12 neoreviews_december2011

EgyptianPediatrics Yahoo Group

http://health.groups.yahoo.com/group/EgyptianPediatrics/

Answer Key: 1. D; 2. A; 3. D; 4. C; 5. D; 6. A; 7. C; 8. C;9. C; 10. E; 11. A; 12. D

ArticlesEducational Perspectives: Creating an EffectivePowerPoint Presentatione687Dara Brodsky, Elizabeth G. Doherty

Developmental Origins of Adult Disease:Part 1: Cardiovasculare698Patricia Y.L. Chan, Jonathan M. Morris, Eileen D.M. Gallery

Developmental Origins of Adult Disease:Part 2: Renale706Patricia Y.L. Chan, Jonathan M. Morris, Eileen D.M. Gallery

Developmental Origins of Adult Disease:Part 3: Metabolice714Patricia Y.L. Chan, Jonathan M. Morris, Eileen D.M. Gallery

Index of Suspicion in the Nursery:Case 1: A 4-day-old Who Has Decreased Activity and

Poor FeedingCase 2: Profuse Diarrhea in a 4-day-old Term Malee721Case 1: Marilisa Elrod, John C. ArnoldCase 2: Resmy P. Gopi, S. Khanna, B.K. Rajrgowda

Legal Briefs:Kernicterus–Still Preventablee727Maureen E. Sims

Strip of the Month: December 2011e731Maurice L. Druzin, Nancy Peterson

Visual Diagnosis: One-day-old Female Infant PresentsWith Mediastinal Mass on Chest Radiographe741Ibrahim Hassan, Kurepa Dalibor, Elnagar Islam Hassan,Megan Desotell, Guillermo Sangster

contentsNeoReviews™ Vol.12 No.12 December 2011

Editorial StaffEditorial StaffEditor in Chief: Alistair G.S. Philip, Palo Alto, CAAssociate Editor: Josef Neu, Gainesville, FLAssociate Editor: Jayant Shenai, Nashville, TNAssistant Editor: Henry C. Lee, San Francisco, CAAssistant Editor, Visual Diagnosis: JoDee Anderson, Portland, OR

Editorial Board:Dara Brodsky, Boston, MARobert Castro, Palo Alto, CAMarilyn B. Escobedo, Oklahoma City, OKIvan Hand, Great Neck, NYM. Gary Karlowicz, Norfolk, VAJane McGowan, Philadelphia, PASteven A. Ringer, Boston, MARenate Savich, Albuquerque, NMKaren Shattuck, Galveston, TXSusan F. Townsend, Colorado Springs, COWilliam Truog, Kansas City, MO

Founding Editor: William W. Hay Jr, Denver, COInternational Advisory Board:Claudine Amiel-Tison, Paris, FranceMalcolm Battin, Auckland, New ZealandMatts Blennow, Stockholm, SwedenJose Diaz Rossello, Montevideo, UruguayLex Doyle, Melbourne, AustraliaJanusz Gadzinowski, Poznan, PolandGorm Greisen, Copenhagen, DenmarkKazushige Ikeda, Tokyo, JapanIan Laing, Edinburgh, ScotlandFrank Pohlandt, Ulm, GermanyJorge Cesar Martinez, Buenos Aires, ArgentinaSiddarth Ramji, New Delhi, IndiaFrancesco Raimondi, Naples, ItalyEric Shinwell, Jerusalem, IsraelBo Sun, Shanghai, ChinaCleide Trindade, Sao Paolo, BrazilAndrew Whitelaw, Bristol, United KingdomDavid Woods, Cape Town, South AfricaKhalid Yunis, Beirut, LebanonTsu-Fuy Yeh, Taichung, TaiwanLiaison, Council of International Neonatal Nurses:Carole Kenner, Boston, MAManaging Editor: Luann ZanzolaEditorial Assistants: Lani Lucente Demchak, Kathleen BernardPublisher: American Academy of PediatricsAssociate Executive Director for Education: Robert PerelmanDivision of Scholarly Journals Director: Michael Held

NeoReviews™NeoReviews™(ISSN 1526-9906) is owned and controlled by the American Academy ofPediatrics. It is published monthly by the American Academy of Pediatrics,141 Northwest Point Blvd., Elk Grove Village, IL 60007-1098.Statements and opinions expressed in NeoReviews™ are those of the authorsand not necessarily those of the American Academy of Pediatrics or itsCommittees. Recommendations included in this publication do not indicatean exclusive course of treatment or serve as a standard of medical care.Subscription price for NeoReviews™ for 2011: AAP Member $109;Nonmember $122; Allied Health/Student $95; AAP Perinatal SectionMember $95. Institutions call for pricing (866-843-2271).© AMERICAN ACADEMY OF PEDIATRICS, 2011. All rights reserved.Printed in USA. No part may be duplicated or reproduced withoutpermission of the American Academy of Pediatrics. POSTMASTER: Sendaddress changes to NEOREVIEWS™, American Academy of Pediatrics, 141Northwest Point Blvd.,Elk Grove Village, IL 60007-1098.

NeoReviews™ is supported, in part, through aneducational grant from Abbott Nutrition, a divisionof Abbott Laboratories, Inc.

NeoReviews™ Editorial Board DisclosuresThe American Academy of Pediatrics (AAP) Policy on Disclosure ofFinancial Relationships and Resolution of Conflicts of Interest for AAPCME Activities is designed to ensure quality, objective, balanced, andscientifically rigorous AAP CME activities by identifying and resolvingall potential conflicts of interest before the confirmation of service ofthose in a position to influence and/or control CME content.

All individuals in a position to influence and/or control the content ofAAP CME activities are required to disclose to the AAP andsubsequently to learners that the individual either has no relevantfinancial relationships or any financial relationships with themanufacturer(s) of any commercial product(s) and/or provider(s) ofcommercial services discussed in CME activities. Commercial interest isdefined as any entity producing, marketing, reselling or distributinghealth-care goods or services consumed by, or used on, patients.

Each of the editorial board members, reviewers, question writers, andstaff has disclosed, if applicable, that the CME content he/she edits/writes/reviews may include discussion/reference to genericpharmaceuticals, off-label pharmaceutical use, investigational therapies,brand names, and manufacturers.

None of the editors, board members, reviewers, question writers, or staffhas any relevant financial relationships to disclose unless noted below. TheAAP has taken steps to resolve any potential conflicts of interest.

Disclosures● Robert Castro, MD, FAAP, disclosed that he participates in the Abbott

Nutrition and Mead Johnson speaker bureaus.● Ivan Hand, MD, FAAP, disclosed that he participates in the Abbott

Nutrition and MedImmune speaker bureaus.● Josef Neu, MD, FAAP, disclosed that he serves as a consultant to

Abbott Nutrition, Life Sciences Research Offices, Environs and Nestlé;and that he has a research grant, serves as a consultant and on theadvisory board of Mead Johnson.

● William Truog, MD, FAAP, disclosed that he participates in a pilotclinical research study for ONY Inc; and participates in the Trial of LateSurfactant (to Prevent BPD) of the National Heart, Blood and LungInstitute.

Continuing Medical Education StatementsThe American Academy of Pediatrics (AAP) is accredited by the Accreditation Council for Continuing Medical Education (ACCME)to provide continuing medical education for physicians.

The AAP designates this journal-based CME activity for a maximum of 18 AMA PRA Category 1 Credit(s)™. Physicians should claimonly the credit commensurate with the extent of their participation in the activity.

This activity is acceptable for a maximum of 18 AAP Credit(s). These credits can be applied toward the AAP CME/CPD Award availableto Fellows and Candidate Members of the AAP.

The American Academy of Physician Assistants accepts AMA PRA Category 1 Credit(s)™ from organizations accredited by the ACCME.

This program is approved for 18 NAPNAP CE contact hours; pharmacology (Rx) contact hours to be determined per the NationalAssociation of Pediatric Nurse Practitioners Continuing Education Guidelines.

It has been established that each month’s question will take the learner a maximum of 1.5 hours to complete.

How to complete this activityNeoReviews can be accessed and reviewed online at http://neoreviews.aappublications.org. Learners can claim credit monthly online. Thedeadline for submitting 2011 answers is December 31, 2013. Credit will be recorded in the year in which it is submitted. It is estimated thatit will take approximately 1.5 hours to complete each issue. This activity is not considered to have been completed until the learner documentsparticipation in that activity to the provider via online submission of answers. Course evaluations will be requested online.

DOI: 10.1542/neo.12-12-e687 2011;12;e687-e697 NeoReviews

Dara Brodsky and Elizabeth G. Doherty Educational Perspectives: Creating an Effective PowerPoint Presentation

http://neoreviews.aappublications.org/cgi/content/full/neoreviews;12/12/e687located on the World Wide Web at:

The online version of this article, along with updated information and services, is

Online ISSN: 1526-9906. Illinois, 60007. Copyright © 2011 by the American Academy of Pediatrics. All rights reserved. by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village,it has been published continuously since 2000. NeoReviews is owned, published, and trademarked NeoReviews is the official journal of the American Academy of Pediatrics. A monthly publication,

. Provided by Health Internetwork on December 1, 2011 http://neoreviews.aappublications.orgDownloaded from

http://neoreviews.aappublications.org/cgi/content/full/neoreviews;12/12/e687

http://http://neoreviews.aappublications.org

Author Disclosures

Drs Brodsky and Doherty 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.

Creating an Effective PowerPointPresentationDara Brodsky, MD,* Elizabeth G. Doherty, MD†

AbstractThis review provides the reader with a comprehensive strategy about howto prepare and deliver a slide presentation by using the most popularsoftware presentation program, Microsoft PowerPoint. With extensivepreparation, keen organization, precise formatting, appropriate use ofaudiovisual aids, and effective delivery, PowerPoint can be a successful toolfor teaching. However, if used ineffectively, this technology can proveto be disadvantageous where listeners may succumb to passive learningwithout critical thinking. This paper will guide novice speakers to refinetheir presentation skills and will encourage experienced presenters torefresh their presentation approach.

Learning Objectives After completing this article, readers should beable to:

1. Describe the essential steps needed to prepare a slide presentation.2. Format a PowerPoint slide presentation by using basic and advanced

formatting tools.3. Modify behaviors to improve their delivery of a presentation.

IntroductionAlthough most neonatology fellowsand neonatologists have experiencepresenting a talk, few have beentaught a systematic approach to cre-ate an effective presentation. This re-view will provide the reader with acomprehensive strategy about howto prepare and deliver a slide presen-tation by using the most popularsoftware presentation program, Mi-crosoft PowerPoint.

PowerPoint is undoubtedly oneof the most useful technological de-velopments for educators and hasrevolutionized medical teaching. It isused in nearly every learning environ-

ment within neonatology, includingclinical lectures, research presenta-tions, grand rounds, and talks atnational conferences. PowerPointcan help presenters emphasize keypoints, explain complicated topics,and provide striking visual images.However, educators are concernedthat PowerPoint has created somebad habits in listeners, such as frag-mented thinking because of the useof bulleted lines; simplified ideas be-cause complex concepts are con-densed; inability to process informa-tion because of the rapid firing ofcontent; and passive learning withlack of critical thinking, partly as aresult of limited audience involve-ment.

We believe that if PowerPoint isused appropriately, speakers can min-imize some of the potential weak-nesses and create a presentation that:

*Department of Neonatology, Beth Israel DeaconessMedical Center, Harvard Medical School, Boston,MA.†Department of Neonatology, Children’s HospitalBoston and Winchester Hospital, Harvard MedicalSchool, Boston, MA.

educational perspectives

NeoReviews Vol.12 No.12 December 2011 e687. Provided by Health Internetwork on December 1, 2011 http://neoreviews.aappublications.orgDownloaded from


● Connects and builds on previousknowledge,

● Teaches complicated concepts,● Allows the audience to process in-

formation,● Engages listeners, and● Motivates the audience to learn

more.

To generate a successful presenta-tion, we encourage the speaker toincorporate the following steps: ex-tensive preparation, keen organiza-tion, precise formatting, appropriateuse of visual aids, and effective deliv-ery. We hope that after reading thisreview, readers of all levels of experi-ence will be able to find new ap-proaches to assist them with theirpresentations.

Planning the PresentationBefore opening the PowerPoint pro-gram, presenters need to carefullyplan their presentation (Table 1).Speakers can begin this process byidentifying some characteristics oftheir listeners:

● Who is the audience?

● What is the audience’s baselineknowledge of the topic?

● What does the audience need tolearn about the topic?

The answers to these questionswill guide the speaker to developcontent that is meaningful and inter-esting to the listeners. A talk aboutcongenital heart disease will be dif-ferent if it is presented to nurses,medical students, or neonatologists.Presenters should also consider addi-tional questions focused on the pro-gram itself (see Table 1 for additionalquestions):

● What has been requested of you?● How much time have you been

allotted?● Are you the only speaker?

Based on the answers to thesequestions, presenters will need to de-cide what they want to convey. Whatis the focus and purpose of the talk?This will enable presenters to targettheir research. It is critical to researchthe topic by using well-respectedpeer-reviewed sources (eg, The New

England Journal of Medicine, Pediat-rics, etc.) and the most recent publi-cations (within the past few years).Speakers must thoroughly under-stand their material and become anexpert on the topic. Ideally, even ifan audience member is an expert inthe field, the speaker should still beable to teach that person somethingabout the topic. For example: If youare presenting a review about surfac-tant deficiency to a group of neonatol-ogists, try to find something fascinat-ing or current about the topic thateven Dr Mary Ellen Avery would findinteresting.

Although it may be tempting tothen go directly to the presentationprogram and create slides, a talk willbe more organized and the present-er’s time will be used more efficientlyif a detailed outline is developed first.By selecting visual aids early duringthis preparation phase, each visualwill serve a specific purpose and be-come integral to the presentation.Although this preparation processhas been presented as a linear ap-proach, most seasoned presentersutilize a feedback loop and backtrackapproach as they continue to refinecontent material. It is importantfor speakers to remember that earlypreparation leads to success by allow-ing for adequate time to modifythe talk, add effective visual aids, andpractice.

Creating Slide ContentAfter researching and mastering thetopic, writing a detailed outline, anddetermining the visual aids, speakersare now ready to create their Power-Point slides. The slide content canbe divided into three components:introduction, body, and conclusion(Table 2).

IntroductionBecause audience concentration, in-terest, and receptiveness are height-

Table 1. Planning the PresentationKnow your audience

• Who are they?• What is their baseline knowledge of your topic?• What do they need to learn about your topic?• How many audience members are anticipated?

Know the program• What are you being asked to do?• How much time do you have?• Where are you in relation to the rest of the program? (Are you the only

presenter or are you the last person to speak after a long list of speakers?)• What is the room layout?• What technology is available to you?• Are you being introduced or do you need to introduce yourself?

Determine the focus of the talk• Use answers to above questions

Research topic• Become an expert

Develop a detailed outline• Include key points and learning objectives• Select visual aids


e688 NeoReviews Vol.12 No.12 December 2011. Provided by Health Internetwork on December 1, 2011 http://neoreviews.aappublications.orgDownloaded from


ened during the first 5 minutes of atalk, the speaker should try to gainthe audience’s attention at the begin-ning of the presentation. Openingthe presentation with a provocativequestion, striking example, short vid-eotape, personal anecdote, dramaticcontrast, powerful quote, or demon-stration will help the speaker obtaineveryone’s attention. It is importantfor the presenter to vary this openingbecause any dramatic introductorytechnique loses impact with repetition.

If the audience is composed oftrainees or students, the speaker mayfind it helpful to disclose the learningobjectives of the talk (ie, what youexpect the trainee/student to learnby the end of the lecture) as a state-ment or a question. For example, “Bythe end of this talk, you will be able toexplain normal cardiac developmentand describe 3 key features of fetalcardiac physiology.”

Ideally, the speaker should thenprovide an overview of the talk. Thisframework will help attendees beaware of the expected sequence andcontent of the talk. This overviewslide can be repeated throughoutthe presentation to let the audienceknow where the talk is currently andwhat is coming next.

BodyWhen crafting the body of the talk,the lecturer must ensure that thecontent is congruent with their ob-jectives. The speaker is required tofocus the material and avoid the ten-dency to cover everything about thetopic. Indeed, studies have shownthat listeners remember more whenthey are told less.

Audiences cite lack of structure asone of the most frequent problems ofpresentations. Thus, speakers musttake the time to make sure that thesequence of the talk makes sense.Most medical presentations can bepresented in one of the followingformats:

1. CLASSICAL The talk has a stan-dard formula (eg, clinical case3 di-agnosis 3 epidemiology 3 clinical,radiographic, and laboratory findings3 management 3 outcome); alter-natively, lecture begins broadly andthen is subdivided.

2. PROBLEM-TO-SOLUTIONS Theproblem is presented and various so-lutions are described.

3. SEQUENTIAL The case is pre-sented in a time sequence with keyconcepts mixed in-between.

4. COMPARATIVE Comparison oftwo or more methods, models, per-spectives, and treatments.

5. THESIS Assertion made andthen proven or refuted.

Within the body of the talk,speakers should reinforce key con-cepts to help the listener understandand retain the presented informa-tion. Speakers can solidify conceptsby incorporating the followingmethods:

● Use examples● Put concepts into various contexts● Provide mini-summaries of key

concepts (particularly useful whenpresenting complicated concepts)

● Pose questions to the audience(helpful for speaker to assess audi-ence understanding before discuss-ing the next concept; added benefitof engaging audience)

By combining these techniques ofreinforcement, the speaker can alsohelp the audience acquire a deeperunderstanding of the topic.

Because most adults have an aver-age attention span of 15 to 20 min-utes during passive listening (duringa less stimulating talk, this time pe-riod may even be shorter), speakersneed to think of strategies to deliber-ately engage the audience. Speakerscan maximize audience attention byvarying their visual aids (eg, radio-graphs, tables, graphs, videotapes)throughout the talk. Presenters caninvolve their listeners by posingquestions, asking for comments, orseeking opinions from the group.Presenters can also ask a member ofthe audience to participate in role-play, perhaps acting as a physician,consultant, or family member. In ad-dition, speakers can intersperse prob-lems that audience members need tosolve individually. Alternatively, speak-ers can ask the audience to break intopairs or three- to four-person groups

Table 2. Creating Slide ContentIntroduction

• Gain the attention of the audience• Review the learning objectives*• Provide an overview of the presentation

Body of talk• Ensure that content is congruent with objectives• Explain concepts clearly• Maintain organization within and between slides• Reinforce key concepts• Keep the audience engaged

Conclusion• Review the learning objectives and key concepts• Encourage self-directed learning

*Educational objectives are particularly applicable if the presentation is being given to trainees orstudents or if CME credits are offered.




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to solve a problem or discuss a topic;this approach even works well withlarge groups. These active learningtactics have an additional benefit offacilitating deeper learning. Present-ers need to be careful not to use toomany activities because an excess canminimize the intended effect.

ConclusionInterestingly, studies have revealedthat audience attention peaks againjust before the presentation ends.Thus, it is important to finish the talkon a positive note. Speakers shouldavoid being in a situation that war-rants saying: “And let me just addone more thing . . .” or “I guess I ranout of time, so I better end now.”Rather, the speaker should use thisopportunity of heightened audienceattention to provide a sense of clo-sure. By reviewing the key conceptsof the talk or the learning objectives,the speaker can retrace his or hersteps. This review shows the audi-ence that their newly acquiredknowledge is a direct benefit of hav-ing heard the lecture.

The last part of the talk also pro-vides the speaker with the opportu-nity to encourage self-directed learn-ing. For example, the presentermight discuss the need for furtherresearch or conclude with a thought-provoking question or problem. Inaddition, the speaker can provide theaudience with handouts, “take-homeproblems,” or a list of resources tofoster continued learning about thetopic.

Formatting in PowerPointAudiences judge not only the con-tent of the slides, but also the format-ting technique. Slides that are diffi-cult to read may lead to attendeefrustration that may cause lack of in-terest for the duration of the talk. Asa rule, speakers should not apologizefor poor quality slides; rather, speak-

ers should not use them! When a talkis formatted correctly, viewers shouldfocus on the content of the slides, notthe details of font style, color, textsize, and bulleting.

Presenters should use their slidesas a means to enhance their presenta-tion, not as a crutch to get throughit. Speakers should meticulously re-view each slide and simplify contentby using key words instead of sen-tences. If slides contain wordy, longsentences, viewers need to decidewhether they are going to read theslide or listen to the speaker, but theycannot do both! In contrast, if theslides have a limited number ofwords, the audience can look at theslides, listen to the speaker, and un-derstand the content at the sametime. It is ideal to limit each slide toone idea and use multiple slides toexplain complex concepts; if there isa wealth of material, consider provid-ing information in a handout. Keepin mind that slides should not be ableto stand alone; they should requirespeaker commentary to provide acomplete story. Basic and advancedformatting guidelines for Power-Point presentations are summarizedin Tables 3 and 4, respectively.

Adding visuals, such as a table,graph, picture, or cartoon, can helpstimulate audience interest and in-crease understanding. Indeed, whenexplained well, visual aids are easierto grasp than words. However, to beeffective, visuals need to be used ap-propriately. Table 5 offers sugges-tions about the use of audiovisualsand animations in PowerPoint pre-sentations.

Practicing the PresentationBy practicing and rehearsing the pre-sentation, the speaker will be morecapable and feel more comfortablepresenting. This allows the speakerto have the ability to interact andT

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connect with the audience during thepresentation. When practicing, thespeaker should factor in the possibil-ity of a delay in start time and leaveseveral minutes for questions; if thetalk is too long, the presenter shouldnot plan on speaking quickly, butinstead, remove content. If the talkis too short, instead of planning tostart late or end early, the speakerneeds to add more content! If thetalk will be presented to a large na-tional audience, the speaker shouldconsider practicing first with a smalllocal group.

Speakers must know the presen-tation environment. Indeed, someprojectors cut off edges and thussome content may not be seen. If thetalk is in a conference room with a

large table in front, the audience maynot be able to see the bottom of theslides. Moreover, some computersmay alter slide images or content (eg,symbols may change, image qualitymay project differently, etc).

As Dr Charles Hatem teaches, onthe day of the presentation, speakersshould “case the joint” by arrivingearly. During this time, the followingsteps should be taken:

● Put the presentation on the roomcomputer or connect your com-puter into the facility’s set-up.

● Quickly view all slides in presenta-tion mode and confirm that videoclips are working.

● Be aware of the nuances of thevenue (lighting, outside noise,

temperature) and if possible/necessary, make adjustments.

● Practice using the slide changerand the laser pointer.

Presenters should be prepared forsomething to go wrong and planahead by having a hard copy of theslides in addition to a flash drivecopy.

Delivering the Presentationand Responding to QuestionsNo matter how much time and efforta speaker puts into preparing thecontent of a PowerPoint presenta-tion, if the delivery is subpar, the talkwill be ineffective. Indeed, the speak-er’s behaviors can either energize

Table 6. Tips to Modify Delivery of a PresentationBehavior Specific Tips for Presenter

Minimize nervousness • Relax and take deep breaths before the talk• Remind yourself that nervousness lessens as you get under way• Memorize the first few slides in anticipation of early anxiety; as a back-up plan,

you can write detailed notes of the first few slides in large font to refer to incase of significant difficulty

Maintain eye contact • Look at as many people as possibleo Mentally divide the lecture room into 3–5 sections and make eye contact with

people in each group during the course of the talko Look in the middle of 2 attendees or look at listener’s foreheads if direct eye

contact disturbs your concentration• Look at someone for <5 sec because a longer glance will make most people

uncomfortable• Observe cues to the audience’s understanding and interest level and adjust talk

accordinglyShow enthusiasm • Use facial expressions

• Vary your pitch• Focus on the meaning of what you are saying because this will make you more

expressiveBe natural • Avoid reading notes (if absolutely necessary to read from notes, limit the amount

of time you are reading)• Speak as if you are having a conversation with the audience• Incorporate anecdotes or stories into your lecture

Monitor pace of delivery • Know midway point in talk and when you get there, assess if you are behind orahead of schedule

• If you are behind schedule, best not to speed up to cover everything (ideal tomake a contingency plan and anticipate possibility of omitting a few slides)

Emphasize key points • Take advantage of the “pause” (eg, after saying “this is really important”)• Let audience know that something is important (eg, “This is a really significant

finding and important for you to remember.”)• Speak more slowly when you want to emphasize key points




or retract from the content. Tips tomodify one’s delivery are summarizedin Table 6. In addition, Table 7 high-lights some practical techniques thatcan be used during the presentation.

The speaker should make everyeffort to answer questions effectivelyand accurately. This process involvesrepeating the question; this ensuresthat the audience has heard thequery, confirms that the speaker hasunderstood the question, and pro-vides the speaker with additionaltime to gather his or her thoughts. Ifthe answer to a question is compli-cated, the speaker can consider abrief response to the question andthen offer the audience member anopportunity to discuss the answer inmore detail after the talk. Alterna-tively, if the presenter had anticipatedthis complicated question, he or shecan refer to additional slides after

the conclusion to assist with this re-sponse.

If the speaker does not know theanswer to the question, he or sheshould acknowledge this and offerto get back to the audience with ananswer. When responding to an ar-gumentative audience member, it isbest not to be confrontational butrather, be respectful, acknowledgethe comment, and offer to meet laterto discuss the issue further. If some-one presents a monologue instead ofposing a question, the speaker shouldfeel free to kindly interrupt and pro-vide his or her thoughts.

Improving the PresentationRegardless of the speaker’s level ofexperience or success of the presen-tation, there is always room for im-provement. Self-reflection about apresentation is perhaps one of the

most useful tools in professional de-velopment. Speakers can ask them-selves:

● “What went well?”● “What could have been im-

proved?”● “What content needs to be ex-

plained better or added to the pre-sentation?” (Think about the ques-tions that were asked and if theaudience seemed confused at anypoint during the talk.)

Some learner evaluations can behelpful, particularly if they offer spe-cific suggestions. Presenters can re-view the videotape of the session withand without sound to gain specificinformation about their behaviors,such as assessing their level of enthu-siasm, degree of nervousness, and useof filler words (eg, “um,” “uh,” “er,”or “like”). Alternatively, speakers can

Table 7. Presentation TechniquesTool General Concepts Specific Tips

Clear slides on screen • Use to temporarily shut off slidepresentation and allow audience toconcentrate on speaker

• If you press the letter “B” on the keyboard whenin “Slide show”, screen will go black

• If you press the letter “W” on the keyboard whenin “Slide show” view, screen will go white

• To return to presentation, press any keyView another item

open on computer• Use “Alt” and “Tab” function to have

this option• Preopen website or document on computer• During slide show view, press “Alt” and keep

finger on “Alt” key• Press and release “Tab” to view options• Continue to hit “Tab” to scroll to item open on

computer• Release “Alt” to view

Access drawing tool • Can use drawing tool duringpresentation to highlight areas

• In presentation mode, right click on mouse• Offers option of “Pointer options”• Select option and draw on slide

Presentation mode (orPresenter’s View)

• Audience sees the presentation as theywould normally; presenter seesadditional information

• Presenter views a scaled down versionwith timeline of the slides along thebottom and the notes from each slide

• Note: this mode can be distracting forthe speaker so not preferable

• In 2007 PowerPoint, click on “Slide Show” tab onupper toolbar, then click on “Set Up Show”, thenlocate “Multiple Monitors” and check box labeled“Show Presenter View”

• In 2010 version, under the “Slide Show” tab,locate the “Monitors” section and check boxlabeled “Use Presenter View”

• In the “Show Presentation On” menu click themonitor you want the slide show presentation toappear on




ask a colleague to observe their talkand provide them with objectivefeedback. In the Harvard Neonatol-ogy Fellowship Training Program,all first year fellows receive feedbackfrom an attending about their pre-sentations through a Grand RoundsMentorship Program (developed byD. Brodsky). We encourage othertraining programs to institute a sim-ilar process.

Speakers should take these collec-tive suggestions and alter the contentof their PowerPoint presentation assoon as possible. In addition, speak-ers should write down recommendedbehavioral changes so that beforetheir next presentation, these notescan be read and serve as reminders.Presenters should attempt to remem-ber at least three positive aspects oftheir talk to capitalize on this insightand build confidence for their nexttalk.

ConclusionPowerPoint has become a standardmeans of presenting lectures, casestudies, research topics, and grand

rounds. Speakers who consistentlyadhere to extensive preparation, keenorganization, precise formatting, ap-propriate use of audiovisual aids, andeffective delivery, as well as diligentpractice and use of constructive feed-back, will raise the level of their pre-sentation to one that is well-receivedand reflects their skill as an effectiveeducator. We hope that this reviewfor creating an effective PowerPointpresentation will guide novice speak-ers to refine their presentation skillsand will encourage experienced pre-senters to refreshen their presenta-tion approach.

Suggested ReadingBellamy K, McLean D. The mechanics of

PowerPoint. J Audiov Media Med.2003;26:74–78

Bellamy K, McLean D. Using PowerPoint.J Audiov Media Med. 2002;26:162–164

Brown G, Manogue M. AMEE Medical Ed-ucation Guide No 22: refreshing lectur-ing; a guide for lecturers. Med Teach.2001;23:231–244

Davis BG. Tools for Teaching. 2nd ed. SanFrancisco: Jossey-Bass Publishers;1993

Giving a presentation. J Vis Commun Med.2006;29:115–118

Harden RM. Death by PowerPoint: theneed for a “fidget index”. Med Teach.2008;30:833–835

Hatem CJ. Crafting effective lectures. Sem-inars for Rabkin Fellowship in MedicalEducation. Boston, MA: Beth IsraelDeaconess Medical Center; 2009

Holzl J. Twelve tips for effective Power-Point presentations for the technologi-cally challenged. Med Teach. 1997;19:175–179

McLaughlin K, Mandin H. A schematic ap-proach to diagnosing and resolving lec-turalgia. Med Ed. 2001;35:1135–1142

Niamtu J. The power of PowerPoint. PlastReconst Surg. 2001;108:466–484

Wear D. A perfect storm: the convergenceof bullet points, competencies, andscreen reading in medical education.Acad Med. 2009;84:1500–1504

American Board of PediatricsNeonatal-Perinatal ContentSpecifications• Understand the

attributes of aneffective learningenvironment.

• Understand thestrengths and weaknesses of variousteaching methods (eg, lecture, smallgroup discussion, bedside teaching,simulation).





Dara Brodsky and Elizabeth G. Doherty Educational Perspectives: Creating an Effective PowerPoint Presentation

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Patricia Y. L. Chan, Jonathan M. Morris and Eileen D. M. Gallery Developmental Origins of Adult Disease: Part 1: Cardiovascular Disease







Developmental Origins of Adult Disease:Part 1: Cardiovascular DiseasePatricia Y. L. Chan,

MBBS(Syd U),

ADip(SMBC), FRANZCOG,

MMed(Clin Epi), PhD,*

Jonathan M. Morris, MB,

ChB, MM, PhD,

FRANZCOG, DDU, CMCF,†

Eileen D. M. Gallery,

MD(Syd), FRACP§

Author Disclosure

Drs Chan, Morris, and

Gallery 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.

AbstractThere is now considerable evidence from numerous epidemiologic, animal, andclinical studies demonstrating the association of early life conditions and increased riskof subsequent adult disease such as cardiovascular, renal, and metabolic disease. Thisfirst of three articles reviews the developmental origins of cardiovascular disease andthe proposed underlying mechanisms.

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

1. Understand the concept of developmental origins applied to cardiovascular disease andassociated controversies.

2. Describe the proposed underlying mechanisms of developmental origins applied tocardiovascular disease such as programming, thrifty hypothesis, developmentalplasticity, epigenetic mechanisms, and predictive adaptive response.

3. Understand the challenge for future research.

IntroductionCardiovascular disease is the leading cause of morbidity and mortality globally and is nolonger limited to economically developed countries. (1) It accounts for almost 30% of alldeaths in the world. (1) The established risk factors for cardiovascular disease such as age,sex, genetic disposition, cigarette smoking, hypertension, diabetes mellitus, hyperlipid-emia, and obesity (2) have limited ability to predict the occurrence of cardiovasculardisease and offer little insight into why one person develops the disease whereas anotherdoes not. (3) The paradoxical social and geographical distribution of ischemic heartdisease, why a disease “associated globally with affluence is now most common in thepoorest parts of Britain and among people with the lowest incomes” led Barker andcolleagues to propose the hypothesis that fetal growth restriction and low weight gain ininfancy are associated with an increased risk of adult cardiovascular disease. (4)(5)(6)

Low Birthweight and Adult Cardiovascular DiseaseThe concept that early life events have long-term effects on adult human health dates backmany years. Kermack et al (1934) (7) reported that death rates from all causes in GreatBritain and Sweden fell with each successive year of birth cohort between 1751 and 1931.They concluded it was the result of improved childhood living conditions and indicatedthe importance of good environmental conditions during childhood in predicting thefuture health of the individual. (7)

Forsdahl (1977) (8) discovered a geographical correlation in Norway between mortal-ity from arteriosclerotic heart disease in men and women aged between 40 and 69 years in1964 to 1967 and infant mortality rates in 1896 to 1925. He suggested that “great povertyin childhood and adolescence followed by prosperity is a risk factor for arterioscleroticheart disease.” (8)

Barker and colleagues studied the records of birthweights and weight at age 1 year of allinfants born in Hertfordshire between 1911 and 1930, and produced the first evidence

*Perinatal Research, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW 2065, Australia.†Professor of Obstetrics and Gynecology, Director Perinatal Research, Associate Dean and Head, Sydney Medical School–Northern, The University of Sydney, Royal North Shore Hospital, St Leonards, NSW 2065, Australia.§Clinical Professor of Medicine, Clinical Professor of Obstetrics and Gynecology, Co-Director Perinatal Research, KollingInstitute of Medical Research, University of Sydney at Royal North Shore Hospital, St Leonards, NSW 2065, Australia.

Article origins of cardiovascular disease



that coronary heart disease might originate in utero orduring infancy. (5)(9) They showed that lower birth-weight and weight at 1 year were each associated with anincreased risk of subsequent death from cardiovasculardisease in adulthood. The trends for premature deathsfrom cardiovascular disease were similar in men andwomen, and rates fell with increasing birthweight up to9.5 lb. (9) There was an approximate doubling of mor-tality from the higher to the lowest extremes of birth-weight similar in men and women. However, there wasan increased mortality in the group whose birthweightwas higher than 9.5 lb, indicating a “U” shape relation-ship.

Subsequent studies in the UK, Europe, and theUnited States have confirmed these findings and indi-cated that restricted fetal growth carries the risk of adultcardiovascular disease. The effects are linear, across therange of birthweights, and independent of adult socio-economic status. Although most of these studies werelimited to birthweight as a measure of fetal growth, thereis evidence that body proportions at birth such as lowponderal index (weight/length3) predicted coronaryheart disease better than birthweight in Finland, (10) anda low birthweight-head circumference ratio predictedstroke mortality in the UK. (11) It has also been sug-gested that discordance between placental and fetal sizemay lead to circulatory adaptation in the fetus, alteredarterial structure in the child, and hypertension in theadult. (12) All of this suggests that impaired nutritionsupplied by the placenta, resulting in fetal growth restric-tion in utero, is the culprit, rather than being small atbirth because of prematurity but of a weight appropriatefor gestational age at birth.

Birthweight and Risk FactorsSubsequent work has shown that while lower birth-weight and other measures of small size at birth areassociated with the development of later cardiovasculardisease, they are also associated with an increase in car-diovascular disease risk factors.

High Blood PressureRaised blood pressure is a well-established risk factorfor cardiovascular disease. (2)(13) The evidence for thisrelationship arises from large scale prospective observa-tional studies, two landmark ones being the FraminghamStudy (2) and the Seven Countries Study. (13)

Birthweight has been the most widely studied mea-sure in retrospective studies, mainly due to its availabilityfrom existing records or personal recall. Blood pressureis the most commonly reported outcome because mea-

surement is noninvasive, quick, and relatively easy at allages. The association between lower birthweight andsubsequent elevated blood pressure levels has been con-sidered to provide some of the strongest and most con-sistent support for the “fetal origins” hypothesis of adultdisease.

The first associations found were between low birth-weight and later life hypertension and cardiovasculardisease. (6) High blood pressure was found to occur at ahigher incidence in children and adults who were of lowbirthweight. (6) Studies have been reviewed by Leon etal, (14) Law et al, (15) Huxley et al, (16) and Adair et al.(17) Most have demonstrated an inverse association be-tween birthweight and later blood pressure or an inverseassociation between birthweight and risk of hyperten-sion. However, the authors of these studies collecteddata and reported their findings in a variety of ways. (18)

Based on a systematic review of multivariate regres-sion coefficients from 34 studies reported before March1996, involving a total of 66,000 people, it was esti-mated that a 1-kg higher birthweight is typically associ-ated with a 2 to 3 mm Hg lower systolic blood pressure.(15) An update of that review, (16) which includedregression coefficients from an additional 45 studies,involving over 444,000 people, indicated an inverse as-sociation of �2 mm Hg/kg, as did another review of thesame studies. (14)

A more recent study of 25,874 men and womenobserved a strong interaction between birthweight andage to predict systolic blood pressure, �1.1 mm Hg/kgafter adjusting for age, sex, and body size. (19) Thisinverse association was amplified with age, (19) givingsupport to the hypothesis that fetal programming of highblood pressure is amplified throughout life.

Not all authors share this view. Huxley et al (18)explored the possible impact of publication bias, mea-surement error, inappropriate adjustment for currentweight, potential confounders such as sex, height, paren-tal socioeconomic status, current socioeconomic status,parental blood pressure, alcohol consumption, race, andgestational age. They concluded that birthweight is oflittle relevance to blood pressure levels in later life whenthe impact of random error, publication bias, inappropri-ate adjustment for current weight, and confoundingfactors are considered.

The strength of association between birthweight andsubsequent hypertension remains widely debated. How-ever, it appears that although the relation is not invariant,the totality of evidence suggests an important direct orindirect interaction between birthweight and subsequenthypertension.

origins of cardiovascular disease



Potential mechanisms linking restricted fetal growthto adult hypertension include redistribution of bloodflow away from the liver, viscera, and the kidneys, inpreference for the brain, leading to underdevelopment ofthese organs. The kidneys of growth-restricted infantsare smaller and contain fewer nephrons than those ofappropriate weight for gestational age infants. The roleof the kidney in the pathogenesis of hypertension is wellestablished and is discussed further in the article on“Developmental Origins of Adult Disease: Part 2: RenalDisease”. Other possible mechanisms include persistingchanges in vascular structure, including loss of elasticityin vessel walls, and the effects of glucocorticoid hor-mones.

Metabolic SyndromeThe metabolic syndrome, insulin resistance syndrome orsyndrome X, which includes combinations of hyperten-sion, type 2 diabetes, and insulin resistance are consis-tently related to low birthweight in a large number ofstudies across different populations. More is discussed inthe article on “Developmental Origins of Adult Disease:Part 3: Metabolic Disease”.

Serum Lipids and Clotting FactorsIncreased plasma concentration of low-density-lipoprotein cholesterol, an established risk factor for car-diovascular disease, (2) has been shown to be related toreduced fetal growth. (20) Raised plasma fibrinogen, ameasure of blood coagulability, is also a strong risk factorfor cardiovascular disease. (2) Studies in Sheffield, UK,showed that the neonate with a short body and lowbirthweight in relation to the size of its head had persist-ing disturbances of cholesterol metabolism and bloodcoagulation. It was specifically the reduction in abdomi-nal circumference at birth that predicted raised serumconcentrations of total and low-density-lipoprotein cho-lesterol and apolipoprotein B in men and women. (20)

In late gestation the fetus responds to under nutritionby sustaining growth of the brain at the expense of thetrunk. This adaptation compromises the liver and seemsto permanently alter its metabolism. (21) As both cho-lesterol and fibrinogen metabolism are regulated by theliver, one interpretation of these findings is that reducedabdominal circumference at birth reflects liver growthand consequent reprogramming of the liver metabolism.(21) An atherogenic lipid profile may be linked to atransition from poor maternal nutrition in early gestationto adequate nutrition later on.

Men who had a small abdominal circumference atbirth had raised serum concentrations of total and low

density lipoprotein cholesterol as adults. (20) They alsohad raised plasma fibrinogen concentrations, anothermajor risk factor for mortality from coronary heart dis-ease that is regulated by the liver. (21)

Overall, the association between serum lipid concen-tration and size at birth is less consistent and not aswell established as the associations with hypertension ordiabetes.

Conceptual ModelsMcCance and Widdowson were among the first to showthat brief periods of undernutrition may permanentlyreduce the number of cells in particular organs. (22) Thisis a powerful mechanism by which undernutrition couldpermanently change or program the body. (4) Under-nutrition may also affect distribution of cell types, pat-terns of hormonal secretion, metabolic activity, and or-gan structure. (4)

The Concept of “Programming”Events in early life may influence long-term outcomes inthree ways, as pointed out by Lucas (23):

1) Direct damage2) Induction, deletion, or impaired development of a

somatic structure resulting from a stimulus or insultduring a critical period

3) Physiologic “setting” by an early stimulus or in-sult at a critical period, with long term consequences forfunction.

The term “programming” has been applied to thelatter two processes in which the programming stimulusonly exerts long-term effects when applied at a “critical”or “sensitive” period. (23) Programming in fetal orpostnatal life may result in the initiation of 1) normaldevelopment process (resulting from endogenous signal-ing), 2) a lasting adaptation to an early environmentstimulus, or 3) an adverse response to an insult at asensitive period. Theoretically, nutritional programmingmay operate in any of these ways. (23)

Nutritional programming has been convincinglyshown to occur in animals. Numerous animal experi-ments have demonstrated that the fetus is “plastic” dur-ing development, that manipulating fetal and neonatalnutrition can permanently change the structure andfunction of many systems, such as persistent changesin blood pressure, cholesterol metabolism, insulin re-sponses to glucose, and several other metabolic, endo-crine, and immune system alterations. (22)(24) Theseobservations laid the foundations of the programminghypothesis.

Nutritional programming in humans has not been




easy to prove or disprove, largely because most studiesare not experimental in design but describe epidemiolog-ical associations often subject to alternative explanations.(23) Another difficulty is that maternal nutrition hasbeen viewed too narrowly as the diet a mother eatsduring pregnancy. The nourishment of the fetus alsodepends on the mother’s nutrient stores, her metaboliccapacity, and her lifelong nutritional experience. It isnow clear from observations on humans and animals thatthe embryo is sensitive to nutrients that it receives andmay be permanently changed by them. (25)(26)

The links between fetal undernutrition over differentstages of pregnancy and cardiovascular disease is summa-rized in Figure 1.

In late gestation, rates of cell division in the fetus falland growth slows. After birth, growth mainly depends onthe development and enlargement of existing cells ratherthan the addition of new ones. (22) Low rates of infantgrowth are highly predictive of coronary heart disease inmen. (9) In Hertfordshire, men who were small at 1year of age were three times more likely to develop ordie from coronary heart disease than those who werelarge, an association not dependent on the way infantswere fed. (27) Low weight gain during infancy is also

followed by hypertrophy of theleft ventricle in childhood andadult life, which predicts coronaryheart disease independent ofblood pressure. (28)

More recent studies have shownthat greater postnatal weight gainis independently associated withdisease risk. (29) There is increas-ing evidence that either low birth-weight, accelerated postnatal weightgain, or a combination of the two,may predispose to the risk for hy-pertension, cardiovascular disease,and type 2 diabetes in adulthood.(30) Currently, the most unfavor-able growth pattern seems to below birthweight, slow growth ininfancy followed by excess weightgain during childhood and adoles-cence—this pattern portends a par-ticularly poor prognosis for thedevelopment of coronary heart dis-ease in adulthood. (30)(31)(32)This has led to the “thrifty pheno-type” concept.

The “Thrifty Phenotype” HypothesisHales and Barker (1992) (33) proposed the “thriftyphenotype” hypothesis, derived from the prior “thriftygenotype” hypothesis. (34) Neel (34) proposed that“thrifty” genes were selected at a time of food scarcity,resulting in a “fast insulin trigger” and enhanced capacityto store fat, thus placing the individual at risk of insulinresistance and type 2 diabetes. (34) The thrifty pheno-type hypothesis suggested that when the fetal environ-ment is poor, there is an adaptive response that optimizesthe growth of vital organs to the detriment of others,leading to altered postnatal metabolism, designed toenhance postnatal survival under intermittently or con-tinuously poor nutritional conditions. (33)(35)(36) Itwas proposed that these adaptations only became detri-mental when nutrition was more abundant in the post-natal environment compared with the prenatal environ-ment. (33)(35)(36) This concept is consistent with thedefinition of “programming” by Lucas (23) as either theinduction, deletion, or impaired development of a per-manent somatic structure or the “setting” of a physio-logic system by an early stimulus or insult operating at a“sensitive” period, resulting in long-term consequences.

Figure 1. Framework of ideas in the fetal origins hypothesis. Reproduced from Barker DJ.Fetal origins of coronary heart disease. BMJ. 1995;311(6998):171–174, (4) withpermission from the BMJ Publishing Group Ltd.




The Concept of“Developmental Plasticity”

It has been recently stated thatwhen developmental physiologistsand physicians use the term “pro-gramming”, they are describing theprocess whereby a stimulus or in-sult at a sensitive or critical periodof development has lasting effectson structure or function of thebody; this term has different mean-ings in ethnology and other areasof biology, (36)(37) and is no lon-ger recommended to describe thedevelopmental origins of adult dis-ease. The term “developmentalplasticity” was proposed and con-sidered more appropriate than“programming”. (37)(38) Theformal definition of developmentalplasticity is the ability of a singlegenotype to produce more thanone alternative form of structure,physiologic state, or behavior in re-sponse to environmental condi-tions. (37) They allow environ-mental influences to “tune thematch” of the organism to its ex-pected environment beyond that achieved through nat-ural selection, ie, inherited genotype. (38)

The organs and systems of the body pass throughcritical developmental periods when they are plastic andsensitive to the environment. (25)(39) Developmentalplasticity enables the production of phenotypes that arebetter matched to their environment than would bepossible if the same phenotype were produced in allenvironments. (25)(39) The developmental plasticityprocesses are triggered by the in utero environment.Thus, adverse events in utero induce compensatoryresponses in the fetus during this critical period, (39)responses that persist permanently, defining an alteredphenotype not only at birth but also for that child’slifetime. Altered developmental programming thereforelimits the range of postnatal adaptability, creating diseasevulnerability. (25) Developmental plasticity therefore ex-plains why individuals who have many latent capacitiesfrom their specific genetic endowments only expressspecific capacities under certain conditions. (25)

Developmental plasticity declines and exposure toenvironmental challenges increases with age as shown inFigure 2. Epigenetic processes are induced by cues from

the developmental environment. They play a role indetermining the phenotype of the offspring as part of alife-course strategy to match it to its environment. Ifnot appropriately matched, the risk of later disease isincreased. (40)

Epigenetic MechanismsDevelopmental plasticity requires stable modulations ofgene expression, and this appears to be mediated in partby epigenetic processes such as DNA methylation andhistone modification. (41)(42) Thus, both genome andthe epigenome interactively influence the mature pheno-type and determine sensitivity to later environmentalfactors and the subsequent risk of disease. (40)(43) Theterm “epigenetics” was coined by Waddington (44) torefer to the ways in which the developmental environ-ment can influence the mature phenotype.

The mismatch concept emphasizes that the degree ofdisparity between the environment experienced duringdevelopment and that experienced later influences therisk of disease. During the period of developmental plas-ticity in prenatal and early postnatal life, epigenetic pro-cesses are thought to alter gene expression based on

Figure 2. Developmental plasticity and exposure to environmental challenges. Epigeneticprocesses play a role in determining the phenotype of the offspring as part of a life-coursestrategy to match it to its environment. If not appropriately matched, the risk of laterdisease is increased. Reproduced from Godfrey KM, Lillycrop KA, Burdge GC, et al.Epigenetic mechanisms and the mismatch concept of the developmental origins of healthand disease. Pediatr Res. 2007;61(5 Pt 2):5R–10R, (40) with permission from WoltersKluwer Health Publisher.




environmental cues transmitted via the mother, to pro-duce phenotypic attributes best suited to the environ-ment in which the individual predicts it will live. Greatermismatch gives greater risk of disease from unpredictedexcessive richness (high calorie density food, sedentarylifestyle) of the environment. Thus, the risk is greaterwith poorer developmental environment (A versus B),and with socioeconomic transitions to an affluent west-ern lifestyle (45) as shown in Figure 3.

Predictive Adaptive ResponseIt has also been proposed to further separate those ho-meostatic responses that represent early adaptations tochanges in the intrauterine environment that may havelong-term consequences, from those which need notconfer immediate advantage but are induced in the ex-pectation of future adaptive changes; this latter group ofresponses has been defined as “predictive adaptive”. (46)In this model, selection across generations operates to fa-vor protection of those predictive adaptive responses thataid survival to reproductive age. (46) The programmedor plastic responses made during development that haveimmediate adaptive advantage may also act to limit therange of postnatal adaptive responses to a new environ-ment and would be considered “inappropriate” predic-tive adaptive responses. (45)(46)(47)(48)(49)(50)

SummaryCardiovascular disease is the lead-ing cause of morbidity and mortal-ity worldwide. The establishedrisk factors do not explain the dif-ferences in susceptibility to car-diovascular disease among indi-viduals. There is now increasingbody of evidence across differentpopulations globally associatingearly life conditions with risk ofdeveloping cardiovascular diseasein later life. To what extent theproposed mechanisms are respon-sible remain to be established.The challenge for future researchis to unravel the underlyingmechanisms and pathways whichwill lead to appropriate, timelyinterventions in early life andthereby reduce the incidence andseverity of cardiovascular disease.

References1. World Health Organization. World Health Statistics 2008. In:Global Burden of Disease. Geneva, Switzerland: World Health Or-ganization; 2008. Accessed October 13, 2011 at: http://www.who.int/healthinfo/global_burden_disease/2004_report_update/en/index.html2. Wilson PW. Established risk factors and coronary artery disease:the Framingham Study. Am J Hypertens. 1994;7(7 Pt 2):7S–12S3. Barker DJ. The origins of the developmental origins theory.J Intern Med. 2007;261:412–4174. Barker DJ. Fetal origins of coronary heart disease. BMJ. 1995;311(6998):171–1745. Barker DJ, Winter PD, Osmond C, et al. Weight in infancy anddeath from ischaemic heart disease. Lancet. 1989;2(8663):577–5806. Barker DJ, Osmond C, Golding J, et al. Growth in utero, bloodpressure in childhood and adult life, and mortality from cardiovas-cular disease. BMJ. 1989;298(6673):564–5677. Kermack WO, McKendrick AG, McKinlay PL. Death-rates in

Figure 3. The mismatch concept. Reproduced from Godfrey KM, Lillycrop KA, Burdge GC,et al. Epigenetic mechanisms and the mismatch concept of the developmental origins ofhealth and disease. Pediatr Res. 2007;61(5 Pt 2):5R–10R, (40) with permission fromWolters Kluwer Health Publisher.

American Board of Pediatrics Neonatal-PerinatalContent Specifications• Know nutritional requirements during

pregnancy and the impact of poor nutritionon fetal growth and development.

• Recognize the effects of fetal programmingand nutrition on the prevalence and typesof adult onset disorders.




Great Britain and Sweden: some general regularities and theirsignificance. Lancet. 1934;223(5770):698–7038. Forsdahl A. Are poor living conditions in childhood and adoles-cence an important risk factor for arteriosclerotic heart disease? Br JPrev Soc Med. 1977;31:91–959. Osmond C, Barker DJ, Winter PD, et al. Early growth and deathfrom cardiovascular disease in women. BMJ. 1993;307(6918):1519–152410. Forsen T, Eriksson JG, Tuomilehto J, et al. Mother’s weight inpregnancy and coronary heart disease in a cohort of Finnish men:follow up study. BMJ. 1997;315(7112):837–84011. Martyn CN, Barker DJ, Osmond C. Mother’s pelvic size, fetalgrowth, and death from stroke and coronary heart disease in men inthe UK. Lancet. 1996;348(9037):1264–126812. Barker DJ, Bull AR, Osmond C, Simmonds SJ. Fetal andplacental size and risk of hypertension in adult life. BMJ. 1990;301(6746):259–26213. Keys A, Menotti A, Aravanis C, et al. The seven countriesstudy: 2,289 deaths in 15 years. Prev Med. 1984;13:141–15414. Leon D, Koupilova I. Birthweight, blood pressure and hyper-tension: epidemiologic studies. In: DJP Barker, ed. Fetal Originsof Cardiovascular and Lung Disease. New York: Marcel Dekker;1999:23–4815. Law CM, Shiell AW. Is blood pressure inversely related to birthweight? The strength of evidence from a systematic review of theliterature. J Hypertens. 1996;14:935–94116. Huxley RR, Shiell AW, Law CM. The role of size at birth andpostnatal catch-up growth in determining systolic blood pressure: asystematic review of the literature. J Hypertens. 2000;18:815–83117. Adair L, Dahly D. Developmental determinants of blood pres-sure in adults. Annual Rev Nutr. 2005;25:407–43418. Huxley R, Neil A, Collins R. Unravelling the fetal originshypothesis: is there really an inverse association between birth-weight and subsequent blood pressure? Lancet. 2002;360(9334):659–66519. Davies AA, Smith GD, May MT, Ben-Shlomo Y. Associationbetween birth weight and blood pressure is robust, amplifies withage, and may be underestimated. Hypertension. 2006;48:431–43620. Barker DJ, Martyn CN, Osmond C, et al. Growth in uteroand serum cholesterol concentrations in adult life. BMJ. 1993;307(6918):1524–152721. Barker DJP, Martyn CN, Osmond C, Wield GA. Abnormalliver growth in utero and death from coronary heart disease. BMJ.1995;310(6981):703–70422. McCance RA, Widdowson EM. Review lecture: the determi-nants of growth and form. Proc R Soc Lond B Biol Sci. 1974;185(1078):1–1723. Lucas A. Role of nutritional programming in determiningadult morbidity. Arch Disease Child. 1994;71:288–29024. Langley-Evans SC. Fetal programming of cardiovascular func-tion through exposure to maternal undernutrition. Proc Nutr Soc.2001;60:505–51325. Bateson P. Developmental plasticity and evolutionary biology.J Nutr. 2007;137:1060–106226. Symonds ME. Integration of physiological and molecularmechanisms of the developmental origins of adult disease: newconcepts and insights. Proc Nutr Soc. 2007;66:442–45027. Fall CH, Vijayakumar M, Barker DJ et al. Weight in infancyand prevalence of coronary heart disease in adult life. BMJ. 1995;310(6971):17–1928. Vijayakumar M, Fall CH, Osmond C, Barker DJ. Birth weight,

weight at one year, and left ventricular mass in adult life. Br Heart J.1995;73:363–36729. Lucas A, Fewtrell MS, Cole TJ. Fetal origins of adult disease-the hypothesis revisited. BMJ. 1999;319(7204):245–24930. Barker DJP, Osmond C, Forsen TJ, et al. Trajectories ofgrowth among children who have coronary events as adults. N EnglJ Med. 2005;353:1802–180931. Rich-Edwards JW, Kleinman K, Michels KB, et al. Longitudi-nal study of birth weight and adult body mass index in predictingrisk of coronary heart disease and stroke in women. BMJ. 2005;330(7500):1115–111832. Gillman MW. Developmental origins of health and disease.N Engl J Med. 2005;353:1848–185033. Hales CN, Barker DJ. Type 2 (non-insulin-dependent) diabe-tes mellitus: the thrifty phenotype hypothesis. Diabetologia. 1992;35:595–60134. Neel JV. Diabetes mellitus: a “thrifty” genotype rendereddetrimental by “progress”? Am J Hum Genet. 1962;14:353–36235. Hales CN, Barker DJ. The thrifty phenotype hypothesis. BrMed Bull 2001;60:5–2036. McMillen IC, MacLaughlin SM, Muhlhausler BS, et al. Devel-opmental origins of adult health and disease: the role of pericon-ceptional and foetal nutrition. Basic Clin Pharmacol Toxicol. 2008;102:82–8937. Barker DJP. Developmental origins of adult health and disease.J Epidemiol Community Health. 2004;58:114–11538. Gluckman PD, Hanson MA. Developmental plasticity andhuman disease: research directions. J Intern Med. 2007;261:461–47139. Bateson P, Barker D, Clutton-Brock T, et al. Developmentalplasticity and human health. Nature. 2004;430(6998):419–42140. Godfrey KM, Lillycrop KA, Burdge GC, et al. Epigeneticmechanisms and the mismatch concept of the developmental ori-gins of health and disease. Pediatr Res. 2007;61(5 Pt 2):5R–10R41. Cutfield WS, Hofman PL, Mitchell M, Morison IM. Couldepigenetics play a role in the developmental origins of health anddisease? Pediatr Res. 2007;61(5 Pt 2):68R–75R42. Tremblay J, Hamet P. Impact of genetic and epigenetic factorsfrom early life to later disease. Metabolism. 2008;57(Suppl 2):S27–S3143. Gluckman PD, Hanson MA, Cooper C, Thornburg KL. Effectof in utero and early-life conditions on adult health and disease.N Engl J Med. 2008;359:61–7344. Van Speybroeck L. From epigenesis to epigenetics: the case ofC. H. Waddington. Ann N Y Acad Sci. 2002;981:61–8145. Gluckman PD, Hanson MA, Beedle AS. Early life events andtheir consequences for later disease: a life history and evolutionaryperspective. Am J Hum Biol. 2007;19:1–1946. Gluckman PD, Hanson MA. The developmental origins of themetabolic syndrome. Trends Endocrinol Metab. 2004;15:183–18747. Gluckman PD, Hanson MA. Developmental origins of diseaseparadigm: a mechanistic and evolutionary perspective. Pediatr Res.2004;56:311–31748. Gluckman PD, Hanson MA, Spencer HG. Predictive adaptiveresponses and human evolution. Trends Ecol Evol. 2005;20:527–53349. Gluckman PD, Hanson MA, Beedle AS, Spencer HG. Predic-tive adaptive responses in perspective. Trends Endocrinol Metab.2008;19:109–11050. Rickard IJ, Lummaa V. The predictive adaptive response andmetabolic syndrome: challenges for the hypothesis. Trends Endocri-nol Metab. 2007;18:94–99




NeoReviews Quiz

1. The hypothesis proposed by Barker and associates claims that fetal growth restriction and low weight gainin infancy are associated with an increased risk of adult cardiovascular disease. Of the following, thevariable at birth most predictive of adult coronary heart disease in Finland is:

A. Discordance between placental and fetal size.B. Estimated gestational age at birth.C. Low birthweight/head circumference ratio.D. Low ponderal index (weight/length3).E. Maternal socioeconomic status.

2. Increased plasma concentration of low-density-lipoprotein cholesterol is an established risk factor forcardiovascular disease. Of the following, the body measurement at birth most predictive of increased serumconcentrations of total and low-density-lipoprotein cholesterol and of apolipoprotein B in adults is a low:

A. Abdominal circumference.B. Birthweight.C. Chest circumference.D. Crown-heel length.E. Head circumference.

3. Periods of undernutrition during fetal life and early infancy may permanently reduce the number of cells inparticular organs. Undernutrition may also affect the distribution of cell types, patterns of hormonalsecretion, metabolic activity, and organ structure. Of the following, one of the first authors to speculatethat undernutrition in fetal life may contribute to adult-onset disease is:

A. Barker.B. Bateson.C. Lucas.D. McCance.E. Symonds.

4. The growth patterns during fetal life, infancy, and early childhood can portend poor prognosis for thedevelopment of coronary heart disease in adulthood. Of the following, the most unfavorable growth patternfor the development of coronary heart disease in adulthood is:

A. Low birthweight, rapid growth in infancy, excess growth in childhood.B. Low birthweight, rapid growth in infancy, slow growth in childhood.C. Low birthweight, slow growth in infancy, excess growth in childhood.D. Low birthweight, slow growth in infancy, slow growth in childhood.E. Normal birthweight, normal growth in infancy, normal growth in childhood.





Patricia Y. L. Chan, Jonathan M. Morris and Eileen D. M. Gallery Developmental Origins of Adult Disease: Part 1: Cardiovascular Disease













Patricia Y. L. Chan, Jonathan M. Morris and Eileen D. M. Gallery Developmental Origins of Adult Disease: Part 2: Renal Disease







Developmental Origins of Adult Disease:Part 2: Renal DiseasePatricia Y. L. Chan,

MBBS(Syd U),




ChB, MM, PhD,



MD(Syd), FRACP§

Author Disclosure



no financial



commentary does not


of an unapproved/


commercial

product/device.

AbstractAn increasing body of evidence suggests the influence of early life events on theseverity of expression and progression of renal disease in later life. This second of threearticles discusses the animal and human data supporting the developmental origins ofrenal disease and some of the underlying proposed mechanisms.


1. Understand the concept of developmental origins applied to renal disease.2. Describe evidence from animal studies.3. Describe evidence from human studies.4. Describe the proposed underlying mechanisms applied to renal disease such as perinatal

programming in thrifty hypothesis, renin-angiotensin system, and steroid metabolism.

IntroductionMillions of people around the world suffer from chronic kidney disease, defined as kidneydamage for �3 months or glomerular filtration rate (GFR) �60 mL/min per 1.73 m2 for�3 months with or without kidney damage. (1) Kidney damage is defined as structural orfunctional abnormalities of the kidney, which over time can lead to decreased GFR. Manypatients with chronic kidney disease progress to chronic renal failure (CRF). CRF isdefined as either GFR �15 mL/min per 1.73 m2, or a need for renal replacement therapyto treat complications of decreased GFR, which would otherwise result in mortality andmorbidity. (1) The progressive nature of CRF and the ensuing end-stage renal disease(ESRD) put a substantial burden on global health care resources. (2)

Over the past 2 decades, an increasing body of evidence suggests that blood pressure,renal function, and general health in later childhood and adult life may be influencedsubstantially before birth or during the perinatal period by the prevalent environment.

Evidence From Animal StudiesMultiple animal models have demonstrated an association of low birthweight (induced bygestational exposure to low protein diet, dexamethasone, gentamicin, vitamin A depriva-tion, or uterine ischemia) with later hypertension. (3)(4)(5)

Pregnant rats fed a low protein diet bear offspring that are relatively small at birth anddevelop hypertension as mature animals. (5)(6)(7) Hypertension has been observed asearly as 4 weeks postnatally, and once present persists throughout life, unrelated to anypostpartum manipulations of either the mother or the offspring. (5)(6)(7) Among themajor organ systems, the kidney appears to be targeted specifically when maternal proteinintake during gestation is restricted, leading to decreased kidney-to-body weight ratio atbirth and fewer nephrons in those kidneys. (5)(6)(7)

One hypothesis linking decreased birthweight and subsequent adult hypertension isthat maternal undernutrition leads to permanent structural changes within the kidneys,thus contributing to a propensity for adult cardiac or renal disease. Hyperfiltration(increased filtration pressure and GFR per glomerulus) has been associated with hyperten-sion and renal insufficiency. (8)(9)


Article origins of renal disease



The link between adult hypertension and low birth-weight in these animal models appears to be in partmediated by an associated congenital deficit of nephronnumber. (3)(4) Unlike organ systems such as the heart,which develop early in gestation, renal developmentoccurs in the latter half of gestation, and in some species,continues after birth. (8) Reduced number of nephronsfrom birth leads to increased arterial pressure in adult-hood as shown in the rat, where rat pups uni-nephrectomized during development had reduced renalfunction and hypertension in adulthood. (10) Vehaskariet al. (4) demonstrated an almost 30% reduction inglomerular number in low birthweight rats comparedwith those of normal weight, and systolic blood pressures20 to 25 mm Hg higher by 8 weeks of age. Celsi et al. (3)also found that prenatal administration of dexametha-sone in rats was followed by low birthweight and fewerglomeruli compared with controls. In these nephron-deficient rats, GFR was reduced, albuminuria was in-creased, urinary sodium excretion was lower, and tissuesodium content was higher than normal. The authorsconcluded that high levels of maternal glucocorticoidsimpair renal development and lead to arterial hyperten-sion in offspring. Even although renal mass eventuallynormalizes, glomerular damage and sodium retentionoccur and these may contribute to the development ofhypertension. (3)

Suppression of the intrarenal renin-angiotensin sys-tem (RAS), reduced levels of renal messenger RNA, andrenin have been described in newborn intrauterinegrowth restricted rats. (5) Despite the suppression ofintrarenal RAS in the neonatal period, angiotensin IItype 1 receptor expression increases above control levelsduring the prehypertensive stage in rats, without feed-back suppression in kidney angiotensin I or II contents.(11) Although direct experimental evidence for in-creased sodium reabsorption is lacking, in that sodiumtransport has not been measured in any nephron seg-ment, studies suggest that activation of RAS withinthe kidney, independent of the systemic RAS, may in-duce sodium retention and sustained hypertension. (12)Accumulating evidence supports the upregulated so-dium reabsorption in the distal tubule involvement inthe pathogenesis of prenatally programmed hyperten-sion. (13)

These findings in animals support the hypothesis ini-tially put forward by Brenner et al. (9) that a congenitaldeficit in nephron number, resulting in a decreased fil-tration surface area and thus a limitation in renal sodiumexcretion, may contribute to susceptibility to essentialhypertension.

Human StudiesConsistent with animal data, many human studies haverevealed an inverse association between low birthweightand higher blood pressure from infancy onwards.

The Kidney and Blood PressureThe kidney is central to the regulation of blood pressure,an association evident since the 1930s. Guyton et al. (14)argued the primacy of the kidney in the long-term deter-mination of blood pressure by its regulation of intra-vascular fluid volume. Their view of the kidney as theultimate regulator of long-term arterial pressure, therelationship between renal sodium handling, intravascular-fluid-volume homeostasis and hypertension, implicatedin the pathogenesis and maintenance of hypertension,(14,15) has gained widespread support.

In addition, all known genetic mutations associatedwith hypertension are mutations in proteins expressed inthe kidney. (16) Intrinsic renal factors affecting bloodpressure have been demonstrated in renal transplanta-tion: blood pressure in the recipient after transplantationhas been shown to be related to the blood pressure of thedonor or the presence of hypertensive risk factors in thedonor before transplantation rather than to the pre-existence of hypertension in the recipient, ie, hyperten-sion “follows” the kidney. (17) Therefore, a congenitalreduction in renal sodium handling, as a result of con-genital reduction in nephron number, is likely to have animpact on blood pressure.

NephrogenesisThe embryonic human kidney develops in three consec-utive structures: the pronephros, the mesonephros, andthe metanephros. The first definitive (metanephric)nephrons are formed at 8 weeks gestation in the humanfetus and urine production begins then. (18) By 20 weeksgestation, the branching of the ureteric bud is complete,urine production is well established, and about one thirdof the final complement of nephrons are present. (18)Numerous factors have been identified as necessary fornephrogenesis, including the RAS, various growth fac-tors including insulinlike growth factor-I, apoptosis, andadequate nutrient supply. Renal development in the hu-man is complete by 36 weeks of gestation; subsequently,no new nephrons are formed. (18) However, infantsborn before 36 weeks gestation are still undergoingnephrogenesis (19) until they reach the equivalent stageof development; as a result, they are exposed postpartumto medications that affect the kidney during its finalstages of renal development. (20) After the comple-tion of nephrogenesis, the kidney grows in length and

origins of renal disease



volume, largely because of increases in the size of therenal tubule, the renal interstitium, and the glomeruli,(18)(20) rather than new numbers of nephrons. Thefinal complement of nephrons is critically dependent ontwo factors: gestational age and a favorable intrauterineenvironment. (21) Fetal response to stress in utero (eg,hypoxia) involves redistribution of blood flow awayfrom intra-abdominal organs (such as kidney, liver,pancreas) and skeletal muscle, and towards vital organssuch as brain, heart, and adrenal glands. (21)(22) Otherintrauterine stress include protein and vitamin deficien-cies, infections, toxins, drugs such as glucocorticoids,certain antibiotics, nonsteroidal anti-inflammatory drugs,angiotensin-converting enzyme inhibitors, and poten-tially, smoking and alcohol abuse.

Nephron NumbersNephron numbers are estimated through the surrogateof glomerular number, the only quantitative informa-tion coming from autopsy studies of whole kidneys.(21)(23)(24) To approximate nephron endowment inliving individuals, kidney size is used as a surrogatemarker. Kidney weight has been shown to correlate withnephron number in the human, (23) but this associa-tion is not sufficiently strong to allow estimation ofindividual glomerular number; this reduces the useful-ness of kidney size in drawing conclusions from popula-tion studies. (25)

Most recent studies have shown that nephron num-ber, when directly assessed in human kidneys, rangesfrom 200,000 nephrons per kidney to slightly more than2 million per kidney, a 10-fold variation. (23)(24)(26)Variation in human nephron number has been knownfor many years and may be due to different measure-ment techniques (23)(26) as direct glomeruli countingis technically demanding. (23)(25) It is only in the lasttwo decades that nephron number has been linked to riskof developing both kidney disease and hypertension.(20)(21)(22)

The concept that nephron number at birth influencesthe risk of development of essential hypertension in laterlife was first proposed by Brenner and colleagues,(8)(9)(27) known as the “Brenner hypothesis”. Theysuggested that maintenance of elevated blood pressurerequires a renal factor favoring sodium retention, therebypreventing pressure-promoted natriuresis from return-ing blood pressure to normal levels. (8)(9) They hypoth-esized that this renal factor was a restricted capacityfor sodium excretion imposed by a congenital deficit ofnephrons. (8) A reduction in renal mass, and therefore inglomerular filtration surface area, tends to produce a rise

in blood pressure. (27) Sustained exposure of nephronsto higher glomerular perfusion pressure gradually resultsin the development of focal and segmental glomerularsclerosis. (28) This subsequently results in further glo-merular loss, further reduced ability to excrete sodium,and a self-perpetuating cycle of increasing blood pressureand progressive kidney disease. (29)

In attempting to determine whether fetal growthrestriction is associated with a reduction in nephronnumber, Hinchliffe et al. (30) examined nephron num-ber in stillbirths and in infants dying at 1 year of age whowere born with appropriate weight for gestational age(controls) compared with those small for gestational age.In both groups, infants with growth restriction had fewernephrons than controls. In addition, the number ofnephrons in control infants dying at 1 year of age had notincreased compared with stillbirths with growth restric-tion, demonstrating a lack of postnatal compensationin nephron number. Similarly, Manalich et al. (31) ex-amined the kidneys of neonates dying within 2 weeks ofbirth in relation to their birthweights. Significant inversecorrelations were found between glomerular numberand glomerular volume, and birthweight and glomerularvolume, independent of sex and race. (24)(31)

As discussed in the “Developmental Origins of Car-diovascular Disease”, the “Barker Hypothesis” proposedthat adverse events in utero induce compensatory re-sponses in the fetus that, reflecting the plasticity of thisdevelopmental period, persist permanently and thus de-fine an altered phenotype at birth. A schematic overviewlinking the Barker and Brenner hypotheses is shown inFigure 1, suggesting mechanisms by which a reduction inrenal filtration area could lead to glomerular and systemichypertension and subsequent glomerulosclerosis (Brennerhypothesis) and how this could be influenced by intra-uterine growth restriction and impaired renal develop-ment (Barker hypothesis). (32)

Diabetes mellitus is the leading cause of ESRD world-wide. Several authors have examined the relationshipbetween birthweight and diabetic nephropathy andfound an increased susceptibility among patients withlow birthweight. Analogous to the studies of the associ-ation of low birthweight with hypertension and nephronnumber, studies in the human have also revealed similarassociations between low birthweight and subsequentpancreatic insufficiency and diabetes mellitus. This isdiscussed in the “Developmental Origins of Adult Dis-ease: Part 3: Metabolic Disease” article in this issue ofNeoReviews.




Perinatal ProgrammingAs discussed in the “Developmental Origins of AdultDisease: Part 1: Cardiovascular Disease” article, the con-cept that intrauterine and perinatal events can influenceorgan function later in life is termed “perinatal program-ming”. The “developmental origins” concept implies aresponse to adversity during development, and responsesrarely have a single facet. Considering both maternal andfetal responses to adverse conditions and the resultingadaptive response can be complex.

Prenatal programming is important to the kidney.Figure 2 illustrates the integration of impaired nephro-genesis, leading to low nephron endowment associatedwith glomerular and systemic hypertension according toBrenner’s hyperfiltration hypothesis. This may be partlyresponsible for the association between low birthweightand hypertension. (25)

Maternal Undernutrition/Protein IntakeHinchliffe et al. (30) proposed a potential pathogeneticmechanism for the linkage between low birthweightand hypertension in adulthood: the undernourished,growth-restricted fetus becomes a low-birthweight new-born whose kidneys have a reduced number of nephrons.In rats fed a low-protein diet, Vehaskari et al. (4) docu-mented a correlation between reduced birthweight, de-creased formation of nephrons, and adult hypertension.In animal studies, experimental maternal undernutritionor placental insufficiency have now been reproduciblyassociated with reduced nephron number (4)(5)(7)(33)and typically with hypertension. In both human (30)

and experimental intrauterine growth restriction, nephronnumber is commonly reduced by �25% to 30%,(4)(5)(34) suggesting that a finite fraction of totalnephrons are subject to nutritional modulation. (22)

The precise physiologic mechanisms by which mater-nal undernutrition and protein restriction duringpregnancy lead to hypertension in the offspring remaincontroversial. Woods et al. (5)(34) hypothesized thatmaternal protein restriction causes suppression of thefetal/newborn intrarenal RAS, and thus impaired renaldevelopment, leading to permanent alterations in kidneystructure and function, including reduced number ofnephrons, resulting in hypertension.

The “Thrifty” HypothesisApplying the “thrifty” hypothesis with the notion offewer beta-cells hyperfunctioning to meet increased in-sulin demands when faced with overnutrition leading tobeta-cell dropout and eventual failure of insulin produc-tion, Mackenzie and Brenner (8) suggested the resem-blance to the proposed cycle of nephron hyperfunctionand obsolescence linking dietary factors with the pro-gressive nature of renal disease.

They proposed that in times of famine, reducingovercapacity both of nephrons and pancreatic islet cellswould represent an integrated metabolic adjustment fa-voring ready availability of energy sources to meet met-abolic needs on the one hand, and the achievement ofelectrolyte conservation at minimal renal energy expen-diture, by reducing redundancy, on the other. (8)

Figure 1. Schematic overview linking two hypotheses: theBarker/Brenner hypotheses. Reproduced from Amann K, PlankC, Dotsch J. Low nephron number: a new cardiovascular riskfactor in children? Pediatr Nephrol. 2004;19:1319–1323,(32) with permission from Springer Publishing Company.

Figure 2. Integration of renal programming (“Barker” hypoth-esis) with hyperfiltration hypothesis (Brenner). Reproducedfrom Schreuder MF, Nauta J. Prenatal programming ofnephron number and blood pressure. Kidney Internat. 2007;72:265–268, (25) with permission from Nature PublishingGroup.




Conversely, in times of plenty, appropriate program-ming would endow the kidney with greater reserves ofnephrons to meet greater excretory demands and thepancreas with a greater capacity to secrete insulin,thereby shifting metabolism towards synthesis, growth,and energy storage. (8)

The major disadvantage of such a homeostatic strat-egy is the ease by which it could be rendered maladaptiveby extreme changes in the availability of food. Undersuch circumstances, in times of “plenty”, the program-ming of fewer pancreatic beta-cells or fewer nephrons isrendered inappropriate, and glomerular hyperfiltration,hyperinsulinemia, hypertension, diabetes, hyperlipid-emia, and glomerulosclerosis could all follow. (8)

The Renin-Angiotensin SystemAlthough mechanisms to explain the association betweenlow birthweight with hypertension and renal functionare still unclear, one possible pathway is the RAS. (35)A number of other specific hormonal systems—endothelin, natriuretic peptides, neuropeptide Y, andnitric oxide—also influence blood pressure regulationand renal function. (36) Furthermore, medications ormanipulations that interrupt the RAS are highly effectivein controlling hypertension. (36) Models of primaryhypertension, such as the spontaneously hypertensive rat,display differences in RAS expression in adult life whencompared with normotensive controls. (37)

Animals transgenic for RAS genes may develop hyper-tension, suggesting that this system is critical in theetiology of hypertension. (38) Animals lacking RASgenes, the “knockout” animals, develop markedly abnor-mal kidneys. (39) Exogenous alteration in the RAS canalter renal development. The administration of drugsthat interfere with the RAS during gestation, eg, angio-tensin converting enzyme inhibitors, cause fetopathy inboth humans and experimental animals. (40) Angioten-sin receptor blockade with an AT1 receptor antagonist,losartan, during the first 12 days of postnatal life in the ratresults in a reduced number of nephrons and hyperten-sion in adulthood. (41)

It has been shown that angiotensin II, known as agrowth factor, is important for normal nephrogenesis.(42) As renal angiotensin II levels in offspring of mothersfed protein-restricted diets in pregnancy appear to besuppressed in the perinatal period, (5) Ingelfinger et al.(36) proposed that interfering with the production ofangiotensin II or blocking its effects on receptors canlead to changes in the usual pattern of renal develop-ment.

Langley-Evans et al. (33) examined circulating renin

levels in offspring of protein-deplete mothers and ob-served decreased plasma renin activity. This was sup-ported by Vehaskari et al. (4)(11) Although individualstudies display some differences in the degree of proteinrestriction and the timing of the measurement of RASactivity, the common findings suggest that maternal di-etary protein restriction leads to suppression of the peri-natal RAS, with subsequent impairment of nephrogen-esis, leading to reduced complement of nephrons, andpredisposing the offspring to adult hypertension. (36)

Such observations have also led some authors to sug-gest that additional substances or factors that suppressthe RAS during nephrogenesis (such as high salt intakein pregnancy) may carry long-term implications forcardio-renal health. (36) Ingelfinger et al. (43) foundthat increasing salt intake in pregnant rats leads to in-trarenal changes in the offspring similar to those seen inpups from protein-restricted maternal rats, and results inhypertension and renal dysfunction.

Steroid MetabolismMaternal protein restriction reduces the activity of pla-cental 11beta-hydroxysteriod dehydrogenase (11�HSD),an enzyme that normally inactivates maternal cortisolor corticosterone. This reduced activity results in higherthan normal exposure of the fetus to maternal glucocor-ticoids. (44) This concurs with Barker et al. (45) thatsmall neonates with large placentas were at highest riskfor cardiovascular disease later in life. Furthermore, pla-cental 11�HSD activity has been reported to be relativelylow in humans with these features. (46) The possibilitythat the placental isoform of 11�HSD is down-regulatedunder conditions of low protein diet would lead toincreased maternal glucocorticoid exposure in the fetus,and therefore affect growth. (36)

Pregnant rats given the synthetic glucocorticoid dexa-methasone, which crosses the placenta and is not metab-olized by 11�HSD, have offspring with low birthweightand adult hypertension. (3) Other studies have adminis-tered carbenoxolone, an inhibitor of 11�HSD to preg-nant rats and produced similar results in the offspring.(47) However, the authors of one study using lowercarbenoxolone doses did not observe significant differ-ences in blood pressure. (48)

Low-sodium diet, given to pregnant rats over the lastweek of gestation induces failure to thrive in the fetus, aswell as postnatal hypertension and renal insufficiency inthe offspring. (32) Another important factor in the gen-esis of hypertension after intrauterine growth restrictionmay be related to an increase in the gene expression ofvarious tubular sodium channels, possibly indicating a




higher reabsorption ratio for sodium chloride (at least inrats). (49)

An important system in the regulation of mineralo-corticoid activity is the renal cortisol/cortisone shuttle.(32) The enzyme 11�HSD type 2 (11�HSD 2) regulatesthe inactivation of mineralocorticoid active cortisol toinactive cortisone (Fig. 3). Newborn and adult rats thatsuffered from intrauterine growth restriction have anincreased renal expression of the mineralocorticoid re-ceptor and a significant reduction of the 11�HSD geneexpression. (50) There is an increase in the cortisol/cortisone shuttle in about 20% of children with intrauter-ine growth restriction, implying a decreased activity of11�HSD 2. (51)

Taken on balance, the data suggest that heightenedfetal exposure to maternal glucocorticoids may hamper fetalrenal growth and lead to hypertension later in life. (36)

SummaryNephrogenesis is a complex process that requires a finebalance of many factors. Intrauterine growth restrictionleading to low birthweight disturbs this balance leading

to a low nephron endowment. Activation of the RAS,inhibition of insulinlike growth factor-I or nitric oxide,raised tubular sodium reabsorption, steroid metabolism,and nutrient deficiency are all mechanisms associatedwith low glomerular number—disturbances in thesemechanisms may explain long-term consequences onblood pressure and renal function. Compensatory glo-merular hyperfiltration may aggravate kidney disease,resulting in systemic hypertension and renal damage andfailure. Further studies are required to clarify the possiblerole for these interactions in perinatal programming.

References1. National Kidney Foundation. K/DOQI Clinical practice guide-lines for chronic kidney disease: evaluation, classification, and strat-ification. Am J Kidney Dis. 2002;39(2 Suppl 1):S1–S2662. El Nahas AM, Bello AK. Chronic kidney disease: the globalchallenge. Lancet. 2005;365(9456):331–3403. Celsi G, Kistner A, Aizman R, et al. Prenatal dexamethasonecauses oligonephronia, sodium retention, and higher blood pres-sure in the offspring. Pediatr Res. 1998;44:317–3224. Vehaskari VM, Aviles DH, Manning J. Prenatal programming ofadult hypertension in the rat. Kidney Internat. 2001;59:238–2455. Woods LL, Ingelfinger JR, Nyengaard JR, Rasch R. Maternalprotein restriction suppresses the newborn renin-angiotensin sys-tem and programs adult hypertension in rats. Pediatr Res. 2001;49:460–4676. Langley-Evans SC, Phillips GJ, Jackson AA. In utero exposureto maternal low protein diets induces hypertension in weaning rats,independently of maternal blood pressure changes. Clin Nutr.1994;13:319–3247. Merlet-Benichou C, Gilbert T, Muffat-Joly M, et al. Intrauter-ine growth retardation leads to a permanent nephron deficit in therat. Pediatr Nephrol. 1994;8:175–1808. Mackenzie HS, Brenner BM. Fewer nephrons at birth: a missinglink in the etiology of essential hypertension? Am J Kidney Dis.1995;26:91–989. Brenner BM, Garcia DL, Anderson S. Glomeruli and bloodpressure. Less of one, more the other? Am J Hypertens. 1988;1:335–34710. Woods LL. Neonatal uninephrectomy causes hypertension inadult rats. Am J Physiol. 1999;276(4 Pt 2):R974–R97811. Vehaskari VM, Stewart T, Lafont D, et al. Kidney angiotensinand angiotensin receptor expression in prenatally programmedhypertension. Am J Physiol Renal Physiol. 2004;287(2):F262–F26712. Vehaskari VM, Woods LL. Prenatal programming of hyperten-

Figure 3. Overview of the potential patho-mechanisms pre-disposing to the development of arterial hypertension afterintrauterine growth restriction. Reproduced from Amann K,Plank C, Dotsch J. Low nephron number: a new cardiovascularrisk factor in children? Pediatr Nephrol. 2004;19:1319–1323,(32) with permission from Springer Publishing Company.







sion: lessons from experimental models. J Am Soc Nephrol. 2005;16:2545–255613. Vehaskari VM. Developmental origins of adult hypertension:new insights into the role of the kidney. Pediatr Nephrol. 2007;22:490–49514. Guyton AC, Coleman TG, Cowley AV, Jr. et al. Arterialpressure regulation: overriding dominance of the kidneys in long-term regulation and in hypertension. Am J Med. 1972;52:584–59415. Guyton AC, Coleman TG, Young DB, et al. Salt balance andlong-term blood pressure control. Annu Rev Med. 1980;31:15–2716. Lifton RP, Wilson FH, Choate KA, Geller DS. Salt and bloodpressure: new insight from human genetic studies. Cold SpringHarb Symp Quant Biol. 2002;67:445–45017. Curtis JJ, Luke RG, Dustan HP, et al. Remission of essentialhypertension after renal transplantation. N Engl J Med. 1983;309:1009–101518. Haycock GB. Development of glomerular filtration and tubu-lar sodium reabsorption in the human fetus and newborn. Br J Urol.1998;81(Suppl 2):33–3819. Rodriguez MM, Gomez AH, Abitbol CL et al. Histomorpho-metric analysis of postnatal glomerulogenesis in extremely preterminfants. Pediatr Dev Pathol. 2004;7:17–2520. Ingelfinger JR. Disparities in renal endowment: causes andconsequences. Adv Chronic Kidney Dis. 2008;15:107–11421. Hoy WE, Hughson MD, Bertram JF, et al. Nephron number,hypertension, renal disease, and renal failure. J Am Soc Nephrol.2005;16:2557–256422. Bagby SP. Maternal nutrition, low nephron number, andhypertension in later life: pathways of nutritional programming.J Nutr. 2007;137:1066–107223. Nyengaard JR, Bendtsen TF. Glomerular number and size inrelation to age, kidney weight, and body surface in normal man.Anat Rec. 1992;232:194–20124. Hughson M, Farris AB, 3rd, Douglas-Denton R, et al. Glo-merular number and size in autopsy kidneys: the relationship tobirth weight. Kidney Internat. 2003;63:2113–212225. Schreuder MF, Nauta J. Prenatal programming of nephronnumber and blood pressure. Kidney Internat. 2007;72:265–26826. Merlet-Benichou C, Gilbert T, Vilar J, et al. Nephron number:variability is the rule: causes and consequences. Laboratory Investi-gation. 1999;79:515–52727. Brenner BM, Chertow GM. Congenital oligonephropathy andthe etiology of adult hypertension and progressive renal injury.Am J Kidney Dis. 1994;23:171–17528. Brenner BM, Goldszer RC, Hostetter TH. Glomerular re-sponse to renal injury. Contrib Nephrol. 1982;33:48–6629. Brenner BM, Mackenzie HS. Nephron mass as a risk factorfor progression of renal disease. Kidney Internat Suppl. 1997;63:S124–S12730. Hinchliffe SA, Lynch MRJ, Sargent PH, et al. The effect ofintrauterine growth retardation on the development of renalnephrons. Br J Obstet Gynaecol. 1992;99:296–30131. Manalich R, Reyes L, Herrera M, et al. Relationship betweenweight at birth and the number and size of renal glomeruli in humans:a histomorphometric study. Kidney Internat. 2000;58:770–77332. Amann K, Plank C, Dotsch J. Low nephron number: a newcardiovascular risk factor in children? Pediatr Nephrol. 2004;19:1319–132333. Langley-Evans SC, Welham SJ, Jackson AA. Fetal exposure to

a maternal low protein diet impairs nephrogenesis and promoteshypertension in the rat. Life Sci. 1999;64:965–97434. Woods LL, Weeks DA, Rasch R. Programming of adult bloodpressure by maternal protein restriction: role of nephrogenesis.Kidney Internat. 2004;65:1339–134835. Woods LL. Fetal origins of adult hypertension: a renal mech-anism? Current Opinion Nephrol Hypertens. 2000;9:419–42536. Ingelfinger JR, Woods LL. Perinatal programming, renal de-velopment, and adult renal function. Am J Hypertens. 2002;15(2 Pt2):46S–49S37. Pratt RE, Zou WM, Naftilan AJ, et al. Altered sodium regula-tion of renal angiotensinogen mRNA in the spontaneously hyper-tensive rat. Am J Physiol. 1989;256(3 Pt 2):F469–F47438. Mullins JJ, Peters J, Ganten D. Fulminant hypertension intransgenic rats harbouring the mouse Ren-2 gene. Nature. 1990;344(6266):541–54439. Nishimura H, Yerkes E, Hohenfellner K, et al. Role of theangiotensin type 2 receptor gene in congenital anomalies of thekidney and urinary tract, CAKUT, of mice and men. Molecular Cell.1999;3:1–1040. Sedman AB, Kershaw DB, Bunchman TE. Recognition andmanagement of angiotensin converting enzyme inhibitor fetopa-thy. Pediatr Nephrol. 1995;9:382–38541. Woods LL, Rasch R. Perinatal ANG II programs adult bloodpressure, glomerular number, and renal function in rats. Am JPhysiol. 1998;275(5 Pt 2):R1593–R159942. Tufro-McReddie A, Romano LM, Harris JM, et al. Angioten-sin II regulates nephrogenesis and renal vascular development.Am J Physiol. 1995;269(1 Pt 2):F110–F11543. Ingelfinger J, Haveran L, Hsu C-Y, Woods LL. Maternal lowprotein or high salt diet in the perinatal period suppresses newbornintrarenal renin-angiotensin system (RAS) and programs for hyper-tension in adult offspring. Pediatr Res. 1998;43:309A44. Seckl JR, Benediktsson R, Lindsay RS, Brown RW. Placental11 beta-hydroxysteroid dehydrogenase and the programming ofhypertension. J Steroid Biochem Mole Biol. 1995;55:447–45545. Barker DJ, Osmond C, Golding J, et al. Growth in utero,blood pressure in childhood and adult life, and mortality fromcardiovascular disease. BMJ. 1989;298(6673):564–56746. Benediktsson R, Lindsay RS, Noble J, et al. Glucocorticoidexposure in utero: new model for adult hypertension. Lancet.1993;341(8841):339–34147. Langley-Evans SC. Maternal carbenoxolone treatment lowersbirthweight and induces hypertension in the offspring of rats fed aprotein-replete diet. Clin Sci. 1997;93:423–42948. Gomez-Sanchez EP, Gomez-Sanchez CE. Maternal hyperten-sion and progeny blood pressure: role of aldosterone and 11beta-HSD. Hypertension. 1999;33:1369–137349. Manning J, Beutler K, Knepper MA, Vehaskari VM. Upregu-lation of renal BSC1 and TSC in prenatally programmed hyperten-sion. Am J Physiol Renal Physiol. 2002;283:F202–F20650. Bertram C, Trowern AR, Copin N, et al. The maternal dietduring pregnancy programs altered expression of the glucocorti-coid receptor and type 2 11beta-hydroxysteroid dehydrogenase:potential molecular mechanisms underlying the programming ofhypertension in utero. Endocrinology. 2001;142:2841–285351. Houang M, Morineau G, le Bouc Y, et al. The cortisol-cortisone shuttle in children born with intrauterine growth retarda-tion. Pediatr Res. 1999;46:189–193




NeoReviews Quiz

5. Chronic kidney disease is defined as structural kidney damage lasting three months or more or functionalreduction in glomerular filtration rate (GFR) lasting three months or more with or without kidney damage.Of the following, the GFR threshold for the definition of chronic kidney disease is closest to:

A. 15 mL/min per 1.73 m2.B. 30 mL/min per 1.73 m2.C. 45 mL/min per 1.73 m2.D. 60 mL/min pre 1.73 m2.E. 75 mL/min per 1.73 m2.

6. Chronic renal failure is characterized by a marked reduction in glomerular filtration rate (GFR) or a need forrenal replacement therapy to treat complications of decreased GFR, which otherwise would result inmortality or morbidity. Of the following, the GFR threshold for the definition of chronic renal failure isclosest to:

A. 15 mL/min per 1.73 m2.B. 30 mL/min per 1.73 m2.C. 45 mL/min per 1.73 m2.D. 60 mL/min pre 1.73 m2.E. 75 mL/min per 1.73 m2.

7. Multiple animal models have shown an association between low birthweight, induced by maternalmanipulation, and subsequent development of hypertension. The link between low birthweight and adulthypertension in these animal models is attributed in part to an associated congenital deficit in nephronnumber. Of the following, the most common effective maternal manipulation that leads to low birthweightand subsequent development of early and persistent hypertension in the offspring is:

A. Dexamethasone treatment.B. Gentamicin treatment.C. Low protein diet.D. Uterine ischemia.E. Vitamin A deficiency.

8. The embryonic human kidney develops in three consecutive structures: pronephros, mesonephros, andmetanephros. The first definitive metanephric nephrons are formed by 8 weeks’ gestation in the humanfetus; the nephrons increase in number to their final complement thereafter. The gestational age in thehuman at which nephrogenesis is complete with the development of a full complement of nephrons is:

A. 20 weeks.B. 28 weeks.C. 36 weeks.D. 44 weeks.E. 52 weeks.

9. The rennin-angiotensin system (RAS) is an important pathway for blood pressure regulation and renaldevelopment. The component in the RAS pathway that is necessary for normal nephrogenesis is:

A. Aldosterone.B. Angiotensin 1.C. Angiotensin 2.D. Angiotensinogen.E. Renin.





Patricia Y. L. Chan, Jonathan M. Morris and Eileen D. M. Gallery Developmental Origins of Adult Disease: Part 2: Renal Disease













Patricia Y. L. Chan, Jonathan M. Morris and Eileen D. M. Gallery Developmental Origins of Adult Disease: Part 3: Metabolic Disease







Developmental Origins of Adult Disease:Part 3: Metabolic DiseasePatricia Y. L. Chan,

MBBS(Syd U),




ChB, MM, PhD,



MD(Syd), FRACP§

Author Disclosure



no financial



commentary does not


of an unapproved/


commercial

product/device.

AbstractThis third of three articles reviews the developmental origins of metabolic disease andthe proposed underlying mechanisms.


1. Understand the concept of developmental origins applied to metabolic disease.2. Describe the proposed underlying mechanisms of developmental origins applied to

metabolic disease such as thrifty hypothesis, programming, developmental plasticity,epigenetic mechanisms, and predictive adaptive response.

3. Understand the challenge of the global obesity epidemic for future research.

IntroductionThe obesity epidemic is a global problem rapidly increasing in the past few decades. (1) TheWorld Health Organization projects that by 2015, approximately 2.3 billion adults willbe overweight with body mass index (BMI) �25 kg/m2 and more than 700 million will beobese with BMI �30 kg/m2. (2)

Obesity plays a central role in insulin resistance and the metabolic syndrome. Alsoknown as syndrome X, the insulin resistance syndrome, and the deadly quartet, thiscommon set of metabolic disorders results from the increasing prevalence of obesity—theconstellation includes several cardio-metabolic risk factors including abdominal obesity,hyperglycemia, dyslipidemia, and elevated blood pressure, all linked to insulin resistance.(3)

There is an urgent need for strategies to prevent this emerging global epidemic, whoseelevated risk is not only of diabetes but also of cardiovascular disease. (3) It is evident thatthe metabolic syndrome represents a massive public health problem.

Developmental Origins of Type 2 Diabetes and the Metabolic SyndromeAlthough there is general agreement that obesity is important for the development of type2 diabetes and the metabolic syndrome, it is also clear that this occurs only in susceptibleindividuals, generally ascribed to the interaction of genetic and environmental conditions(such as changes in nutrition and lack of physical activity, as societies move towardsincreasing affluence). Among monozygotic twins, the twin with diabetes was found tohave a lower birthweight than the genetically identical twin without diabetes. (4) It has alsobeen shown that body size tracks from birth through late adolescence, into adulthood. (5)There is therefore growing evidence that conditions in utero “program” an increase in thesubsequent risk for obesity, type 2 diabetes, and the metabolic syndrome.

Birthweight and Type 2 DiabetesBoth animal and human studies have demonstrated an association between low birth-weight and subsequent pancreatic insufficiency and type 2 diabetes. (6) Epidemiologic andclinical evidence indicate a role for prenatal factors in the origin of the metabolic syndrome


Article origins of metabolic disease



and its components: hypertension, insulin resistance,central obesity, and dyslipidemia. (7)(8)

In a systematic review of 48 studies, most reported aninverse relationship between birthweight and measuresof reduced glucose tolerance and insulin resistance, notexplained by differences among studies in the sex, age, orcurrent size of subjects. (9) The relationship betweenbirthweight and insulin secretion was, however, incon-sistent, (9) and this review was criticized as being essen-tially qualitative providing no information on the shape,strength, or independence of the birthweight–diabetesassociation. (10)

A more recent meta-analysis of 14 studies of birth-weight and subsequent risk of type 2 diabetes by Harderet al. (11) demonstrated a U-shaped rather than a linearinverse association, with both low and high birthweightssubstantially increasing the risk of developing type 2diabetes later in life. This U-shaped relationship was alsoshown among Pima Indians, where diabetes in preg-nancy is unusually common (12)—the prevalence wasgreatest in those with birthweights in the lowest (30%with �2.5 kg) and highest (32% in �4.5 kg) range. (13)When adjusted for age, sex, BMI, maternal diabetesduring pregnancy, and birth year, those with birth-weights �2.5 kg had a higher rate than those withbirthweights 2.5 to 4.49 kg (odds ratio 3.8). (13) Therisk for subsequent diabetes among higher birthweightinfants (birthweights �4.5 kg) was associated with ma-ternal diabetes during pregnancy. (13)

Most recently, Whincup et al (10) conducted a quan-titative systematic review examining 31 articles with un-duplicated information (out of 327 identified articlespublished by June 2008) on the association of birth-weight and type 2 diabetes in adults. Their analyses wereconsistent with those of Harder et al (11) in suggestingthat low birthweights (�2.5 kg) are associated withincreased type 2 diabetes risk. (10) They emphasizedfurther that the inverse pattern of association betweenbirthweight and type 2 diabetes is the dominant one inmost populations and extends at least to 3 kg, although amodest positive birthweight–type 2 diabetes associationat higher birthweights (�4 kg) cannot be excluded. (10)This is biologically plausible given the recognized asso-ciation of both prepregnancy type 2 diabetes and gesta-tional diabetes to macrosomia. (13)

Birthweight, Insulin Resistance, and theMetabolic Syndrome

The development of insulin resistance has a major role intype 2 diabetes and the metabolic syndrome. Disruptionin insulin binding and postbinding effects have been

reported in offspring in association with peri-conceptualmaternal undernutrition, and this may also result inimpaired insulin activity. (14) Saturated fat consumptionin rats results in insulin resistance and impaired glucosetransporter function. (15)

Men and women with low birthweight have a higherprevalence of the “insulin resistance syndrome” or the“metabolic syndrome.” (8) Barker et al(8) in their studyof 407 men in Hertfordshire, UK, with a mean age of64 years, found that 22% of men with birthweights�2.95 kg had syndrome X. Their risk of developingsyndrome X was over 10 times greater than men withbirthweights �4.31 kg.

Phillips et al (16) performed insulin tolerance tests on103 men and women in Preston, UK, following 12 hoursovernight fast. At each current BMI, insulin resistancewas increased in people who had a low ponderal index atbirth. At each ponderal index, insulin resistance wasgreater in those with high current body mass. (16) Thegreatest insulin resistance was therefore found in thosewho were thin at birth but obese as adults. (16) Beingthin at birth and being thin as an adult had opposingeffects on insulin resistance. (16)

A study in San Antonio, Texas, extended the associa-tion between low birthweight and the insulin resistancesyndrome to a biethnic population. (17) The studyincluded 564 Mexican Americans and non-Hispanicwhite men and women with mean age of 32 years.Among men and women in the lowest tertile (third ofthe population) of birthweight (mean �2.78 kg) andhighest tertile of current BMI (mean 34.3 kg/m2), 25%had the metabolic syndrome. (17) By contrast, none inthe highest tertile of birthweight (mean �3.85 kg) orlowest tertile of current BMI (mean 21.8 kg/m2) mani-fested the syndrome. (17)

A French study of 517 men and women with meanage of 21 years, in the metropolitan area of Haguenau,revealed that those who were �3rd percentile of localstandard values at birth had significantly higher insulinand proinsulin concentrations compared with those withnormal weight, after adjusting for sex and current BMI.(18)

Recent studies demonstrate that the growth-restricted fetus is insulin-sensitive at birth and developsinsulin resistance well after birth. (19) While reducedfetal growth remain an independent risk factor for insulinresistance later in life, insulin resistance is sharply ampli-fied by obesity in childhood or adulthood or familyhistory of type 2 diabetes. (20)

origins of metabolic disease



Proposed Mechanisms for DevelopmentalOrigins of Metabolic DiseaseStudies in animals have facilitated the elucidation of theunderlying mechanisms involved in fetal growth restric-tion’s induction of components of the metabolic syn-drome. Manipulation of maternal dietary intake andcomposition, induction of anemia in the mother, restric-tion of placental growth by uterine artery ligation, andembolization of the placental circulation or prepreg-nancy reduction in the number of placental attachmentsites have all been used in various animals including rats,mice, rabbits, guinea pigs, pigs, sheep, and primates.

The “Thrifty” HypothesisTHE “THRIFTY GENOTYPE” HYPOTHESIS As discussed

in the “Developmental Origins of Adult Disease: Part 1:Cardiovascular Disease” article, the thrifty genotypewould trigger a level of insulin resistance that allowed apopulation to cope in times of nutritional stress but intimes of plenty and in a modern nutritionally rich envi-ronment would lead to the development of obesity andtype 2 diabetes.

Although it is acknowledged that genetic polymor-phisms play a role in determining the strength of devel-opmental gene–environment interactions, it is difficultto reconcile a purely genetic explanation from a briefepisode such as the Dutch famine or with the widespreadevidence of such relationships between early environ-ment and long-term outcomes in different populationssuch as European, and Asian, Indian subcontinent.There has also been criticism of the controversial natureof data supporting the notion that obese individuals havelower metabolic rates than nonobese individuals. (21)Critics have also pointed out that the processes of muta-tion, genetic drift, and selection may have created geno-types that were thrifty. (22) Genome-wide scans havefailed to identify any common diabetes susceptibilitygenes. Furthermore, the ease with which “program-ming” can be induced experimentally in a variety oforgan systems and across species suggests that the basicunderlying mechanisms are not purely genetic. (23) Fi-nally, the thrifty genotype hypothesis does not ade-quately explain the rapid changes in obesity and type 2diabetes incidence in modern societies. (24)

THE “THRIFTY PHENOTYPE” HYPOTHESIS As discussedin the “Developmental Origins of Cardiovascular Dis-ease,” Hales and Barker (25) proposed a model focusedon environmental factors. Under conditions of intrauter-ine deprivation that exceed a threshold beyond usualcompensatory mechanisms, the fetus adopts several strat-

egies to maximize its chances of survival in utero andpostnatally. The immediate response is the reduction ofsomatic growth to selectively distribute nutrients to thebrain and heart, at the expense of other organs such asthe liver, pancreas, and muscle. The poor development ofpancreatic beta-cell mass and function (including islet ofLangerhans vasculature and possibly innervation) wereproposed to be key elements leading to type 2 diabetes.The undernourished fetus also develops insulin resis-tance, abnormalities of insulin secretion or action, andother metabolic changes for immediate survival to down-regulate and prioritize growth. This adaptive responseleads to an altered postnatal metabolism, designed toenhance postnatal survival under conditions of intermit-tent or poor nutrition. It was proposed that these adap-tations only become detrimental when nutrition is moreabundant in the postnatal environment compared withthe prenatal environment.

Although the “thrifty phenotype” model can readilyexplain the long-term consequences of extreme intra-uterine growth restriction, it is less clear how (or why) areduction in birth size from the 80th percentile to the60th would be associated with an increased disease risk.It could not explain how a very transient fetal exposureto a stimulus could lead to long-term consequences,the graded manner of disease risk across the normalbirthweight range seen in the epidemiologic data, norhow early life events can induce long-term physiologicchanges without changes in birth size. (26)

ProgrammingThis was also discussed in the “Developmental Origins ofCardiovascular Disease” article. With regards to the met-abolic axis, programming can occur in early life modu-lated by the intrauterine environment. (27) For type 2diabetes this may result from an altered development andinsulin-secreting capacity of the endocrine pancreas, orby altered insulin sensitivity of target tissues. It is possiblethat perturbations of prenatal growth may lead to inap-propriate beta-cell ontogeny and result in a population ofbeta cells qualitatively ill-suited to subsequent manage-ment of metabolic stress. (27) A reduced availability ofinsulin prenatally is a major contributor to intrauterinegrowth restriction. This is demonstrated by the severegrowth restriction of human infants with pancreaticagenesis. (28) Insulin deficiency may result from eithergenetic mutations in transcription factors active duringbeta-cell formation or from altered expression of tran-scription factors and peptide growth factors due to envi-ronmental influences in utero. (27) Intrauterine growthrestriction in human results in a reduced population of




pancreatic beta cells at birth. (29) Abnormal program-ming of the fetal pancreas could be a major risk factor foradult diabetes. (27)

The term “programming,” however, has differentmeanings in other areas of biology. It implies a determin-istic process and set of mechanisms akin to a genetic“program” of development and the use of the word mayinfluence the mindset of investigators. (30) It is nolonger recommended in description of the developmen-tal origins of adult disease and replaced by the term“developmental plasticity.”

Developmental PlasticityDevelopmental plasticity encompasses those processesthat generate alternative phenotypes from a single geno-type through the actions of environmental cues actingduring development. (30) They allow environmentalinfluences to “tune the match” of the organism to itsexpected environment beyond that achieved throughnatural selection, ie, inherited genotype. (30)

The concept of developmental plasticity and exposureto environmental challenges, with epigenetic processesplaying a role in determining the phenotype of theoffspring to match its environment, is discussed inthe “Developmental Origins of Adult Disease: Part 1:Cardiovascular Disease” article.

Plasticity exists in the fetal and neonatal pancreasfollowing changes in the beta-cell number through bothbeta-cell replication and neogenesis but later becomesrestricted. (27) Consequently, any deficiency in beta-cellmass occurring in utero as a result of either geneticmutations with transcription factors, or maternal malnu-trition or placental dysfunction leading to inappropriateexpression of transcription or growth factors, will havelimited opportunity for correction postnatally. (27)

EpigeneticsAs discussed in “Developmental Origins of Cardiovascu-lar Disease,” epigenetic mechanisms provide the molec-ular basis to the processes of developmental plasticity.

An article proposing DNA methylation profiling indiabetes reviewed indirect evidence that epigenetic dys-regulation contributes to type 2 diabetes. (31) The mostdirect evidence implicating epigenetic dysregulation inhuman diabetes is from studies of transient neonataldiabetes, (32) a rare form of diabetes that presents withinthe first few days after birth and although resolvingwithin 1 year, often recurs later in life. These studiesshow that infants with sporadic transient neonatal diabe-tes have aberrant methylation of several imprinted genesin peripheral blood leukocytes. (32)

Epigenetic change may be a major mechanism under-lying programming, with implications for subsequentgenerations. Effects of parental and grandparental nutri-tion on diabetes risk in humans have been reported,suggesting trans-generational inheritance of epigeneticalterations that affect diabetes susceptibility. (33) In theDutch winter famine, women who were exposed tofamine while in the womb later had grandchildren whowere born with reduced birth size. (34) There remains apossibility that trans-generational epigenetic change mayplay a role in clustering or family linkage effects fordisease such as type 2 diabetes. (35)

Predictive Adaptive ResponsesIt is conventional in clinical medicine to think of re-sponses to the environment as being of immediate ad-vantage, ie, homeostatic (to maintain internal equilib-rium by adjusting physiologic processes) if the challengeis short lasting; or homeorhetic (where orchestratedor coordinated control in metabolism of body tissuesis developed as necessary to support a change in physio-logic state), if more prolonged. (36) The programmingparadigm raises the possibility of an additional kind ofenvironmental response, one in which the benefit neednot be immediate but in which the response is made inexpectation of a future environment. (35)

A more general model combining features of theabove concepts was developed by Gluckman and Han-son. (26)(30)(35)(37)(38) In their model, the fetusconstantly interprets the environment created by thematernal milieu and placental function. A predictiveadaptive response may be appropriate or inappropriate.If the prediction is correct, ie, the postnatal environmentis as predicted during prenatal development, the predic-tive adaptive response is appropriate. If the predictionturns out to be incorrect, then the predictive adaptiveresponse is inappropriate. (35) Such a distinction canonly be made retrospectively.

Gluckman et al (19)(26)(35)(38)(39) proposed thatthere are many physiologic systems in which predictiveadaptive responses operate. Any aspect of developmentalplasticity that can be irreversibly affected by the environ-ment can be considered to be a predictive adaptiveresponse if it confers a long-term survival advantagewhen the predicted and actual future environmentsmatch. (35)

The maternal environment is transmitted to the fetusby means of nutritional and endocrine signals. The fetusmakes a set of adaptive responses in expectation of thepostnatal environment that it perceives to be extant onthe basis of these maternal signals, but the perception




may be wrong. (35) At one extreme, the mother maybe in poor health or the placenta dysfunctional, either ofwhich limits nutrient transfer to the fetus, making nutri-tion unbalanced or altering fetal hormonal levels. (35)Such effects occur in preeclampsia and in gestationaldiabetes.

The fetal environment is normally controlled by bothmaternal and placental factors, the basis for maternalconstraints that limit the role of the offspring’s genomeon growth before birth. (40) Thus both maternal con-straints and patho-physiologic processes can initiateadaptive responses by the fetus. (41) Postnatally, therewill be minimal consequences if the environmentmatches the prediction, but if there is severe disease orconstraint or if the postnatal environment changes rap-idly by, for example, migration to a nutritionally richhabitat, the predictive response will turn out to be inap-propriate. (35)

The role of maternal constraint is evident by therelationship between maternal and infant birthweights,whereas the relationship with paternal birthweight isweak. (42) Stettler et al (43) and Morton (44) showedthat first-born children have a greater risk of developingobesity than their subsequent siblings, demonstratingthe influence of parity as an aspect of the constraint thatinduces predictive adaptive responses.

From this model, it is evident that the greater theadversity of the fetal environment or the degree of con-straint, the greater the risk of a mismatch between theprenatal, constrained environment and the postnatal,energy-rich environment. (35) This is exemplified inreference to a Southern Indian population versus a Eu-ropean population. (45) In rural India, women are smallbecause of generations of relative nutritional deprivation,giving birth to small infants as a result of maternalconstraints. Although small at birth, these infants havetruncal obesity, an adaptation that gives them energyreserves for early independent life, and relatively lessskeletal muscle, which limits glucose consumption. (45)Although maternal size constraints still operate, the post-natal energy environment has improved rapidly in partsof India, especially for those who have migrated tothe cities, making the predictive adaptive responses inap-propriate, giving rise to the rapidly increasing incidenceand current epidemic of type 2 diabetes and obesity.(35)(45) Similar observations are reported with respectto the prevalence of diabetes in migrants as migrationusually entails a rapid shift to a richer nutritional environ-ment. (46)

The predictive adaptive responses model is not with-out debate and criticism. (47)(48)(49)(50) The main

point of contention relates to the nature and functionof the cues directing early metabolic plasticity in contrib-uting to later disease in the human. (37)(47)(50)(51)There is, however, agreement that there is “maternalmanipulation of offspring phenotype” in humans, medi-ated by maternal constraint, advantageous to bothmother and infant. (37)

ConclusionThe global epidemic of obesity demands a solution. Thegrowing prevalence of metabolic disease worldwide chal-lenges many disciplines to provide an explanation for themultiple causal and underlying mechanisms to define thebest ways to intervene.

References1. Sturm R. Stemming the global obesity epidemic: what can welearn from data about social and economic trends? Public Health.2008;122:739–7462. World Health Organization. Obesity and overweight. Fact sheetNo. 311. Accessed September 27, 2011 at: www.who.int/mediacentre/factsheets/fs311/en/index.html3. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome.Lancet. 2005;365(9468):1415–14284. Poulsen P, Vaag A. Glucose and insulin metabolism in twins:influence of zygosity and birth weight. Twin Res. 2001;4:350–3555. Serdula MK, Ivery D, Coates RJ, et al. Do obese childrenbecome obese adults? A review of the literature. Prev Med. 1993;22:167–1776. Simmons R. Developmental origins of adult disease. PediatrClin N Am. 2009;56:449–4667. Curhan GC, Willett WC, Rimm EB, et al. Birth weight and adulthypertension, diabetes mellitus, and obesity in US men. Circula-tion. 1996;94:3246–32508. Barker DJP, Hales CN, Fall CHD, et al. Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia(syndrome X): relation to reduced fetal growth. Diabetologia. 1993;36:62–679. Newsome CA, Shiell AW, Fall CH, et al. Is birth weight relatedto later glucose and insulin metabolism? A systematic review. DiabetMed. 2003;20:339–34810. Whincup PH, Kaye SJ, Owen CG, et al. Birth weight andrisk of type 2 diabetes: a systematic review. JAMA. 2008;300:2886–289711. Harder T, Rodekamp E, Schellong K, et al. Birth weight and







subsequent risk of type 2 diabetes: a meta-analysis. Am J Epidemiol.2007;165:849–85712. Pettitt DJ, Bennett PH, Saad MF, et al. Abnormal glucosetolerance during pregnancy in Pima Indian women: long-termeffects on offspring. Diabetes. 1991;40(Suppl 2):126–13013. McCance DR, Pettitt DJ, Hanson RL, et al. Birth weight andnon-insulin dependent diabetes: thrifty genotype, thrifty pheno-type, or surviving small baby genotype? BMJ. 1994;308(6934):942–94514. Gallaher BW, Breier BH, Keven CL, et al. Fetal programmingof insulin-like growth factor (IGF)-I and IGF-binding protein-3:evidence for an altered response to undernutrition in late gestationfollowing exposure to periconceptual undernutrition in the sheep.J Endocrinol. 1998;159:501–50815. Fryer LG, Kruszynska YT. Insulin resistance in high fat fed rats:role of glucose transporters, membrane lipids, and triglyceridestores. Ann N Y Acad Sci. 1993;683:91–9716. Phillips DI, Barker DJ, Hales CN, et al. Thinness at birth andinsulin resistance in adult life. Diabetologia. 1994;37:150–15417. Valdez R, Athens MA, Thompson GH, et al. Birthweight andadult health outcomes in a biethnic population in the USA. Diabe-tologia. 1994;37:624–63118. Leger J, Levy-Marchal C, Bloch J, et al. Reduced final heightand indications for insulin resistance in 20 year olds born smallfor gestational age: regional cohort study. BMJ. 1997;315(7104):341–34719. Godfrey KM, Gluckman PD, Hanson MA. Developmentalorigins of metabolic disease: life course and intergenerational per-spectives. Trends Endocrinol Metab. 2010;21:199–20520. Levy-Marchal C, Jaquet D. Long-term metabolic conse-quences of being born small for gestational age. Pediatr Diabet.2004;5:147–15321. Garrow J. The thrifty genotype and non-insulin dependentdiabetes. BMJ. 1993;306(6882):933–93422. Kagawa Y, Yanagisawa Y, Hasegawa K, et al. Single nucleotidepolymorphisms of thrifty genes for energy metabolism: evolution-ary origins and prospects for intervention to prevent obesity-relateddiseases. Biochem Biophys Res Commun. 2002;295:207–22223. Bertram CE, Hanson MA. Animal models and programmingof the metabolic syndrome. Br Med Bull. 2001;60:103–12124. Stoger R. The thrifty epigenotype: an acquired and heritablepredisposition for obesity and diabetes? Bioessays. 2008;30:156–16625. Hales CN, Barker DJ. Type 2 (non-insulin-dependent) diabe-tes mellitus: the thrifty phenotype hypothesis. Diabetologia. 1992;35(7):595–60126. Gluckman PD, Hanson MA. Developmental Origins of Healthand Disease. Cambridge, UK: Cambridge University Press; 200627. Hill DJ, Duvillie B. Pancreatic development and adult diabe-tes. Pediatr Res. 2000;48:269–27428. Stoffers DA, Zinkin NT, Stanojevic V, et al. Pancreatic agenesisattributable to a single nucleotide deletion in the human IPF1 genecoding sequence. Nature Genetics. 1997;15:106–11029. Van Assche FA, De Prins F, Aerts L, Verjans M. The endocrinepancreas in small-for-dates infants. Br J Obstet Gynaecol. 1977;84:751–75330. Gluckman PD, Hanson MA. Developmental plasticity andhuman disease: research directions. J Intern Med. 2007;261:461–47131. Maier S, Olek A. Diabetes: a candidate disease for efficient

DNA methylation profiling. J Nutr. 2002;132(8 Suppl):2440S–2443S.32. Mackay DJ, Boonen SE, Clayton-Smith J, et al. A maternalhypomethylation syndrome presenting as transient neonatal diabe-tes mellitus. Hum Genet. 2006;120:262–26933. Pembrey ME, Bygren LO, Kaati G, et al. Sex-specific, male-line transgenerational responses in humans. Eur J Hum Genet.2006;14:159–16634. Lumey LH. Decreased birthweights in infants after maternalin utero exposure to the Dutch famine of 1944–1945. PaediatrPerinat Epidemiol. 1992;6:240–25335. Gluckman PD, Hanson MA. Developmental origins of diseaseparadigm: a mechanistic and evolutionary perspective. Pediatr Res.2004;56:311–31736. Bauman DE, Currie WB. Partitioning of nutrients duringpregnancy and lactation: a review of mechanisms involving homeo-stasis and homeorhesis. J Dairy Sci. 1980;63:1514–152937. Gluckman PD, Hanson MA, Beedle AS, Spencer HG. Predic-tive adaptive responses in perspective. Trends Endocrinol Metab.2008;19:109–11038. Gluckman PD, Hanson MA, Buklijas T. A conceptual frame-work for the developmental origins of health and disease. J Dev OrigHealth Dis. 2010;1:6–1839. Gluckman PD, Hanson MA, Cooper C, Thornburg KL. Effectof in utero and early-life conditions on adult health and disease.N Engl J Med. 2008;359:61–7340. Gluckman PD, Liggins GC. The regulation of fetal growth. In:RW Beard, PW Nathanielsz, eds. Fetal Physiology and Medicine:Basis of Perinatology. Reproductive Medicine. Vol 6, 2nd rev ed.New York: M. Dekker; 1984:511–55841. Gluckman PD, Hanson M. The Fetal Matrix: Evolution, Devel-opment and Disease. Cambridge, UK: Cambridge University Press;200542. Morton NE. The inheritance of human birth weight. AnnHum Genet. 1955;20:125–13443. Stettler N, Tershakovec AM, Zemel BS, et al. Early risk factorsfor increased adiposity: a cohort study of African American subjectsfollowed from birth to young adulthood. Am J Clin Nutr. 2000;72:378–38344. Morton SM. Life Course Determinants of Offspring Size atBirth: An Intergenerational Study of Aberdeen Woman. London:University of London; 200245. Yajnik CS, Fall CH, Coyaji KJ, et al. Neonatal anthropometry:the thin-fat Indian baby. The Pune Maternal Nutrition Study. Int JObes Relat Metab Disord. 2003;27:173–18046. Stanhope JM, Prior IA. The Tokelau island migrant study:prevalence and incidence of diabetes mellitus. N Z Med J. 1980;92(673):417–42147. Wells JC. Is early development in humans a predictive adaptiveresponse anticipating the adult environment? Trends Ecol Evol.2006;21:424–42548. Rickard IJ, Lummaa V. The predictive adaptive response andmetabolic syndrome: challenges for the hypothesis. Trends Endocri-nol Metab. 2007;18:94–9949. Wells JCK. Flaws in the theory of predictive adaptive responses.Trends Endocrinol Metab. 2007;18:331–33750. Wells JCK. Response to Gluckman et al. and Bateson: predic-tive adaptive responses. Trends Endocrinol Metab. 2008;19:11251. Spencer HG, Hanson MA, Gluckman PD. Response to Wells:phenotypic responses to early environmental cues can be adaptive inadults. Trends Ecol Evol. 2006;21:425–426




NeoReviews Quiz

10. Metabolic syndrome, a constellation of several cardio-metabolic risk factors, represents a significant publichealth concern. Of the following, the central feature of the metabolic syndrome is:

A. Atherosclerosis.B. Dyslipidemia.C. Hyperglycemia.D. Hypertension.E. Obesity.

11. Several epidemiologic studies have shown an association between birthweight and subsequentdevelopment of type 2 diabetes later in life. Of the following, the highest prevalence of type 2 diabetesamongst adult Pima Indians is seen among infants with birthweights:

A. <2.5 kg.B. 2.5–3.0 kg.C. 3.0–3.5 kg.D. 3.5–4.0 kg.E. 4.0–4.5 kg.

12. The growth patterns during fetal life, infancy, and early childhood can portend poor prognosis for thedevelopment of insulin resistance in adulthood. Of the following, the most unfavorable growth pattern forthe development of insulin resistance in adulthood is:

A. Normal weight at birth, normal weight as an adult.B. Obese at birth, obese as an adult.C. Obese at birth, thin as an adult.D. Thin at birth, obese as an adult.E. Thin at birth, thin as an adult.





Patricia Y. L. Chan, Jonathan M. Morris and Eileen D. M. Gallery Developmental Origins of Adult Disease: Part 3: Metabolic Disease













Marilisa Elrod, John C. Arnold, Resmy P. Gopi, S. Khanna and B. K. Rajrgowda Activity and Poor Feeding • Case 2: Profuse Diarrhea in a 4-day-old Term Male

Index of Suspicion in The Nursery • Case 1: A 4-day-old Who Has Decreased







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 Elrod, Arnold, Gopi, Khanna, and

Rajrgowda have disclosed no

financial relationships relevant to

these cases. This commentary does

not contain a discussion of an

unapproved/investigative use of a

commercial product/device.

Case 1: A 4-day-old Who Has Decreased Activityand Poor Feeding

Case 2: Profuse Diarrhea in a 4-day-old Term MaleCase 1 PresentationA 4-day-old male infant presents inlate November to the pediatrics clinicwith decreased activity and poorfeeding. The mother reports that hehad been feeding and acting welluntil 1 day before presentation. Themother states that he has not had anyrhinorrhea, nasal congestion, cough,vomiting, diarrhea, rash, or any atyp-ical movements that could be sei-zures. She had not taken his temper-ature, and she states that he has notfelt hot. The pediatrician becomesimmediately concerned as she recog-nizes a lethargic infant in respiratorydistress. A code is called, and theresuscitation is begun.

The infant was a 3,083-g productof a 38�1 week gestation to a 28-year-old G2P1 woman. The preg-nancy was only complicated by a pos-itive group B streptococcus screen at35 weeks’ gestation and a history ofherpes simplex virus in the past, butno lesions were noted before or dur-ing delivery. On presentation to la-bor and delivery, the fetus was notedto be tachycardic and the mother hadmild abdominal tenderness, leadingto initiation of ampicillin and genta-micin 16 hours before delivery. Theduration of rupture of membraneswas 4 hours. The infant was bornvia spontaneous vaginal delivery andwas vigorous, with Apgar scores of9 and 9 at 1 and 5 minutes. Becausethe mother was neither febrile nortachycardic, it was decided that shedid not have chorioamnionitis, so theinfant received no further laboratoryevaluation or antibiotics. The motherand infant were discharged from thehospital after 2 uneventful days.

In the clinic, the 4-day-old infanthas initial vital signs that included a

temperature of 98.9°F, a heart rate of170 beats per minute, a respiratoryrate of 71 breaths per minute, anoxygen saturation (SaO2) of 80% onroom air, and blood pressure 84/35 mm Hg. The infant is minimallyresponsive during attempts to insertan intravenous (IV) catheter. Exam-ination is significant for an anteriorfontanel that is soft and slightly full,minimally icteric eyes, and pupils thatare equal round and reactive at3 mm. Mucous membranes areslightly dry and there are no oropha-ryngeal lesions. Examination of theheart and lungs reveals no murmursand clear breath sounds. The abdo-men is moderately distended, butnormal in color with no organo-megaly. Examination of the skin issignificant for no jaundice, vesicles,or other lesions. The extremities areunremarkable except for a capillaryrefill time of 5 seconds. A brief neu-rologic examination reveals no ab-normal movements consistent withseizures and normal patellar reflexes.One hundred percent oxygen is ad-ministered via face-mask with imme-diate rise in SaO2 to 99% and somerelief of respiratory effort. IV accessis obtained and 10 mL/kg normalsaline bolus is given with a corre-sponding decrease in heart rate andcapillary refill time. Two millilitersper kilogram of D10-Water is givenfor a serum dextrose of 52 mg/dL.The infant is subsequently admitted,and ampicillin and cefotaxime are ini-tiated.

During the admission, the infantis initially stable following the admin-istration of oxygen and crystalloid.Initial laboratories are significant fora normal electrolyte panel, exceptfor a serum glucose of 52 mg/dL

index of suspicion in the nursery



as noted above. Total bilirubin is5.5 mg/dL (direct 0.5 mg/dL) andthe remainder of the liver enzymesare normal. A complete blood countdemonstrates a white blood cellcount of 5.3�103/mm3 (52% neu-trophils, 38% lymphocytes, 1% atypi-cal lymphocytes, 8% monocytes, 1%metamyelocytes), hemoglobin levelof 12.9 g/dL, and a platelet countof 69�103/mm3. A blood culture isobtained. The urinalysis is normal,and urine culture is obtained. CSFstudies included a white blood cellcount of 14/mm3 (25% neutrophils,20% lymphocytes, 55% monocytes),red blood cell count of 11/mm3,protein of 49 mg/dL, and glucoseof 31 mg/dL. CSF cultures are ob-tained. The chest radiograph showsa normal heart size and normal lungfields with no consolidation. The ab-dominal radiograph shows nonspe-cific abundant bowel-gas with no ev-idence of obstruction or free air.

Six hours after admission the in-fant again becomes less arousableand is noted to be hypopneic with a

respiratory rate of 18. He is trans-ferred to the intensive care unit forincreased observation and possibleintubation, although the venousblood gasses are reassuring (pH, 7.4;PCO2, 42). A concern for an under-lying heart abnormality (such ascoarctation of the aorta) is consid-ered as the etiology for his compro-mise. An echocardiogram is ob-tained, which demonstrates normalanatomy, mild pulmonary hyperten-sion, and left ventricular dysfunction.Studies of the blood and CSF lead toa definitive diagnosis.

Case 2 PresentationA term male with a birthweight of3,015 g is born by normal spontane-ous vaginal delivery to an immigrantmother from Ghana. The infant isadmitted to the newborn unit; phys-ical examination is significant for anatal tooth. The infant is fed mostlyhuman milk with occasional formulafeeds without any problem On day 3,the infant developed hyperbiliru-binemia and required phototherapy.On the fourth day, the infant devel-ops severe watery diarrhea, which isinterpreted as phototherapy related.Diarrhea continues and serum chem-istry shows hyperchloremic meta-bolic acidosis (arterial blood gasshows bicarbonate level of 7.9 mEq/dL; BE, �15). The infant is trans-ferred to the neonatal intensive careunit for further evaluation. Clinicallythe infant is active and alert with avoracious appetite. He is taking 4 to5 oz/feed, without clinical evidenceof dehydration. Weight loss is only155 g (about 5% of birthweight).

Family history reveals that a sib-ling had diarrhea as an infant, whichresolved following cessation ofbreastfeeding.

The infant is admitted to the neo-natal intensive care unit on the fifthday, made NPO, and diarrhea de-

creases soon after and then stops.The infant is restarted on humanmilk and diarrhea reappears. The in-fant is made NPO again and diarrheastops again. The infant is tried onAlimentum/pregestamil, and the in-fant feeds well, is always hungry withno vomiting, but watery diarrhea be-comes worse. After consultation witha pediatric gastroenterologist, the in-fant is made NPO for 1 day and startson Neocate, which is tolerated well.The diarrhea stops, birthweight is re-gained, and he is discharged from thehospital to have follow up with thepediatric gastroenterologist and hispediatrician. At present the infant isdoing well and is gaining weight withnormal growth and development.

Laboratory values showed hy-perchloremic metabolic acidosis(sodium, 141 mmol/L; potassium,4.6 mmol/L; chloride, 120 mmol/L;CO2, 14 mmol/L; RpT: sodium,137 mmol/L; potassium, 3.8 mmol/L;chloride, 117 mmol/L; CO2,9 mmol/L; anion gap, 12 mmol/L,NL range 7 to 14). The infant’s elec-trolytes showed hyperchloremic, no-nanionic gap metabolic acidosis dur-ing episodes of diarrhea, whichstabilized once the infant was placedNPO on intravenous fluids. Oncethe infant was started on Neocate,hyperchloremic/metabolic acidosisresolved: arterial blood gas (pH,7.31; PCO2, 16 mm Hg; PO2,138 mm Hg; HCO3, 7.9 mmol/L;BE, �15.4 mmol/L); stool culturewas negative, negative for occultblood, fat 2�, and positive for reduc-ing substance. Blood culture wasnegative; pancreatic elastase, 242(NL �200); vasoactive intestinalpeptide, 24.4 (20 to 42 pg/mL);ammonia,115 mmol/L; CBC(WBC, 15.3 k; Hgb, 13.4 g/dL; Plt.445 K; G6PD, NL; liver functiontests, NL). Metabolic screen wasnegative for galactosemia and thy-

Frequently Used Abbreviations

ALT: alanine aminotransferaseAST: aspartate aminotransferaseBUN: blood urea nitrogenCBC: complete blood countCNS: central nervous systemCSF: cerebrospinal fluidCT: computed tomographyECG: electrocardiographyED: emergency departmentEEG: electroencephalographyESR: erythrocyte sedimentation

rateGI: gastrointestinalGU: genitourinaryHct: hematocritHgb: hemoglobinMRI: magnetic resonance imagingWBC: white blood cell




roid disorder. Urine for organic acidswas negative.

Case 1 DiscussionThe Diagnosis

Serum and CSF were both sent onthe day of admission for enterovirus(EV) polymerase chain reaction(PCR) testing and both are found tobe positive for the presence of EVRNA. The infant improves slowlyover the 10-day admission and is dis-charged from the hospital in goodcondition.

The PathogenEVs are RNA viruses in the Enterovi-rus genus, which belongs to the fam-ily Picornaviridae. Other picornavi-ruses include rhinoviruses, hepatitisA virus, and the relatively newly de-scribed human parechoviruses. His-torically, the term “enterovirus” re-fers to a large number of differentgroups, including A and B coxsacki-eviruses, echoviruses, and the num-bered EVs. Poliovirus is also in theenterovirus family, but the commonuse of the term “enterovirus” doesnot often refer to polioviruses, whichcause a specific clinical disease. Beinghardy viruses, the EVs can remainviable for several days at room tem-perature. The most common modesof transmission are fecal–oral or re-spiratory; however, when the hostbecomes viremic, blood borne ortransplacental transmission are possi-ble.

The ConditionMost EV infections occur during thesummer and early fall and are asymp-tomatic. Despite the name “entero-virus,” which implies a gastrointesti-nal pathogen, the most commonmanifestation of enteroviral infec-tions is an uncomplicated upper re-spiratory tract infection or undiffer-entiated febrile illness. However,

EVs can be found in both the upperairway and the lower gastrointestinaltract, accounting for its variablemodes of transmission. NonpolioEVs are responsible for a myriad ofclinical manifestations, ranging fromuncomplicated respiratory infectionto fatal viremia. There are, however,some classic enteroviral syndromes,which are often attributed to specificserotypes. For example, hand, foot,and mouth disease is often associatedwith coxsackie A10 and A16, pleuro-dynia and myocarditis with coxsackieB, and severe meningoencephalitis orflaccid paralysis with EV 71. How-ever, the overlap between clinical en-tities and viral serotypes is broad.

As with older children, the major-ity of neonates infected with EVsare asymptomatic. Those with symp-toms usually have an undifferentiatedfever or aseptic meningitis. However,neonates are also uniquely suscepti-ble to severe enteroviral infections.This was first described during poliooutbreaks, when a neonate born to amother recently infected with poliohad a 40% chance of paralysis. Thevariety of different presentations inneonates and children is thought tobe dependent on age and mode oftransmission. For example, postnatalexposure of a newborn with high lev-els of cross reacting maternal anti-body may result in a mild or asymp-tomatic infection, whereas an olderinfant who lacks maternal antibodymight be more symptomatic. Alter-natively, a mother who is infectednear the time of delivery could beviremic and can infect the infantwithout any of the benefit of protec-tive maternal antibody. In the latterscenario, the infant is susceptible tothe most severe manifestations ofEV: carditis, encephalitis, and hepa-titis. For those infants that developan EV sepsis syndrome, mortality ishigh, but unlike herpes simplex virusinfections, those children who sur-

vive often do so without severe long-term sequelae. Of the EVs implicatedin neonatal disease, group B cox-sackieviruses and echovirus 11 are as-sociated with severe illness. Entero-viral neonatal myocarditis caused bycoxsackieviruses B1–B5 is the mostcommon cause of myocardial infarc-tion in neonates. Echovirus 11 is as-sociated with neonatal hepatic necro-sis.

Diagnostic TestsDiagnosis was previously made byviral cell culture. Viral culture of thestool can be a valuable tool for “afterthe fact” diagnosis, as EVs are oftenshed in the stool for weeks after in-fection. However, nucleic acid am-plification tests like PCR are now thediagnostic methods of choice. PCRfor the viral RNA has been found tobe more sensitive than culture assome serotypes do not grow well incell culture and PCR can detect amuch smaller amount of virus. Somecaution must always be exercisedwith interpretation of PCR results asfalse–positive and false–negative re-sults are possible with this methodol-ogy. CSF PCR is now the standarddiagnostic methodology at most in-stitutions, and serum PCR can be avaluable adjunct especially in younginfants and immunocompromisedpatients.

TreatmentTreatment of EV is generally sup-portive. However, in neonates withlife-threatening infections, intrave-nous immunoglobulin (IVIG) andpleconaril have been used. IVIG hasbeen administered with mixed suc-cess as the effectiveness of such aproduct depends on the presence ofneutralizing antibody to the infect-ing serotype, which may not be pres-ent in the available IVIG. Adminis-tration of maternal convalescentplasma has been proposed due to the




likelihood of high titer antibodies,but is often not practical and cannotbe given in a timely manner. Pleco-naril is a compound that binds thecapsid of EVs and disrupts the virusattachment to cellular receptors, thusits ability to uncoat and insert itsRNA into the cell. Pleconaril hasbeen used with some success in im-munocompromised patients. How-ever, there are limited data regardingpleconaril safety and efficacy in neo-nates and it is no longer available,even for emergency use. The largenumber of unique serotypes and gen-erally mild disease makes an EV vac-cine unlikely.

Lessons for the ClinicianEVs are a common cause of illness inchildren and young adults and causea wide spectrum of clinical disease.They will most commonly be en-countered by the pediatrician as up-per respiratory infections; hand, foot,and mouth disease; fever; and asepticmeningitis. The uncommon butpotentially devastating scenario of apregnant woman infected with EVjust before delivery should be consid-ered when a neonate presents withfever and a sepsis syndrome. Hall-mark signs that would suggest en-teroviral sepsis might be a combina-tion of cardiac, CNS, or liverinvolvement, especially in the sum-mer and early fall. Early administra-tion of IVIG could be considered,although supportive care is the main-stay of therapy.

(Marilisa Elrod, Department of Pedi-atrics, Naval Medical Center, SanDiego, CA; John C. Arnold, MD, De-partment of Pediatrics, Division of In-fectious Diseases, Naval Medical Cen-ter, San Diego, CA)

Disclaimer: The views expressedin this article are those of the au-thor(s) and do not necessarily reflectthe official policy or position of the

Department of the Navy, Depart-ment of Defense, or the UnitedStates Government.

Suggested ReadingJenista JA, Powell KR, Menegus MA. Epi-

demiology of neonatal enterovirus infec-tion. J Pediatr. 1984;104:685–690

Knipe DM, Howley PM. Fields Virology,5th ed. Philadelphia, PA: LippincottWilliams and Wilkins; 2007

Sawyer MH. Enterovirus infections: diag-nosis and treatment [Review]. PediatrInfect Dis J. 1999;18:1033–1040

Case 2 DiscussionClinical Presentation

Based on the clinical presentationand response to the treatment, thisinfant seems to have “congenitalglucose/galactose malabsorption(GGM).” Infant had profuse diar-rhea starting on the fourth day afterbirth despite switching the feedings(human milk/Alimentum/Preges-tamil). Diarrhea stops with discon-tinuance of the feeds and restartedsoon after reintroduction of thosefeeds. Infant also developed hyper-chloremic-nonanion gap metabolicacidosis. Clinically infant was an ac-tive alert hungry infant with a goodappetite and suck.

Infant responded well to Neocate

with no diarrhea and normal growthand development.

Genetics of the DiseaseGGM is an autosomal recessive dis-order caused by a mutation in Na/glucose cotransporter (SGLT) geneSLC5A1. More than 40 mutations ofSLC5A1 responsible for GGM havebeen described. (1)

In a report in 1962 from Sweden,GGM has been reported from severaldifferent parts of the world. (2)(3)There is no ethnic predilection, butconsanguinity plays a very importantrole as there are multiple case reportsfrom Middle Eastern countries andthe Amish population. It is morecommon in female infants. (1) Morethan 200 cases have been reportedworld wide since its first report. (1)

Pathophysiology of theDisease

Glucose is the main fuel providingenergy for regular metabolic needsof humans. Glucose is transportedacross the plasma membrane by acarrier protein called “glucose trans-porter.” Glucose transporters(GLUTs) are divided into two fami-lies: 1) the facilitative diffusionGLUT and 2) SGLT. Both GLUTsand SGLTs belong to one of the43 families of solute carrier genes(SLC1-SLC43).

Transepithelial glucose transportoccurs by a coordinated action ofSGLTs (in small intestine/renaltubules/salivary glands) allowingglucose influx through Luminalmembrane. GLUTs allow glucoseefflux through the basolateral mem-brane.

Glucose/galactose is handled bySGLT1. Fructose is absorbed pas-sively across brush border by fructoseuniporter GLUT5 and by GLUT2across basolateral membrane asshown in the Figure. (4)

American Board of PediatricsNeonatal-Perinatal MedicineContent Specifications• Know the

epidemiology,pathogenesis, andprevention ofperinatal infectionswith coxsackievirus, echovirus,enterovirus, and poliovirus.

• Understand the clinical manifestations,diagnostic criteria, treatment, andcomplications of perinatal infectionswith coxsackievirus, echovirus,enterovirus, and poliovirus.




Diagnostic Criteria for Glucose/Galactose Malabsorption

1) watery diarrhea soon after birth,a) clinical improvement on with-drawal of dietary glucose and galac-tose, b) relapse on reintroductionof glucose/galactose, c) biopsy—histological normal small intestinalmucosa–normal mucosal disacchari-dase activities, d) absorptive defectconfined to glucose and galactose

2) Prenatal diagnosis in affectedfamilies

3) Intermittent or permanent gly-cosuria after fasting or after a glucoseload

4) Finding of positive reducingsubstance in watery stool and slightglycosuria despite low blood sugar ishighly suggestive

5) Interval breath hydrogen test

Differential DiagnosisDiarrheal diseases presenting in theneonatal period (Table, used withpermission, modified for this re-view).

DiscussionThis case had the classical presentationof an active alert infant with a voraciousappetite presented with severe wateryexplosive diarrhea and hyperchloremicacidosis. There was also a family historyof a 9-year-old sibling with a similarclinical presentation. The infant re-sponded well to Neocate with no diar-rhea and normal growth and develop-ment. Human milk and Similac bothhave lactose as the sugar, which breaksinto glucose and galactose.

On the other hand Alimentumand Pregestamil are extensively hy-drolyzed proteins (cow milk proteinbased). Pregestamil contains cornsyrup and modified corn starch. Ali-mentum contains sucrose and modi-fied Tapioca starch, which is glucosepolymers, which break down tod-glucose. In contrast Neocate is anamino acid-based formula (not cowmilk protein) and has fructose assugar base (carbohydrate as cornsyrup, which is fructose). Fructose isabsorbed passively by fructose un-

iporter in the brush border mem-brane (GLUT5) and by GLUT2 inthe basolateral membrane.

The disease classically presentsduring the neonatal period or soonafter the introduction of feedings ofeither human milk or formula, withlife-threatening profuse watery diar-rhea and hypernatremic dehydrationwith metabolic acidosis. (5) Infantsare usually very vigorous, nurse verywell, and have a voracious appetite,regardless of their illness, and haveirritability with abdominal distensionand increased bowel sounds and fail-ure to thrive. There is sudden cessa-tion of diarrhea with fasting or theremoval of offending sugar lactose(glucose/galactose), which is pres-ent in human milk and standard for-mula and glucose polymers presentin Pregestamil and Alimentum, fol-lowed by normal growth and devel-opment. However, diarrhea reap-pears rapidly with reintroduction ofdiet containing the offending sugar.

After going through the list ofdifferential diagnoses (see the tableabove), family history of similarclinical presentation, and the clinicalresponse to Neocate (fructose as car-bohydrate), the diagnosis of GGMwas made. Since the introduction ofNeocate, the infant’s growth and de-velopment has been normal.

Biopsy was not offered to the fam-ily to confirm the diagnosis because1) there was a family history of similarillness, 2) there was a clinical presen-tation of watery diarrhea with hyper-chloremic acidosis and an active, alertinfant with voracious appetite, and3) diarrhea resolved with removal ofoffending sugar. Had the infant notresponded to our current managementwe would have considered biopsy.

Nutrition ManagementOnce a presumptive diagnosis ismade based on the clinical features,nutritional management involves

Figure 1. Illustration of the current model for glucose and galactose transport acrossthe mature enterocytes of the small intestine. SGLT1 refers to the Na�/glucosecotransporter and GLUT2 refers to the facilitated glucose transporter (uniporter).Fructose is absorbed passively by a fructose uniporter in the brush-border membrane(GLUT5) and by GLUT2 in the basolateral membrane. With kind permission fromSpringer Science�Business Media: Cell Biochemistry and Biophysics, “Molecular basisfor glucose-galactose malabsorption,” vol 36, 2002, Ernest M. Wright, Eric Turk,Martin G. Martin, figure 1.




providing the infant with glucose/galactose free formulas. As regularformulas contain lactose (source ofglucose/galactose), specialized for-mulas containing corn syrup as sugarsource, such as Neocate or Ross Car-bohydrate Free Formula or MeadJohnson Product 3232A monosac-charide and disaccharide-free pow-der, need to be used. Fructose isadded to meet the energy require-ment. Detailed dietary guidelines areavailable. (6)

Long-Term PrognosisTolerance to carbohydrate-contain-ing drinks improves gradually over-time. Most of the patients are ableto tolerate regular carbohydrate-containing diets, although the de-gree of improvement varies. Themechanism remains unclear.

Nephrocalcinosis and proximaltubular dysfunction have been re-ported as complication.

Lessons for the ClinicianDiarrhea in the newborn is a veryuncommon disorder, but it could befatal if there is a delay in the diagno-sis. A high index of suspicion and afew simple tests will help the cliniciantreat such infants without doingcomplicated investigations.

(Resmy P. Gopi, MD, S. Khanna,MD, B. K. Rajrgowda, MD, Depart-ment of Pediatrics/Division of Neona-

tology, Lincoln Medical and MentalHealth Center, Bronx, NY)

References1. Xin B, Wang H. Multiple sequence vari-ations in SLC5A1 gene are associated withglucose-galactose malabsorption in a largecohort of Old Order Amish. Clin Genet.2011;79:86–912. Lindquist B, Meeuwisse GW. Chronicdiarrhoea caused by monosaccharide malab-sorption. Acta Pediatr Scand. 1963;51:674–6853. Abdullah AMA, El-Mouzan MI, SheikhOKE, Mazyad AA. Congenital glucose-galactose malabsorption in Arab children.J Pediatr Gastroenterol Nutrition. 1996;53:561–5644. Wright EM, Turk E, Martin MG. Molec-ular basis of glucose-galactose malabsorption.Cell Biochem Biophys. 2002;36:115–1215. Steinhart R, Nitzan M, Iancu TC. Hy-pernatremic dehydration as a sign leading tothe diagnosis of glucose-galactose malab-sorption in breast-fed neonates. Helv Paedi-atr Acta. 1984;39:275–2776. Abad-Sinden A, Borowitz S, Meyers R,Sutphen J. Nutrition management of con-genital glucose-galactose malabsorption:A case study. J Am Diet Assoc. 1997;97:1417–1421

Table. Differential Diagnosis: Diarrheal Diseases Presenting in theNeonatal PeriodCondition:

Congenital microvillus atrophyTufting enteropathyCongenital glucose-Galactose malabsorptionCongenital lactase deficiencyCongenital chloride diarrheaCong. defective Na/H exchangeCong. bile acid malabsorptionCong. enterokinase def.Enteric anendocrinios (NEUROG 3 mutation)

Other causes:Congenital sucrase isomaltase deficiencyGastrinoma, VIPoma-Milk protein allergy

Clinical features:Intractable watery diarrhea-Hypotonic dehydrationIntractable diarrhea-Partially respond to fastingIntractable watery diarrhea-Hyperchloremic metabolic acidosisAcidic diarrheaAcidic diarrheaIntractable watery diarrhea-Hypocholoremia/HyponatremiaAlkalosisIntractable watery diarrhea–Hyponatremia/metabolic acidosisSteatorrheaFailure to thrive, edemaHyperchloremic acidosis-accompanying features, vomiting, diarrhea

ceases with fasting, but returned with glucose/amino acids solution.Infant asymptomatic when on diet containing Lactose (BF), in Eskimos

Neuroendocrine tumors: Older age group, Tea colored odorlesswater stool-persists with fasting. Hypokalemia, Hypochlorhydriausually presents later, GE reflux constipation

This table was published in Nelson Text Book Of Pediatrics, 18th ed., Kliegman RM, Behrman RE, Jenson HB, Stanton BF, eds. “Diarrheal Disease Presentingin the Newborn Period”, p. 1589, Copyright Saunders Elsevier, 2007.

American Board of PediatricsNeonatal-Perinatal MedicineContent Specifications• Recognize clinical

features associatedwith autosomalrecessive disorders.

• Know the etiology,clinical manifestations, diagnosis,and treatment of congenitalmalabsorption syndromes innewborn infants, including thecongenital mineral and electrolytemalabsorption syndromes.





Marilisa Elrod, John C. Arnold, Resmy P. Gopi, S. Khanna and B. K. Rajrgowda Activity and Poor Feeding • Case 2: Profuse Diarrhea in a 4-day-old Term Male

Index of Suspicion in The Nursery • Case 1: A 4-day-old Who Has Decreased













Maureen E. Sims Legal Briefs: Kernicterus�Still Preventable







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.

Kernicterus—Still PreventableMaureen E. Sims, MD*

IntroductionA 3,760-g 38 weeks’ gestation Afri-can American male was vaginallydelivered to an 18-year-old womanwhose pregnancy was normal. Apgarscores were 8 and 9, at 1 and 5 min-utes, respectively. The mother’sblood type was O Rh-positive. TheDirect Coombs was negative. He wasgavaged once and put to breasttwice, but data on latching or audibleswallow were not documented. Themother and infant were discharged at31 hours after delivery. The nursesnoted that there was “no jaundice”when the infant left the hospital. Nobilirubin assessments were made. Atthe time of discharge the mother wastold to call the pediatrician’s officeafter a week to obtain an appoint-ment. A phone number was pro-vided. She was told to call sooner ifthere were problems.

Before the delivery, the motherhad been living in a group fosterhome for many years. Because shehad just turned 18 years old, she wasnot allowed to return to the grouphome, but was told to go an apart-ment that had been set up for herthrough social services. The plaintiffexperts were critical of the hospitalfor early discharge because 1) feed-ing issues existed, 2) the mother wasa teenager and had no support struc-ture, and 3) an immediate follow-upappointment either by a visiting nurseor a pediatrician was not scheduled.

The mother stated in her deposi-tion that she did not feel that herinfant ever fed well, in the hospitalor at home. She said she felt scaredstaying in her new apartment andtried staying with her sister. How-

ever, because of overcrowding at hersister’s, she returned to her apart-ment. She called her mother for feed-ing advice and was told to keep try-ing, that every infant is different,and there was probably no problem.The defense experts pointed out thatthe infant’s mother never called thepediatrician after being dischargedfor problems. They said she did nottake responsibility for her child. Theplaintiff experts pointed out that sheherself was very young and needed asafety net at the time of dischargewith either a follow-up appointmentthe next day or a visiting nurse.

At 72 hours, the mother broughtthe infant to the emergency depart-ment (ED) because he became verysleepy, had some choking with feeds,and eventually stopped sucking en-tirely. An ED physician was at hisbeside 41 minutes after the infantentered the hospital. The plaintiffexperts pointed out that a newbornhas very little reserve and that heneeded to be examined sooner. Hepresented with a history of poor feed-ing, choking, and being very sleepy.The ED physician found a lethargicinfant with poor tone and suck. Nomention was made of the color ofthe sclera. The infant’s weight was3,150 g, a decrease of 16% frombirthweight. The plaintiff expertspointed out that this was an excessiveweight loss and represented howpoorly the infant was feeding. Hisrespiratory rate was 40 breaths/min,his heart rate was 107 beats/min,and his mean blood pressure was48 mm Hg. The result of the bedsideglucose check was 61 mg/dL. TheED physician ordered a completeblood count (CBC) and a chemistrypanel. These tests were drawn 1 hour

*Professor of Pediatrics, University of California LosAngeles, Los Angeles, CA.

legal briefs



later. Urine and blood cultures, anda urine analysis were done as well.A chest radiograph was ordered, andwhen the infant was returned fromthe radiology department his tem-perature was 34.4°C. At this point alumbar puncture was performed andthe cerebral spinal fluid was unre-markable. Three and one-half hourslater, the results of the CBC andchemistry panel were available. Thewhite blood cell count was15.8�103/uL, the hematocrit was43% (0.43), and the platelet countwas 317�103/uL. Electrolyte con-centrations were normal except forthe serum sodium being slightly ele-vated at 146 mEq/L. A serum albu-min was not evaluated. The total bil-irubin was 44.7 mg/dL, and thedirect fraction was 2.1 mg/dL. Theurine analysis results were negative.A course of antibiotics was started forpresumed infection. When the labo-ratory technician was questioned inthe deposition why it required morethan 1 hour for the bilirubin resultsto be available to the physician, hesaid he had to keep diluting the se-rum to obtain a precise value becausethe bilirubin level was so high.

Thirty minutes after the bilirubinresults were available, the ED physi-cian contacted the neonatologist,who requested that the infant becross-matched for blood. Four andone-half hours after admission to theED, the infant was admitted to thenewborn intensive care unit wherephototherapy was begun. The plain-tiff experts were critical of the exces-sive time lag before starting photo-therapy. The ED physician said hedid not have phototherapy lights inthe ED. The plaintiff experts saidthat was an unacceptable situation.Either somebody should have ob-tained phototherapy lights andbrought them to the ED or a setshould have been kept in the ED. TheED physician also stated that he

called the pediatrician on-call shortlyafter finding out the results of thebilirubin but was told to call the neo-natologist on-call, causing a furtherdelay in the consult.

By the time all the communica-tion was accomplished, much timehad elapsed. The plaintiff expertspointed out that bilirubin encepha-lopathy should have been included inthe differential. Because jaundice ismore difficult to discern on anAfrican American infant, one can-not count on seeing yellow skin. Italso was pointed out that 10% ofAfrican American males areglucose-6-phosphate (G6PD) defi-cient, thereby placing them at ahigher risk for a hemolytic jaundice.The plaintiff experts pointed out thatthe ED physician did not embrace thesense of urgency that this level of bil-irubin was in a dangerous zone. Thedefense stated that because the infantwas already encephalopathic, it wastoo late. The plaintiff experts pointedout that duration of the dangerouslevels of hyperbilirubinemia as wellas the peak were important in caus-ing the brain damage.

One hour after phototherapy be-gan, the bilirubin level was 33.9 mg/dL. At this point, the physician at-tempted to locate blood for anexchange transfusion. The plaintiffexperts pointed out that the level ofinitial bilirubin was so dangerouslyhigh that emergency release bloodshould have been used for an imme-diate exchange transfusion as soon asthe high level of bilirubin was ini-tially reported. The plaintiff expertspointed out that the blood bankshould have been alerted immedi-ately so that a double volume ex-change would be done as soon as vas-cular access was achieved. Thetreating neonatologist said that itwas dangerous to exchange withblood that was not specifically cross-matched for the infant. The plaintiff

pointed out that group O blood withAB serum should have been recog-nized as the appropriate emergencyblood for the urgent situation. Be-cause the blood bank was not alertedto the critical situation, timely andemergency release blood was notrequested and blood from othersources only began being soughtmany hours later than was appropri-ate. Five and one-half hours afterbeing admitted to the neonatal in-tensive care unit (10 h after admis-sion to the ED), the neonatologistattempted to place an umbilical ve-nous catheter. The plaintiff expertspointed out that the neonatologistshould have been trying to achievevascular access immediately and notwaited for blood to do so. The treat-ing neonatologist said he did not tryaccess because he was waiting forcross-matched blood. The attempt tocannulate the umbilical vein was un-successful. Therefore, a pediatric sur-geon was paged. Many delays incommunication occurred, but even-tually a cut-down for vascular accesswas achieved and a double volumeexchange transfusion was completed18 hours after the infant arrived inthe ED. A pre-exchange bilirubinwas 24.9 mg/dL. And the postex-change bilirubin was 18.8 mg/dL.Screening for G6PD deficiency wasnot done at the time of birth becausethe state did not mandate it at thistime. A G6PD evaluation was donein the hospital and it was positive.Nothing could be identified as astress for provoking the G6PD he-molysis. After a few more days ofphototherapy, the infant was dis-charged from the hospital with themother.

On follow-up examinations, theinfant developed athetoid cerebralpalsy and mental retardation. Thebirthing hospital, the pediatricianwho discharged the infant at31 hours, the hospital where the in-

legal briefs



fant was admitted at 72 hours, theED physician, and the neonatologistwere sued. A settlement agreementwas reached.

DiscussionKernicterus is preventable. It shouldbe a “never” disease. In 2001 theNational Quality Forum, an agencyfor healthcare research and quality,listed kernicterus as a “never-event”and equated its occurrence to egre-gious, nonreversible, iatrogenic ca-tastrophe that should be viewed asan irreproachable medical error.Over the last two decades, nationalhealthcare organizations includingthe Academy of Pediatrics, Centersfor Disease Control and Prevention(CDC), and the Joint Commissionon Accreditation of Healthcare Or-ganizations have alerted practitionersand hospitals about the reemer-gence of this devastating disorderand need for vigilance and a system-atic approach. They have under-scored that there is a biologic cer-tainty that kernicterus will occur insome infants if the pattern of hyper-bilirubinemia’s progression is in-adequately monitored or if interven-tion with phototherapy or exchangetransfusion is not timely.

An incremental relationship ofincreasing levels of total serum bili-rubin �19 mg/dL to kernicterus isapparent. Most nurseries in theUnited States discharge infants with-out screening for hemolysis otherthan Rh disease. In the Pilot Ker-nicterus Registry the causes of ker-nicterus were attributed to threeequivalent categories: 1) hemolyticdisorders (mostly ABO isoimmuni-zation), 2) G6PD deficiency (associ-ated with both hemolysis and bili-rubin conjugation disorder), and3) idiopathic causes presumed to besecondary to delayed or impairedfunction of the glucuronyl trans-ferase enzyme system coupled with

breastfeeding and inadequate nutri-tional intake. This infant probablyhad a combination of breastfeedingwith inadequate nutritional intake aswell as the G6PD deficiency.

G6PD deficiency is one of thecommonest enzyme deficiencies inhumans. It occurs in 10% of AfricanAmerican males. Hemolysis with thisdisorder has been associated with anumber of stressors: bacterial and vi-ral infections, certain analgesics, sul-fonamides, antimalarial drugs, andexposure to maternal ingestion offava beans. None of these factors wasidentified. Functional severe muta-tions may cause hemolysis in the ab-sence of stress. It is possible that asyet unidentifiable chemical offendersmay be included in the vast array ofcleaning and other household mate-rials available.

Multiple initial missteps occurredin the care of this infant. An evalua-tion of the infant’s poor feeding afterbirth was not done. Lactation sup-port was not provided. The motherwas a teenager without an appropri-ate support structure. A timelyfollow-up system for this infant wasnot provided. No education aboutjaundice was provided at the time ofdischarge. Neither a serum nor trans-cutaneous bilirubin assessment wasdone, and therefore a risk assessmentto determine the chance for a sig-nificant hyperbilirubinemia was notmade. Perhaps the severe dehydra-tion stress triggered the hemolysis.Undoubtedly, the severe hyperbiliru-binemia could have been avoided ifappropriate care had been provided.The subsequent missteps involvedphysicians who did not appreciatethe time-sensitive nature of this in-fant’s condition, thereby creatingmajor delays in the initiation of pho-totherapy and his exchange transfu-sion.

The lack of the physician’s vigi-lance, the early discharge, failure to

provide a safety net for this teenagemother, subsequent long delay inthe evaluation of this encephalo-pathic infant, and prolonged timebefore intervention caused the in-fant’s adverse outcome.

Suggested ReadingAmerican Academy of Pediatrics. Hospital

stay for healthy term newborns. Pediat-rics. 1995;96:788–790

Bhutani VK, Johnson L. Predictive ability ofa predischarge hour-specific serum bili-rubin for subsequent significant hyper-bilirubinemia in healthy term and near-term newborns. Pediatrics. 1999;103:6–14

Bhutani V, Johnson LH. Lessons for the fu-ture from a current tragedy. NeoReviews.2003;4:e30–e32

Brown AK, Johnson L. Loss of concernabout jaundice and the reemergence ofkernicterus in full-term infants in the eraof managed care. In: Fanaroff AA, KlausMH, eds. The Year Book of Neonatal andPerinatal Medicine. Philadelphia, PA:Mosby Yearbook;1996:17–28

Brown AR. Kernicterus: past, present, andfuture. NeoReviews. 2003;4:e33–e40

Joint Commission on Accreditation ofHealthcare Organizations. Revisedguidance to help prevent kernicterus.Sentinel Event Alert. 2004;31:1–2

Johnson LH, Brown AK, Bhutani VK.System-based approach to managementof neonatal jaundice and prevention

American Board of PediatricsNeonatal-Perinatal ContentSpecifications• Know the

pathologic findingsof kernicterus.

• Know the factorsthat increase therisk of the development ofkernicterus

• Know the clinical features of acutebilirubin encephalopathy in newborninfants

• Know the clinical features ofkernicterus.

legal briefs



of kernicterus. J Pediatr. 2002;140:396–403

Maisels MJ, Baltz RD, Bhutani VK, et al;American Academy of Pediatrics, Sub-committee on Hyperbilirubinemia.Clinical practice guideline: managementof hyperbilirubinemia in the newborn

infant 35 or more weeks of gestation.Pediatrics. 2004;114:297–316

Robertson WO, Almquist JR, Light IJ, et al;American Academy of Pediatrics, Provi-sional Committee for Quality Commit-tee for Quality Improvement. Practiceparameter: management of hyperbiliru-

binemia in the healthy term newborn.Pediatrics. 1994;94:558–565

Soorani-Lunsing I, Woltil H, Hadders-Algra M. Are moderate degrees of hy-perbilirubinemia in healthy term neo-nates really safe for the brain? PediatrRes. 2001;50:701–705

legal briefs




Maureen E. Sims Legal Briefs: Kernicterus�Still Preventable













Maurice L. Druzin and Nancy Peterson Strip of the Month: December 2011







Strip of the Month: December 2011Maurice L. Druzin, MD,*

Nancy Peterson, RNC,

PNNP, MSN, IBLC†

Author Disclosure

Dr Druzin and

Ms Peterson have

disclosed no financial



commentary does not


of an unapproved/


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 of 2years of work by a panel of experts in the field of fetal monitoring and was endorsed in 2005by 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 wavelike 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

*Charles B. and Ann L. Johnson Professor of Obstetrics; Chief, Division of Maternal-Fetal Medicine; Co-Medical Director, Mid-Coastal California Perinatal Outreach Program, Stanford University School of Medicine, Palo Alto, CA.†Director of Perinatal Outreach, Stanford University, Palo Alto, CA.

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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 min-utes

● May be episodic (occurs without a contraction) orperiodic

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 eval-uation and continued surveillance and reevaluation.Examples of these tracings include any of the follow-ing:

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

lation

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

Normal* >7.20 <60 >20 < �10(7.15–7.38) (35–70) (�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 vari-

ability�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 Gynecol. 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 30-year-old, G 1, P0 woman at 363⁄7 weeks’ gestationis sent to labor and delivery from the perinatal diagnosticcenter for extended fetal monitoring after a nonreactivenonstress test (NST), a biophysical profile (BPP) of 8/10with vibroacoustic stimulation, and an amniotic fluidindex of 10.4. This is the second admission for similarsymptoms of decreased fetal movement in 2 days. Herhistory is significant for type 1 diabetes mellitus, hypo-thyroidism, and nonproliferative retinopathy. Duringher prenatal care, the patient was controlled on an insulin

pump; however, her blood sugars were difficult to con-trol and required frequent adjustments of her insulinregimen. Her glycosylated hemoglobin (HbAIc) hasranged from 6.9 to 7.5 throughout pregnancy and is areflection of glucose control over the previous 4 to6 weeks. HbAIc levels above 6 indicate elevated glucoselevels. She has also been on levothyroxine 25 mcg dailyfor her hypothyroid condition. Her vital signs are a bloodpressure of 126/84 mm Hg, 80, temperature and respi-rations not documented. A FHR admission tracing isobtained shortly after admission to labor and delivery(Fig. 1).

Figure 1. EFM Strip #1.

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Findings on EFM Strip #1 are:

● Variability: Minimal● Baseline rate: 150 beats/min● Episodic patterns: None● Periodic patterns: None● Uterine contractions: None● Interpretation: Category II tracing● Differential diagnosis: Indeterminate fetal tracing, rule

out evolving hypoxia● Action: A biophysical score of 8/10 with adequate amni-

otic fluid volume despite a nonreactive NST for the past2 days and minimal variability is considered a normalfinding, and is a reliable predictor of fetal well-being. Thefalse-negative rate of a BPP is superior to that of the NSTalone and is comparable to the false-negative rate of acontraction stress test. The BPP assesses five components:

fetal breathing movement, gross body movement, fetaltone, amniotic fluid volume, and FHR reactivity (NST).The plan at this point is to continue with continuous fetalmonitoring overnight in labor and delivery, and repeatBPP in the morning if FHR tracing does not improve.However, if there is a recurrent deceleration pattern, fetalbradycardia or BPP score of �6, an immediate deliverywill be considered.

Case ProgressionEight hours later, the patient denies feeling irregularcontractions that are seen on the tracing. Her tempera-ture is 36.6°C; heart rate, 79 beats/min; and bloodpressure, 121/77 mm Hg. Her finger stick blood glu-cose (FSBG) is 158. A cervical exam reveals a closed,long, posterior cervix and the following tracing is ob-tained (Fig. 2).



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● Variability: Moderate● Baseline rate: 145 beats/min● Episodic patterns: None● Periodic patterns: Variable deceleration● Uterine contractions: Irregular, palpate for intensity

and tone● Interpretation: Category II● Differential diagnoses: Normal FHR tracing● Action: The repeat BPP score is 8/8 with an amniotic

fluid index (AFI) of 14. Given the moderate variability,normal BPP score, and gestational age of 36 4/7 weeks, the plan is to continue with expectant man-

agement and continuous inpatient monitoring. In ad-dition, Category II tracings warrant close observationand may benefit from various therapeutic interventionsto optimize fetal oxygenation such as, maternal posi-tion change, O2 per rebreather mask, and intravenous(IV) hydration. It is important to inform the patientand family, however, of the possibility of induction oflabor or cesarean section if the fetal or maternal statusworsens.

Seven hours later, the patient is still not feeling anycontractions and her vital signs remain stable with aFSBG of 125. A repeat BPP is still reassuring with a scoreof 8/10. The associated tracing is seen in Figure 3.



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● Variability: Minimal● Baseline rate: 145 beats/min● Episodic patterns: Variable Deceleration● Periodic patterns: None● Uterine contractions: None noted, palpation for tone● Interpretation: Category II● Differential diagnosis: Same● Action: Variable decelerations are caused by cord com-

pression and are commonly seen in about 50% of allpregnancies. They can usually be resolved with mater-nal lateral positioning and IV hydration. Will continuewith expectant management as there is no indication toexpedite the delivery at this time.

Eight hours later, a cervical exam reveals no change inthe cervix; it is still long and closed; see Figure 4 for thefetal tracing.



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● Variability: Minimal-absent● Baseline rate: 150 beats/min● Episodic patterns: None● Periodic patterns: Late deceleration● Uterine contractions: None felt by patient or per pal-

pation● Interpretation: Category II evolving to a Category III● Action: The tracing shown is quickly evolving to a

Category III tracing, which reflects a fetus that isdecompensating and becoming increasingly hypoxicand possibly acidotic. A consultation with a perinata-

logist was obtained and given the persistent minimalvariability in addition to decelerations as well as anunfavorable cervix, a decision was made to proceed todelivery by cesarean section for nonreassuring FHR.Immediate interventions should focus on optimizingfetal oxygenation by lateral maternal positioning, O2

per rebreather mask, and IV hydration. Clear commu-nication with the charge nurse, anesthesia, neonatalintensive care unit (NICU) staff, and operating roomteam is imperative to ensure a timely, safe delivery. Thefinal tracing (Fig. 5) was obtained approximately60 minutes later.



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● Variability: Minimal - Absent● Baseline rate: 150 beats/min● Episodic patterns: None● Periodic patterns: None● Uterine contractions: None● Interpretation: Category II, progressing to Category

III● Action: In cases of diabetes and pregnancy, with

periods of suboptimal glucose control throughoutthe pregnancy, the possibility of nonhyperglycemicdiabetic ketoacidosis (DKA) should be entertained.DKA is an important etiology of nonreassuring fetalstatus as manifested by a Category III tracing withdecreased variability and late decelerations. This pat-tern was apparent in this patient. The simplest diag-nostic tool for a diagnosis of DKA in pregnancy is toevaluate the anion gap, which is easily calculatedfrom a metabolic panel and is often calculated by thelaboratory. Anion gap of less than 12 essentially rulesout DKA, and one of greater than 12 should raise the

possibility of this condition. Correction of DKA willoften result in improvement of a Category III trac-ing. Continue with interventions to improve bloodflow and oxygenation to the fetus (ie, maternalposition change, IV hydration, O2 per nonre-breather mask). Proceed with plans to deliver thefetus by cesarean.

OutcomeThe patient was prepped and transported to the ORwhere spinal anesthesia was administered. Approximately30 minutes later, a viable male infant weighing 3,420 kgis delivered by cesarean section with Apgars of 5 and 7.There was a nuchal cord X 1 that was reduced easilywithout incident. The infant was handed off to theNICU team, and responded quickly to stimulation andO2, and was transported to the NICU for further evalu-ation. Cord gases were obtained and the placenta wassent to pathology. The final pathology report revealedchanges of acute and chronic ischemia of the deciduacapsularis and extensive compensatory chorangiosis.


Table 2. Arterial Umbilical Cord Gas ValuespH Pco2 (mm Hg) Po2 (mm Hg) Base Excess

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

Respiratory Acidosis <7.20 >60 Variable < �10Metabolic Acidosis <7.20 <60 Variable > �10Mixed Acidosis <7.20 >60 Variable > �10Patient 6.89 118.2 <5 �10

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

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Cord gases revealed a mixed respiratory metabolic acido-sis (Table 2), which correlates with a Category II tracingthat is evolving to a Category III tracing. This case is anexcellent example of the importance of utilizing adjunctantepartum testing such as BPP to confirm fetal well-

being. In this case, close observation with continuousfetal monitoring and recognition of evolving fetal com-promise, allowed a few more days for fetal lung maturityand a good outcome. Both mother and infant were dis-charged 4 days later in stable condition.

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Maurice L. Druzin and Nancy Peterson Strip of the Month: December 2011












THE CASE:

One-day-old female infant presents with a posterior mediastinal mass on chest radiograph.

Prenatal History:

• 34-year-old white mother, gravida 13, para 4, abortus 8 • Estimated gestational age: 34 1/7 weeks • Uneventful pregnancy; ultrasonography at 22 weeks’ gestation did not reveal any

problems • Blood type A+, rapid plasma reagin nonreactive, hepatitis B surface antigen

negative, rubella immune, group B Streptococcus (GBS) screen negative • Spontaneous rupture of membranes at 9 hours before delivery and amniotic fluid

was clear

Birth History and Presentation: The infant was delivered from vertex presentation by spontaneous vaginal delivery at a weight of 1.5 kg. Infant had poor tone and respiratory effort, received positive pressure ventilation with Neopuff set at 5, and scores on the Apgar scale were 6 at 1 minute and 7 at 5 minutes. Upon admission to the NICU a chest radiograph was ordered (Fig. 1).

Continue with case progression...

Case Progression: Vital Signs:

• Heart rate, 120 beats/min • Respiratory rate, 44 breaths/min • Blood pressure, 58/32 mm Hg • Temperature, 98.6ºF (37ºC)

Physical Examination:

• Head: Normal, open fontanelles; no dysmorphic facial features; intact palate; patent nares

• Lungs: Clear; equal breath sounds • Cardiovascular Examination: Normal S1, S2; regular rhythm; no

murmur; equal peripheral pulses; capillary refill time 3 seconds • Abdomen: Soft; liver is 1 cm below the right costal margin; spleen is

not palpable; three-vessel umbilical cord • Genitourinary Examination: Normal female features • Extremities: Normal • Skin: No icterus, birthmarks, rashes, or lesions

Initial chest radiograph showed a mediastinal mass, which prompted a lateral decubitus to be ordered to locate the mass. The mass was located,

http://hinari-gw.who.int/whalecomneoreviews.aappublications.org/whalecom0/case95/progress.shtml

subcutaneous posterior to the vertebral column (Fig. 2). A thorough physical exam showed a cystic mass measuring 6x3 cm above the right scapula, compressible and mobile. The cystic mass is positive for trans-illumination (Fig. 3). Ultrasound of the mass was done.

Figure 2

Figure 3

What is your differential diagnosis.....

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http://hinari-gw.who.int/whalecomneoreviews.aappublications.org/whalecom0/case95/diagnose.shtml

Differential Diagnosis: Cystic hygroma. Teratoma. Lipoma. Sebaceous cyst. Bronchogenic subcutaneous cyst of the scapular area. Dermoid cyst.

Think first then...go to the actual diagnosis

Actual Diagnosis:

Cystic Hygroma

Continue to what "the experts" have to say... The Experts:

Cystic hygroma (CH) was first described by Wernher in 1843. CH is a congenital lymphatic malformation that occurs at sites of lymphatic-venous connection due to lack of venous outflow tract. It is considered to be a common benign tumor in childhood, which usually occurs everywhere in the body, except for the brain. CHs mainly affect the head and neck. CHs tend to form in loose areolar tissue. They may be single or multiple cysts distended with lymph. They are often classified according to the size of the fluid-containing components. Macrocystic is composed of large cysts (more than 2 cm in diameter), whereas a microcystic lymphatic malformation has small cysts or soft tissue enlargement without visible cysts.

They are frequently associated with Turner syndrome (girl), Noonan syndrome, Down syndrome, and Milroy's disease. An increased risk of cystic hygroma has been found in cases of maternal exposure to teratogens, such as alcohol, aminopterin, and trimethadione.

CH can often be diagnosed by clinical examination, especially if the skin is involved. An MRI scan is the best diagnostic test to show the extent of the malformation and the number and size of the cysts. Ultrasonography also

http://hinari-gw.who.int/whalecomneoreviews.aappublications.org/whalecom0/case95/finldiag.shtml

http://hinari-gw.who.int/whalecomneoreviews.aappublications.org/whalecom0/case95/experts.shtml

demonstrates cysts for a CH that is near the skin surface.

Signs and symptoms generally depend on the location of the lymphatic malformations. Those involving the mouth and airway can interfere with breathing and speech, while those in the arms and legs can cause swelling and heaviness.Lymphatic malformations typically produce enlargement of the affected tissues. This is often present at birth and increases in proportion with the growth of the individual. Occasionally, they can expand suddenly due to either infection or bleeding into the cysts.

Macrocystic lymphatic malformations can be treated by either sclerotherapy or surgical removal. Microcystic lymphatic malformations, especially those with no visible cysts, are more difficult to treat, and generally require surgical removal.

Recurrence of CH is rare if it is removed completely; however, there is a 15% recurrence rate if residual tissue is left after treatment. Continue to links to other resources...

Suggested Reading:

Abramowicz JS, Warsof SL, Doyle DL, et al. Congenital cystic hygroma of the neck diagnosed prenatally: outcome with normal and abnormal karyotype. Prenant Diagn. 1989;9:321–327

Chervenak FA, Isaacson G, Blakemore KJ, et al. Fetal cystic hygroma: cause and natural history. N Engl J Med. 1983;309:822–825

Edwards MJ, Graham Jr JM. Posterior nuchal cystic hygroma. Clin Perinatol. 1990;17:611–640

Geifman-Holtzman O, Drury HE, Holmes LB. Increased detection of cystic hygroma: a “technology-induced phenomenon.” Teratology. 1996;54:298–302

Machin G. Hydrops, cystic hygroma, hydrothorax, pericardial effusions, and fetal ascites. In: Gilbert-Barness E, ed. Potter's Pathology of the Fetusand Infant. St. Louis, MO: Mosby; 1997:163–181

Marchese C, Savin E, Dragone E, et al. Cystic hygroma: prenatal diagnosis and genetic counselling. Prenat Diagn. 1985;5:221–227

Siegel MJ, Glazer HS, St Amour TS, et al. Lymphangiomas in children: MR

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imaging. Radiology. 1989;170:467–470

Tanigawa N, Shimomatsuya T, Takahashi K, et al. Treatment of cystic hygroma and lymphangioma with the use of bleomycin fat emulsion. Cancer. 1987;60:741–749

Author: Ibrahim Hassan, MD, Kurepa Dalibor, MD, Elnagar Islam Hassan, MD, Megan Desotell, ARRN, NNP-BC, Guillermo Sangster, MD, Louisiana State University Health Science Center, Shreveport, LA

Prepared by: JoDee M. Anderson, MD, MEd, Division of Neonatal Medicine, Oregon Health & Science University, Portland, OR

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