readily availablefrom whey-based than casein-based formula. (63)(64)Estimated availability of iron from soy-based formulasvaries. The whey-to-casein ratio, (64) type of iron com-pound, (65) and amounts of ascorbic acid and phytates

Figure 3. Zinc replaces iron in the center of protoporphyrin IXwhen iron is in low supply.

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(66) all affect availability. Although iron may be lessreadily available from soy-based formulas, it is similar tocow milk formulas in preventing iron deficiency in in-fancy. However, soy-based infant formulas are not rec-ommended for use in preterm infants (unless other for-mulas are contraindicated).

Although iron is best absorbed from human milk,because the iron content of human milk is low, the totalamount of iron an infant absorbs may be higher fromformulas. The ideal amount of iron to provide in iron-fortified formulas is still an area of investigation; mostpreterm formulas in the United States contain 1.8 mg/100 kcal. The estimated oral iron requirement for pre-term infants is 2 to 4 mg/kg per day, which may be lessin an infant receiving red blood cell transfusions. The Amer-ican Academy of Pediatrics recommends that infants notreceiving human milk receive an iron-fortified formula andthat preterm infants receive at least 2 mg/kg per day ofelemental iron from 1 to 12 months of age. (34)

Iron Supplementation: ParenteralParenteral iron has been considered as an option forpatients who are unable to absorb adequate iron enter-ally. It has been used effectively to improve iron statusand promote erythropoiesis in preterm infants. However,parenteral iron is not as safe as enteral iron. Risks includeneonatal sepsis, (67) iron overload, (68) and anaphylaxis.(69) Consensus on the best iron solution, dosage, androute of administration has not been reached. Dosage,timing, route of administration, and use with Epo hasvaried in studies of preterm infants. (70)(71) In uteroiron accretion is estimated at 1.6 to 2.0 mg/kg per dayduring the third trimester. (72) It has been suggestedthat a parenteral iron dose of 1 mg/kg per day may meetiron needs; (71) this dose has been successfully used inpreterm infants also receiving recombinant Epo.

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American Board of Pediatrics Neonatal-PerinatalMedicine Content Specifications• Understand the mechanism and gestational

timing of placental transfer of iron to thefetus and its effect on iron stores innewborn infants.

• Recognize the causes of iron deficiencyanemia and various prevention measures.

• Recognize the clinical and diagnostic features, laboratoryfindings, management, and long-term consequences of irondeficiency anemia.

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21. Felt B, Beard J, Schallert T, et al. Persistent neurochemical andbehavioral abnormalities in adulthood despite early iron supple-mentation for perinatal iron deficiency anemia in rats. Behav BrainRes. 2006;171:261–27022. Beard JL, Erikson KM, Jones BC. Neurobehavioral analysis ofdevelopmental iron deficiency in rats. Behav Brain Res. 2002;134:517–52423. Hokama T, Takenaka S, Hirayama K, et al. Iron status ofnewborns born to iron deficient anaemic mothers. J Trop Pediatr.1996;42:75–7724. Georgieff MK, Wewerka SW, Nelson CA, deRegnier RA. Ironstatus at 9 months of infants with low iron stores at birth. J Pediatr.2002;141:405–40925. Lozoff B, Clark K, Jing Y, Armony-Sivan R, Angelilli M,Jacobson S. Dose-response relationships between iron deficiencywith or without anemia and infant social-emotional behavior.J Pediatr. 2008;152:696–70226. Roncagliolo M, Garrido M, Walter T, Peirano P, Lozoff B.Evidence of altered central nervous system development in infantswith iron deficiency anemia at 6 mo: delayed maturation of auditorybrainstem responses. Am J Clin Nutr. 1998;68:683–69027. Carter RC, Jacobson JL, Burden MJ, et al. Iron deficiencyanemia and cognitive function in infancy. Pediatrics. 2010;126:e427–e43428. Peirano PD, Algarin CR, Garrido MI, Lozoff B. Iron defi-ciency anemia in infancy is associated with altered temporal organi-zation of sleep states in childhood. Pediatr Res. 2007;62:715–71929. Palti H, Meijer A, Adler B. Learning achievement and behaviorat school of anemic and non-anemic infants. Early Hum Dev.1985;10:217–22330. Corapci F, Calatroni A, Kaciroti N, Jimenez E, Lozoff B.Longitudinal evaluation of externalizing and internalizing behaviorproblems following iron deficiency in infancy. J Pediatr Psychol.2010;35:296–30531. Lukowski AF, Koss M, Burden MJ, et al. Iron deficiency ininfancy and neurocognitive functioning at 19 years: evidence oflong-term deficits in executive function and recognition memory.Nutr Neurosci. 2010;13:54–7032. Friel JK, Aziz K, Andrews WL, Harding SV, Courage ML,Adams RJ. A double-masked, randomized control trial of ironsupplementation in early infancy in healthy term breast-fed infants.J Pediatr. 2003;143:582–58633. Gera T, Sachdev HP. Effect of iron supplementation on in-cidence of infectious illness in children: systematic review. BMJ.2002;325:114234. Baker RD, Greer FR. Clinical report–diagnosis and preventionof iron deficiency and iron-deficiency anemia in infants and youngchildren (0–3 years of age). Pediatrics. 2010;126:1040–105035. Tsunenobu T, Goldenberg RL, Hou J, et al. Cord serumferritin concentrations and mental and psychomotor developmentof children at five years of age. J Pediatr. 2002;140:165–17036. Steinmacher J, Pohlandt F, Bode H, Sander S, Kron M, FranzAR. Randomized trial of early versus late enteral iron supplementa-tion in infants with a birth weight of less than 1301 grams: neuro-cognitive development at 5.3 years corrected age. Pediatrics. 2007;120:538–54637. Arnon S, Regev RH, Bauer S, et al. Vitamin E levels duringearly iron supplementation in preterm infants. Am J Perinatol.2009;26:387–39238. Gahagan S, Yu S, Kaciroti N, Castillo M, Lozoff B. Linear andponderal growth trajectories in well-nourished, iron-sufficient in-

fants are unimpaired by iron supplementation. J Nutr. 2009;139:2106–211239. Ozment CP, Turi JL. Iron overload following red blood celltransfusion and its impact on disease severity. Biochim Biophys Acta.2009;1790:694–70140. Collard K. Iron homeostasis in the neonate. Pediatrics. 2009;123:1208–121641. Inder TE, Clemett RS, Austin NC, Graham P, Darlow BA.High iron status in very low birth weight infants is associated withan increased risk of retinopathy of prematurity. J Pediatr. 1997;131:541–54442. Silvers KM, Gibson AT, Russell JM, Powers HJ. Antioxidantactivity, packed cell transfusions, and outcome in premature infants.Arch Dis Child Fetal Neonatal Ed. 1998;78:F214–F21943. Braekke K, Bechensteen AG, Halvorsen BL, Blomhoff R,Haaland K, Staff AC. Oxidative stress markers and antioxidantstatus after oral iron supplementation to very low birth weightinfants. J Pediatr. 2007;151:23–2844. Miller SM, McPherson RJ, Juul SE. Iron sulfate supplementa-tion decreases zinc protoporphyrin to heme ratio in prematureinfants. J Pediatr. 2006;148:44–4845. Widness JA. Pathophysiology of anemia during the neonatalperiod, including anemia of prematurity. NeoReviews. 2008;9:e52046. Kirpalani H, Whyte RK, Andersen C, et al. The PrematureInfants in Need of Transfusion (PINT) study: a randomized, con-trolled trial of a restrictive (low) versus liberal (high) transfusionthreshold for extremely low birth weight infants. J Pediatr. 2006;149:301–30747. Bell EF, Strauss RG, Widness JA, et al. Randomized trial ofliberal versus restrictive guidelines for red blood cell transfusion inpreterm infants. Pediatrics. 2005;115:1685–169148. Whyte RK, Kirpalani H, Asztalos EV, et al. Neurodevelopmen-tal outcome of extremely low birth weight infants randomly as-signed to restrictive or liberal hemoglobin thresholds for bloodtransfusion. Pediatrics. 2009;123:207–21349. Labbe RF, Dewanji A. Iron assessment tests: transferrin recep-tor vis-a-vis zinc protoporphyrin. Clin Biochem. 2004;37:165–17450. Worwood M. The laboratory assessment of iron status—anupdate. Clin Chim Acta Int J Clin Chem. 1997;259:3–2351. Siddappa AM, Rao R, Long JD, Widness JA, Georgieff MK.The assessment of newborn iron stores at birth: a review of theliterature and standards for ferritin concentrations. Neonatology.2007;92:73–8252. Vendt N, Talvik T, Kool P, et al. Reference and cut-off valuesfor serum ferritin, mean cell volume, and hemoglobin to diagnoseiron deficiency in infants aged 9 to 12 months. Medicina (Kaunas).2007;43:698–70253. Chockalingam UM, Murphy E, Ophoven JC, Weisdorf SA,Georgieff MK. Cord transferrin and ferritin values in newborninfants at risk for prenatal uteroplacental insufficiency and chronichypoxia. J Pediatr. 1987;111:283–28654. Olivares M, Walter T, Cook JD, Hertrampf E, Pizarro F.Usefulness of serum transferrin receptor and serum ferritin indiagnosis of iron deficiency in infancy. Am J Clin Nutr. 2000;72:1191–119555. Bishara N, Ohls RK. Current controversies in the managementof the anemia of prematurity. Semin Perinatol. 2009;33:29–3456. Blohowiak SE, Chen ME, Repyak KS, et al. Reticulocyteenrichment of zinc protoporphyrin/heme discriminates impairediron supply during early development. Pediatr Res. 2008;64:63–67

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57. Juul SE, Zerzan JC, Strandjord TP, Woodrum DE. Zincprotoporphyrin/heme as an indicator of iron status in NICUpatients. J Pediatr. 2003;142:273–27858. Buccigrossi V, De Marco G, Bruzzese E, et al. Lactoferrininduces concentration-dependent functional modulation of intesti-nal proliferation and differentiation. Pediatr Res. 2007;61:410–41459. Lundstrom U, Siimes MA, Dallman PR. At what age does ironsupplementation become necessary in low-birth-weight infants?J Pediatr. 1977;91:878–88360. Franz AR, Mihatsch WA, Sander S, Kron M, Pohlandt F.Prospective randomized trial of early versus late enteral iron supple-mentation in infants with a birth weight of less than 1301 grams.Pediatrics. 2000;106:700–70661. Sankar MJ, Saxena R, Mani K, Agarwal R, Deorani AK, PaulVK. Early iron supplementation in very low birth weight infants—arandomized controlled trial. Acta Paediatr. 2009;98:953–95862. Bharti B, Bharti S. Early iron supplementation for very lowbirth weight preterm newborns: statistical vs. clinical significance!!Acta Paediatr. 2009;98:1704–170563. Bosscher D, Van Caillie-Bertrand M, Robberecht H, Van DyckK, Van Cauwenbergh R, Deelstra H. In vitro availability of calcium,iron, and zinc from first-age infant formulae and human milk.J Pediatr Gastroenterol Nutr. 2001;32:54–5864. Drago SR, Valencia ME. Influence of components of infant

formulas on in vitro iron, zinc, and calcium availability. J AgriculFood Chem. 2004;52:3202–320765. Hendricks GM, Guo MR, Kindstedt PS. Solubility and relativeabsorption of copper, iron, and zinc in two milk-based liquid infantformulae. Int J Food Sci Nutr. 2001;52:419–42866. Davidsson L, Galan P, Kastenmayer P, et al. Iron bioavailabilitystudied in infants: the influence of phytic acid and ascorbic acid ininfant formulas based on soy isolate. Pediatr Res. 1994;36:816–82267. Barry DMJ, Reeve AW. Increased incidence of gram-negativeneonatal sepsis with intramuscular iron administration. Pediatrics.1977;60:908–91268. Ben Hariz M, Goulet O, De Potter S, et al. Iron overload inchildren receiving prolonged parenteral nutrition. J Pediatr. 1993;123:238–24169. Hamstra RD, Block MH, Schocket AL. Intravenous iron dex-tran in clinical medicine. JAMA. 1980;243:1726–173170. Pollak A, Hayde M, Hayn M, et al. Effect of intravenous ironsupplementation on erythropoiesis in erythropoietin-treated pre-mature infants. Pediatrics. 2001;107:78–8571. Friel JK, Andrews WL, Hall MS, et al. Intravenous iron admin-istration to very-low-birth-weight newborns receiving total andpartial parenteral nutrition. JPEN J Parenter Enteral Nutr. 1995;19:114–11872. Shaw JCL. Parenteral nutrition in the management of sick lowbirthweight infants. Pediatr Clin North Am. 1973;20:333–358

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NeoReviews Quiz

11. The uptake of iron by the enterocyte is an important regulatory step in body iron homeostasis. Of thefollowing, the absorption of heme iron in the enterocyte is primarily regulated by:

A. Beta-3 integrin.B. Divalent metal transporter-1.C. Duodenal cytochrome B.D. Heme carrier protein 1.E. Paraferritin.

12. The release of iron from the enterocyte into the bloodstream is a tightly regulated process, influenced bythe iron status of the body. Of the following, the release of iron from the enterocyte into the bloodstreamis primarily regulated by:

A. Ferroportin.B. Hephaestin.C. Mobilferrin.D. Paraferritin.E. Transferrin.

13. Preterm infants are at increased risk for long-term neurodevelopmental consequences of iron deficiencybecause they are deprived of placental iron transfer from shortened gestation. Conversely, preterm infantsare also at increased risk for potential oxidative complications of iron excess from repeated bloodtransfusions. Assessment of iron status, therefore, is important in the nutritional management of preterminfants. Of the following, the most specific blood test of iron status in preterm infants is themeasurement of:

A. Erythropoietin.B. Ferritin.C. Hemoglobin.D. Soluble transferrin receptor.E. Total iron-binding capacity.

14. In iron deficiency, another trace element is incorporated into the protoporphyrin ring of the hememolecule. This observation has led to the development of a new test that can be used as a sensitivemarker of iron-deficient erythropoiesis. Of the following, the candidate trace element used as a measureof iron-deficient erythropoiesis is:

A. Chromium.B. Copper.C. Manganese.D. Selenium.E. Zinc.

15. The optimal timing and dosage of iron supplementation for preterm infants has been studied extensively.Of the following, the best suggested postnatal age for starting iron supplementation (2.0 mg/kg per day)in preterm infants is at:

A. Birth.B. 2 weeks.C. 4 weeks.D. 2 months.E. 4 months.

nutrition iron




Carissa Cheng and Sandra Juul Iron Balance in the Neonate













Sunita Sridhar, Stacey Arguello and Henry Chong Lee Transition to Oral Feeding in Preterm Infants







Transition to Oral Feedingin Preterm InfantsSunita Sridhar,* Stacey

Arguello, MS, CCC-SLP,†

Henry Chong Lee, MD,

MS§

Author Disclosure

Dr Lee, Ms Sridhar,

and Ms Arguello have

disclosed no financial

relationships relevant

to this article. This

commentary does not


of an unapproved/


commercial product/

device.

AbstractLearning to eat is an integral aspect of a preterm infant’s development. It is especiallyimportant to ensure that infants are able to breastfeed effectively and transition safelyfrom other types of feeding. This article describes the mechanisms of sucking andswallowing involved in oral feeding and proposes strategies to address the challengesthat preterm infants face in transitioning to breast- or bottle-feeding.


1. Understand the mechanisms of oral feeding in preterm infants.2. Recognize the different challenges in breastfeeding and bottle-feeding for the preterm

infant.3. Have strategies for helping preterm infants make the transition to oral feeding.

Mechanism of Oral Feeding in InfantsSucking

For a newborn, the mechanisms of sucking and swallowing milk require complex coordi-nation. Sucking has two components: suction and expression. Suction is the negativeintraoral pressure exerted by the infant when milk is pulled into the mouth, creating avacuum. This vacuum leads to milk being drawn from alveoli into mammary ducts whenbreastfeeding and facilitates milk flow when bottle-feeding. Expression is the positivepressure that corresponds to the stripping or compression of the nipple between the hardpalate and tongue (Figure). As a result of these forces, milk is ejected into the infant’smouth. (2) Recent studies suggest that the vacuum component may be the key mechanismin breastfeeding. In ultrasonographic imaging of breastfeeding, the peak vacuum coincideswith the lowering of the infant’s tongue; subsequent raising of the tongue is associatedwith decrease in the vacuum and a cessation of milk flow. (3)

SwallowingThe subsequent act of swallowing requires further coordinated effort. For effective and safeswallowing, all of the following structures must act in a well-coordinated process: thetongue, lips, cheeks, soft palate, pharynx, larynx, and esophagus. An external stimulus,such as a feeding bolus, activates the medullary swallowing center, which initiates theswallowing process. (2) The oropharyngeal muscles act in a coordinated effort to ensurethat the airway is protected and that the bolus is propelled into the esophagus.

Coordination of Swallowing and BreathingThe coordination of swallowing and breathing is a developmental process that continues tomature after birth. A study of term infants demonstrated that 2- to 3-day-old newbornshad significant interruption of breathing when swallowing compared with 4- to 5-day-oldbabies, in whom interruption was less noticeable due to improved coordination. (1)Swallows occurred at the “boundary between expiration and inspiration,” as the babiespaused in swallowing while breathing. (1) In 2- to 3-day-old babies, sucking was not wellcoordinated with breathing, but in 4- to 5-day-old babies, sucks occurred at specific timesin the breathing cycle. Feeding and swallowing rates increase over the first postnatal

*University of California, Berkeley, CA.†ValleyCare Hospital, Pleasanton, CA.§Department of Pediatrics, University of California, San Francisco, CA.

Article nutrition



month. (4) Feeding maturation is indicated by stabiliza-tion of the suck rhythm and aggregation of sucks andswallows into periodic runs. (5)

Coordination of Feeding in Preterm InfantsConsidering that even term infants require time to ma-ture in the development of feeding, it is not surprisingthat preterm infants have even less coordination in theirsuck, swallowing, and breathing processes. This immatu-rity places them at higher risk of apneic and bradycardicepisodes, aspiration, and development of feeding aver-sions or feeding hypersensitivities later in childhood.Immature patterns of oral feeding of 3 to 5 sucks perburst are seen in infants at 32 weeks’ gestation; termfeeding patterns consist of 10 to 30 sucks per burst, withincreased length of sucking bursts as infants age. (6) Thecoordination and stability of sucking and swallowing inpreterm infants appears to be dependent more onpostconceptional than on chronologic age, reflectingneurologic maturation processes. (5) For example, al-though the maturation and skills for adequate feedingprocesses would be very unusual for an infant at 32 weeks

postconceptional age, this coordination often is emerg-ing at 34 weeks’ gestation.

Differences in Coordination BetweenBreastfeeding and Bottle-feeding

The primary difference between breastfeeding andbottle-feeding is that breastfeeding is a more active pro-cess for the infant that relies more heavily on suction. Inbreastfeeding, the infant is required to grasp the nipple,stay attached, and squeeze to receive the milk. Thebreastfeeding infant also needs to have an active alterna-tion between sucking and swallowing. However, inbottle-feeding, the caregiver can manipulate the nippleso the infant receives the milk more easily. The end of thebottle is always filled with milk, so the infant only needsto apply slight pressure to the nipple to extract the milk.

Breastfeeding also requires more coordination thanbottle-feeding. The infant needs to use his or her lips,cheeks, tongue, and jaw in a coordinated process, moreso than in bottle-feeding. The lips, cheeks, and tonguehelp to locate the nipple, stabilize it in the mouth, andform a seal. Then, the oral cavity expands to create thecorrect amount of negative pressure. The hard palate inboth breast- and bottle-feeding facilitates positioningand stabilizing the nipple as well as elevating it duringswallowing. (2) On the other hand, the mother’s breast ismore versatile than the bottle because it can adapt to theinfant’s needs, changing to the infant’s size, shape, andthe positioning of his or her mouth. (7)

Oxygen Saturation in Breast- VersusBottle-fed Infants

Breastfed infants tend to maintain higher oxygen satura-tions than do bottle-fed infants. One proposed explana-tion is that bottle-fed babies swallow more and, thus,breathing is interrupted more frequently. They do notbreathe during sucking bursts but rather breathe rapidlyduring breaks in sucking. Breastfed infants, however, areable to integrate breathing within bursts of sucking and,thus, may have a better coordination of sucking, swal-lowing, and breathing. (8) There may also be a mechan-ical explanation for the difference in breathing and swal-lowing coordination because tongue positioning affectsmechanisms of breathing and feeding. In breastfeeding,the tongue is under the nipple during feeding, produc-ing peristalsis so that swallowing occurs concurrently.On the other hand, for bottle-feeding infants, the tonguemay be more piston-like, which may intermittently com-promise breathing by causing obstruction. (7)

Figure. Still picture from ultrasonographic recording andartist’s rendition of infant at close to the maximum point ofcompression of the nipple by the tongue during the suckingcycle. Reprinted with permission from Weber et al. (1)

nutrition transition to oral feeding



Overcoming Challenges in the Transition toOral Feeding

Milk ExpressionInadequate expressed milk volume is a common problemof mothers of preterm infants, and a concerted effortshould be made to help the mother mechanically pumpher milk soon and frequently after delivery. Mothersshould be encouraged to pump as soon as feasible afterdelivery, preferably within 6 hours after birth, and thenevery 3 hours. Maintenance of adequate pumping toensure milk supply helps in the transition to oral feedingwhen the infant has matured developmentally. (9) Theinvolvement of lactation consultants who have specialtraining in caring for preterm infants may be desirable atan early point in the hospital course. (10) Lactationconsultants can assist in educating mothers on the ben-efits of human milk for preterm infants, aid with pump-ing, and help with the transition to oral feeding. Encour-aging mothers to spend as much time as possible in theneonatal intensive care unit and facilitating kangaroocare (skin-to-skin contact) may increase the volume ofmilk in mothers who are pumping, promote physiologicstability for the infants, and facilitate the process ofmothers gaining confidence in holding their infants forfeeding. (11)(12)(13)

Even after the infant has started to breastfeed, themother should be vigilant in maintaining an adequatemilk supply because initial breastfeeding is likely to in-volve immature sucking patterns that are not adequate toprotect the mother’s milk supply without supplementaluse of a hospital-grade electric pump. This immaturepattern may be termed “nonnutritive sucking.”

Nonnutritive SuckingThe term “nonnutritive suck” can refer to the short,choppy, or weak character of the preterm infant who isnot sufficiently mature to have the sucking behavior

result in a nutritive function. On the other hand, a“nutritive” pattern of suck in breastfeeding consists ofa deep, rhythmical pattern, with each suck followed by aswallow. (14) Term infants also exhibit a nonnutritivesucking pattern in the absence of milk flow, and thisappears to be the normal behavior of an infant satisfyingthe sucking urge and a state regulatory mechanism. (15)Characteristics of the patterns of nutritive versus non-nutritive sucking are listed in Table 1. (14)(15)

The term “nonnutritive sucking” in the context ofpreterm infants is more often used to describe the role ofsucking “exercises,” often with a pacifier, that are usedbefore an infant is ready to feed orally. (16)

Nonnutritive breastfeeding (also referred to as dry orrecreational breastfeeding) allows the mother and childto practice proper positioning before actual breast-feeding begins. The mother pumps her breast beforeputting the infant to breast. In some instances, the infantcan also be tube-fed while suckling on the empty breast.Gradually, the mother pumps out less milk so the infantcan transition to obtaining milk from the mother’s breastand adjust to stronger milk flow. (17) Nonnutritivebreastfeeding may be an alternative to initiation ofactual breastfeeding for the early course of very low-birthweight infants, who may encounter problems suchas inadequate weight gain or weight loss if introducedto the breast before they are fully ready. Nonnutritivebreastfeeding may also promote maternal milk flow, helpwith maternal emotional stability, and prolong lactationin mothers. (18) Nonnutritive sucking in conjunctionwith additional oral stimulation has also been shown toimprove oral feeding performance of preterm infants anddecrease their hospital stay. In one study, infants whoreceived sensory-motor-oral stimulation and nonnutri-tive sucking were able to begin oral feeding 8 days earlier,wean off the gavage tube 8 days earlier, and be dis-charged from the hospital 10 days earlier. (19)

Table 1. Typical Patterns of Nutritive Versus Nonnutritive Sucking (14)(15)

Nutritive Sucking Nonnutritive Sucking

Temporal organization Continuous stream of bursts: transitioning toshorter bursts and longer pauses withprogression of feeding

Alternation of burst and rest periods:repetitive pattern of cycling

Rate 1 suck per second Preterm infant: 1.5 to 2 sucks per secondMature infant: 2 sucks per second

Suck-to-Swallow Ratio Young infant: 1:1, may be higher toward endof feeding

6:1 to 8:1

Older infant: 2:1 to 3:1Purpose Obtain nourishment State regulation, satisfy sucking desire,

exploration




Nonnutritive sucking on a pacifier may also improvephysiologic stability and nutrition in preterm infants.Sucking on a pacifier during tube or gavage feeding mayencourage the infant to develop sucking behavior andmay have a calming effect. In one study, nonnutritivesucking was associated with decreased hospital stay andbabies were less defensive and fussy during and aftertube feedings, with a perception of an easier transitionfrom tube to bottle-feeding. (16) Nonnutritive suckbefore bottle-feeding may also lead to a more alert andreceptive behavioral state and physiologic stability duringfeeding. (20)

Observations of nonnutritive suck may be used as ameasure of infants’ oral feeding readiness. Infants whohad more mature suck patterns, as determined by evalu-ations of consistency and “burst organization,” had ashorter oral transition time and were able to begin suc-cessful oral feeding at a younger age. (21) As infantsprogress in nonnutritive suck, their suck wave becomesmore regular, the bursts lengthen, and there is greaterconsistency between each suck and burst. Nonnutritivesuck can also be used as an assessment tool to determinewhich infants will experience greater oral feeding diffi-culties. (21) However, other studies have not demon-strated a significant effect of prefeeding nonnutritivesuck on effectiveness of bottle-feeding. (22) More re-search is needed to determine the impact of such prac-

tices on the effectiveness of encouraging feeding devel-opment. Nonnutritive suck can be used as just one part ofa more comprehensive assessment and efforts to increasestability and organization.

Strategies to Optimize the Transition toOral Feeding

Based on techniques such as nonnutritive suck, the readi-ness of an infant for oral feeding can be assessed tofacilitate the transition to oral feeding at an optimal time.This decision is based on the preterm infant’s medicalcondition and physiologic maturity. Various techniquesmay ease this transition (Table 2). Infants should betransferred from tube feeding to oral feeding when theyare physiologically capable, largely irrespective of weightor age criteria. If the infant is stable, as indicated by nopersistent physiologic decompensation (such as brady-cardia or oxygen desaturation when handled), has ade-quate handling of secretions, and shows sucking be-havior, introducing the infant to breastfeeding beforebottle-feeding may help in later success with breast-feeding. (11) Infants do not typically need to be testedon a bottle before breastfeeding; breastfeeding may ac-tually promote better stability in oxygen saturation dueto less interruption in breathing while feeding. However,it is likely that less milk may be transferred with breast-feeding in a given time.

Table 2. Strategies to Address Challenges in the Transition to Oral Feedingof the Preterm Infant

Oral Feeding Challenge Interventions or Management Strategies

Clinical instability during feeding Cue-based feedingsSlow-flow nipplesPacing

Difficulty latching or maintaining seal on Nipple shieldsbreast Provide proper head support and proper positioning

Disorganization of suck, swallow, breathesequence

Swaddle infant with proper positioning (slightly in flexion withhands under chin) to assist with state regulation

Cue-based feedingsPacing

Lack of latch, lack of suction, or weak suctionin an atypically developing preterm infant

Chin supportCheek supportCleft palate feeding systems

Poor endurance for feeding Adhere to a feeding schedule with limited length of feedingsLimit stimulation, nursing care, during nonfeeding timesFeed “on demand” (with supplemental nutrition as needed)Swaddle infant with proper positioning (slightly in flexion with

hands under chin)Assist with state regulationCue-based feedingsPacing




Facilitating Attachment to the NippleThe process of transitioning from tube feedings to oralfeeding can be a challenge for mothers and their infants,especially in terms of infants latching onto the nipple. Insome cases, breastfeeding infants may have fewer prob-lems because the breast can adapt to each infant’s mouthsize. (7) However, in many cases, breastfeeding may posemore of a challenge because it requires more cheek andlip coordination than bottle-feeding. In terms of oral-motor kinetics, breastfeeding is much more active thanbottle-feeding because the infant has to grasp the nippleand compress the correct tissues for milk delivery tooccur. (2)

Inability to maintain effective attachment to the nip-ple can be indicative of weak suction (negative) pressures.One potential solution is to introduce a nipple shieldon the mother’s breast. Nipple shields prevent the infantfrom slipping off the mother’s breast during pauses insucking because they provide a stable nipple shape ontowhich the infant can latch. Thus, they effectively increasemilk transfer to the infant and lengthen the duration ofbreastfeeding. (23)(24)(25) As a result, negative suck-ing pressure can be generated effectively, increasing theavailability of milk in the shield. These shields help theinfant maintain a proper suction pressure on the nippleuntil adequate milk has been consumed. Newer ultra-thin silicone nipple shields have been shown to be par-ticularly effective. Once the infant has developed ade-quate sucking skills, nipple shields can gradually bediscontinued. (26) Nipple shields can help with thetransition from gavage to breastfeeding. (24)

In terms of positioning for optimal latch, head sup-port may be particularly important for effective breast-feeding in the preterm infant. (27)(28) In traditionalbreastfeeding positions, an infant may have difficultyattaching to the nipple because of weak neck muscula-ture. Positions such as the football and cross cradle,where the mother holds the infant’s head with her handand keeps it close to the breast, may help with nipplelatching. (26)

Addressing Special Needs: SupplementalFeeding Techniques

Infants who have specific needs may benefit from certainmethods of feeding, such as supplemental nursing sys-tems or nipple shields. (11) These systems may facilitatethe transition from tube feeding for some mothers andinfants. In one nursing system, tubing is taped to thebreast and ends at nipple. Although such systems mayhelp the infant to learn suckling technique, they can becomplicated to use and clean. (17)

Finger feeding or feeding the infant small amounts ofmilk through tubing taped to the caregiver’s finger mayassist with transitioning to oral feedings in very young orfragile infants. Cup feeding, which had been advocatedpreviously to prevent nipple confusion, has questionableeffectiveness because it may result in decreased boluscontrol, possibly increasing aspiration risk and discom-fort during feedings. (29)

General improvement in sucking, swallowing, andcoordination in bottle-feeding and breastfeeding can alsobe achieved by using certain techniques. The flow ratemay need to be adjusted to assist in airway protectionwhile feeding, whether by changing to a slow-flow bottlenipple or by pacing. Strategies to pace flow may improvebottle-feeding when milk flow is too rapid. Pacing canbe achieved by removing the bottle or tilting the bottleto cease milk flow after a predetermined number of sucksor based on the infant’s cues. Slow-flow nipples may helppace the infant but may also be too taxing, leadingto early fatigue with decreased intake. To improvebreathing-sucking-swallowingcoordinationwhilebreast-feeding, mothers can employ external pacing by period-ically removing the nipple from the infant’s mouth toallow breathing. (2) Cheek and jaw supports are oftenused to increase the flow of milk into the infant’s mouth,but they should be used cautiously because the infantmay not be developmentally ready to manage a largerbolus. Generally, cheek and jaw support should be usedonly when the infant would otherwise be incapable ofachieving adequate suction independently, as with cleftpalate or hypotonia.

Swaddling while feeding supports general physicalorganization while reducing extraneous movements, re-sulting in increased endurance and focus for feeding.(30) Feeding plans for preterm infants should be individ-ualized and cue-based. (31) Overt as well as subtle signsof stress should be monitored closely, and the feedingshould be adjusted or stopped accordingly. Speech-language pathologists or occupational therapists specifi-cally trained in feeding development and strategies canbe helpful at identifying appropriate methods of inter-vention.

Ensuring Adequate NutritionNutrition status should be closely monitored during thetransition to oral feeding because caloric requirementsare likely to increase as the infant expends more energy inthe act of feeding. Intake and daily weights should bemonitored closely, particularly because it is difficult togauge the exact amount of intake during breastfeeding.Test weighing (before and after feeding) may be another




approach to gauging breastfeeding volume, but it canbe difficult to determine exact differences in very lowweights and requires excessive handling of the infantafter a feeding. Test weighing after discharge at homemay benefit some mothers who are trying to reach vol-ume targets. (28)

Most preterm infants born before 34 weeks’ gestationrequire added supplementation because human milkalone or term formulas do not have adequate nutrientsto optimize growth. (32) Such infants, therefore, aredischarged from the hospital on a regimen that maycombine some breastfeeding with bottle-feeding ofsupplemented human milk or formula and require closefollow-up, with adjustments in their feeding regimens asneeded.

ConclusionLearning to feed is a key developmental process for thepreterm infant. The coordination of sucking, swallowing,and breathing is largely dependent on postconceptionalage but may vary from infant to infant. Employing vari-ous strategies to facilitate the transition from tube feed-ing may increase success in breastfeeding, decrease thetime to full oral feedings, and shorten the hospitalcourse.

References1. Weber F, Woolridge MW, Baum JD. An ultrasonographic studyof the organisation of sucking and swallowing by newborn infants.Dev Med Child Neurol. 1986;28:19–242. Lau C, Hurst N. Oral feeding in infants. Curr Probl Pediatr.1999;29:105–1243. Geddes DT, Kent JC, Mitoulas LR, Hartmann PE. Tonguemovement and intra-oral vacuum in breastfeeding infants. EarlyHum Dev. 2008;84:471–4774. Qureshi MA, Vice FL, Taciak VL, Bosma JF, Gewolb IH.Changes in rhythmic suckle feeding patterns in term infants in thefirst month of life. Dev Med Child Neurol. 2002;44:34–395. Gewolb IH, Vice FL, Schwietzer-Kenney EL, Taciak VL, Bosma

JF. Developmental patterns of rhythmic suck and swallow in pre-term infants. Dev Med Child Neurol. 2001;43:22–276. Palmer MM. Identification and management of the transitionalsuck pattern in premature infants. J Perinat Neonatal Nurs. 1993;7:66–757. Goldfield EC, Richardson MJ, Lee KG, Margetts S. Coordina-tion of sucking, swallowing, and breathing and oxygen saturationduring early infant breast-feeding and bottle-feeding. Pediatr Res.2006;60:450–4558. Meier PP, Brown LP. State of the science. Breastfeeding formothers and low birth weight infants. Nurs Clin North Am. 1996;31:351–3659. Merewood A. Breastfeeding: promotion of a low-tech lifesaver.NeoReviews. 2007;8:e296–e30010. Sisk PM, Lovelady CA, Dillard RG, Gruber KJ. Lactationcounseling for mothers of very low birth weight infants: effect onmaternal anxiety and infant intake of human milk. Pediatrics. 2006;117:e67–e7511. California Perinatal Quality Care Collaborative. Section 5.Transitioning to oral feedings. In: Nutritional Support of the VeryLow Birth Weight Infant Toolkit. 2008:60–6212. Boo NY, Jamli FM. Short duration of skin-to-skin contact:effects on growth and breastfeeding. J Paediatr Child Health.2007;43:831–83613. Hurst NM, Valentine CJ, Renfro L, Burns P, Ferlic L. Skin-to-skin holding in the neonatal intensive care unit influences mater-nal milk volume. J Perinatol. 1997;17:213–21714. Wolff PH. The serial organization of sucking in the younginfant. Pediatrics. 1968;42:943–95615. Wolf LS, Glass RP. Feeding and Swallowing Disorders in In-fancy. Tucson, AZ: Therapy Skill Builders; 199216. Pinelli J, Symington A. Non-nutritive sucking for promotingphysiologic stability and nutrition in preterm infants. CochraneDatabase Syst Rev. 2005;4:CD00107117. Wight NE, Morton JA, Kim JH. Managing breastfeeding inthe NICU. In: Best Medicine: Human Milk in the NICU. Amarillo,TX: Hale; 2008:111–13518. Narayanan I, Mehta R, Choudhury DK, Jain BK. Sucking onthe ‘emptied’ breast: non-nutritive sucking with a difference. ArchDis Child. 1991;66:241–24419. Rocha AD, Moreira ME, Pimenta HP, Ramos JR, Lucena SL.A randomized study of the efficacy of sensory-motor-oral stimula-tion and non-nutritive sucking in very low birthweight infant. EarlyHum Dev. 2007;83:385–38820. Pickler RH, Frankel HB, Walsh KM, Thompson NM. Effectsof nonnutritive sucking on behavioral organization and feedingperformance in preterm infants. Nurs Res. 1996;45:132–13521. Bingham PM, Ashikaga T, Abbasi S. Prospective study ofnon-nutritive sucking and feeding skills in premature infants. ArchDis Child Fetal Neonatal Ed. 2010;95:F194–F20022. Pickler RH, Reyna BA. Effects of non-nutritive sucking onnutritive sucking, breathing, and behavior during bottle feedings ofpreterm infants. Adv Neonatal Care. 2004;4:226–23423. Chertok IR, Schneider J, Blackburn S. A pilot study of mater-nal and term infant outcomes associated with ultrathin nipple shielduse. J Obstet Gynecol Neonatal Nurs. 2006;35:265–27224. Meier PP, Brown LP, Hurst NM, et al. Nipple shields forpreterm infants: effect on milk transfer and duration of breast-feeding. J Hum Lact. 2000;16:106–114

American Board of Pediatrics Neonatal-PerinatalMedicine Content Specifications• Know that human milk needs to be

fortified in order to meet the nutritionalneeds of preterm infants.

• Realize common problems associated withbreast milk production in the NICU, andtheir management.




25. Wilson-Clay B. Clinical use of silicone nipple shields. J HumLact. 1996;12:279–28526. Meier PP, Engstrom JL. Evidence-based practices to promoteexclusive feeding of human milk in very low-birthweight infants.NeoReviews. 2007;8:e467–e47727. Meier PP. Breastfeeding in the special care nursery. Prematuresand infants with medical problems. Pediatr Clin North Am. 2001;48:425–44228. Meier PP. Supporting lactation in mothers with very low birthweight infants. Pediatr Ann. 2003;32:317–32529. Dowling DA, Meier PP, DiFiore JM, Blatz M, Martin RJ.

Cup-feeding for preterm infants: mechanics and safety. J Hum Lact.2002;18:13–2030. Ross ES. Feeding in the NICU and issues that influencesuccess. Perspect Swallow Swallow Disord (Dysphagia). 2008;17:94–10031. Shaker CS. Nipple feeding preterm infants: an individualized,developmentally supportive approach. Neonatal Netw. 1999;18:15–2232. Adamkin DH. Nutrition management of the very low-birthweight infant: II. Optimizing enteral nutrition and postdis-charge nutrition. NeoReviews. 2006;7:e608–e614

NeoReviews Quiz

8. Learning to suck, swallow, and breathe in a coordinated manner is a developmental process that maturesafter birth. Of the following, the most accurate statement regarding the suck/swallow process in newbornsis that:

A. Peak vacuum created during sucking coincides with lowering of the infant’s tongue.B. Suck/swallow/breathing coordination typically emerges at a gestational age of 32 weeks.C. Suck/swallow maturation depends more on chronologic age than on postmenstrual age.D. Swallowing occurs at the end of expiration and before inspiration of the breathing cycle.E. Term feeding patterns typically consists of 3 to 5 sucks per burst of suck/swallow activity.

9. Nonnutritive sucking refers to short, choppy, or weak type of sucking seen in the preterm infant that doesnot provide a nutritive function. Of the following, the typical suck/swallow ratio during nonnutritivesucking is:

A. 1:1 to 2:1.B. 2:1 to 4:1.C. 4:1 to 6:1.D. 6:1 to 8:1.E. 8:1 to 10:1.

10. Various strategies have been developed to ease the transition from tube feeding to oral feeding in thepreterm infant. Of the following, the strategy most likely to be effective in the transition to oral feedingin a preterm infant who has clinical instability is:

A. Cheek and jaw support.B. Cue-based feeding.C. Cup feeding.D. Nipple shield.E. Swaddling.





Sunita Sridhar, Stacey Arguello and Henry Chong Lee Transition to Oral Feeding in Preterm Infants













Nahed O. ElHassan and Jeffrey R. Kaiser Parenteral Nutrition in the Neonatal Intensive Care Unit







Parenteral Nutrition in theNeonatal Intensive Care UnitNahed O. ElHassan, MD,

MPH,* Jeffrey R. Kaiser,

MD, MA†

Author Disclosure

Drs ElHassan and

Kaiser have disclosed

no financial

relationships relevant

to this article. This

commentary does


of an unapproved/


commercial

product/device.

AbstractNeonatal parenteral nutrition (PN) is readily available in many hospitals and plays anessential role in the management of sick and growing preterm and term infants. PNcan be used as the sole source of nutrition support for infants who cannot be fed or asan adjunct to enteral feeding. Preterm infants are a particularly vulnerable populationbecause they are born at a time, if they had remained in utero, of rapid intrauterinebrain and body growth. The impact of early malnutrition can have long-lastingnegative effects on central nervous system development and growth. Despite this, PNis often provided to preterm infants based on local traditions rather than experimentalevidence. The quality of PN and its early initiation are critical in providing the mostadequate substrates for appropriate development. This article reviews the energy andfluid requirements of infants and presents by component (protein, carbohydrates,lipids, minerals such as calcium and phosphorus, trace elements, and multivitamins)the available literature on neonatal PN and its complications. In addition, suggestedguidelines for PN administration for preterm and term neonates are presented.


1. Describe the different components of PN for neonates.2. Review the suggested recommendations for macro/micronutrients in PN for neonates.3. Understand the function and benefits of macro/micronutrients in PN for neonates.4. Discuss the neonatal morbidities and possible complications associated with each of

the PN components.

IntroductionNeonatal PN was first used in 1967 for an infant who had intestinal atresia and postoper-ative weight loss. (1) The goal of PN in preterm neonates has been to approximate the

nutrition they would have received if they have remained inutero for appropriate extrauterine growth and development.(2) PN can be used as the sole source of nutrition support forneonates who cannot be fed or as an adjunct to enteralfeeding. Since its implementation, many lessons have beenlearned about the benefits and complications of PN. Animportant milestone in neonatal nutrition research was therealization of the valuable impact of early initiation onneurocognitive development. Despite this fact, the clinicalpractice of providing PN is often based on local tradition anddogma rather than experimental evidence. (2)(3) Althoughfetuses receive continuous nutrition from the placentathrough the umbilical vein, many preterm newborns haveessential nutrients limited or entirely withheld due totheoretical concerns and previous experiences with olderPN preparations. The quality of PN and its early initiationare critical in providing the most appropriate substrates for

*Assistant Professor of Pediatrics, Department of Pediatrics, Neonatology, University of Arkansas for Medical Sciences, Collegeof Medicine, Arkansas Children’s Hospital, Little Rock, AR.†Associate Professor, Departments of Pediatrics and Obstetrics and Gynecology, Neonatology, University of Arkansas forMedical Sciences, College of Medicine, Arkansas Children’s Hospital, Little Rock, AR.

Abbreviations

AA: amino acidALA: alpha-linolenic acidBUN: blood urea nitrogenCa: calciumEFAD: essential fatty acid deficiencyELBW: extremely low birthweightFDA: United States Food and Drug AdministrationFFA: free fatty acidLA: linoleic acidP: phosphorusPN: parenteral nutritionVLBW: very low birthweight

Article parenteral nutrition



appropriate growth and development. (2)(3) This articleaims to discuss the “art and science” of PN in neonatesand reviews the benefits and potential complications ofthe multiple components provided in PN for pretermand term neonates. When there is limited evidence, andrecommendations are made, this is stated. Definitions ofpreterm infants for this article are stated in Table 1.

Energy RequirementsKnowing the appropriate energy requirements for neo-nates is fundamental in prescribing PN. Energy is essen-tial for body maintenance and growth. The basal restingmetabolic rate reflects the energy expenditure requiredfor maintenance of vital processes. The resting metabolicrate has been estimated to be 40 to 60 kcal/kg per day inparenterally fed neonates maintained in a thermoneutralenvironment. (4) Each gram of weight gain for growth,including the stored energy and the energy costs ofcomponent synthesis, requires between 3 and 4.5 kcal.(4) Thus, an ideal daily weight gain of 15 g/kg (whichestimates daily fetal growth) requires an additional ca-loric requirement of 45 to 67 kcal/kg above the esti-mated resting metabolic rate. (4) A summary of theenergy requirements during the neonatal period is pre-sented in Table 2. These estimated energy requirementshave been calculated in healthy growing preterm in-fants at 3 to 4 weeks of age. There is relatively minimalinformation, however, on the energy requirements forsick infants and especially extremely low-birthweight(ELBW) infants during early postnatal life. ELBW in-fants are believed to have increased metabolic demandsdue to their large body proportion of metabolically activeorgans, including the heart, liver, kidney, and brain. (4)

Fluid RequirementsThe percentage of total body water in fetuses decreasesfrom approximately 95% early in development to 80%by 8 months’ gestation and to 75% at term. (5) Duringthe first day after birth, term infants require a minimum

of 60 mL/kg per day to meet maintenance fluid needs(replacing net losses). As infants mature, fluid needsgradually increase to a total of 120 to 150 mL/kg per dayto allow for increased renal solute load, stool wateroutput, and growth. (5) Preterm infants have more in-sensible water losses than term infants due to their largesurface area, skin immaturity, and ensuing increasedevaporation. Thus, fluid needs are higher on the firstpostnatal day at 80 to 100 mL/kg per day and increaseby 10 to 20 mL/kg per day to a total of 130 to 180 mL/kgper day as preterm infants mature (Table 2). (5)

Infusion RoutesPN may be infused via peripheral and central catheters.Peripheral infusion typically is used for short-term nutri-tion support. Peripheral vein osmolarity tolerance rangesfrom 700 to 1,000 mOsm/L. Osmolarity is calculatedusing the equation: (6)

osmolarity (mOsm/L)�([amino acids (g/L) � 8]� [glucose (g/L) � 7] � [sodium (mEq/L) � 2]� [phosphorus (mg/L) � 0.2] � 50)

The osmolarity of glucose solutions rises from 255 to1,020 mOsm/L with increasing concentration from 5%to 20%, respectively. Generally, glucose concentrationsof 12.5% or less are well tolerated by peripheral veins aslong as no other osmolarity-increasing agents are added.Central infusion of PN is delivered via central venouscatheters and is the preferred route for long-term PN.

Components of Parenteral Nutrition (Table 2)Protein

Previously used intravenous amino acid (AA) prepara-tions were based on casein hydrolysates. Current crystal-line AA solutions have elevated ratios of essential tononessential AAs, leading to the endogenous produc-tion of higher concentrations of the branch amino acids:leucine, isoleucine, and valine. (7) Despite extensiveendeavors to create optimized AA preparations, how-ever, plasma AA concentrations in infants receiving cur-rent intravenous solutions are still reduced comparedwith breastfed infants. (8) This is partly due to the poorsolubility or stability of various intravenous AAs (eg,glutamine, tyrosine, and cysteine). (8) Cysteine is oftenconsidered a semi-essential AA in the newborn periodand is, therefore, routinely added to AA preparationsto circumvent low cysteine synthesis, low plasma concen-trations, and impaired protein synthesis. (9) Cysteine isa major substrate for glutathione, a tripeptide (glutamicacid/cysteine/glycine) antioxidant, and is important inmaintaining redox potential and calcium homeostasis.

Table 1. Classification of PretermInfants• Preterm infants are born <37 weeks’ gestation.• Low-birthweight infants weigh <2,500 g at birth.• Very low-birthweight infants weigh <1,500 g at

birth.• Extremely low-birthweight infants weigh <1,000 g

at birth.

parenteral nutrition



Tab

le2.

Sugg

este

dRe

com

men

dati

ons

for

Pare

nter

alN

utrit

ion

Mac

ronu

trie

nts

for

Neo

nate

s

Sour

ceIn

itial

Adm

inis

trat

ion

Adva

ncem

ent

Goal

Neo

nate

Bloo

dCo

ncen

trat

ion

Pote

ntia

lCom

plic

atio

ns

Flui

d60

to70

mL/

kgpe

rda

y80

to10

0m

L/kg

per

day

10to

20m

L/kg

per

day

10to

20m

L/kg

per

day

130

to15

0m

L/kg

per

day

130

to18

0m

L/kg

per

day

Term

Pret

erm

——

Tota

lEne

rgy

Inta

ke—

—90

kcal

/kg

per

day

Term

——

120

kcal

/kg

per

day

Pret

erm

Ener

gyEx

pend

ed40

to60

kcal

/kg

per

day

Rest

ing

met

abol

icra

te40

to50

kcal

/kg

per

day

Activ

ity0

to5

kcal

/kg

per

day

Ther

mor

egul

atio

n0

to5

kcal

/kg

per

day

Synt

hesi

s15

kcal

/kg

per

day

Ener

gyEx

cret

ed15

kcal

/kg

per

day

Ener

gySt

ored

20to

30kc

al/k

gpe

rda

yAm

ino

Acid

s12

to3

g/kg

per

day

1g/

kgpe

rda

y3

g/kg

per

day

Term

—Ch

oles

tasi

s2

to3

g/kg

per

day

0.5

to1

g/kg

per

day

3.5

to4

g/kg

per

day

Pret

erm

Dext

rose

8m

g/kg

per

min

ute

4to

6m

g/kg

per

min

ute2

1to

3m

g/kg

per

min

ute

1to

3m

g/kg

per

min

ute

12m

g/kg

per

min

ute

12m

g/kg

per

min

ute

Term

Pret

erm

>45

to<

150

to22

0m

g/dL

>45

to<

150

to22

0m

g/dL

Hyp

ergl

ycem

iais

asso

ciat

edw

ith:

1.De

ath

2.Pr

olon

ged

hosp

itals

tay

3.In

trav

entr

icul

arhe

mor

rhag

eGr

ade

3&

44.

Nec

rotiz

ing

ente

rcol

itis

5.Se

psis

Fat3

2to

3g/

kgpe

rda

y0.

5to

1g/

kgpe

rda

y3

to3.

5g/

kgpe

rda

yTe

rm<

150

to25

0m

g/dL

4Ch

oles

tasi

s2

to3

g/kg

per

day

0.5

to1

g/kg

per

day

3to

3.5

g/kg

per

day

Pret

erm

<15

0to

250

mg/

dL4

1E

arly

and

aggr

essi

vede

liver

yof

amin

oac

ids

does

not

lead

toth

ede

velo

pmen

tof

azot

emia

,hyp

eram

mon

emia

,or

met

abol

icac

idos

is.

2G

luco

sein

fusi

onra

teis

som

etim

eslim

ited

to4

mg/

kgpe

rm

inut

ein

extr

emel

ylo

w-b

irth

wei

ght

infa

nts

who

have

hype

rgly

cem

ia.

320

%in

trav

enou

sfa

tem

ulsi

ons

are

typi

cally

used

and

infu

sed

over

24ho

urs

tom

axim

ize

clea

ranc

e.4So

me

drug

s(e

g,am

phot

eric

inB

and

ster

oids

)le

adto

elev

ated

trig

lyce

ride

conc

entr

atio

ns.




(9) Because the inclusion of cysteine in AA solutions istechnically difficult due to its low solubility, it is typicallyadded last to the solution at a dose of 30 to 40 mg/g AA.Cysteine also decreases the pH of AA solutions andreduces calcium and phosphorus precipitation. (10)

Protein accretion rates by fetuses at 24 to 25 weeks’,27 to 28 weeks’, and 30 to 32 weeks’ gestation have beenestimated to be 4.0, 3.6, and 3.3 g/kg per day, respec-tively. (11)(12) Infusion of AA with glucose as early asthe first postnatal day decreases protein catabolism andenhances net protein accretion. (13)(14) Thus, reducingthe number of hours that infants receive suboptimalnutrition (without AAs) has been emphasized recently asan important goal of neonatal intensive care. (13)(14)(15) The purpose of early AA supplementation is toprovide preterm infants with substrate that promotesprotein deposition that closely approximates fetal energyproduction and growth. (13) For most preterm infants,1.0 to 1.5 g/kg per day of intravenous AA along withglucose prevents protein catabolism. (15) When nonpro-tein energy intake is 80 to 85 kcal/kg per day and AAintake is 2.7 to 3.5 g/kg per day, nitrogen retention andgrowth might actually approach the intrauterine rate.(16) Recent studies have challenged the older practice ofstarting at 0.5 to 1 g/kg per day of AA and graduallyadvancing the AA infusion rate. (13)(14)(15)(16)(17)(18) In a retrospective study, Valentine and associates(13) suggested that providing 3 g/kg per day ofAA within 24 hours of birth to very low-birthweight(VLBW) infants was safe and associated with betterweight gain and shorter duration of PN administration.ELBW infants may require up to 4 g/kg per day ofintravenous AA to maintain stores and promote growth.(15) More research is needed to establish the optimal AArequirements in critically ill infants and in those who havesepsis and renal and hepatic dysfunction.

The major concerns about early and aggressive deliv-ery of AA, especially to ELBW infants, are the develop-ment of azotemia, hyperammonemia, and metabolic ac-idosis. These complications of PN were reported usingearlier AA preparations and rarely occur with currentcrystalline solutions. Blood urea nitrogen (BUN) repre-sents the complex interaction of hydration status, renalfunction, energy quality and quantity, and degree ofillness. (19)(20)(21) Rising BUN values are, therefore,not just a reflection of the ELBW infant’s intolerance toAA infusion. (19)(20)(21) In fact, studies of fetal AAoxidation suggest that higher BUN reflects appropriateAA utilization for both energy and lean mass production.In addition, metabolic acidosis during the first postnatalweek occurs independently of the duration and amount

of AA delivery. (20) Metabolic acidosis in VLBW infantscan be caused by multiple factors (eg, defects of urinaryacidification, acute illness, hypotension, poor perfusion)and cannot be solely attributed to AA administration.(21) Prolonged exposure to intravenous AA solutionsdoes contribute to the development of PN-associatedcholestasis. (22)

CarbohydrateGlucose is transported across the placenta via facilitateddiffusion and is the principal energy substrate for thefetus. The primary storage form of glucose is glycogen,which is only produced during the third trimester. Glu-cose is the chief energy source for the neonatal brain andis of paramount importance for preterm infants who, inaddition to having limited glycogen stores, also haveespecially metabolically active organs. (7) Endogenousglucose production varies with age and was estimated tobe 8 mg/kg per minute in term newborns and 6 mg/kgper minute in preterm infants. (23)(24) These produc-tion rates provide an appropriate starting point for glu-cose infusion rates in PN for term and preterm infants.The upper rate of glucose administration is dictated bythe maximal glucose oxidative capacity for energy pro-duction and glycogen deposition. When glucose is givenin excess, it is converted into lipid via lipogenesis. Thisconversion is inefficient, increases energy expenditure,and may have additional clinical consequences via in-creased carbon dioxide production and exacerbation oflung disease. (23)(25)(26) The maximum glucose oxi-dation capacity is 12 mg/kg per minute in term new-borns and preterm infants receiving long-term PN (27)and generally should not exceed this concentration. Ges-tational age and clinical status modify glucose oxidativecapacity. For example, it has been estimated to be7 mg/kg per minute in preterm infants during the first2 postnatal weeks and 5 mg/kg per minute in critically illchildren who have burns. (28)

The minimum recommended blood glucose concen-tration is 45 mg/dL (2.5 mmol/L). (8) Despite limitedglycogen storage capacity, ELBW infants often experi-ence episodes of hyperglycemia during the first few post-natal days. This may be due to surges in glucose produc-tion caused by birth-related increases in catecholamines,possibly compounded by an exogenous supply of cat-echolamines and inotropic drugs, a decrease in endoge-nous production of insulin, and an increase in peripheraland hepatic insulin resistance. (7) In addition, ELBWinfants often fail to suppress endogenous glucose pro-duction completely in response to an exogenous supplyof PN glucose. (29) Although there is no consensus




definition of hyperglycemia, especially in ELBW infants,a suggested range may be 150 to 220 mg/dL (8.3 to12.2 mmol/L). (29) The primary concern for hyper-glycemia in infants is its association with death, pro-longed hospitalization, intraventricular hemorrhagegrades 3 and 4, necrotizing enterocolitis, and late-onsetbacterial and fungal sepsis. (29) Early AA supplementa-tion on the first day after birth seems to stabilize highblood glucose concentrations by stimulating endoge-nous insulin secretion. (7) Other interventions for hyper-glycemia include reducing the glucose infusion rate ortreating with intravenous insulin. (29) Of note, a Coch-rane review evaluating these two strategies for treatmentof hyperglycemia found no difference in death or seriousmorbidities. (29) A randomized trial in preterm infantswho have hyperglycemia needs to be conducted to ad-dress this question.

There is also a concern about the potential risk oflactic acidemia in infants receiving high insulin and glu-cose administration. (7) Because the safety of insulintherapy and its impact on hyperglycemia-related morbid-ities have not been established, the consensus in theliterature points toward incrementally decreasing theglucose infusion rate to approximately 4 mg/kg perminute and reserving insulin use for infants whose bloodglucose concentrations are greater than 250 mg/dL(13.9 mmol/L) while receiving this infusion rate.

LipidsLipid emulsions are especially important components ofneonatal PN because they supply an energy source thathas low osmolarity and high energy content per unitvolume. (30) Intravenous fat emulsions currently avail-able in the United States are 10% (1.1 kcal/mL) or20% (2 kcal/mL) soy or soy/safflower oil-based emul-sions. (30) The 10% emulsion is typically not used be-cause it contains high amounts of phospholipids that cancontribute to hyperphospholipidemia and subsequenthypercholesterolemia. (8)

It is crucial to provide a minimum of 0.5 to 1.0 g/kgper day of lipids to prevent essential fatty acid deficiency(EFAD), which can develop in preterm infants duringthe first postnatal week and as early as the second dayafter birth. (8)(18)(30)(31) Essential fatty acids havedouble bonds in the �-6 and �-3 positions and cannot besynthesized endogenously by humans. (31) Therefore,specific �-6 and �-3 fatty acids or their precursors withdouble bonds at these positions (ie, linoleic acid [LA,18:2 �-6] and alpha-linolenic acid [ALA, 18:3 �-3])must be provided in PN. (12) LA and ALA have criticalroles in postnatal brain development. EFAD is associated

with poor growth, scaly skin lesions, and visual andneurologic abnormalities and has been observed in in-fants who have been maintained for several weeks on PNwithout essential fatty acids.

Because lipids are the primary source of energy supplyin PN, inadequate lipid intake can lead to caloric under-nutrition and proteolysis. (32)(33) Although it has beencommon practice to increase lipid intake incrementallyover several days in preterm infants requiring PN, thereis no scientifically valid argument why these newbornsshould not be offered 2 to 3 g/kg per day of AA and 2 to3 g/kg per day of lipids immediately after birth. In fact,it has been shown that provision of 3.5 g/kg per day ofAA and 3 g/kg per day of lipids within the first 24 hoursof birth to VLBW infants was well tolerated and withoutadverse effects. (34) In addition, despite phobias aboutbeginning lipids early, a Cochrane meta-analysis reportedno increased risk of necrotizing enterocolitis, sepsis,thrombocytopenia, or significant jaundice or increasedduration of ventilation when lipids were introduced early(�12 hours) versus later (�6 days). (35)

Moreover, several investigators have shown that in-fants treated with the “traditional” practices of restrictedprotein supplementation and limited energy supply dur-ing the immediate postnatal period had significant post-natal growth restriction and poor neurodevelopmentaloutcomes. (36)(37)(38) Ehrenkranz and associates (37)showed that increased growth velocity in ELBW new-borns (presumably due to better nutrient intake) exerts asignificant positive influence on neurodevelopment andgrowth outcomes at 18 to 22 months corrected age. Inaddition, preterm infants who had increased energy sup-ply during the first postnatal week have been shown tohave a 4.6-point increase in Bailey Mental DevelopmentIndex for each additional 10 kcal/kg per day they re-ceived. (36) Although data showing the specific benefitsof early initiation of lipids are limited, early and aggres-sive supplementation has not been associated with in-creased adverse effects. Lipids may be initiated earlyduring the first day after birth at doses of more than 1 to2 g/kg per day to increase energy supply and improvelong-term growth and neurodevelopment.

The maximum lipid dose is determined by an infant’sability to metabolize fat emulsions. (30) Lipoproteinlipase in the capillary endothelium of extrahepatic tissues,hepatic lipase in the endothelium of hepatic capillaries,and lecithin cholesterol acyltransferase are the three en-zymes that determine the rate of PN lipid clearance. (39)Although high doses of heparin can stimulate lipoproteinlipase activity, heparin infusion does not improve theutilization of intravenous lipids because it also causes an




increase in free fatty acids (FFAs) beyond the infant’sclearance ability. (40) Intravenous lipids should be in-fused over 24 hours to maximize clearance. (13) Whenthe lipid infusion rate exceeds hydrolysis rates, concen-trations of plasma triglycerides and FFAs increase. Al-though there is no clear consensus in the literature,current recommendations for maximal plasma triglycer-ide concentrations range between 150 mg/dL and250 mg/dL. (7)(13)(18)(30)

Some drugs and medical conditions lead to elevatedserum triglyceride concentrations. (30) Liposomal am-photericin B contains fat emulsion (30) and steroids,such as hydrocortisone, that can lead to transient in-creases in triglyceride concentrations. (30)

Carnitine facilitates the transport of long-chain fattyacids across the mitochondrial membrane, making themavailable for beta-oxidation. (40) Studies evaluating car-nitine supplementation in infants and children, however,have yielded controversial results. Carnitine concentra-tions decrease during prolonged carnitine-free PN, espe-cially in immature preterm infants, (40) but a meta-analysis showed no benefit of carnitine supplementationon lipid tolerance, ketogenesis, or weight gain in infantsrequiring PN. (41) Nonetheless, carnitine supplementa-tion at 2 to 10 mg/kg is recommended in infants exclu-sively receiving PN for more than 4 weeks. (18)

Intravenous fat emulsions used in the United Statesare comprised of either soybean oil or a combination ofsafflower and soybean oil and are rich in proinflammatory�-6 fatty acids. (42) Many clinicians believe that the high�-6 content of these fat emulsions contribute to PN-associated cholestasis. (43)

Another fat emulsion prepared from fish oils that isnot yet approved for use in the United States has beenshown to reverse cholestasis in infants six times fasterthan in those receiving soybean oil-based fat emulsions,probably because this emulsion has �-3 fatty acids thathave anti-inflammatory properties. (43)(44) In addition,use of the fish oils emulsion is not associated with hyper-triglyceridemia, coagulopathy, or EFAD. (43)(44) Cur-rently, this emulsion can only be prescribed in the UnitedStates via United States Food and Drug Administration(FDA) compassionate approval.

Calcium (Ca) and Phosphorus (P)Although there is no consensus on optimal parenteralrequirements for Ca and P, the third-trimester fetal ac-cretion rates of 3.5 mmol/kg per day (140 mg/kg perday) for Ca and 2.4 mmol/kg per day (75 mg/kg perday) for P are often used. (11) Fetal accretion rates peakduring the third trimester, with upwards of 80% of fetal

skeletal mineralization taking place during this period.(11) Thus, the goal of PN in preterm infants is to achieveintrauterine rates of bone mineralization, and preterminfants who lack part or all of the fetal third trimester areat increased risk of osteopenia. (8)(11)(18) Unfortu-nately, due to delayed establishment of full enteral feed-ings, prolonged PN, and chronic use of certain medica-tions (diuretics and corticosteroids) that increase mineralexcretion, attaining this goal is often very difficult. (11)

Further, the ability to provide neonates with the rec-ommended amounts of Ca and P has been limited in theUnited States by their precipitation in PN solution. (45)(46) The solubility of Ca and P are affected by pH,temperature, Ca and P concentrations, AA product andconcentration, lipid emulsions, dextrose, and magne-sium concentration. Another very critical component ofCa-P compatibility has been the type of phosphate saltsused. Organic phosphate, used in Europe and Canada,has far superior compatibility with Ca salts than inorganicphosphate, approved for use in the United States. (45)(46) Organic phosphates consist of a phosphate groupcovalently bonded to an organic molecule such as glyc-erol, glucose, or fructose. The phosphate group, there-fore, cannot be fully ionized and is much less available tointeract with Ca. (46) As natural substrates for extra-cellular phosphatases, nutritional bioavailability of or-ganic phosphates is assured. In addition, organic phos-phates are well tolerated without significant toxicity. (46)

In the United States, P is typically supplemented assodium phosphate, a constituent contaminated by alumi-num. The FDA guidelines for aluminum content recom-mend PN components to have less than 4 to 5 �g/kg perday. (47) Aluminum overexposure may cause hypochro-mic microcytic anemia, neurotoxicity, and metabolicbone disease in which infants chronically exposed toparenteral aluminum have reduced lumbar spine and hipbone mass during adolescence. (47)(48) Although it isdifficult to adhere to the current FDA recommendationsbecause of the high aluminum content in PN compo-nents, one method to reduce aluminum intake is to usesodium phosphate (9.5 mg of aluminum/mmol) ratherthan potassium phosphate (24 mg of aluminum/mmol).

Ca in PN is typically provided as Ca gluconate, a saferchoice than calcium chloride. (45) The 12-carbon or-ganic gluconate salt of Ca is only partially ionized inaqueous solutions, and the degree of its dissociationdecreases as the concentration increases. (45) This de-crease in the availability of freely dissociated Ca ions issufficient to reduce the potential for precipitation withphosphate ions. In contrast, the dissociation of Ca ions




from the inorganic chloride salt is constant, irrespectiveof its final concentration.

Trace ElementsTrace mineral preparations are commercially availableas single agents or as combination products. Thetrace elements currently recommended for neonatal PNare zinc, copper, manganese, chromium, selenium, andmolybdenum. Although the optimum time to start traceelements supplementation has not undergone extensive

testing, most neonatologists begin supplementationwithin the first few days after birth (11) and provide itdaily in PN. A summary of trace element doses, func-tions, deficiencies, and toxicities is shown in Tables 3and 4.

None of the combination preparations of neonataltrace elements meet the needs of every gestational orpostnatal age or clinical condition, and manganese con-tent may be up to five times the recommended dose inthe currently available combination preparations. (11)

Table 3. Trace Elements in Neonatal Parenteral Nutrition (PN)1

Dosing Category(weight)

Zinc2

(�g/kg per day)Copper3(�g/kg per day)

Manganese3

(�g/kg per day)Chromium4,5

(�g/kg per day)Selenium2,5

(�g/kg per day)

<3 kg 400 20 1.0 0.05 to 0.2 2>3 to 10 kg 200 20 1.0 0.2 2>10 to 15 kg 100 20 1.0 0.14 to 0.2 21Molybdenum at 1 �g/kg per day is recommended for low-birthweight infants receiving PN for more than 4 weeks. (11)(18)2Infants who have short bowel syndrome lose significant amounts of zinc and selenium in diarrhea and small bowel effluent, necessitating close monitoringof serum zinc and selenium. (11)(18)3Copper supplementation is limited to 10 �g/kg per day, and no manganese is given to infants who have cholestasis. (11)(18)4Chromium is a contaminant of PN solutions that results in a 10% to 100% increase in amount of chromium delivered, necessitating serum chromiummonitoring for infants receiving long-term PN. (11)(18)5No chromium or selenium supplementation is recommended for infants who have chronic renal failure. (11)(18)

Table 4. Function, Deficiencies, and Toxicities of Trace Elements (11)(18)

Trace Elements Function Reported Deficiencies Reported Toxicities

Zinc Important component of severalenzymes (eg, carbonic anhydraseand carboxypeptidase), importantfor growth

Failure to thrive, alopecia, diarrhea,dermatitis (commonly perianal),ocular changes, rash (crusted,erythematous, involving face,extremities, and anogenitalareas), nail hypoplasia ordysplasia

Depresses phagocytic andbacterial leukocyticactivity, pancreatitis

Copper Component of several enzymes suchas cytochrome oxidase,superoxidase dismutase,monoamine oxidase, andlysyl oxidase

Anemia, osteoporosis,depigmentation of hair andskin, neutropenia, poor weightgain, hypotonia, and ataxialater in life

Hepatic cirrhosis

Manganese Role in enzyme activation (eg,superoxide dismutase), importantfor normal bone structure, rolein carbohydrate metabolism

Nausea, vomiting, dermatitis, hairdepigmentation, growthretardation

Basal ganglia damage,neurotoxicity, cholestasis

Chromium Role in carbohydrate and lipidmetabolism, regulator of insulinaction

None Chronic renal failure

Selenium Component of glutathioneperoxidase, important in thyroidmetabolism

Implicated in oxidative diseasessuch as bronchopulmonarydysplasia and retinopathy ofprematurity, hypothyroidism,myopathy

None

Molybdenum Essential for several enzymesinvolved in DNA metabolism

None Interferes with coppermetabolism




Manganese neurotoxicity is a special concern for infants(18) because the element may be deposited in the basalganglia. (49) Excessive intakes of parenteral manganesemay also induce PN-associated liver disease. (49) There-fore, individual trace elements should be used in neonatalPN instead of combination products at this time.

MultivitaminsAlthough the optimal time to begin vitamin supplemen-tation in PN is unknown, most practitioners administerthem within the first few days of birth and provide themon a daily basis. Preterm infants are especially at risk forvitamin deficiency due to their poor vitamin stores andincreased requirement for rapid growth. (11) A summaryof multivitamin doses and composition is presented inTable 5.

The clinical impact of free radicals, which can developin intravenous multivitamin preparations, has been eval-uated. (50) Hydrogen peroxide and other peroxides aregenerated in light-exposed PN. Light-sensitized ribofla-vin available in parenteral multivitamin preparations cat-alyzes electron transfer between electron donors, such asvitamin C, AA, or lipids and oxygen dissolved in PNsolution. (50) Shielding PN from light has been associ-ated with a decreased risk of death or bronchopulmonarydysplasia and with lower triglyceride concentrations.(50) The amount of hydrogen peroxide infused with PNcan be reduced by half when the entire PN solution anddelivery system (ie, PN constituents, dextrose bag, lipidsyringe, and tubing) is light-protected. As an alternative,studies in animals have shown that the mixture of multi-vitamins with lipid emulsion can dramatically decreasethe generation of lipid peroxides and protect against theloss of antioxidant vitamins. (50) Light protection of PN,however, is not currently widely used in neonatal inten-sive care units.

ConclusionThe nutritional management of term and preterm neo-nates presents a constant challenge in adapting an ap-proach that maximizes both short- and long-term out-comes while reducing morbidities. In addition, manyclinicians still prescribe PN based on local dogma andoutdated concerns. Although substantial experimentalevidence has been acquired in recent years, there are stillmany gaps of knowledge in the provision of the mostoptimal neonatal intravenous nutrition, especially forextremely preterm infants. As is evident in this review,further research and evaluation are needed in many areasof neonatal PN, such as the most appropriate approach totreat hyperglycemia in the first few postnatal days inELBW infants, the safety of providing early aggressiveintravenous lipids, the optimal time to add multivitaminsor trace elements to intravenous PN, and the impact ofprotecting PN from light exposure. In addition, otherproblems must be dealt with by the manufacturers, in-cluding producing combination trace elements packagesthat meet the needs of all neonates and reducing alumi-num content of PN components. Hopefully, over time,the previously noted suggested PN guidelines will bechallenged by new and emerging knowledge and re-search, and clinicians will initiate and advance PN ac-cording to this evidence rather than local lore.

Table 5. Daily DoseRecommendations forPediatric Multivitamins (18)*

Weight Dose

<1 kg 1.5 mL1 to 3 kg 3.25 mL>3 kg 5 mL

*Assumes normal age-related organ function. Pediatric multivitaminformulation (5 mL): Vitamin A, 2,300 IU; Vitamin D, 400 IU;Vitamin E, 7 IU; Vitamin K, 200 �g; Ascorbic acid, 80 mg; Thiamine,1.2 mg; Riboflavin, 1.4 mg; Niacin, 17 mg; Pantothenic acid, 5 mg;Pyridoxine, 1 mg; Cyanocobalamin, 1 �g; Biotin, 20 �g; Folic acid,140 �g.

American Board of Pediatrics Neonatal-PerinatalMedicine Content Specifications• Know the caloric requirements for optimal

postnatal growth of preterm andterm infants, accounting for caloricexpenditures needed for physical activityand maintenance of bodily temperature.

• Distinguish between indispensable, essential, andnon-essential amino acids.

• Know the protein requirements of preterm and full-terminfants.

• Know the fat requirements of preterm and full-term infants.• Know the carbohydrate requirements for preterm and full-

term infants.• Know the changing requirements of calcium and phosphorous

by the neonate at various gestational ages.• Know the requirements for vitamins in newborn infants, and

the differences between preterm and full-term infants.• Know the clinical manifestations, diagnosis, management, and

prevention of zinc, copper, selenium, manganese, andchromium deficiency.

• Know the nutritional composition of parenteral solutions.• Recognize the relationship between the calcium and

phosphorus content of parenteral nutrition solutions andosteopenia.




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NeoReviews Quiz

1. Energy is essential for body maintenance and growth. Knowing the energy balance and its components isimportant for prescribing parenteral nutrition (PN) in neonates. Of the following, the estimated energy costin preterm infants is highest for:A. Basal metabolism.B. Body growth.C. Excretory loss.D. Physical activity.E. Temperature regulation.

2. PN solutions may be infused via peripheral or central catheters. Peripheral infusion is usually reserved forshort-term nutrition support. The osmolarity of the infusate that can be safely administered via theperipheral route is less than that of the infusate administered via the central route. Of the following, theupper threshold of osmolarity tolerance range for peripherally infused PN solutions is closest to:A. 500 mOsm/L.B. 750 mOsm/L.C. 1,000 mOsm/L.D. 1,250 mOsm/L.E. 1,500 mOsm/L.

3. Previously used intravenous amino acid preparations were based on casein hydrolysates. Current crystallineamino acid preparations have elevated ratios of essential-to-nonessential amino acids. Of the following, theamino acid considered semi-essential in the newborn period and required for the synthesis of glutathioneantioxidant is:A. Arginine.B. Cysteine.C. Leucine.D. Tyrosine.E. Valine.




4. Endogenous glucose production varies with gestational age, and its estimate provides an appropriatestarting point for glucose infusion rate in neonatal PN. The upper rate of glucose administration withadvancing PN is influenced by the maximal glucose oxidation capacity of the infant. Of the following, themost appropriate initial rate, daily rate of increase, and maximal rate of glucose infusion in extremelypreterm infants receiving PN is:

Initial infusion(mg/kg per minute)

Daily increment(mg/kg per minute)

Maximal rate(mg/kg per minute)

A. 1 to 2 4 to 6 8B. 1 to 2 4 to 6 9C. 2 to 4 2 to 4 10D. 4 to 6 1 to 2 12E. 4 to 6 1 to 2 16

5. Lipid emulsions are important components of neonatal PN because they provide an energy source with lowosmolarity and high energy content per unit volume. Withholding lipid can lead to essential fatty aciddeficiency, which can develop in preterm infants within the first postnatal week and as early as the secondday after birth. Of the following, the minimal amount of lipid required to prevent essential fatty aciddeficiency in preterm infants is:

A. 0.1 to 0.4 g/kg per day.B. 0.5 to 1.0 g/kg per day.C. 1.1 to 1.4 g/kg per day.D. 1.5 to 2.0 g/kg per day.E. 2.1 to 2.4 g/kg per day.

6. The trace elements currently recommended for neonatal PN are zinc, copper, manganese, chromium,selenium, and molybdenum. Although the optimal dose of each trace element remains unconfirmed, thegoal in nutrition is to prevent deficiency of the trace element and avoid its toxicity. Of the following, themost typical manifestation of zinc deficiency in neonates is:

A. Acquired hypothyroidism.B. Diffuse osteopenia.C. Hair depigmentation.D. Hepatic cholestasis.E. Perianal dermatitis.

7. The trace element preparations for neonatal PN are commercially available as single agents or ascombination products. None of the combination products meets the needs of neonates of every gestationalor postnatal age or clinical condition, and each may inadvertently provide a specific trace element inamounts in excess of the recommended dose, leading to potential toxicity. Of the following, theneurotoxicity from trace element deposition in the basal ganglia as a special concern for infants receivingparenteral nutrition is most attributed to:

A. Chromium.B. Copper.C. Manganese.D. Molybdenum.E. Selenium.





Nahed O. ElHassan and Jeffrey R. Kaiser Parenteral Nutrition in the Neonatal Intensive Care Unit












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