12 Neoreviews - December2011

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Editorial Staff
Editor in Chief: Alistair G.S. Philip, Palo Alto, CA Associate Editor: Josef Neu, Gainesville, FL Associate Editor: Jayant Shenai, Nashville, TN Assistant Editor: Henry C. Lee, San Francisco, CA Assistant Editor, Visual Diagnosis: JoDee Anderson, Portland, OR Editorial Board: Dara Brodsky, Boston, MA Robert Castro, Palo Alto, CA Marilyn B. Escobedo, Oklahoma City, OK Ivan Hand, Great Neck, NY M. Gary Karlowicz, Norfolk, VA Jane McGowan, Philadelphia, PA Steven A. Ringer, Boston, MA Renate Savich, Albuquerque, NM Karen Shattuck, Galveston, TX Susan F. Townsend, Colorado Springs, CO William Truog, Kansas City, MO Founding Editor: William W. Hay Jr, Denver, CO International Advisory Board: Claudine Amiel-Tison, Paris, France Malcolm Battin, Auckland, New Zealand Matts Blennow, Stockholm, Sweden Jose Diaz Rossello, Montevideo, Uruguay Lex Doyle, Melbourne, Australia Janusz Gadzinowski, Poznan, Poland Gorm Greisen, Copenhagen, Denmark Kazushige Ikeda, Tokyo, Japan Ian Laing, Edinburgh, Scotland Frank Pohlandt, Ulm, Germany Jorge Cesar Martinez, Buenos Aires, Argentina Siddarth Ramji, New Delhi, India Francesco Raimondi, Naples, Italy Eric Shinwell, Jerusalem, Israel Bo Sun, Shanghai, China Cleide Trindade, Sao Paolo, Brazil Andrew Whitelaw, Bristol, United Kingdom David Woods, Cape Town, South Africa Khalid Yunis, Beirut, Lebanon Tsu-Fuy Yeh, Taichung, Taiwan Liaison, Council of International Neonatal Nurses: Carole Kenner, Boston, MA Managing Editor: Luann Zanzola Editorial Assistants: Lani Lucente Demchak, Kathleen Bernard Publisher: American Academy of Pediatrics Associate Executive Director for Education: Robert Perelman Division of Scholarly Journals Director: Michael Held
NeoReviews
contents
Vol.12 No.12 December 2011
Articles
e687 e698 e706 e714 e721 e727 e731 e741
Educational Perspectives: Creating an Effective

PowerPoint Presentation
Dara Brodsky, Elizabeth G. Doherty
Developmental Origins of Adult Disease:

Part 1: Cardiovascular
Patricia Y.L. Chan, Jonathan M. Morris, Eileen D.M. Gallery
NeoReviews
(ISSN 1526-9906) is owned and controlled by the American Academy of Pediatrics. 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 authors and not necessarily those of the American Academy of Pediatrics or its Committees. Recommendations included in this publication do not indicate an 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 Section Member $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 without permission of the American Academy of Pediatrics. POSTMASTER: Send address changes to NEOREVIEWS, American Academy of Pediatrics, 141 Northwest Point Blvd., Elk Grove Village, IL 60007-1098. NeoReviews is supported, in part, through an educational grant from Abbott Nutrition, a division of Abbott Laboratories, Inc.

Part 2: Renal

Part 3: Metabolic
Index of Suspicion in the Nursery:

Case 1: A 4-day-old Who Has Decreased Activity and Poor Feeding Case 2: Profuse Diarrhea in a 4-day-old Term Male
Case 1: Marilisa Elrod, John C. Arnold Case 2: Resmy P. Gopi, S. Khanna, B.K. Rajrgowda
NeoReviews Editorial Board Disclosures

The American Academy of Pediatrics (AAP) Policy on Disclosure of Financial Relationships and Resolution of Conicts of Interest for AAP CME Activities is designed to ensure quality, objective, balanced, and scientically rigorous AAP CME activities by identifying and resolving all potential conicts of interest before the conrmation of service of those in a position to inuence and/or control CME content. All individuals in a position to inuence and/or control the content of AAP CME activities are required to disclose to the AAP and subsequently to learners that the individual either has no relevant nancial relationships or any nancial relationships with the manufacturer(s) of any commercial product(s) and/or provider(s) of commercial services discussed in CME activities. Commercial interest is dened as any entity producing, marketing, reselling or distributing health-care goods or services consumed by, or used on, patients. Each of the editorial board members, reviewers, question writers, and staff has disclosed, if applicable, that the CME content he/she edits/ writes/reviews may include discussion/reference to generic pharmaceuticals, off-label pharmaceutical use, investigational therapies, brand names, and manufacturers. None of the editors, board members, reviewers, question writers, or staff has any relevant nancial relationships to disclose unless noted below. The AAP has taken steps to resolve any potential conicts of interest.
Legal Briefs:
KernicterusStill Preventable
Maureen E. Sims
Strip of the Month: December 2011

Maurice L. Druzin, Nancy Peterson
Visual Diagnosis: One-day-old Female Infant Presents With Mediastinal Mass on Chest Radiograph
Ibrahim Hassan, Kurepa Dalibor, Elnagar Islam Hassan, Megan Desotell, Guillermo Sangster
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 Ofces, Environs and Nestl; and that he has a research grant, serves as a consultant and on the advisory board of Mead Johnson. William Truog, MD, FAAP, disclosed that he participates in a pilot clinical research study for ONY Inc; and participates in the Trial of Late Surfactant (to Prevent BPD) of the National Heart, Blood and Lung Institute.
Continuing Medical Education Statements The 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 claim only 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 available to 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 National Association of Pediatric Nurse Practitioners Continuing Education Guidelines. It has been established that each months question will take the learner a maximum of 1.5 hours to complete. How to complete this activity NeoReviews can be accessed and reviewed online at http://neoreviews.aappublications.org. Learners can claim credit monthly online. The deadline for submitting 2011 answers is December 31, 2013. Credit will be recorded in the year in which it is submitted. It is estimated that it will take approximately 1.5 hours to complete each issue. This activity is not considered to have been completed until the learner documents participation in that activity to the provider via online submission of answers. Course evaluations will be requested online.
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
Educational Perspectives: Creating an Effective PowerPoint Presentation Dara Brodsky and Elizabeth G. Doherty NeoReviews 2011;12;e687-e697 DOI: 10.1542/neo.12-12-e687
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://neoreviews.aappublications.org/cgi/content/full/neoreviews;12/12/e687
NeoReviews is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 2000. NeoReviews is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2011 by the American Academy of Pediatrics. All rights reserved. Online ISSN: 1526-9906.
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educational perspectives
Creating an Effective PowerPoint Presentation

Dara Brodsky, MD,* Elizabeth G. Doherty, MD
Abstract
This review provides the reader with a comprehensive strategy about how to prepare and deliver a slide presentation by using the most popular software presentation program, Microsoft PowerPoint. With extensive preparation, keen organization, precise formatting, appropriate use of audiovisual aids, and effective delivery, PowerPoint can be a successful tool for teaching. However, if used ineffectively, this technology can prove to be disadvantageous where listeners may succumb to passive learning without critical thinking. This paper will guide novice speakers to rene their presentation skills and will encourage experienced presenters to refresh their presentation approach.
Learning Objectives
able to:
Author Disclosures Drs Brodsky and Doherty have disclosed no nancial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/device.
After completing this article, readers should be
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.
Introduction
Although most neonatology fellows and neonatologists have experience presenting a talk, few have been taught a systematic approach to create an effective presentation. This review will provide the reader with a comprehensive strategy about how to prepare and deliver a slide presentation by using the most popular software presentation program, Microsoft PowerPoint. PowerPoint is undoubtedly one of the most useful technological developments for educators and has revolutionized medical teaching. It is used in nearly every learning environ-
*Department of Neonatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. Department of Neonatology, Childrens Hospital Boston and Winchester Hospital, Harvard Medical School, Boston, MA.
ment within neonatology, including clinical lectures, research presentations, grand rounds, and talks at national conferences. PowerPoint can help presenters emphasize key points, explain complicated topics, and provide striking visual images. However, educators are concerned that PowerPoint has created some bad habits in listeners, such as fragmented thinking because of the use of bulleted lines; simplied ideas because complex concepts are condensed; inability to process information because of the rapid ring of content; and passive learning with lack of critical thinking, partly as a result of limited audience involvement. We believe that if PowerPoint is used appropriately, speakers can minimize some of the potential weaknesses and create a presentation that:
NeoReviews Vol.12 No.12 December 2011 e687
Table 1.
Planning the Presentation
Know 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
Connects and builds on previous knowledge, Teaches complicated concepts, Allows the audience to process information, Engages listeners, and Motivates the audience to learn more.
What is the audiences baseline knowledge of the topic? What does the audience need to learn about the topic?
To generate a successful presentation, we encourage the speaker to incorporate the following steps: extensive preparation, keen organization, precise formatting, appropriate use of visual aids, and effective delivery. We hope that after reading this review, readers of all levels of experience will be able to nd new approaches to assist them with their presentations.
The answers to these questions will guide the speaker to develop content that is meaningful and interesting to the listeners. A talk about congenital heart disease will be different if it is presented to nurses, medical students, or neonatologists. Presenters should also consider additional questions focused on the program itself (see Table 1 for additional questions):

England Journal of Medicine, Pediatrics, etc.) and the most recent publications (within the past few years). Speakers must thoroughly understand their material and become an expert on the topic. Ideally, even if an audience member is an expert in the eld, the speaker should still be able to teach that person something about the topic. For example: If you are presenting a review about surfactant deciency to a group of neonatologists, try to nd something fascinating or current about the topic that even Dr Mary Ellen Avery would nd interesting. Although it may be tempting to then go directly to the presentation program and create slides, a talk will be more organized and the presenters time will be used more efciently if a detailed outline is developed rst. By selecting visual aids early during this preparation phase, each visual will serve a specic purpose and become integral to the presentation. Although this preparation process has been presented as a linear approach, most seasoned presenters utilize a feedback loop and backtrack approach as they continue to rene content material. It is important for speakers to remember that early preparation leads to success by allowing for adequate time to modify the talk, add effective visual aids, and practice.
What has been requested of you? How much time have you been allotted? Are you the only speaker?
Creating Slide Content

After researching and mastering the topic, writing a detailed outline, and determining the visual aids, speakers are now ready to create their PowerPoint slides. The slide content can be divided into three components: introduction, body, and conclusion (Table 2).
Planning the Presentation

Before opening the PowerPoint program, presenters need to carefully plan their presentation (Table 1). Speakers can begin this process by identifying some characteristics of their listeners:
Who is the audience?
Based on the answers to these questions, presenters will need to decide what they want to convey. What is the focus and purpose of the talk? This will enable presenters to target their research. It is critical to research the topic by using well-respected peer-reviewed sources (eg, The New
Introduction
Because audience concentration, interest, and receptiveness are height-
e688 NeoReviews Vol.12 No.12 December 2011
Table 2.
Creating Slide Content
4. COMPARATIVE Comparison of two or more methods, models, perspectives, and treatments. 5. THESIS Assertion made and then proven or refuted. Within the body of the talk, speakers should reinforce key concepts to help the listener understand and retain the presented information. Speakers can solidify concepts by incorporating the following methods:

Introduction 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 or students or if CME credits are offered.
ened during the rst 5 minutes of a talk, the speaker should try to gain the audiences attention at the beginning of the presentation. Opening the presentation with a provocative question, striking example, short videotape, personal anecdote, dramatic contrast, powerful quote, or demonstration will help the speaker obtain everyones attention. It is important for the presenter to vary this opening because any dramatic introductory technique loses impact with repetition. If the audience is composed of trainees or students, the speaker may nd it helpful to disclose the learning objectives of the talk (ie, what you expect the trainee/student to learn by the end of the lecture) as a statement or a question. For example, By the end of this talk, you will be able to explain normal cardiac development and describe 3 key features of fetal cardiac physiology. Ideally, the speaker should then provide an overview of the talk. This framework will help attendees be aware of the expected sequence and content of the talk. This overview slide can be repeated throughout the presentation to let the audience know where the talk is currently and what is coming next.
Body
When crafting the body of the talk, the lecturer must ensure that the content is congruent with their objectives. The speaker is required to focus the material and avoid the tendency to cover everything about the topic. Indeed, studies have shown that listeners remember more when they are told less. Audiences cite lack of structure as one of the most frequent problems of presentations. Thus, speakers must take the time to make sure that the sequence of the talk makes sense. Most medical presentations can be presented in one of the following formats: 1. CLASSICAL The talk has a standard formula (eg, clinical case 3 diagnosis 3 epidemiology 3 clinical, radiographic, and laboratory ndings 3 management 3 outcome); alternatively, lecture begins broadly and then is subdivided. 2. PROBLEM-TO-SOLUTIONS The problem is presented and various solutions are described. 3. SEQUENTIAL The case is presented in a time sequence with key concepts mixed in-between.
Use examples Put concepts into various contexts Provide mini-summaries of key concepts (particularly useful when presenting complicated concepts) Pose questions to the audience (helpful for speaker to assess audience understanding before discussing the next concept; added benet of engaging audience)
By combining these techniques of reinforcement, the speaker can also help the audience acquire a deeper understanding of the topic. Because most adults have an average attention span of 15 to 20 minutes during passive listening (during a less stimulating talk, this time period may even be shorter), speakers need to think of strategies to deliberately engage the audience. Speakers can maximize audience attention by varying their visual aids (eg, radiographs, tables, graphs, videotapes) throughout the talk. Presenters can involve their listeners by posing questions, asking for comments, or seeking opinions from the group. Presenters can also ask a member of the audience to participate in roleplay, perhaps acting as a physician, consultant, or family member. In addition, speakers can intersperse problems that audience members need to solve individually. Alternatively, speakers can ask the audience to break into pairs or three- to four-person groups
Table 3.
Basic Formatting Guidelines for PowerPoint Presentations

Specic Tips Change the font style and size Modify color scheme Create background Add images that will automatically be part of each slide PowerPoint View
Slide Feature
General Concepts
Master slide
Use master slide to ensure consistent formatting throughout
Font type
Use simple, legible font
Use standard font common to all computers to avoid font substitution if font not available on presentation computer Avoid serif fonts, which have short lines at ends of each character (eg, Times New Roman)
Prefer smooth fonts, known as sans serif, which do not have short lines at the ends of each character (eg, Arial)
Ideal if consistent font (at most 2) throughout presentation
Font size
Use 8-foot rule: Print out slide and tape it to the wall; should be able to read the slide from 8 feet away
Use font size of 2848 pt for headings Use font size of 2432 pt for body (if absolutely necessary can use 22)
Downloaded from http://neoreviews.aappublications.org. Provided by Health Internetwork on December 1, 2011 Prefer white or bright yellow text on a blue background (easiest to read in dim light) Use of a white background can lead to screen glare but this is minimized with black text Use of a black background provides too much contrast (Continued)
Colors
Create sharp contrast between text and background color
Use basic background so audience is not distracted
Remember that colors on computer screen do not always appear the same when projected
Table 3.
Basic Formatting Guidelines for PowerPoint Presentationscontinued

Specic Tips Try to limit words to 7 or less per bulleted line Try to limit bullet points to 5 or less per slide PowerPoint View
Slide Feature
General Concepts
Bulleted lines
Limit number of words on line
Content should be abridged version of speakers content
Line spacing
Adjust line spacing
Instead of placing an extra line between bulleted lines, explicitly dene space by using Line spacing Paragraph refers to a group of words followed by enter; also refers to a bulleted or numbered list and a title or subtitle Use of Before paragraph designates the space before the paragraph Use of After paragraph designates the space after the paragraph
Set Line spacing value at 0.85 lines or higher to minimize overlapping lines
2007 PowerPoint view:
Downloaded from http://neoreviews.aappublications.org. Provided by Health Internetwork on December 1, 2011 (Continued)
Find line spacing option in 2007 PowerPoint by clicking Format and then Paragraph; in 2010 PowerPoint version, nd by clicking symbol below and then clicking Line Spacing Options
Left image normal view Middle image slide sorter view Right image slide show view Of note, in 2010 version, a reading view is also an option
PowerPoint View
to solve a problem or discuss a topic; this approach even works well with large groups. These active learning tactics have an additional benet of facilitating deeper learning. Presenters need to be careful not to use too many activities because an excess can minimize the intended effect.
Conclusion
Interestingly, studies have revealed that audience attention peaks again just before the presentation ends. Thus, it is important to nish the talk on a positive note. Speakers should avoid being in a situation that warrants saying: And let me just add one more thing . . . or I guess I ran out of time, so I better end now. Rather, the speaker should use this opportunity of heightened audience attention to provide a sense of closure. By reviewing the key concepts of the talk or the learning objectives, the speaker can retrace his or her steps. This review shows the audience that their newly acquired knowledge is a direct benet of having heard the lecture. The last part of the talk also provides the speaker with the opportunity to encourage self-directed learning. For example, the presenter might discuss the need for further research or conclude with a thoughtprovoking question or problem. In addition, the speaker can provide the audience with handouts, take-home problems, or a list of resources to foster continued learning about the topic.
Basic Formatting Guidelines for PowerPoint Presentationscontinued
Slide sorter view helps to assess ow of talk and easily rearrange slide order
Refer to slide sorter to obtain a quick overview of all the slides
General Concepts
Formatting in PowerPoint
Audiences judge not only the content of the slides, but also the formatting technique. Slides that are difcult to read may lead to attendee frustration that may cause lack of interest for the duration of the talk. As a rule, speakers should not apologize for poor quality slides; rather, speak-
ers should not use them! When a talk is formatted correctly, viewers should focus on the content of the slides, not the details of font style, color, text size, and bulleting. Presenters should use their slides as a means to enhance their presentation, not as a crutch to get through it. Speakers should meticulously review each slide and simplify content by using key words instead of sentences. If slides contain wordy, long sentences, viewers need to decide whether they are going to read the slide or listen to the speaker, but they cannot do both! In contrast, if the slides have a limited number of words, the audience can look at the slides, listen to the speaker, and understand the content at the same time. It is ideal to limit each slide to one idea and use multiple slides to explain complex concepts; if there is a wealth of material, consider providing information in a handout. Keep in mind that slides should not be able to stand alone; they should require speaker commentary to provide a complete story. Basic and advanced formatting guidelines for PowerPoint presentations are summarized in Tables 3 and 4, respectively. Adding visuals, such as a table, graph, picture, or cartoon, can help stimulate audience interest and increase understanding. Indeed, when explained well, visual aids are easier to grasp than words. However, to be effective, visuals need to be used appropriately. Table 5 offers suggestions about the use of audiovisuals and animations in PowerPoint presentations.
Can also access within View in upper toolbar (Slide Sorter)
Access via bottom toolbar
Specic Tips
Practicing the Presentation

By practicing and rehearsing the presentation, the speaker will be more capable and feel more comfortable presenting. This allows the speaker to have the ability to interact and
Slide Feature
Table 3.
Sort slides
Table 4.
Advanced Formatting Tools for PowerPoint Presentations

Specic Tips PowerPoint View
Tool
General Concepts
Adjust font size
Can adjust font size by highlighting words or selecting text box
Indent lines
Can adjust bulleted lines to a specic level
For adjusting fonts of all words in a text box by 46 pt, click on border of text box and then click on large or small A within toolbar on top screen To move text to next or prior level, can use symbol (shown to right) located in top toolbar To move text to next level, pressing Tab at beginning of line will also work
Order, align, and group objects
Quicker and simpler to use automatic computer commands than using your eye or grids To order, align, and group objects, use Draw tab in Drawing toolbar
To control relative positions of two or more objects, select one object and Order to . . . To align objects, select all objects (press Shift and then select each item) and position using Align or Distribute To group objects, select all objects then Group; all grouped objects will move or be resized together
Reposition images or text boxes
Use this tool for making small adjustments in location of text boxes, shapes, and images
Navigate between slides
Example of action button on slide:
Downloaded from http://neoreviews.aappublications.org. Provided by Health Internetwork on December 1, 2011 Click on image or text box that you want to move; then click Control button on keyboard, then move image or text by using arrows on keyboard For PowerPoint 2007: Go to Slide Show in upper toolbar, view Action buttons; select one For PowerPoint 2010: click Insert 3 Shapes 3 Action Button Next, place action button within slide Then, determine what action occurs when this button is clicked (options include: end show, rst slide . . .) To return to previous slide, insert action button: Note: these actions will only work in Slide Show mode
Use action button to navigate from one slide to another within the same presentation Alternatively, can use action button to navigate from slide to hyperlink (note: can also insert hyperlink directly by clicking on Insert in upper toolbar and then choosing Hyperlink)
Table 5.
Using Audiovisual and Animations in PowerPoint Presentations

General Concepts Use visuals to stimulate interest and increase understanding Use only legible images; if you need to say: I know you cannot read this table but . . . then that table should not be included in the presentation During the presentation: o Take the time to explain the visual (eg, x and y axes are represented as . . .) o Give the audience enough time to absorb the information in the visual Insert videos as embedded (stand alone within presentation, preferred form) or object linked (requires original computer folder to be open) Practice opening video before talk by using presentation computer; use personal computer if object linked video Specic Tips
Tool
Visuals (such as a table, picture, cartoon, graph)
Videos
Animations
Use animation judiciously to add emphasis, explain a complicated concept by building layers of information, or force audience to focus on just one part of slide at a time Consider reducing the size of the slide show le by compressing graphics Helpful if computer has limited memory, saving to ash drive, or transferring via email
Downloaded from http://neoreviews.aappublications.org. Provided by Health Internetwork on December 1, 2011 Try to eliminate any distractions in graphs, such as minor tick marks and background lines Highlight important components of a visual with circles or boxes Increase contrast between visual and background by adding a border Eliminate any patient identiers It is a common misconception that material downloaded from the Web is available for anyone to use as they choose; however, you need to cite the source and may need copyright permission; if you cannot nd the source, best not to use the visual To increase chance of embedding in 2007 version, create video and slide presentation within same folder; 2010 version allows easier insertion of embedded video (also allows for customization of video) For inserting videos: o 2007 version: Click Insert 3 Movies and Sound 3 Movie from File o 2010 version: Click Insert 3 Video o Most convenient if video played When clicked Use consistent type of animation throughout talk Keep animation style simple Avoid adding sound to animation Avoid using many animations because that may be distracting Go to any slide that has an inserted picture or clip art graphic Right click on the graphic and choose Format Picture On the Picture tab, click Compress Mark All pictures in document in the Apply to section Mark Web/Screen in the Change resolution section Check both boxes in the Options section Click OK twice Slide show le should now be up to 75% smaller
Reduction of le size
Table 6.
Tips to Modify Delivery of a Presentation

Specic Tips for Presenter Relax and take deep breaths before the talk Remind yourself that nervousness lessens as you get under way Memorize the rst few slides in anticipation of early anxiety; as a back-up plan, you can write detailed notes of the rst few slides in large font to refer to in case of signicant difculty Look at as many people as possible o Mentally divide the lecture room into 35 sections and make eye contact with people in each group during the course of the talk o Look in the middle of 2 attendees or look at listeners 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 audiences understanding and interest level and adjust talk accordingly Use facial expressions Vary your pitch Focus on the meaning of what you are saying because this will make you more expressive 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 Know midway point in talk and when you get there, assess if you are behind or ahead of schedule If you are behind schedule, best not to speed up to cover everything (ideal to make a contingency plan and anticipate possibility of omitting a few slides) Take advantage of the pause (eg, after saying this is really important) Let audience know that something is important (eg, This is a really signicant nding and important for you to remember.) Speak more slowly when you want to emphasize key points
Behavior Minimize nervousness
Maintain eye contact
Show enthusiasm
Be natural
Monitor pace of delivery
Emphasize key points
connect with the audience during the presentation. When practicing, the speaker should factor in the possibility of a delay in start time and leave several minutes for questions; if the talk is too long, the presenter should not plan on speaking quickly, but instead, remove content. If the talk is too short, instead of planning to start late or end early, the speaker needs to add more content! If the talk will be presented to a large national audience, the speaker should consider practicing rst with a small local group. Speakers must know the presentation environment. Indeed, some projectors cut off edges and thus some content may not be seen. If the talk is in a conference room with a
large table in front, the audience may not be able to see the bottom of the slides. Moreover, some computers may alter slide images or content (eg, symbols may change, image quality may project differently, etc). As Dr Charles Hatem teaches, on the day of the presentation, speakers should case the joint by arriving early. During this time, the following steps should be taken:
temperature) and if possible/ necessary, make adjustments. Practice using the slide changer and the laser pointer.
Presenters should be prepared for something to go wrong and plan ahead by having a hard copy of the slides in addition to a ash drive copy.
Put the presentation on the room computer or connect your computer into the facilitys set-up. Quickly view all slides in presentation mode and conrm that video clips are working. Be aware of the nuances of the venue (lighting, outside noise,
Delivering the Presentation and Responding to Questions

No matter how much time and effort a speaker puts into preparing the content of a PowerPoint presentation, if the delivery is subpar, the talk will be ineffective. Indeed, the speakers behaviors can either energize
Table 7.
Presentation Techniques
General Concepts Use to temporarily shut off slide presentation and allow audience to concentrate on speaker Use Alt and Tab function to have this option Specic Tips If you press the letter B on the keyboard when in Slide show, screen will go black If you press the letter W on the keyboard when in Slide show view, screen will go white To return to presentation, press any key Preopen website or document on computer During slide show view, press Alt and keep nger 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 In presentation mode, right click on mouse Offers option of Pointer options Select option and draw on slide In 2007 PowerPoint, click on Slide Show tab on upper toolbar, then click on Set Up Show, then locate Multiple Monitors and check box labeled Show Presenter View In 2010 version, under the Slide Show tab, locate the Monitors section and check box labeled Use Presenter View In the Show Presentation On menu click the monitor you want the slide show presentation to appear on
Tool Clear slides on screen
View another item open on computer
Access drawing tool Presentation mode (or Presenters View)
Can use drawing tool during presentation to highlight areas Audience sees the presentation as they would normally; presenter sees additional information Presenter views a scaled down version with timeline of the slides along the bottom and the notes from each slide Note: this mode can be distracting for the speaker so not preferable
or retract from the content. Tips to modify ones delivery are summarized in Table 6. In addition, Table 7 highlights some practical techniques that can be used during the presentation. The speaker should make every effort to answer questions effectively and accurately. This process involves repeating the question; this ensures that the audience has heard the query, conrms that the speaker has understood the question, and provides the speaker with additional time to gather his or her thoughts. If the answer to a question is complicated, the speaker can consider a brief response to the question and then offer the audience member an opportunity to discuss the answer in more detail after the talk. Alternatively, if the presenter had anticipated this complicated question, he or she can refer to additional slides after
the conclusion to assist with this response. If the speaker does not know the answer to the question, he or she should acknowledge this and offer to get back to the audience with an answer. When responding to an argumentative audience member, it is best not to be confrontational but rather, be respectful, acknowledge the comment, and offer to meet later to discuss the issue further. If someone presents a monologue instead of posing a question, the speaker should feel free to kindly interrupt and provide his or her thoughts.
most useful tools in professional development. Speakers can ask themselves:

What went well? What could have been improved? What content needs to be explained better or added to the presentation? (Think about the questions that were asked and if the audience seemed confused at any point during the talk.)
Improving the Presentation

Regardless of the speakers level of experience or success of the presentation, there is always room for improvement. Self-reection about a presentation is perhaps one of the
Some learner evaluations can be helpful, particularly if they offer specic suggestions. Presenters can review the videotape of the session with and without sound to gain specic information about their behaviors, such as assessing their level of enthusiasm, degree of nervousness, and use of ller words (eg, um, uh, er, or like). Alternatively, speakers can
ask a colleague to observe their talk and provide them with objective feedback. In the Harvard Neonatology Fellowship Training Program, all rst year fellows receive feedback from an attending about their presentations through a Grand Rounds Mentorship Program (developed by D. Brodsky). We encourage other training programs to institute a similar process. Speakers should take these collective suggestions and alter the content of their PowerPoint presentation as soon as possible. In addition, speakers should write down recommended behavioral changes so that before their next presentation, these notes can be read and serve as reminders. Presenters should attempt to remember at least three positive aspects of their talk to capitalize on this insight and build condence for their next talk.
rounds. Speakers who consistently adhere to extensive preparation, keen organization, precise formatting, appropriate use of audiovisual aids, and effective delivery, as well as diligent practice and use of constructive feedback, will raise the level of their presentation to one that is well-received and reects their skill as an effective educator. We hope that this review for creating an effective PowerPoint presentation will guide novice speakers to rene their presentation skills and will encourage experienced presenters to refreshen their presentation approach.
Suggested Reading
Bellamy 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;26:162164 Brown G, Manogue M. AMEE Medical Education Guide No 22: refreshing lecturing; a guide for lecturers. Med Teach. 2001;23:231244 Davis BG. Tools for Teaching. 2nd ed. San Francisco: Jossey-Bass Publishers;1993 Giving a presentation. J Vis Commun Med. 2006;29:115118 Harden RM. Death by PowerPoint: the need for a dget index. Med Teach. 2008;30:833 835 Hatem CJ. Crafting effective lectures. Seminars for Rabkin Fellowship in Medical Education. Boston, MA: Beth Israel Deaconess Medical Center; 2009 Holzl J. Twelve tips for effective PowerPoint presentations for the technologically challenged. Med Teach. 1997;19: 175179 McLaughlin K, Mandin H. A schematic approach to diagnosing and resolving lecturalgia. Med Ed. 2001;35:11351142 Niamtu J. The power of PowerPoint. Plast Reconst Surg. 2001;108:466 484 Wear D. A perfect storm: the convergence of bullet points, competencies, and screen reading in medical education. Acad Med. 2009;84:1500 1504
American Board of Pediatrics Neonatal-Perinatal Content Specications

Understand the attributes of an effective learning environment. Understand the strengths and weaknesses of various teaching methods (eg, lecture, small group discussion, bedside teaching, simulation).
Conclusion
PowerPoint has become a standard means of presenting lectures, case studies, research topics, and grand
Educational Perspectives: Creating an Effective PowerPoint Presentation Dara Brodsky and Elizabeth G. Doherty NeoReviews 2011;12;e687-e697 DOI: 10.1542/neo.12-12-e687
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Developmental Origins of Adult Disease: Part 1: Cardiovascular Disease Patricia Y. L. Chan, Jonathan M. Morris and Eileen D. M. Gallery NeoReviews 2011;12;e698-e705 DOI: 10.1542/neo.12-12-e698
Article
origins of cardiovascular disease
Developmental Origins of Adult Disease: Part 1: Cardiovascular Disease

Patricia 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
Abstract
There is now considerable evidence from numerous epidemiologic, animal, and clinical studies demonstrating the association of early life conditions and increased risk of subsequent adult disease such as cardiovascular, renal, and metabolic disease. This rst of three articles reviews the developmental origins of cardiovascular disease and the proposed underlying mechanisms.
Objectives
After completing this article, readers should be able to:
Author Disclosure Drs Chan, Morris, and Gallery have disclosed no nancial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/device.
1. Understand the concept of developmental origins applied to cardiovascular disease and associated controversies. 2. Describe the proposed underlying mechanisms of developmental origins applied to cardiovascular disease such as programming, thrifty hypothesis, developmental plasticity, epigenetic mechanisms, and predictive adaptive response. 3. Understand the challenge for future research.
Introduction
Cardiovascular disease is the leading cause of morbidity and mortality globally and is no longer limited to economically developed countries. (1) It accounts for almost 30% of all deaths in the world. (1) The established risk factors for cardiovascular disease such as age, sex, genetic disposition, cigarette smoking, hypertension, diabetes mellitus, hyperlipidemia, and obesity (2) have limited ability to predict the occurrence of cardiovascular disease and offer little insight into why one person develops the disease whereas another does not. (3) The paradoxical social and geographical distribution of ischemic heart disease, why a disease associated globally with afuence is now most common in the poorest parts of Britain and among people with the lowest incomes led Barker and colleagues to propose the hypothesis that fetal growth restriction and low weight gain in infancy are associated with an increased risk of adult cardiovascular disease. (4)(5)(6)
Low Birthweight and Adult Cardiovascular Disease

The concept that early life events have long-term effects on adult human health dates back many years. Kermack et al (1934) (7) reported that death rates from all causes in Great Britain 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 indicated the importance of good environmental conditions during childhood in predicting the future health of the individual. (7) Forsdahl (1977) (8) discovered a geographical correlation in Norway between mortality from arteriosclerotic heart disease in men and women aged between 40 and 69 years in 1964 to 1967 and infant mortality rates in 1896 to 1925. He suggested that great poverty in childhood and adolescence followed by prosperity is a risk factor for arteriosclerotic heart disease. (8) Barker and colleagues studied the records of birthweights and weight at age 1 year of all infants born in Hertfordshire between 1911 and 1930, and produced the rst 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, Kolling Institute of Medical Research, University of Sydney at Royal North Shore Hospital, St Leonards, NSW 2065, Australia. e698 NeoReviews Vol.12 No.12 December 2011
that coronary heart disease might originate in utero or during infancy. (5)(9) They showed that lower birthweight and weight at 1 year were each associated with an increased risk of subsequent death from cardiovascular disease in adulthood. The trends for premature deaths from cardiovascular disease were similar in men and women, and rates fell with increasing birthweight up to 9.5 lb. (9) There was an approximate doubling of mortality from the higher to the lowest extremes of birthweight similar in men and women. However, there was an increased mortality in the group whose birthweight was higher than 9.5 lb, indicating a U shape relationship. Subsequent studies in the UK, Europe, and the United States have conrmed these ndings and indicated that restricted fetal growth carries the risk of adult cardiovascular disease. The effects are linear, across the range of birthweights, and independent of adult socioeconomic status. Although most of these studies were limited to birthweight as a measure of fetal growth, there is evidence that body proportions at birth such as low ponderal index (weight/length3) predicted coronary heart disease better than birthweight in Finland, (10) and a low birthweight-head circumference ratio predicted stroke mortality in the UK. (11) It has also been suggested that discordance between placental and fetal size may lead to circulatory adaptation in the fetus, altered arterial structure in the child, and hypertension in the adult. (12) All of this suggests that impaired nutrition supplied by the placenta, resulting in fetal growth restriction in utero, is the culprit, rather than being small at birth because of prematurity but of a weight appropriate for gestational age at birth.
Birthweight and Risk Factors

Subsequent work has shown that while lower birthweight and other measures of small size at birth are associated with the development of later cardiovascular disease, they are also associated with an increase in cardiovascular disease risk factors.
High Blood Pressure

Raised blood pressure is a well-established risk factor for cardiovascular disease. (2)(13) The evidence for this relationship arises from large scale prospective observational studies, two landmark ones being the Framingham Study (2) and the Seven Countries Study. (13) Birthweight has been the most widely studied measure in retrospective studies, mainly due to its availability from existing records or personal recall. Blood pressure is the most commonly reported outcome because mea-
surement is noninvasive, quick, and relatively easy at all ages. The association between lower birthweight and subsequent elevated blood pressure levels has been considered to provide some of the strongest and most consistent support for the fetal origins hypothesis of adult disease. The rst associations found were between low birthweight and later life hypertension and cardiovascular disease. (6) High blood pressure was found to occur at a higher incidence in children and adults who were of low birthweight. (6) Studies have been reviewed by Leon et al, (14) Law et al, (15) Huxley et al, (16) and Adair et al. (17) Most have demonstrated an inverse association between birthweight and later blood pressure or an inverse association between birthweight and risk of hypertension. However, the authors of these studies collected data and reported their ndings in a variety of ways. (18) Based on a systematic review of multivariate regression coefcients from 34 studies reported before March 1996, involving a total of 66,000 people, it was estimated that a 1-kg higher birthweight is typically associated with a 2 to 3 mm Hg lower systolic blood pressure. (15) An update of that review, (16) which included regression coefcients from an additional 45 studies, involving over 444,000 people, indicated an inverse association of 2 mm Hg/kg, as did another review of the same studies. (14) A more recent study of 25,874 men and women observed a strong interaction between birthweight and age to predict systolic blood pressure, 1.1 mm Hg/kg after adjusting for age, sex, and body size. (19) This inverse association was amplied with age, (19) giving support to the hypothesis that fetal programming of high blood pressure is amplied throughout life. Not all authors share this view. Huxley et al (18) explored the possible impact of publication bias, measurement error, inappropriate adjustment for current weight, potential confounders such as sex, height, parental socioeconomic status, current socioeconomic status, parental blood pressure, alcohol consumption, race, and gestational age. They concluded that birthweight is of little relevance to blood pressure levels in later life when the impact of random error, publication bias, inappropriate adjustment for current weight, and confounding factors are considered. The strength of association between birthweight and subsequent hypertension remains widely debated. However, it appears that although the relation is not invariant, the totality of evidence suggests an important direct or indirect interaction between birthweight and subsequent hypertension.
Potential mechanisms linking restricted fetal growth to adult hypertension include redistribution of blood ow away from the liver, viscera, and the kidneys, in preference for the brain, leading to underdevelopment of these organs. The kidneys of growth-restricted infants are smaller and contain fewer nephrons than those of appropriate weight for gestational age infants. The role of the kidney in the pathogenesis of hypertension is well established and is discussed further in the article on Developmental Origins of Adult Disease: Part 2: Renal Disease. Other possible mechanisms include persisting changes in vascular structure, including loss of elasticity in vessel walls, and the effects of glucocorticoid hormones.
density lipoprotein cholesterol as adults. (20) They also had raised plasma brinogen concentrations, another major risk factor for mortality from coronary heart disease that is regulated by the liver. (21) Overall, the association between serum lipid concentration and size at birth is less consistent and not as well established as the associations with hypertension or diabetes.
Conceptual Models
McCance and Widdowson were among the rst to show that brief periods of undernutrition may permanently reduce the number of cells in particular organs. (22) This is a powerful mechanism by which undernutrition could permanently change or program the body. (4) Undernutrition may also affect distribution of cell types, patterns of hormonal secretion, metabolic activity, and organ structure. (4)
Metabolic Syndrome
The metabolic syndrome, insulin resistance syndrome or syndrome X, which includes combinations of hypertension, type 2 diabetes, and insulin resistance are consistently related to low birthweight in a large number of studies across different populations. More is discussed in the article on Developmental Origins of Adult Disease: Part 3: Metabolic Disease.
The Concept of Programming

Events in early life may inuence long-term outcomes in three ways, as pointed out by Lucas (23): 1) Direct damage 2) Induction, deletion, or impaired development of a somatic structure resulting from a stimulus or insult during a critical period 3) Physiologic setting by an early stimulus or insult at a critical period, with long term consequences for function. The term programming has been applied to the latter two processes in which the programming stimulus only exerts long-term effects when applied at a critical or sensitive period. (23) Programming in fetal or postnatal life may result in the initiation of 1) normal development process (resulting from endogenous signaling), 2) a lasting adaptation to an early environment stimulus, or 3) an adverse response to an insult at a sensitive period. Theoretically, nutritional programming may operate in any of these ways. (23) Nutritional programming has been convincingly shown to occur in animals. Numerous animal experiments have demonstrated that the fetus is plastic during development, that manipulating fetal and neonatal nutrition can permanently change the structure and function of many systems, such as persistent changes in blood pressure, cholesterol metabolism, insulin responses to glucose, and several other metabolic, endocrine, and immune system alterations. (22)(24) These observations laid the foundations of the programming hypothesis. Nutritional programming in humans has not been
Serum Lipids and Clotting Factors

Increased plasma concentration of low-densitylipoprotein cholesterol, an established risk factor for cardiovascular disease, (2) has been shown to be related to reduced fetal growth. (20) Raised plasma brinogen, a measure of blood coagulability, is also a strong risk factor for cardiovascular disease. (2) Studies in Shefeld, UK, showed that the neonate with a short body and low birthweight in relation to the size of its head had persisting disturbances of cholesterol metabolism and blood coagulation. It was specically the reduction in abdominal circumference at birth that predicted raised serum concentrations of total and low-density-lipoprotein cholesterol and apolipoprotein B in men and women. (20) In late gestation the fetus responds to under nutrition by sustaining growth of the brain at the expense of the trunk. This adaptation compromises the liver and seems to permanently alter its metabolism. (21) As both cholesterol and brinogen metabolism are regulated by the liver, one interpretation of these ndings is that reduced abdominal circumference at birth reects liver growth and consequent reprogramming of the liver metabolism. (21) An atherogenic lipid prole may be linked to a transition from poor maternal nutrition in early gestation to adequate nutrition later on. Men who had a small abdominal circumference at birth had raised serum concentrations of total and low
Figure 1. Framework of ideas in the fetal origins hypothesis. Reproduced from Barker DJ.
Fetal origins of coronary heart disease. BMJ. 1995;311(6998):171174, (4) with permission from the BMJ Publishing Group Ltd.
followed by hypertrophy of the left ventricle in childhood and adult life, which predicts coronary heart disease independent of blood pressure. (28) More recent studies have shown that greater postnatal weight gain is independently associated with disease risk. (29) There is increasing evidence that either low birthweight, accelerated postnatal weight gain, or a combination of the two, may predispose to the risk for hypertension, cardiovascular disease, and type 2 diabetes in adulthood. (30) Currently, the most unfavorable growth pattern seems to be low birthweight, slow growth in infancy followed by excess weight gain during childhood and adolescencethis pattern portends a particularly poor prognosis for the development of coronary heart disease in adulthood. (30)(31)(32) This has led to the thrifty phenotype concept.
easy to prove or disprove, largely because most studies are not experimental in design but describe epidemiological associations often subject to alternative explanations. (23) Another difculty is that maternal nutrition has been viewed too narrowly as the diet a mother eats during pregnancy. The nourishment of the fetus also depends on the mothers nutrient stores, her metabolic capacity, and her lifelong nutritional experience. It is now clear from observations on humans and animals that the embryo is sensitive to nutrients that it receives and may be permanently changed by them. (25)(26) The links between fetal undernutrition over different stages of pregnancy and cardiovascular disease is summarized in Figure 1. In late gestation, rates of cell division in the fetus fall and growth slows. After birth, growth mainly depends on the development and enlargement of existing cells rather than the addition of new ones. (22) Low rates of infant growth are highly predictive of coronary heart disease in men. (9) In Hertfordshire, men who were small at 1 year of age were three times more likely to develop or die from coronary heart disease than those who were large, an association not dependent on the way infants were fed. (27) Low weight gain during infancy is also
The Thrifty Phenotype Hypothesis

Hales and Barker (1992) (33) proposed the thrifty phenotype hypothesis, derived from the prior thrifty genotype hypothesis. (34) Neel (34) proposed that thrifty genes were selected at a time of food scarcity, resulting in a fast insulin trigger and enhanced capacity to store fat, thus placing the individual at risk of insulin resistance and type 2 diabetes. (34) The thrifty phenotype hypothesis suggested that when the fetal environment is poor, there is an adaptive response that optimizes the growth of vital organs to the detriment of others, leading to altered postnatal metabolism, designed to enhance postnatal survival under intermittently or continuously poor nutritional conditions. (33)(35)(36) It was proposed that these adaptations only became detrimental when nutrition was more abundant in the postnatal environment compared with the prenatal environment. (33)(35)(36) This concept is consistent with the denition of programming by Lucas (23) as either the induction, deletion, or impaired development of a permanent somatic structure or the setting of a physiologic system by an early stimulus or insult operating at a sensitive period, resulting in long-term consequences.
The Concept of Developmental Plasticity

It has been recently stated that when developmental physiologists and physicians use the term programming, they are describing the process whereby a stimulus or insult at a sensitive or critical period of development has lasting effects on structure or function of the body; this term has different meanings in ethnology and other areas of biology, (36)(37) and is no longer recommended to describe the developmental origins of adult disease. The term developmental plasticity was proposed and considered more appropriate than programming. (37)(38) The formal denition of developmental plasticity is the ability of a single Figure 2. Developmental plasticity and exposure to environmental challenges. Epigenetic genotype to produce more than processes play a role in determining the phenotype of the offspring as part of a life-course one alternative form of structure, strategy to match it to its environment. If not appropriately matched, the risk of later physiologic state, or behavior in re- disease is increased. Reproduced from Godfrey KM, Lillycrop KA, Burdge GC, et al. Epigenetic mechanisms and the mismatch concept of the developmental origins of health sponse to environmental condiand disease. Pediatr Res. 2007;61(5 Pt 2):5R10R, (40) with permission from Wolters tions. (37) They allow environ- Kluwer Health Publisher. mental inuences to tune the match of the organism to its expected environment beyond that achieved through natthe developmental environment. They play a role in ural selection, ie, inherited genotype. (38) determining the phenotype of the offspring as part of a The organs and systems of the body pass through life-course strategy to match it to its environment. If critical developmental periods when they are plastic and not appropriately matched, the risk of later disease is sensitive to the environment. (25)(39) Developmental increased. (40) plasticity enables the production of phenotypes that are Epigenetic Mechanisms better matched to their environment than would be Developmental plasticity requires stable modulations of possible if the same phenotype were produced in all gene expression, and this appears to be mediated in part environments. (25)(39) The developmental plasticity by epigenetic processes such as DNA methylation and processes are triggered by the in utero environment. histone modication. (41)(42) Thus, both genome and Thus, adverse events in utero induce compensatory the epigenome interactively inuence the mature phenoresponses in the fetus during this critical period, (39) type and determine sensitivity to later environmental responses that persist permanently, dening an altered factors and the subsequent risk of disease. (40)(43) The phenotype not only at birth but also for that childs term epigenetics was coined by Waddington (44) to lifetime. Altered developmental programming therefore refer to the ways in which the developmental environlimits the range of postnatal adaptability, creating disease ment can inuence the mature phenotype. vulnerability. (25) Developmental plasticity therefore exThe mismatch concept emphasizes that the degree of plains why individuals who have many latent capacities disparity between the environment experienced during from their specic genetic endowments only express development and that experienced later inuences the specic capacities under certain conditions. (25) risk of disease. During the period of developmental plasDevelopmental plasticity declines and exposure to ticity in prenatal and early postnatal life, epigenetic proenvironmental challenges increases with age as shown in cesses are thought to alter gene expression based on Figure 2. Epigenetic processes are induced by cues from
Summary
Cardiovascular disease is the leading cause of morbidity and mortality worldwide. The established risk factors do not explain the differences in susceptibility to cardiovascular disease among individuals. There is now increasing body of evidence across different populations globally associating early life conditions with risk of developing cardiovascular disease in later life. To what extent the proposed mechanisms are responsible remain to be established. The challenge for future research is to unravel the underlying mechanisms and pathways which will lead to appropriate, timely interventions in early life and thereby reduce the incidence and severity of cardiovascular disease.
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 of health and disease. Pediatr Res. 2007;61(5 Pt 2):5R10R, (40) with permission from Wolters Kluwer Health Publisher.
environmental cues transmitted via the mother, to produce phenotypic attributes best suited to the environment in which the individual predicts it will live. Greater mismatch gives greater risk of disease from unpredicted excessive richness (high calorie density food, sedentary lifestyle) of the environment. Thus, the risk is greater with poorer developmental environment (A versus B), and with socioeconomic transitions to an afuent western lifestyle (45) as shown in Figure 3.

Know nutritional requirements during pregnancy and the impact of poor nutrition on fetal growth and development. Recognize the effects of fetal programming and nutrition on the prevalence and types of adult onset disorders.
Predictive Adaptive Response

It has also been proposed to further separate those homeostatic responses that represent early adaptations to changes in the intrauterine environment that may have long-term consequences, from those which need not confer immediate advantage but are induced in the expectation of future adaptive changes; this latter group of responses has been dened as predictive adaptive. (46) In this model, selection across generations operates to favor protection of those predictive adaptive responses that aid survival to reproductive age. (46) The programmed or plastic responses made during development that have immediate adaptive advantage may also act to limit the range of postnatal adaptive responses to a new environment and would be considered inappropriate predictive adaptive responses. (45)(46)(47)(48)(49)(50)
References
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Global Burden of Disease. Geneva, Switzerland: World Health Organization; 2008. Accessed October 13, 2011 at: http://www. who.int/healthinfo/global_burden_disease/2004_report_update/ en/index.html 2. Wilson PW. Established risk factors and coronary artery disease: the Framingham Study. Am J Hypertens. 1994;7(7 Pt 2):7S12S 3. Barker DJ. The origins of the developmental origins theory. J Intern Med. 2007;261:412 417 4. Barker DJ. Fetal origins of coronary heart disease. BMJ. 1995; 311(6998):171174 5. Barker DJ, Winter PD, Osmond C, et al. Weight in infancy and death from ischaemic heart disease. Lancet. 1989;2(8663): 577580 6. Barker DJ, Osmond C, Golding J, et al. Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. BMJ. 1989;298(6673):564 567 7. Kermack WO, McKendrick AG, McKinlay PL. Death-rates in
Great Britain and Sweden: some general regularities and their signicance. Lancet. 1934;223(5770):698 703 8. Forsdahl A. Are poor living conditions in childhood and adolescence an important risk factor for arteriosclerotic heart disease? Br J Prev Soc Med. 1977;31:9195 9. Osmond C, Barker DJ, Winter PD, et al. Early growth and death from cardiovascular disease in women. BMJ. 1993;307(6918): 1519 1524 10. Forsen T, Eriksson JG, Tuomilehto J, et al. Mothers weight in pregnancy and coronary heart disease in a cohort of Finnish men: follow up study. BMJ. 1997;315(7112):837 840 11. Martyn CN, Barker DJ, Osmond C. Mothers pelvic size, fetal growth, and death from stroke and coronary heart disease in men in the UK. Lancet. 1996;348(9037):1264 1268 12. Barker DJ, Bull AR, Osmond C, Simmonds SJ. Fetal and placental size and risk of hypertension in adult life. BMJ. 1990; 301(6746):259 262 13. Keys A, Menotti A, Aravanis C, et al. The seven countries study: 2,289 deaths in 15 years. Prev Med. 1984;13:141154 14. Leon D, Koupilova I. Birthweight, blood pressure and hypertension: epidemiologic studies. In: DJP Barker, ed. Fetal Origins of Cardiovascular and Lung Disease. New York: Marcel Dekker; 1999:23 48 15. Law CM, Shiell AW. Is blood pressure inversely related to birth weight? The strength of evidence from a systematic review of the literature. J Hypertens. 1996;14:935941 16. Huxley RR, Shiell AW, Law CM. The role of size at birth and postnatal catch-up growth in determining systolic blood pressure: a systematic review of the literature. J Hypertens. 2000;18:815 831 17. Adair L, Dahly D. Developmental determinants of blood pressure in adults. Annual Rev Nutr. 2005;25:407 434 18. Huxley R, Neil A, Collins R. Unravelling the fetal origins hypothesis: is there really an inverse association between birthweight and subsequent blood pressure? Lancet. 2002;360(9334): 659 665 19. Davies AA, Smith GD, May MT, Ben-Shlomo Y. Association between birth weight and blood pressure is robust, amplies with age, and may be underestimated. Hypertension. 2006;48:431 436 20. Barker DJ, Martyn CN, Osmond C, et al. Growth in utero and serum cholesterol concentrations in adult life. BMJ. 1993; 307(6918):1524 1527 21. Barker DJP, Martyn CN, Osmond C, Wield GA. Abnormal liver growth in utero and death from coronary heart disease. BMJ. 1995;310(6981):703704 22. McCance RA, Widdowson EM. Review lecture: the determinants of growth and form. Proc R Soc Lond B Biol Sci. 1974; 185(1078):117 23. Lucas A. Role of nutritional programming in determining adult morbidity. Arch Disease Child. 1994;71:288 290 24. Langley-Evans SC. Fetal programming of cardiovascular function through exposure to maternal undernutrition. Proc Nutr Soc. 2001;60:505513 25. Bateson P. Developmental plasticity and evolutionary biology. J Nutr. 2007;137:1060 1062 26. Symonds ME. Integration of physiological and molecular mechanisms of the developmental origins of adult disease: new concepts and insights. Proc Nutr Soc. 2007;66:442 450 27. Fall CH, Vijayakumar M, Barker DJ et al. Weight in infancy and prevalence of coronary heart disease in adult life. BMJ. 1995; 310(6971):1719 28. 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;73:363367 29. Lucas A, Fewtrell MS, Cole TJ. Fetal origins of adult diseasethe hypothesis revisited. BMJ. 1999;319(7204):245249 30. Barker DJP, Osmond C, Forsen TJ, et al. Trajectories of growth among children who have coronary events as adults. N Engl J Med. 2005;353:18021809 31. Rich-Edwards JW, Kleinman K, Michels KB, et al. Longitudinal study of birth weight and adult body mass index in predicting risk of coronary heart disease and stroke in women. BMJ. 2005; 330(7500):11151118 32. Gillman MW. Developmental origins of health and disease. N Engl J Med. 2005;353:1848 1850 33. Hales CN, Barker DJ. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia. 1992; 35:595 601 34. Neel JV. Diabetes mellitus: a thrifty genotype rendered detrimental by progress? Am J Hum Genet. 1962;14:353362 35. Hales CN, Barker DJ. The thrifty phenotype hypothesis. Br Med Bull 2001;60:520 36. McMillen IC, MacLaughlin SM, Muhlhausler BS, et al. Developmental origins of adult health and disease: the role of periconceptional and foetal nutrition. Basic Clin Pharmacol Toxicol. 2008; 102:82 89 37. Barker DJP. Developmental origins of adult health and disease. J Epidemiol Community Health. 2004;58:114 115 38. Gluckman PD, Hanson MA. Developmental plasticity and human disease: research directions. J Intern Med. 2007;261:461 471 39. Bateson P, Barker D, Clutton-Brock T, et al. Developmental plasticity and human health. Nature. 2004;430(6998):419 421 40. Godfrey KM, Lillycrop KA, Burdge GC, et al. Epigenetic mechanisms and the mismatch concept of the developmental origins of health and disease. Pediatr Res. 2007;61(5 Pt 2):5R10R 41. Cuteld WS, Hofman PL, Mitchell M, Morison IM. Could epigenetics play a role in the developmental origins of health and disease? Pediatr Res. 2007;61(5 Pt 2):68R75R 42. Tremblay J, Hamet P. Impact of genetic and epigenetic factors from early life to later disease. Metabolism. 2008;57(Suppl 2): S27S31 43. Gluckman PD, Hanson MA, Cooper C, Thornburg KL. Effect of in utero and early-life conditions on adult health and disease. N Engl J Med. 2008;359:6173 44. Van Speybroeck L. From epigenesis to epigenetics: the case of C. H. Waddington. Ann N Y Acad Sci. 2002;981:61 81 45. Gluckman PD, Hanson MA, Beedle AS. Early life events and their consequences for later disease: a life history and evolutionary perspective. Am J Hum Biol. 2007;19:119 46. Gluckman PD, Hanson MA. The developmental origins of the metabolic syndrome. Trends Endocrinol Metab. 2004;15:183187 47. Gluckman PD, Hanson MA. Developmental origins of disease paradigm: a mechanistic and evolutionary perspective. Pediatr Res. 2004;56:311317 48. Gluckman PD, Hanson MA, Spencer HG. Predictive adaptive responses and human evolution. Trends Ecol Evol. 2005;20: 527533 49. Gluckman PD, Hanson MA, Beedle AS, Spencer HG. Predictive adaptive responses in perspective. Trends Endocrinol Metab. 2008;19:109 110 50. Rickard IJ, Lummaa V. The predictive adaptive response and metabolic syndrome: challenges for the hypothesis. Trends Endocrinol Metab. 2007;18:94 99
NeoReviews Quiz
1. The hypothesis proposed by Barker and associates claims that fetal growth restriction and low weight gain in infancy are associated with an increased risk of adult cardiovascular disease. Of the following, the variable at birth most predictive of adult coronary heart disease in Finland is: A. B. C. D. E. Discordance between placental and fetal size. Estimated gestational age at birth. Low birthweight/head circumference ratio. Low ponderal index (weight/length3). Maternal socioeconomic status.
2. Increased plasma concentration of low-density-lipoprotein cholesterol is an established risk factor for cardiovascular disease. Of the following, the body measurement at birth most predictive of increased serum concentrations of total and low-density-lipoprotein cholesterol and of apolipoprotein B in adults is a low: A. B. C. D. E. Abdominal circumference. Birthweight. Chest circumference. Crown-heel length. Head circumference.
3. Periods of undernutrition during fetal life and early infancy may permanently reduce the number of cells in particular organs. Undernutrition may also affect the distribution of cell types, patterns of hormonal secretion, metabolic activity, and organ structure. Of the following, one of the rst authors to speculate that undernutrition in fetal life may contribute to adult-onset disease is: A. B. C. D. E. Barker. Bateson. Lucas. McCance. Symonds.
4. The growth patterns during fetal life, infancy, and early childhood can portend poor prognosis for the development of coronary heart disease in adulthood. Of the following, the most unfavorable growth pattern for the development of coronary heart disease in adulthood is: A. B. C. D. E. Low birthweight, rapid growth in infancy, excess growth in childhood. Low birthweight, rapid growth in infancy, slow growth in childhood. Low birthweight, slow growth in infancy, excess growth in childhood. Low birthweight, slow growth in infancy, slow growth in childhood. Normal birthweight, normal growth in infancy, normal growth in childhood.
Developmental Origins of Adult Disease: Part 1: Cardiovascular Disease Patricia Y. L. Chan, Jonathan M. Morris and Eileen D. M. Gallery NeoReviews 2011;12;e698-e705 DOI: 10.1542/neo.12-12-e698
Reprints
Developmental Origins of Adult Disease: Part 2: Renal Disease Patricia Y. L. Chan, Jonathan M. Morris and Eileen D. M. Gallery NeoReviews 2011;12;e706-e713 DOI: 10.1542/neo.12-12-e706
Article
origins of renal disease
Developmental Origins of Adult Disease: Part 2: Renal Disease

Abstract
An increasing body of evidence suggests the inuence of early life events on the severity of expression and progression of renal disease in later life. This second of three articles discusses the animal and human data supporting the developmental origins of renal disease and some of the underlying proposed mechanisms.
Objectives
1. 2. 3. 4.
Understand the concept of developmental origins applied to renal disease. Describe evidence from animal studies. Describe evidence from human studies. Describe the proposed underlying mechanisms applied to renal disease such as perinatal programming in thrifty hypothesis, renin-angiotensin system, and steroid metabolism.
Introduction
Millions of people around the world suffer from chronic kidney disease, dened as kidney damage for 3 months or glomerular ltration rate (GFR) 60 mL/min per 1.73 m2 for 3 months with or without kidney damage. (1) Kidney damage is dened as structural or functional abnormalities of the kidney, which over time can lead to decreased GFR. Many patients with chronic kidney disease progress to chronic renal failure (CRF). CRF is dened as either GFR 15 mL/min per 1.73 m2, or a need for renal replacement therapy to treat complications of decreased GFR, which would otherwise result in mortality and morbidity. (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 inuenced substantially before birth or during the perinatal period by the prevalent environment.
Evidence From Animal Studies

Multiple animal models have demonstrated an association of low birthweight (induced by gestational exposure to low protein diet, dexamethasone, gentamicin, vitamin A deprivation, or uterine ischemia) with later hypertension. (3)(4)(5) Pregnant rats fed a low protein diet bear offspring that are relatively small at birth and develop hypertension as mature animals. (5)(6)(7) Hypertension has been observed as early as 4 weeks postnatally, and once present persists throughout life, unrelated to any postpartum manipulations of either the mother or the offspring. (5)(6)(7) Among the major organ systems, the kidney appears to be targeted specically when maternal protein intake during gestation is restricted, leading to decreased kidney-to-body weight ratio at birth and fewer nephrons in those kidneys. (5)(6)(7) One hypothesis linking decreased birthweight and subsequent adult hypertension is that maternal undernutrition leads to permanent structural changes within the kidneys, thus contributing to a propensity for adult cardiac or renal disease. Hyperltration (increased ltration pressure and GFR per glomerulus) has been associated with hypertension and renal insufciency. (8)(9)
The link between adult hypertension and low birthweight in these animal models appears to be in part mediated by an associated congenital decit of nephron number. (3)(4) Unlike organ systems such as the heart, which develop early in gestation, renal development occurs in the latter half of gestation, and in some species, continues after birth. (8) Reduced number of nephrons from birth leads to increased arterial pressure in adulthood as shown in the rat, where rat pups uninephrectomized during development had reduced renal function and hypertension in adulthood. (10) Vehaskari et al. (4) demonstrated an almost 30% reduction in glomerular number in low birthweight rats compared with those of normal weight, and systolic blood pressures 20 to 25 mm Hg higher by 8 weeks of age. Celsi et al. (3) also found that prenatal administration of dexamethasone in rats was followed by low birthweight and fewer glomeruli compared with controls. In these nephrondecient rats, GFR was reduced, albuminuria was increased, urinary sodium excretion was lower, and tissue sodium content was higher than normal. The authors concluded that high levels of maternal glucocorticoids impair renal development and lead to arterial hypertension in offspring. Even although renal mass eventually normalizes, glomerular damage and sodium retention occur and these may contribute to the development of hypertension. (3) Suppression of the intrarenal renin-angiotensin system (RAS), reduced levels of renal messenger RNA, and renin have been described in newborn intrauterine growth restricted rats. (5) Despite the suppression of intrarenal RAS in the neonatal period, angiotensin II type 1 receptor expression increases above control levels during the prehypertensive stage in rats, without feedback suppression in kidney angiotensin I or II contents. (11) Although direct experimental evidence for increased sodium reabsorption is lacking, in that sodium transport has not been measured in any nephron segment, studies suggest that activation of RAS within the kidney, independent of the systemic RAS, may induce sodium retention and sustained hypertension. (12) Accumulating evidence supports the upregulated sodium reabsorption in the distal tubule involvement in the pathogenesis of prenatally programmed hypertension. (13) These ndings in animals support the hypothesis initially put forward by Brenner et al. (9) that a congenital decit in nephron number, resulting in a decreased ltration surface area and thus a limitation in renal sodium excretion, may contribute to susceptibility to essential hypertension.
Human Studies
Consistent with animal data, many human studies have revealed an inverse association between low birthweight and higher blood pressure from infancy onwards.
The Kidney and Blood Pressure

The 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 determination of blood pressure by its regulation of intravascular uid volume. Their view of the kidney as the ultimate regulator of long-term arterial pressure, the relationship between renal sodium handling, intravascularuid-volume homeostasis and hypertension, implicated in the pathogenesis and maintenance of hypertension, (14,15) has gained widespread support. In addition, all known genetic mutations associated with hypertension are mutations in proteins expressed in the kidney. (16) Intrinsic renal factors affecting blood pressure have been demonstrated in renal transplantation: blood pressure in the recipient after transplantation has been shown to be related to the blood pressure of the donor or the presence of hypertensive risk factors in the donor before transplantation rather than to the preexistence of hypertension in the recipient, ie, hypertension follows the kidney. (17) Therefore, a congenital reduction in renal sodium handling, as a result of congenital reduction in nephron number, is likely to have an impact on blood pressure.
Nephrogenesis
The embryonic human kidney develops in three consecutive structures: the pronephros, the mesonephros, and the metanephros. The rst denitive (metanephric) nephrons are formed at 8 weeks gestation in the human fetus and urine production begins then. (18) By 20 weeks gestation, the branching of the ureteric bud is complete, urine production is well established, and about one third of the nal complement of nephrons are present. (18) Numerous factors have been identied as necessary for nephrogenesis, including the RAS, various growth factors including insulinlike growth factor-I, apoptosis, and adequate nutrient supply. Renal development in the human is complete by 36 weeks of gestation; subsequently, no new nephrons are formed. (18) However, infants born before 36 weeks gestation are still undergoing nephrogenesis (19) until they reach the equivalent stage of development; as a result, they are exposed postpartum to medications that affect the kidney during its nal stages of renal development. (20) After the completion of nephrogenesis, the kidney grows in length and
volume, largely because of increases in the size of the renal tubule, the renal interstitium, and the glomeruli, (18)(20) rather than new numbers of nephrons. The nal complement of nephrons is critically dependent on two factors: gestational age and a favorable intrauterine environment. (21) Fetal response to stress in utero (eg, hypoxia) involves redistribution of blood ow away from intra-abdominal organs (such as kidney, liver, pancreas) and skeletal muscle, and towards vital organs such as brain, heart, and adrenal glands. (21)(22) Other intrauterine stress include protein and vitamin deciencies, infections, toxins, drugs such as glucocorticoids, certain antibiotics, nonsteroidal anti-inammatory drugs, angiotensin-converting enzyme inhibitors, and potentially, smoking and alcohol abuse.
Nephron Numbers
Nephron numbers are estimated through the surrogate of glomerular number, the only quantitative information coming from autopsy studies of whole kidneys. (21)(23)(24) To approximate nephron endowment in living individuals, kidney size is used as a surrogate marker. Kidney weight has been shown to correlate with nephron number in the human, (23) but this association is not sufciently strong to allow estimation of individual glomerular number; this reduces the usefulness of kidney size in drawing conclusions from population studies. (25) Most recent studies have shown that nephron number, when directly assessed in human kidneys, ranges from 200,000 nephrons per kidney to slightly more than 2 million per kidney, a 10-fold variation. (23)(24)(26) Variation in human nephron number has been known for many years and may be due to different measurement techniques (23)(26) as direct glomeruli counting is technically demanding. (23)(25) It is only in the last two decades that nephron number has been linked to risk of developing both kidney disease and hypertension. (20)(21)(22) The concept that nephron number at birth inuences the risk of development of essential hypertension in later life was rst proposed by Brenner and colleagues, (8)(9)(27) known as the Brenner hypothesis. They suggested that maintenance of elevated blood pressure requires a renal factor favoring sodium retention, thereby preventing pressure-promoted natriuresis from returning blood pressure to normal levels. (8)(9) They hypothesized that this renal factor was a restricted capacity for sodium excretion imposed by a congenital decit of nephrons. (8) A reduction in renal mass, and therefore in glomerular ltration surface area, tends to produce a rise
in blood pressure. (27) Sustained exposure of nephrons to higher glomerular perfusion pressure gradually results in the development of focal and segmental glomerular sclerosis. (28) This subsequently results in further glomerular loss, further reduced ability to excrete sodium, and a self-perpetuating cycle of increasing blood pressure and progressive kidney disease. (29) In attempting to determine whether fetal growth restriction is associated with a reduction in nephron number, Hinchliffe et al. (30) examined nephron number in stillbirths and in infants dying at 1 year of age who were born with appropriate weight for gestational age (controls) compared with those small for gestational age. In both groups, infants with growth restriction had fewer nephrons than controls. In addition, the number of nephrons in control infants dying at 1 year of age had not increased compared with stillbirths with growth restriction, demonstrating a lack of postnatal compensation in nephron number. Similarly, Manalich et al. (31) examined the kidneys of neonates dying within 2 weeks of birth in relation to their birthweights. Signicant inverse correlations were found between glomerular number and glomerular volume, and birthweight and glomerular volume, independent of sex and race. (24)(31) As discussed in the Developmental Origins of Cardiovascular Disease, the Barker Hypothesis proposed that adverse events in utero induce compensatory responses in the fetus that, reecting the plasticity of this developmental period, persist permanently and thus dene an altered phenotype at birth. A schematic overview linking the Barker and Brenner hypotheses is shown in Figure 1, suggesting mechanisms by which a reduction in renal ltration area could lead to glomerular and systemic hypertension and subsequent glomerulosclerosis (Brenner hypothesis) and how this could be inuenced by intrauterine growth restriction and impaired renal development (Barker hypothesis). (32) Diabetes mellitus is the leading cause of ESRD worldwide. Several authors have examined the relationship between birthweight and diabetic nephropathy and found an increased susceptibility among patients with low birthweight. Analogous to the studies of the association of low birthweight with hypertension and nephron number, studies in the human have also revealed similar associations between low birthweight and subsequent pancreatic insufciency and diabetes mellitus. This is discussed in the Developmental Origins of Adult Disease: Part 3: Metabolic Disease article in this issue of NeoReviews.
Figure 1. Schematic overview linking two hypotheses: the
Barker/Brenner hypotheses. Reproduced from Amann K, Plank C, Dotsch J. Low nephron number: a new cardiovascular risk factor in children? Pediatr Nephrol. 2004;19:1319 1323, (32) with permission from Springer Publishing Company.
Figure 2. Integration of renal programming (Barker hypoth-
Perinatal Programming
As discussed in the Developmental Origins of Adult Disease: Part 1: Cardiovascular Disease article, the concept that intrauterine and perinatal events can inuence organ function later in life is termed perinatal programming. The developmental origins concept implies a response to adversity during development, and responses rarely have a single facet. Considering both maternal and fetal responses to adverse conditions and the resulting adaptive response can be complex. Prenatal programming is important to the kidney. Figure 2 illustrates the integration of impaired nephrogenesis, leading to low nephron endowment associated with glomerular and systemic hypertension according to Brenners hyperltration hypothesis. This may be partly responsible for the association between low birthweight and hypertension. (25)
esis) with hyperltration hypothesis (Brenner). Reproduced from Schreuder MF, Nauta J. Prenatal programming of nephron number and blood pressure. Kidney Internat. 2007; 72:265268, (25) with permission from Nature Publishing Group.
and experimental intrauterine growth restriction, nephron number is commonly reduced by 25% to 30%, (4)(5)(34) suggesting that a nite fraction of total nephrons are subject to nutritional modulation. (22) The precise physiologic mechanisms by which maternal undernutrition and protein restriction during pregnancy lead to hypertension in the offspring remain controversial. Woods et al. (5)(34) hypothesized that maternal protein restriction causes suppression of the fetal/newborn intrarenal RAS, and thus impaired renal development, leading to permanent alterations in kidney structure and function, including reduced number of nephrons, resulting in hypertension.
The Thrifty Hypothesis

Applying the thrifty hypothesis with the notion of fewer beta-cells hyperfunctioning to meet increased insulin demands when faced with overnutrition leading to beta-cell dropout and eventual failure of insulin production, Mackenzie and Brenner (8) suggested the resemblance to the proposed cycle of nephron hyperfunction and obsolescence linking dietary factors with the progressive nature of renal disease. They proposed that in times of famine, reducing overcapacity both of nephrons and pancreatic islet cells would represent an integrated metabolic adjustment favoring ready availability of energy sources to meet metabolic needs on the one hand, and the achievement of electrolyte conservation at minimal renal energy expenditure, by reducing redundancy, on the other. (8)
Maternal Undernutrition/Protein Intake

Hinchliffe et al. (30) proposed a potential pathogenetic mechanism for the linkage between low birthweight and hypertension in adulthood: the undernourished, growth-restricted fetus becomes a low-birthweight newborn whose kidneys have a reduced number of nephrons. In rats fed a low-protein diet, Vehaskari et al. (4) documented a correlation between reduced birthweight, decreased formation of nephrons, and adult hypertension. In animal studies, experimental maternal undernutrition or placental insufciency have now been reproducibly associated with reduced nephron number (4)(5)(7)(33) and typically with hypertension. In both human (30)
Conversely, in times of plenty, appropriate programming would endow the kidney with greater reserves of nephrons to meet greater excretory demands and the pancreas with a greater capacity to secrete insulin, thereby shifting metabolism towards synthesis, growth, and energy storage. (8) The major disadvantage of such a homeostatic strategy is the ease by which it could be rendered maladaptive by extreme changes in the availability of food. Under such circumstances, in times of plenty, the programming of fewer pancreatic beta-cells or fewer nephrons is rendered inappropriate, and glomerular hyperltration, hyperinsulinemia, hypertension, diabetes, hyperlipidemia, and glomerulosclerosis could all follow. (8)
The Renin-Angiotensin System

Although mechanisms to explain the association between low birthweight with hypertension and renal function are still unclear, one possible pathway is the RAS. (35) A number of other specic hormonal systems endothelin, natriuretic peptides, neuropeptide Y, and nitric oxidealso inuence blood pressure regulation and renal function. (36) Furthermore, medications or manipulations that interrupt the RAS are highly effective in controlling hypertension. (36) Models of primary hypertension, such as the spontaneously hypertensive rat, display differences in RAS expression in adult life when compared with normotensive controls. (37) Animals transgenic for RAS genes may develop hypertension, suggesting that this system is critical in the etiology of hypertension. (38) Animals lacking RAS genes, the knockout animals, develop markedly abnormal kidneys. (39) Exogenous alteration in the RAS can alter renal development. The administration of drugs that interfere with the RAS during gestation, eg, angiotensin converting enzyme inhibitors, cause fetopathy in both humans and experimental animals. (40) Angiotensin receptor blockade with an AT1 receptor antagonist, losartan, during the rst 12 days of postnatal life in the rat results in a reduced number of nephrons and hypertension in adulthood. (41) It has been shown that angiotensin II, known as a growth factor, is important for normal nephrogenesis. (42) As renal angiotensin II levels in offspring of mothers fed protein-restricted diets in pregnancy appear to be suppressed in the perinatal period, (5) Ingelnger et al. (36) proposed that interfering with the production of angiotensin II or blocking its effects on receptors can lead to changes in the usual pattern of renal development. Langley-Evans et al. (33) examined circulating renin
levels in offspring of protein-deplete mothers and observed decreased plasma renin activity. This was supported by Vehaskari et al. (4)(11) Although individual studies display some differences in the degree of protein restriction and the timing of the measurement of RAS activity, the common ndings suggest that maternal dietary protein restriction leads to suppression of the perinatal RAS, with subsequent impairment of nephrogenesis, leading to reduced complement of nephrons, and predisposing the offspring to adult hypertension. (36) Such observations have also led some authors to suggest that additional substances or factors that suppress the RAS during nephrogenesis (such as high salt intake in pregnancy) may carry long-term implications for cardio-renal health. (36) Ingelnger et al. (43) found that increasing salt intake in pregnant rats leads to intrarenal changes in the offspring similar to those seen in pups from protein-restricted maternal rats, and results in hypertension and renal dysfunction.
Steroid Metabolism
Maternal protein restriction reduces the activity of placental 11beta-hydroxysteriod dehydrogenase (11 HSD), an enzyme that normally inactivates maternal cortisol or corticosterone. This reduced activity results in higher than normal exposure of the fetus to maternal glucocorticoids. (44) This concurs with Barker et al. (45) that small neonates with large placentas were at highest risk for cardiovascular disease later in life. Furthermore, placental 11 HSD activity has been reported to be relatively low in humans with these features. (46) The possibility that the placental isoform of 11 HSD is down-regulated under conditions of low protein diet would lead to increased maternal glucocorticoid exposure in the fetus, and therefore affect growth. (36) Pregnant rats given the synthetic glucocorticoid dexamethasone, which crosses the placenta and is not metabolized by 11 HSD, have offspring with low birthweight and adult hypertension. (3) Other studies have administered carbenoxolone, an inhibitor of 11 HSD to pregnant rats and produced similar results in the offspring. (47) However, the authors of one study using lower carbenoxolone doses did not observe signicant differences in blood pressure. (48) Low-sodium diet, given to pregnant rats over the last week of gestation induces failure to thrive in the fetus, as well as postnatal hypertension and renal insufciency in the offspring. (32) Another important factor in the genesis of hypertension after intrauterine growth restriction may be related to an increase in the gene expression of various tubular sodium channels, possibly indicating a
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 deciency are all mechanisms associated with low glomerular number disturbances in these mechanisms may explain long-term consequences on blood pressure and renal function. Compensatory glomerular hyperltration may aggravate kidney disease, resulting in systemic hypertension and renal damage and failure. Further studies are required to clarify the possible role for these interactions in perinatal programming.

Figure 3. Overview of the potential patho-mechanisms pre-
disposing to the development of arterial hypertension after intrauterine growth restriction. Reproduced from Amann K, Plank C, Dotsch J. Low nephron number: a new cardiovascular risk factor in children? Pediatr Nephrol. 2004;19:1319 1323, (32) with permission from Springer Publishing Company.
References
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higher reabsorption ratio for sodium chloride (at least in rats). (49) An important system in the regulation of mineralocorticoid activity is the renal cortisol/cortisone shuttle. (32) The enzyme 11 HSD type 2 (11 HSD 2) regulates the inactivation of mineralocorticoid active cortisol to inactive cortisone (Fig. 3). Newborn and adult rats that suffered from intrauterine growth restriction have an increased renal expression of the mineralocorticoid receptor and a signicant reduction of the 11 HSD gene expression. (50) There is an increase in the cortisol/ cortisone shuttle in about 20% of children with intrauterine growth restriction, implying a decreased activity of 11 HSD 2. (51) Taken on balance, the data suggest that heightened fetal exposure to maternal glucocorticoids may hamper fetal renal growth and lead to hypertension later in life. (36)
Summary
Nephrogenesis is a complex process that requires a ne balance of many factors. Intrauterine growth restriction leading to low birthweight disturbs this balance leading
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a maternal low protein diet impairs nephrogenesis and promotes hypertension in the rat. Life Sci. 1999;64:965974 34. Woods LL, Weeks DA, Rasch R. Programming of adult blood pressure by maternal protein restriction: role of nephrogenesis. Kidney Internat. 2004;65:1339 1348 35. Woods LL. Fetal origins of adult hypertension: a renal mechanism? Current Opinion Nephrol Hypertens. 2000;9:419 425 36. Ingelnger JR, Woods LL. Perinatal programming, renal development, and adult renal function. Am J Hypertens. 2002;15(2 Pt 2):46S 49S 37. Pratt RE, Zou WM, Naftilan AJ, et al. Altered sodium regulation of renal angiotensinogen mRNA in the spontaneously hypertensive rat. Am J Physiol. 1989;256(3 Pt 2):F469 F474 38. Mullins JJ, Peters J, Ganten D. Fulminant hypertension in transgenic rats harbouring the mouse Ren-2 gene. Nature. 1990; 344(6266):541544 39. Nishimura H, Yerkes E, Hohenfellner K, et al. Role of the angiotensin type 2 receptor gene in congenital anomalies of the kidney and urinary tract, CAKUT, of mice and men. Molecular Cell. 1999;3:110 40. Sedman AB, Kershaw DB, Bunchman TE. Recognition and management of angiotensin converting enzyme inhibitor fetopathy. Pediatr Nephrol. 1995;9:382385 41. Woods LL, Rasch R. Perinatal ANG II programs adult blood pressure, glomerular number, and renal function in rats. Am J Physiol. 1998;275(5 Pt 2):R1593R1599 42. Tufro-McReddie A, Romano LM, Harris JM, et al. Angiotensin II regulates nephrogenesis and renal vascular development. Am J Physiol. 1995;269(1 Pt 2):F110 F115 43. Ingelnger J, Haveran L, Hsu C-Y, Woods LL. Maternal low protein or high salt diet in the perinatal period suppresses newborn intrarenal renin-angiotensin system (RAS) and programs for hypertension in adult offspring. Pediatr Res. 1998;43:309A 44. Seckl JR, Benediktsson R, Lindsay RS, Brown RW. Placental 11 beta-hydroxysteroid dehydrogenase and the programming of hypertension. J Steroid Biochem Mole Biol. 1995;55:447 455 45. Barker DJ, Osmond C, Golding J, et al. Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. BMJ. 1989;298(6673):564 567 46. Benediktsson R, Lindsay RS, Noble J, et al. Glucocorticoid exposure in utero: new model for adult hypertension. Lancet. 1993;341(8841):339 341 47. Langley-Evans SC. Maternal carbenoxolone treatment lowers birthweight and induces hypertension in the offspring of rats fed a protein-replete diet. Clin Sci. 1997;93:423 429 48. Gomez-Sanchez EP, Gomez-Sanchez CE. Maternal hypertension and progeny blood pressure: role of aldosterone and 11betaHSD. Hypertension. 1999;33:1369 1373 49. Manning J, Beutler K, Knepper MA, Vehaskari VM. Upregulation of renal BSC1 and TSC in prenatally programmed hypertension. Am J Physiol Renal Physiol. 2002;283:F202F206 50. Bertram C, Trowern AR, Copin N, et al. The maternal diet during pregnancy programs altered expression of the glucocorticoid receptor and type 2 11beta-hydroxysteroid dehydrogenase: potential molecular mechanisms underlying the programming of hypertension in utero. Endocrinology. 2001;142:28412853 51. Houang M, Morineau G, le Bouc Y, et al. The cortisolcortisone shuttle in children born with intrauterine growth retardation. Pediatr Res. 1999;46:189 193
NeoReviews Quiz
5. Chronic kidney disease is dened as structural kidney damage lasting three months or more or functional reduction in glomerular ltration rate (GFR) lasting three months or more with or without kidney damage. Of the following, the GFR threshold for the denition of chronic kidney disease is closest to: A. B. C. D. E. 15 30 45 60 75 mL/min mL/min mL/min mL/min mL/min per per per pre per 1.73 1.73 1.73 1.73 1.73 m2. m2. m2. m2. m2.
6. Chronic renal failure is characterized by a marked reduction in glomerular ltration rate (GFR) or a need for renal replacement therapy to treat complications of decreased GFR, which otherwise would result in mortality or morbidity. Of the following, the GFR threshold for the denition of chronic renal failure is closest to: A. B. C. D. E. 15 30 45 60 75 mL/min mL/min mL/min mL/min mL/min per per per pre per 1.73 1.73 1.73 1.73 1.73 m2. m2. m2. m2. m2.
7. Multiple animal models have shown an association between low birthweight, induced by maternal manipulation, and subsequent development of hypertension. The link between low birthweight and adult hypertension in these animal models is attributed in part to an associated congenital decit in nephron number. Of the following, the most common effective maternal manipulation that leads to low birthweight and subsequent development of early and persistent hypertension in the offspring is: A. B. C. D. E. Dexamethasone treatment. Gentamicin treatment. Low protein diet. Uterine ischemia. Vitamin A deciency.
8. The embryonic human kidney develops in three consecutive structures: pronephros, mesonephros, and metanephros. The rst denitive metanephric nephrons are formed by 8 weeks gestation in the human fetus; the nephrons increase in number to their nal complement thereafter. The gestational age in the human at which nephrogenesis is complete with the development of a full complement of nephrons is: A. B. C. D. E. 20 28 36 44 52 weeks. weeks. weeks. weeks. weeks.
9. The rennin-angiotensin system (RAS) is an important pathway for blood pressure regulation and renal development. The component in the RAS pathway that is necessary for normal nephrogenesis is: A. B. C. D. E. Aldosterone. Angiotensin 1. Angiotensin 2. Angiotensinogen. Renin.
Developmental Origins of Adult Disease: Part 2: Renal Disease Patricia Y. L. Chan, Jonathan M. Morris and Eileen D. M. Gallery NeoReviews 2011;12;e706-e713 DOI: 10.1542/neo.12-12-e706
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Developmental Origins of Adult Disease: Part 3: Metabolic Disease Patricia Y. L. Chan, Jonathan M. Morris and Eileen D. M. Gallery NeoReviews 2011;12;e714-e720 DOI: 10.1542/neo.12-12-e714
Article
origins of metabolic disease
Developmental Origins of Adult Disease: Part 3: Metabolic Disease

Abstract
This third of three articles reviews the developmental origins of metabolic disease and the proposed underlying mechanisms.
Objectives
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.
Introduction
The obesity epidemic is a global problem rapidly increasing in the past few decades. (1) The World Health Organization projects that by 2015, approximately 2.3 billion adults will be overweight with body mass index (BMI) 25 kg/m2 and more than 700 million will be obese with BMI 30 kg/m2. (2) Obesity plays a central role in insulin resistance and the metabolic syndrome. Also known as syndrome X, the insulin resistance syndrome, and the deadly quartet, this common set of metabolic disorders results from the increasing prevalence of obesitythe constellation 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, whose elevated risk is not only of diabetes but also of cardiovascular disease. (3) It is evident that the metabolic syndrome represents a massive public health problem.
Developmental Origins of Type 2 Diabetes and the Metabolic Syndrome

Although there is general agreement that obesity is important for the development of type 2 diabetes and the metabolic syndrome, it is also clear that this occurs only in susceptible individuals, generally ascribed to the interaction of genetic and environmental conditions (such as changes in nutrition and lack of physical activity, as societies move towards increasing afuence). Among monozygotic twins, the twin with diabetes was found to have a lower birthweight than the genetically identical twin without diabetes. (4) It has also been 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 the subsequent risk for obesity, type 2 diabetes, and the metabolic syndrome.
Birthweight and Type 2 Diabetes

Both animal and human studies have demonstrated an association between low birthweight and subsequent pancreatic insufciency and type 2 diabetes. (6) Epidemiologic and clinical evidence indicate a role for prenatal factors in the origin of the metabolic syndrome
and its components: hypertension, insulin resistance, central obesity, and dyslipidemia. (7)(8) In a systematic review of 48 studies, most reported an inverse relationship between birthweight and measures of reduced glucose tolerance and insulin resistance, not explained by differences among studies in the sex, age, or current size of subjects. (9) The relationship between birthweight and insulin secretion was, however, inconsistent, (9) and this review was criticized as being essentially qualitative providing no information on the shape, strength, or independence of the birthweight diabetes association. (10) A more recent meta-analysis of 14 studies of birthweight and subsequent risk of type 2 diabetes by Harder et al. (11) demonstrated a U-shaped rather than a linear inverse association, with both low and high birthweights substantially increasing the risk of developing type 2 diabetes later in life. This U-shaped relationship was also shown among Pima Indians, where diabetes in pregnancy is unusually common (12)the prevalence was greatest 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 diabetes during pregnancy, and birth year, those with birthweights 2.5 kg had a higher rate than those with birthweights 2.5 to 4.49 kg (odds ratio 3.8). (13) The risk for subsequent diabetes among higher birthweight infants (birthweights 4.5 kg) was associated with maternal diabetes during pregnancy. (13) Most recently, Whincup et al (10) conducted a quantitative systematic review examining 31 articles with unduplicated information (out of 327 identied articles published by June 2008) on the association of birthweight and type 2 diabetes in adults. Their analyses were consistent with those of Harder et al (11) in suggesting that low birthweights ( 2.5 kg) are associated with increased type 2 diabetes risk. (10) They emphasized further that the inverse pattern of association between birthweight and type 2 diabetes is the dominant one in most populations and extends at least to 3 kg, although a modest positive birthweighttype 2 diabetes association at higher birthweights ( 4 kg) cannot be excluded. (10) This is biologically plausible given the recognized association of both prepregnancy type 2 diabetes and gestational diabetes to macrosomia. (13)
Birthweight, Insulin Resistance, and the Metabolic Syndrome

The development of insulin resistance has a major role in type 2 diabetes and the metabolic syndrome. Disruption in insulin binding and postbinding effects have been
reported in offspring in association with peri-conceptual maternal undernutrition, and this may also result in impaired insulin activity. (14) Saturated fat consumption in rats results in insulin resistance and impaired glucose transporter function. (15) Men and women with low birthweight have a higher prevalence of the insulin resistance syndrome or the metabolic syndrome. (8) Barker et al(8) in their study of 407 men in Hertfordshire, UK, with a mean age of 64 years, found that 22% of men with birthweights 2.95 kg had syndrome X. Their risk of developing syndrome X was over 10 times greater than men with birthweights 4.31 kg. Phillips et al (16) performed insulin tolerance tests on 103 men and women in Preston, UK, following 12 hours overnight fast. At each current BMI, insulin resistance was increased in people who had a low ponderal index at birth. At each ponderal index, insulin resistance was greater in those with high current body mass. (16) The greatest insulin resistance was therefore found in those who were thin at birth but obese as adults. (16) Being thin at birth and being thin as an adult had opposing effects on insulin resistance. (16) A study in San Antonio, Texas, extended the association between low birthweight and the insulin resistance syndrome to a biethnic population. (17) The study included 564 Mexican Americans and non-Hispanic white men and women with mean age of 32 years. Among men and women in the lowest tertile (third of the population) of birthweight (mean 2.78 kg) and highest tertile of current BMI (mean 34.3 kg/m2), 25% had the metabolic syndrome. (17) By contrast, none in the highest tertile of birthweight (mean 3.85 kg) or lowest tertile of current BMI (mean 21.8 kg/m2) manifested the syndrome. (17) A French study of 517 men and women with mean age of 21 years, in the metropolitan area of Haguenau, revealed that those who were 3rd percentile of local standard values at birth had signicantly higher insulin and proinsulin concentrations compared with those with normal weight, after adjusting for sex and current BMI. (18) Recent studies demonstrate that the growthrestricted fetus is insulin-sensitive at birth and develops insulin resistance well after birth. (19) While reduced fetal growth remain an independent risk factor for insulin resistance later in life, insulin resistance is sharply amplied by obesity in childhood or adulthood or family history of type 2 diabetes. (20)
Proposed Mechanisms for Developmental Origins of Metabolic Disease

Studies in animals have facilitated the elucidation of the underlying mechanisms involved in fetal growth restrictions induction of components of the metabolic syndrome. Manipulation of maternal dietary intake and composition, induction of anemia in the mother, restriction of placental growth by uterine artery ligation, and embolization of the placental circulation or prepregnancy reduction in the number of placental attachment sites have all been used in various animals including rats, mice, rabbits, guinea pigs, pigs, sheep, and primates.
The Thrifty Hypothesis

THE THRIFTY GENOTYPE HYPOTHESIS As discussed in the Developmental Origins of Adult Disease: Part 1: Cardiovascular Disease article, the thrifty genotype would trigger a level of insulin resistance that allowed a population to cope in times of nutritional stress but in times of plenty and in a modern nutritionally rich environment would lead to the development of obesity and type 2 diabetes. Although it is acknowledged that genetic polymorphisms play a role in determining the strength of developmental gene environment interactions, it is difcult to reconcile a purely genetic explanation from a brief episode such as the Dutch famine or with the widespread evidence of such relationships between early environment and long-term outcomes in different populations such as European, and Asian, Indian subcontinent. There has also been criticism of the controversial nature of data supporting the notion that obese individuals have lower metabolic rates than nonobese individuals. (21) Critics have also pointed out that the processes of mutation, genetic drift, and selection may have created genotypes that were thrifty. (22) Genome-wide scans have failed to identify any common diabetes susceptibility genes. Furthermore, the ease with which programming can be induced experimentally in a variety of organ systems and across species suggests that the basic underlying mechanisms are not purely genetic. (23) Finally, the thrifty genotype hypothesis does not adequately explain the rapid changes in obesity and type 2 diabetes incidence in modern societies. (24) THE THRIFTY PHENOTYPE HYPOTHESIS As discussed in the Developmental Origins of Cardiovascular Disease, Hales and Barker (25) proposed a model focused on environmental factors. Under conditions of intrauterine deprivation that exceed a threshold beyond usual compensatory mechanisms, the fetus adopts several strate716 NeoReviews Vol.12 No.12 December 2011
egies to maximize its chances of survival in utero and postnatally. The immediate response is the reduction of somatic growth to selectively distribute nutrients to the brain and heart, at the expense of other organs such as the liver, pancreas, and muscle. The poor development of pancreatic beta-cell mass and function (including islet of Langerhans vasculature and possibly innervation) were proposed to be key elements leading to type 2 diabetes. The undernourished fetus also develops insulin resistance, abnormalities of insulin secretion or action, and other metabolic changes for immediate survival to downregulate and prioritize growth. This adaptive response leads to an altered postnatal metabolism, designed to enhance postnatal survival under conditions of intermittent or poor nutrition. It was proposed that these adaptations only become detrimental when nutrition is more abundant in the postnatal environment compared with the prenatal environment. Although the thrifty phenotype model can readily explain the long-term consequences of extreme intrauterine growth restriction, it is less clear how (or why) a reduction in birth size from the 80th percentile to the 60th would be associated with an increased disease risk. It could not explain how a very transient fetal exposure to a stimulus could lead to long-term consequences, the graded manner of disease risk across the normal birthweight range seen in the epidemiologic data, nor how early life events can induce long-term physiologic changes without changes in birth size. (26)
Programming
This was also discussed in the Developmental Origins of Cardiovascular Disease article. With regards to the metabolic axis, programming can occur in early life modulated by the intrauterine environment. (27) For type 2 diabetes this may result from an altered development and insulin-secreting capacity of the endocrine pancreas, or by altered insulin sensitivity of target tissues. It is possible that perturbations of prenatal growth may lead to inappropriate beta-cell ontogeny and result in a population of beta cells qualitatively ill-suited to subsequent management of metabolic stress. (27) A reduced availability of insulin prenatally is a major contributor to intrauterine growth restriction. This is demonstrated by the severe growth restriction of human infants with pancreatic agenesis. (28) Insulin deciency may result from either genetic mutations in transcription factors active during beta-cell formation or from altered expression of transcription factors and peptide growth factors due to environmental inuences in utero. (27) Intrauterine growth restriction in human results in a reduced population of
pancreatic beta cells at birth. (29) Abnormal programming of the fetal pancreas could be a major risk factor for adult diabetes. (27) The term programming, however, has different meanings in other areas of biology. It implies a deterministic process and set of mechanisms akin to a genetic program of development and the use of the word may inuence the mindset of investigators. (30) It is no longer recommended in description of the developmental origins of adult disease and replaced by the term developmental plasticity.
Epigenetic change may be a major mechanism underlying programming, with implications for subsequent generations. Effects of parental and grandparental nutrition on diabetes risk in humans have been reported, suggesting trans-generational inheritance of epigenetic alterations that affect diabetes susceptibility. (33) In the Dutch winter famine, women who were exposed to famine while in the womb later had grandchildren who were born with reduced birth size. (34) There remains a possibility that trans-generational epigenetic change may play a role in clustering or family linkage effects for disease such as type 2 diabetes. (35)
Developmental Plasticity
Developmental plasticity encompasses those processes that generate alternative phenotypes from a single genotype through the actions of environmental cues acting during development. (30) They allow environmental inuences to tune the match of the organism to its expected environment beyond that achieved through natural selection, ie, inherited genotype. (30) The concept of developmental plasticity and exposure to environmental challenges, with epigenetic processes playing a role in determining the phenotype of the offspring to match its environment, is discussed in the Developmental Origins of Adult Disease: Part 1: Cardiovascular Disease article. Plasticity exists in the fetal and neonatal pancreas following changes in the beta-cell number through both beta-cell replication and neogenesis but later becomes restricted. (27) Consequently, any deciency in beta-cell mass occurring in utero as a result of either genetic mutations with transcription factors, or maternal malnutrition or placental dysfunction leading to inappropriate expression of transcription or growth factors, will have limited opportunity for correction postnatally. (27)
Predictive Adaptive Responses

It is conventional in clinical medicine to think of responses to the environment as being of immediate advantage, ie, homeostatic (to maintain internal equilibrium by adjusting physiologic processes) if the challenge is short lasting; or homeorhetic (where orchestrated or coordinated control in metabolism of body tissues is developed as necessary to support a change in physiologic state), if more prolonged. (36) The programming paradigm raises the possibility of an additional kind of environmental response, one in which the benet need not be immediate but in which the response is made in expectation of a future environment. (35) A more general model combining features of the above concepts was developed by Gluckman and Hanson. (26)(30)(35)(37)(38) In their model, the fetus constantly interprets the environment created by the maternal milieu and placental function. A predictive adaptive response may be appropriate or inappropriate. If the prediction is correct, ie, the postnatal environment is as predicted during prenatal development, the predictive adaptive response is appropriate. If the prediction turns out to be incorrect, then the predictive adaptive response is inappropriate. (35) Such a distinction can only be made retrospectively. Gluckman et al (19)(26)(35)(38)(39) proposed that there are many physiologic systems in which predictive adaptive responses operate. Any aspect of developmental plasticity that can be irreversibly affected by the environment can be considered to be a predictive adaptive response if it confers a long-term survival advantage when the predicted and actual future environments match. (35) The maternal environment is transmitted to the fetus by means of nutritional and endocrine signals. The fetus makes a set of adaptive responses in expectation of the postnatal environment that it perceives to be extant on the basis of these maternal signals, but the perception
Epigenetics
As discussed in Developmental Origins of Cardiovascular Disease, epigenetic mechanisms provide the molecular basis to the processes of developmental plasticity. An article proposing DNA methylation proling in diabetes reviewed indirect evidence that epigenetic dysregulation contributes to type 2 diabetes. (31) The most direct evidence implicating epigenetic dysregulation in human diabetes is from studies of transient neonatal diabetes, (32) a rare form of diabetes that presents within the rst few days after birth and although resolving within 1 year, often recurs later in life. These studies show that infants with sporadic transient neonatal diabetes have aberrant methylation of several imprinted genes in peripheral blood leukocytes. (32)
may be wrong. (35) At one extreme, the mother may be in poor health or the placenta dysfunctional, either of which limits nutrient transfer to the fetus, making nutrition unbalanced or altering fetal hormonal levels. (35) Such effects occur in preeclampsia and in gestational diabetes. The fetal environment is normally controlled by both maternal and placental factors, the basis for maternal constraints that limit the role of the offsprings genome on growth before birth. (40) Thus both maternal constraints and patho-physiologic processes can initiate adaptive responses by the fetus. (41) Postnatally, there will be minimal consequences if the environment matches the prediction, but if there is severe disease or constraint or if the postnatal environment changes rapidly by, for example, migration to a nutritionally rich habitat, the predictive response will turn out to be inappropriate. (35) The role of maternal constraint is evident by the relationship between maternal and infant birthweights, whereas the relationship with paternal birthweight is weak. (42) Stettler et al (43) and Morton (44) showed that rst-born children have a greater risk of developing obesity than their subsequent siblings, demonstrating the inuence of parity as an aspect of the constraint that induces predictive adaptive responses. From this model, it is evident that the greater the adversity of the fetal environment or the degree of constraint, the greater the risk of a mismatch between the prenatal, constrained environment and the postnatal, energy-rich environment. (35) This is exemplied in reference to a Southern Indian population versus a European population. (45) In rural India, women are small because of generations of relative nutritional deprivation, giving birth to small infants as a result of maternal constraints. Although small at birth, these infants have truncal obesity, an adaptation that gives them energy reserves for early independent life, and relatively less skeletal muscle, which limits glucose consumption. (45) Although maternal size constraints still operate, the postnatal energy environment has improved rapidly in parts of India, especially for those who have migrated to the cities, making the predictive adaptive responses inappropriate, giving rise to the rapidly increasing incidence and current epidemic of type 2 diabetes and obesity. (35)(45) Similar observations are reported with respect to the prevalence of diabetes in migrants as migration usually entails a rapid shift to a richer nutritional environment. (46) The predictive adaptive responses model is not without debate and criticism. (47)(48)(49)(50) The main
point of contention relates to the nature and function of the cues directing early metabolic plasticity in contributing to later disease in the human. (37)(47)(50)(51) There is, however, agreement that there is maternal manipulation of offspring phenotype in humans, mediated by maternal constraint, advantageous to both mother and infant. (37)
Conclusion
The global epidemic of obesity demands a solution. The growing prevalence of metabolic disease worldwide challenges many disciplines to provide an explanation for the multiple causal and underlying mechanisms to dene the best ways to intervene.

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subsequent risk of type 2 diabetes: a meta-analysis. Am J Epidemiol. 2007;165:849 857 12. Pettitt DJ, Bennett PH, Saad MF, et al. Abnormal glucose tolerance during pregnancy in Pima Indian women: long-term effects on offspring. Diabetes. 1991;40(Suppl 2):126 130 13. McCance DR, Pettitt DJ, Hanson RL, et al. Birth weight and non-insulin dependent diabetes: thrifty genotype, thrifty phenotype, or surviving small baby genotype? BMJ. 1994;308(6934): 942945 14. Gallaher BW, Breier BH, Keven CL, et al. Fetal programming of insulin-like growth factor (IGF)-I and IGF-binding protein-3: evidence for an altered response to undernutrition in late gestation following exposure to periconceptual undernutrition in the sheep. J Endocrinol. 1998;159:501508 15. Fryer LG, Kruszynska YT. Insulin resistance in high fat fed rats: role of glucose transporters, membrane lipids, and triglyceride stores. Ann N Y Acad Sci. 1993;683:9197 16. Phillips DI, Barker DJ, Hales CN, et al. Thinness at birth and insulin resistance in adult life. Diabetologia. 1994;37:150 154 17. Valdez R, Athens MA, Thompson GH, et al. Birthweight and adult health outcomes in a biethnic population in the USA. Diabetologia. 1994;37:624 631 18. Leger J, Levy-Marchal C, Bloch J, et al. Reduced nal height and indications for insulin resistance in 20 year olds born small for gestational age: regional cohort study. BMJ. 1997;315(7104): 341347 19. Godfrey KM, Gluckman PD, Hanson MA. Developmental origins of metabolic disease: life course and intergenerational perspectives. Trends Endocrinol Metab. 2010;21:199 205 20. Levy-Marchal C, Jaquet D. Long-term metabolic consequences of being born small for gestational age. Pediatr Diabet. 2004;5:147153 21. Garrow J. The thrifty genotype and non-insulin dependent diabetes. BMJ. 1993;306(6882):933934 22. Kagawa Y, Yanagisawa Y, Hasegawa K, et al. Single nucleotide polymorphisms of thrifty genes for energy metabolism: evolutionary origins and prospects for intervention to prevent obesity-related diseases. Biochem Biophys Res Commun. 2002;295:207222 23. Bertram CE, Hanson MA. Animal models and programming of the metabolic syndrome. Br Med Bull. 2001;60:103121 24. Stoger R. The thrifty epigenotype: an acquired and heritable predisposition for obesity and diabetes? Bioessays. 2008;30: 156 166 25. Hales CN, Barker DJ. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia. 1992; 35(7):595 601 26. Gluckman PD, Hanson MA. Developmental Origins of Health and Disease. Cambridge, UK: Cambridge University Press; 2006 27. Hill DJ, Duvillie B. Pancreatic development and adult diabetes. Pediatr Res. 2000;48:269 274 28. Stoffers DA, Zinkin NT, Stanojevic V, et al. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nature Genetics. 1997;15:106 110 29. Van Assche FA, De Prins F, Aerts L, Verjans M. The endocrine pancreas in small-for-dates infants. Br J Obstet Gynaecol. 1977;84: 751753 30. Gluckman PD, Hanson MA. Developmental plasticity and human disease: research directions. J Intern Med. 2007;261: 461 471 31. Maier S, Olek A. Diabetes: a candidate disease for efcient
DNA methylation proling. J Nutr. 2002;132(8 Suppl):2440S 2443S. 32. Mackay DJ, Boonen SE, Clayton-Smith J, et al. A maternal hypomethylation syndrome presenting as transient neonatal diabetes mellitus. Hum Genet. 2006;120:262269 33. Pembrey ME, Bygren LO, Kaati G, et al. Sex-specic, maleline transgenerational responses in humans. Eur J Hum Genet. 2006;14:159 166 34. Lumey LH. Decreased birthweights in infants after maternal in utero exposure to the Dutch famine of 1944 1945. Paediatr Perinat Epidemiol. 1992;6:240 253 35. Gluckman PD, Hanson MA. Developmental origins of disease paradigm: a mechanistic and evolutionary perspective. Pediatr Res. 2004;56:311317 36. Bauman DE, Currie WB. Partitioning of nutrients during pregnancy and lactation: a review of mechanisms involving homeostasis and homeorhesis. J Dairy Sci. 1980;63:1514 1529 37. Gluckman PD, Hanson MA, Beedle AS, Spencer HG. Predictive adaptive responses in perspective. Trends Endocrinol Metab. 2008;19:109 110 38. Gluckman PD, Hanson MA, Buklijas T. A conceptual framework for the developmental origins of health and disease. J Dev Orig Health Dis. 2010;1:6 18 39. Gluckman PD, Hanson MA, Cooper C, Thornburg KL. Effect of in utero and early-life conditions on adult health and disease. N Engl J Med. 2008;359:6173 40. 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; 1984:511558 41. Gluckman PD, Hanson M. The Fetal Matrix: Evolution, Development and Disease. Cambridge, UK: Cambridge University Press; 2005 42. Morton NE. The inheritance of human birth weight. Ann Hum Genet. 1955;20:125134 43. Stettler N, Tershakovec AM, Zemel BS, et al. Early risk factors for increased adiposity: a cohort study of African American subjects followed from birth to young adulthood. Am J Clin Nutr. 2000; 72:378 383 44. Morton SM. Life Course Determinants of Offspring Size at Birth: An Intergenerational Study of Aberdeen Woman. London: University of London; 2002 45. Yajnik CS, Fall CH, Coyaji KJ, et al. Neonatal anthropometry: the thin-fat Indian baby. The Pune Maternal Nutrition Study. Int J Obes Relat Metab Disord. 2003;27:173180 46. Stanhope JM, Prior IA. The Tokelau island migrant study: prevalence and incidence of diabetes mellitus. N Z Med J. 1980; 92(673):417 421 47. Wells JC. Is early development in humans a predictive adaptive response anticipating the adult environment? Trends Ecol Evol. 2006;21:424 425 48. Rickard IJ, Lummaa V. The predictive adaptive response and metabolic syndrome: challenges for the hypothesis. Trends Endocrinol Metab. 2007;18:94 99 49. Wells JCK. Flaws in the theory of predictive adaptive responses. Trends Endocrinol Metab. 2007;18:331337 50. Wells JCK. Response to Gluckman et al. and Bateson: predictive adaptive responses. Trends Endocrinol Metab. 2008;19:112 51. Spencer HG, Hanson MA, Gluckman PD. Response to Wells: phenotypic responses to early environmental cues can be adaptive in adults. Trends Ecol Evol. 2006;21:425 426
NeoReviews Quiz
10. Metabolic syndrome, a constellation of several cardio-metabolic risk factors, represents a signicant public health concern. Of the following, the central feature of the metabolic syndrome is: A. B. C. D. E. Atherosclerosis. Dyslipidemia. Hyperglycemia. Hypertension. Obesity.
11. Several epidemiologic studies have shown an association between birthweight and subsequent development of type 2 diabetes later in life. Of the following, the highest prevalence of type 2 diabetes amongst adult Pima Indians is seen among infants with birthweights: A. B. C. D. E. <2.5 kg. 2.53.0 kg. 3.0 3.5 kg. 3.5 4.0 kg. 4.0 4.5 kg.
12. The growth patterns during fetal life, infancy, and early childhood can portend poor prognosis for the development of insulin resistance in adulthood. Of the following, the most unfavorable growth pattern for the development of insulin resistance in adulthood is: A. B. C. D. E. Normal weight at birth, normal weight as an adult. Obese at birth, obese as an adult. Obese at birth, thin as an adult. Thin at birth, obese as an adult. Thin at birth, thin as an adult.
Developmental Origins of Adult Disease: Part 3: Metabolic Disease Patricia Y. L. Chan, Jonathan M. Morris and Eileen D. M. Gallery NeoReviews 2011;12;e714-e720 DOI: 10.1542/neo.12-12-e714
Reprints
Index of Suspicion in The Nursery Case 1: A 4-day-old Who Has Decreased Activity and Poor Feeding Case 2: Profuse Diarrhea in a 4-day-old Term Male Marilisa Elrod, John C. Arnold, Resmy P. Gopi, S. Khanna and B. K. Rajrgowda NeoReviews 2011;12;e721-e726 DOI: 10.1542/neo.12-12-e721
index of suspicion in the nursery
Case 1: A 4-day-old Who Has Decreased Activity and Poor Feeding Case 2: Profuse Diarrhea in a 4-day-old Term Male
Case 1 Presentation
A 4-day-old male infant presents in late November to the pediatrics clinic with decreased activity and poor feeding. The mother reports that he had been feeding and acting well until 1 day before presentation. The mother states that he has not had any rhinorrhea, nasal congestion, cough, vomiting, diarrhea, rash, or any atypical movements that could be seizures. She had not taken his temperature, and she states that he has not felt hot. The pediatrician becomes immediately concerned as she recognizes a lethargic infant in respiratory distress. A code is called, and the resuscitation is begun. The infant was a 3,083-g product of a 38 1 week gestation to a 28year-old G2P1 woman. The pregnancy was only complicated by a positive group B streptococcus screen at 35 weeks gestation and a history of herpes simplex virus in the past, but no lesions were noted before or during delivery. On presentation to labor and delivery, the fetus was noted to be tachycardic and the mother had mild abdominal tenderness, leading to initiation of ampicillin and gentamicin 16 hours before delivery. The duration of rupture of membranes was 4 hours. The infant was born via spontaneous vaginal delivery and was vigorous, with Apgar scores of 9 and 9 at 1 and 5 minutes. Because the mother was neither febrile nor tachycardic, it was decided that she did not have chorioamnionitis, so the infant received no further laboratory evaluation or antibiotics. The mother and infant were discharged from the hospital after 2 uneventful days. In the clinic, the 4-day-old infant has initial vital signs that included a temperature of 98.9F, a heart rate of 170 beats per minute, a respiratory rate of 71 breaths per minute, an oxygen saturation (SaO2) of 80% on room air, and blood pressure 84/ 35 mm Hg. The infant is minimally responsive during attempts to insert an intravenous (IV) catheter. Examination is signicant for an anterior fontanel that is soft and slightly full, minimally icteric eyes, and pupils that are equal round and reactive at 3 mm. Mucous membranes are slightly dry and there are no oropharyngeal lesions. Examination of the heart and lungs reveals no murmurs and clear breath sounds. The abdomen is moderately distended, but normal in color with no organomegaly. Examination of the skin is signicant for no jaundice, vesicles, or other lesions. The extremities are unremarkable except for a capillary rell time of 5 seconds. A brief neurologic examination reveals no abnormal movements consistent with seizures and normal patellar reexes. One hundred percent oxygen is administered via face-mask with immediate rise in SaO2 to 99% and some relief of respiratory effort. IV access is obtained and 10 mL/kg normal saline bolus is given with a corresponding decrease in heart rate and capillary rell time. Two milliliters per kilogram of D10-Water is given for a serum dextrose of 52 mg/dL. The infant is subsequently admitted, and ampicillin and cefotaxime are initiated. During the admission, the infant is initially stable following the administration of oxygen and crystalloid. Initial laboratories are signicant for a normal electrolyte panel, except for a serum glucose of 52 mg/dL
The reader is encouraged to write possible diagnoses for each case before turning to the discussion. We invite readers to contribute case presentations and discussions. Please inquire rst by contacting Dr. Philip at aphilip@stanford.edu.
Author Disclosure Drs Elrod, Arnold, Gopi, Khanna, and Rajrgowda have disclosed no nancial relationships relevant to these cases. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.
as noted above. Total bilirubin is 5.5 mg/dL (direct 0.5 mg/dL) and the remainder of the liver enzymes are normal. A complete blood count demonstrates a white blood cell count of 5.3 103/mm3 (52% neutrophils, 38% lymphocytes, 1% atypical lymphocytes, 8% monocytes, 1% metamyelocytes), hemoglobin level of 12.9 g/dL, and a platelet count of 69 103/mm3. A blood culture is obtained. The urinalysis is normal, and urine culture is obtained. CSF studies included a white blood cell count of 14/mm3 (25% neutrophils, 20% lymphocytes, 55% monocytes), red blood cell count of 11/mm3, protein of 49 mg/dL, and glucose of 31 mg/dL. CSF cultures are obtained. The chest radiograph shows a normal heart size and normal lung elds with no consolidation. The abdominal radiograph shows nonspecic abundant bowel-gas with no evidence of obstruction or free air. Six hours after admission the infant again becomes less arousable and is noted to be hypopneic with a
respiratory rate of 18. He is transferred to the intensive care unit for increased observation and possible intubation, although the venous blood gasses are reassuring (pH, 7.4; PCO2, 42). A concern for an underlying heart abnormality (such as coarctation of the aorta) is considered as the etiology for his compromise. An echocardiogram is obtained, which demonstrates normal anatomy, mild pulmonary hypertension, and left ventricular dysfunction. Studies of the blood and CSF lead to a denitive diagnosis.
Case 2 Presentation
A term male with a birthweight of 3,015 g is born by normal spontaneous vaginal delivery to an immigrant mother from Ghana. The infant is admitted to the newborn unit; physical examination is signicant for a natal tooth. The infant is fed mostly human milk with occasional formula feeds without any problem On day 3, the infant developed hyperbilirubinemia and required phototherapy. On the fourth day, the infant develops severe watery diarrhea, which is interpreted as phototherapy related. Diarrhea continues and serum chemistry shows hyperchloremic metabolic acidosis (arterial blood gas shows bicarbonate level of 7.9 mEq/ dL; BE, 15). The infant is transferred to the neonatal intensive care unit for further evaluation. Clinically the infant is active and alert with a voracious appetite. He is taking 4 to 5 oz/feed, without clinical evidence of dehydration. Weight loss is only 155 g (about 5% of birthweight). Family history reveals that a sibling had diarrhea as an infant, which resolved following cessation of breastfeeding. The infant is admitted to the neonatal intensive care unit on the fth day, made NPO, and diarrhea de-
Frequently Used Abbreviations

alanine aminotransferase aspartate aminotransferase blood urea nitrogen complete blood count central nervous system cerebrospinal uid computed tomography electrocardiography emergency department electroencephalography erythrocyte sedimentation rate GI: gastrointestinal GU: genitourinary Hct: hematocrit Hgb: hemoglobin MRI: magnetic resonance imaging WBC: white blood cell ALT: AST: BUN: CBC: CNS: CSF: CT: ECG: ED: EEG: ESR:
creases soon after and then stops. The infant is restarted on human milk and diarrhea reappears. The infant is made NPO again and diarrhea stops again. The infant is tried on Alimentum/pregestamil, and the infant feeds well, is always hungry with no vomiting, but watery diarrhea becomes worse. After consultation with a pediatric gastroenterologist, the infant is made NPO for 1 day and starts on Neocate, which is tolerated well. The diarrhea stops, birthweight is regained, and he is discharged from the hospital to have follow up with the pediatric gastroenterologist and his pediatrician. At present the infant is doing well and is gaining weight with normal growth and development. Laboratory values showed hyperchloremic 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 infants electrolytes showed hyperchloremic, nonanionic gap metabolic acidosis during episodes of diarrhea, which stabilized once the infant was placed NPO on intravenous uids. Once the infant was started on Neocate, hyperchloremic/metabolic acidosis resolved: 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 culture was negative, negative for occult blood, fat 2 , and positive for reducing substance. Blood culture was negative; pancreatic elastase, 242 (NL 200); vasoactive intestinal peptide, 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 function tests, NL). Metabolic screen was negative for galactosemia and thy-
roid disorder. Urine for organic acids was negative.
Case 1 Discussion
The Diagnosis
Serum and CSF were both sent on the day of admission for enterovirus (EV) polymerase chain reaction (PCR) testing and both are found to be positive for the presence of EV RNA. The infant improves slowly over the 10-day admission and is discharged from the hospital in good condition.
The Pathogen
EVs are RNA viruses in the Enterovirus genus, which belongs to the family Picornaviridae. Other picornaviruses include rhinoviruses, hepatitis A virus, and the relatively newly described human parechoviruses. Historically, the term enterovirus refers to a large number of different groups, including A and B coxsackieviruses, echoviruses, and the numbered EVs. Poliovirus is also in the enterovirus family, but the common use of the term enterovirus does not often refer to polioviruses, which cause a specic clinical disease. Being hardy viruses, the EVs can remain viable for several days at room temperature. The most common modes of transmission are fecal oral or respiratory; however, when the host becomes viremic, blood borne or transplacental transmission are possible.
The Condition
Most EV infections occur during the summer and early fall and are asymptomatic. Despite the name enterovirus, which implies a gastrointestinal pathogen, the most common manifestation of enteroviral infections is an uncomplicated upper respiratory tract infection or undifferentiated febrile illness. However,
EVs can be found in both the upper airway and the lower gastrointestinal tract, accounting for its variable modes of transmission. Nonpolio EVs are responsible for a myriad of clinical manifestations, ranging from uncomplicated respiratory infection to fatal viremia. There are, however, some classic enteroviral syndromes, which are often attributed to specic serotypes. For example, hand, foot, and mouth disease is often associated with coxsackie A10 and A16, pleurodynia and myocarditis with coxsackie B, and severe meningoencephalitis or accid paralysis with EV 71. However, the overlap between clinical entities and viral serotypes is broad. As with older children, the majority of neonates infected with EVs are asymptomatic. Those with symptoms usually have an undifferentiated fever or aseptic meningitis. However, neonates are also uniquely susceptible to severe enteroviral infections. This was rst described during polio outbreaks, when a neonate born to a mother recently infected with polio had a 40% chance of paralysis. The variety of different presentations in neonates and children is thought to be dependent on age and mode of transmission. For example, postnatal exposure of a newborn with high levels of cross reacting maternal antibody may result in a mild or asymptomatic infection, whereas an older infant who lacks maternal antibody might be more symptomatic. Alternatively, a mother who is infected near the time of delivery could be viremic and can infect the infant without any of the benet of protective maternal antibody. In the latter scenario, the infant is susceptible to the most severe manifestations of EV: carditis, encephalitis, and hepatitis. For those infants that develop an EV sepsis syndrome, mortality is high, but unlike herpes simplex virus infections, those children who sur-
vive often do so without severe longterm sequelae. Of the EVs implicated in neonatal disease, group B coxsackieviruses and echovirus 11 are associated with severe illness. Enteroviral neonatal myocarditis caused by coxsackieviruses B1B5 is the most common cause of myocardial infarction in neonates. Echovirus 11 is associated with neonatal hepatic necrosis.
Diagnostic Tests
Diagnosis was previously made by viral cell culture. Viral culture of the stool can be a valuable tool for after the fact diagnosis, as EVs are often shed in the stool for weeks after infection. However, nucleic acid amplication tests like PCR are now the diagnostic methods of choice. PCR for the viral RNA has been found to be more sensitive than culture as some serotypes do not grow well in cell culture and PCR can detect a much smaller amount of virus. Some caution must always be exercised with interpretation of PCR results as falsepositive and falsenegative results are possible with this methodology. CSF PCR is now the standard diagnostic methodology at most institutions, and serum PCR can be a valuable adjunct especially in young infants and immunocompromised patients.
Treatment
Treatment of EV is generally supportive. However, in neonates with life-threatening infections, intravenous immunoglobulin (IVIG) and pleconaril have been used. IVIG has been administered with mixed success as the effectiveness of such a product depends on the presence of neutralizing antibody to the infecting serotype, which may not be present in the available IVIG. Administration of maternal convalescent plasma has been proposed due to the
likelihood of high titer antibodies, but is often not practical and cannot be given in a timely manner. Pleconaril is a compound that binds the capsid of EVs and disrupts the virus attachment to cellular receptors, thus its ability to uncoat and insert its RNA into the cell. Pleconaril has been used with some success in immunocompromised patients. However, there are limited data regarding pleconaril safety and efcacy in neonates and it is no longer available, even for emergency use. The large number of unique serotypes and generally mild disease makes an EV vaccine unlikely.
Department of the Navy, Department of Defense, or the United States Government.
with no diarrhea and normal growth and development.
Genetics of the Disease

American Board of Pediatrics Neonatal-Perinatal Medicine Content Specications
Know the epidemiology, pathogenesis, and prevention of perinatal infections with coxsackievirus, echovirus, enterovirus, and poliovirus. Understand the clinical manifestations, diagnostic criteria, treatment, and complications of perinatal infections with coxsackievirus, echovirus, enterovirus, and poliovirus.
Lessons for the Clinician

EVs are a common cause of illness in children and young adults and cause a wide spectrum of clinical disease. They will most commonly be encountered by the pediatrician as upper respiratory infections; hand, foot, and mouth disease; fever; and aseptic meningitis. The uncommon but potentially devastating scenario of a pregnant woman infected with EV just before delivery should be considered when a neonate presents with fever and a sepsis syndrome. Hallmark signs that would suggest enteroviral sepsis might be a combination of cardiac, CNS, or liver involvement, especially in the summer and early fall. Early administration of IVIG could be considered, although supportive care is the mainstay of therapy. (Marilisa Elrod, Department of Pediatrics, Naval Medical Center, San Diego, CA; John C. Arnold, MD, Department of Pediatrics, Division of Infectious Diseases, Naval Medical Center, San Diego, CA) Disclaimer: The views expressed in this article are those of the author(s) and do not necessarily reect the ofcial policy or position of the
GGM is an autosomal recessive disorder caused by a mutation in Na/ glucose cotransporter (SGLT) gene SLC5A1. More than 40 mutations of SLC5A1 responsible for GGM have been described. (1) In a report in 1962 from Sweden, GGM has been reported from several different parts of the world. (2)(3) There is no ethnic predilection, but consanguinity plays a very important role as there are multiple case reports from Middle Eastern countries and the Amish population. It is more common in female infants. (1) More than 200 cases have been reported world wide since its rst report. (1)
Suggested Reading
Jenista JA, Powell KR, Menegus MA. Epidemiology of neonatal enterovirus infection. J Pediatr. 1984;104:685 690 Knipe DM, Howley PM. Fields Virology, 5th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2007 Sawyer MH. Enterovirus infections: diagnosis and treatment [Review]. Pediatr Infect Dis J. 1999;18:10331040
Pathophysiology of the Disease

Glucose is the main fuel providing energy for regular metabolic needs of humans. Glucose is transported across the plasma membrane by a carrier protein called glucose transporter. Glucose transporters (GLUTs) are divided into two families: 1) the facilitative diffusion GLUT and 2) SGLT. Both GLUTs and SGLTs belong to one of the 43 families of solute carrier genes (SLC1-SLC43). Transepithelial glucose transport occurs by a coordinated action of SGLTs (in small intestine/renal tubules/salivary glands) allowing glucose inux through Luminal membrane. GLUTs allow glucose efux through the basolateral membrane. Glucose/galactose is handled by SGLT1. Fructose is absorbed passively across brush border by fructose uniporter GLUT5 and by GLUT2 across basolateral membrane as shown in the Figure. (4)
Case 2 Discussion
Clinical Presentation
Based on the clinical presentation and response to the treatment, this infant seems to have congenital glucose/galactose malabsorption (GGM). Infant had profuse diarrhea starting on the fourth day after birth despite switching the feedings (human milk/Alimentum/Pregestamil). Diarrhea stops with discontinuance of the feeds and restarted soon after reintroduction of those feeds. Infant also developed hyperchloremic-nonanion gap metabolic acidosis. Clinically infant was an active alert hungry infant with a good appetite and suck. Infant responded well to Neocate
Figure 1. Illustration of the current model for glucose and galactose transport across
the mature enterocytes of the small intestine. SGLT1 refers to the Na /glucose cotransporter 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 from Springer Science Business Media: Cell Biochemistry and Biophysics, Molecular basis for glucose-galactose malabsorption, vol 36, 2002, Ernest M. Wright, Eric Turk, Martin G. Martin, gure 1.
Diagnostic Criteria for Glucose/ Galactose Malabsorption

1) watery diarrhea soon after birth, a) clinical improvement on withdrawal of dietary glucose and galactose, b) relapse on reintroduction of glucose/galactose, c) biopsy histological normal small intestinal mucosanormal mucosal disaccharidase activities, d) absorptive defect conned to glucose and galactose 2) Prenatal diagnosis in affected families 3) Intermittent or permanent glycosuria after fasting or after a glucose load 4) Finding of positive reducing substance in watery stool and slight glycosuria despite low blood sugar is highly suggestive 5) Interval breath hydrogen test
Discussion
This case had the classical presentation of an active alert infant with a voracious appetite presented with severe watery explosive diarrhea and hyperchloremic acidosis. There was also a family history of a 9-year-old sibling with a similar clinical presentation. The infant responded well to Neocate with no diarrhea and normal growth and development. Human milk and Similac both have lactose as the sugar, which breaks into glucose and galactose. On the other hand Alimentum and Pregestamil are extensively hydrolyzed proteins (cow milk protein based). Pregestamil contains corn syrup and modied corn starch. Alimentum contains sucrose and modied Tapioca starch, which is glucose polymers, which break down to d-glucose. In contrast Neocate is an amino acid-based formula (not cow milk protein) and has fructose as sugar base (carbohydrate as corn syrup, which is fructose). Fructose is absorbed passively by fructose un-
iporter in the brush border membrane (GLUT5) and by GLUT2 in the basolateral membrane. The disease classically presents during the neonatal period or soon after the introduction of feedings of either human milk or formula, with life-threatening profuse watery diarrhea and hypernatremic dehydration with metabolic acidosis. (5) Infants are usually very vigorous, nurse very well, and have a voracious appetite, regardless of their illness, and have irritability with abdominal distension and increased bowel sounds and failure to thrive. There is sudden cessation of diarrhea with fasting or the removal of offending sugar lactose (glucose/galactose), which is present in human milk and standard formula and glucose polymers present in Pregestamil and Alimentum, followed by normal growth and development. However, diarrhea reappears rapidly with reintroduction of diet containing the offending sugar. After going through the list of differential diagnoses (see the table above), family history of similar clinical presentation, and the clinical response to Neocate (fructose as carbohydrate), the diagnosis of GGM was made. Since the introduction of Neocate, the infants growth and development has been normal. Biopsy was not offered to the family to conrm the diagnosis because 1) there was a family history of similar illness, 2) there was a clinical presentation of watery diarrhea with hyperchloremic acidosis and an active, alert infant with voracious appetite, and 3) diarrhea resolved with removal of offending sugar. Had the infant not responded to our current management we would have considered biopsy.
Differential Diagnosis
Diarrheal diseases presenting in the neonatal period (Table, used with permission, modied for this review).
Nutrition Management
Once a presumptive diagnosis is made based on the clinical features, nutritional management involves
Differential Diagnosis: Diarrheal Diseases Presenting in the Neonatal Period

Table.
Condition: Congenital microvillus atrophy Tufting enteropathy Congenital glucose-Galactose malabsorption Congenital lactase deciency Congenital chloride diarrhea Cong. defective Na/H exchange Cong. bile acid malabsorption Cong. enterokinase def. Enteric anendocrinios (NEUROG 3 mutation) Other causes: Congenital sucrase isomaltase deciency Gastrinoma, VIPomaMilk protein allergy
Clinical features: Intractable watery diarrhea-Hypotonic dehydration Intractable diarrhea-Partially respond to fasting Intractable watery diarrhea-Hyperchloremic metabolic acidosis Acidic diarrhea Acidic diarrhea Intractable watery diarrhea-Hypocholoremia/Hyponatremia Alkalosis Intractable watery diarrheaHyponatremia/metabolic acidosis Steatorrhea Failure to thrive, edema Hyperchloremic 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 odorless water stool-persists with fasting. Hypokalemia, Hypochlorhydria usually presents later, GE reux constipation
This table was published in Nelson Text Book Of Pediatrics, 18th ed., Kliegman RM, Behrman RE, Jenson HB, Stanton BF, eds. Diarrheal Disease Presenting in the Newborn Period, p. 1589, Copyright Saunders Elsevier, 2007.
providing the infant with glucose/ galactose free formulas. As regular formulas contain lactose (source of glucose/galactose), specialized formulas containing corn syrup as sugar source, such as Neocate or Ross Carbohydrate Free Formula or Mead Johnson Product 3232A monosaccharide and disaccharide-free powder, need to be used. Fructose is added to meet the energy requirement. Detailed dietary guidelines are available. (6)
Lessons for the Clinician

Diarrhea in the newborn is a very uncommon disorder, but it could be fatal if there is a delay in the diagnosis. A high index of suspicion and a few simple tests will help the clinician treat such infants without doing complicated investigations. (Resmy P. Gopi, MD, S. Khanna, MD, B. K. Rajrgowda, MD, Department of Pediatrics/Division of Neona-
tology, Lincoln Medical and Mental Health Center, Bronx, NY)
References
1. Xin B, Wang H. Multiple sequence variations in SLC5A1 gene are associated with glucose-galactose malabsorption in a large cohort of Old Order Amish. Clin Genet. 2011;79:86 91 2. Lindquist B, Meeuwisse GW. Chronic diarrhoea caused by monosaccharide malabsorption. Acta Pediatr Scand. 1963;51: 674 685 3. Abdullah AMA, El-Mouzan MI, Sheikh OKE, Mazyad AA. Congenital glucosegalactose malabsorption in Arab children. J Pediatr Gastroenterol Nutrition. 1996;53: 561564 4. Wright EM, Turk E, Martin MG. Molecular basis of glucose-galactose malabsorption. Cell Biochem Biophys. 2002;36:115121 5. Steinhart R, Nitzan M, Iancu TC. Hypernatremic dehydration as a sign leading to the diagnosis of glucose-galactose malabsorption in breast-fed neonates. Helv Paediatr Acta. 1984;39:275277 6. Abad-Sinden A, Borowitz S, Meyers R, Sutphen J. Nutrition management of congenital glucose-galactose malabsorption: A case study. J Am Diet Assoc. 1997;97: 14171421
Long-Term Prognosis
Tolerance to carbohydrate-containing drinks improves gradually overtime. Most of the patients are able to tolerate regular carbohydratecontaining diets, although the degree of improvement varies. The mechanism remains unclear. Nephrocalcinosis and proximal tubular dysfunction have been reported as complication.
American Board of Pediatrics Neonatal-Perinatal Medicine Content Specications

Recognize clinical features associated with autosomal recessive disorders. Know the etiology, clinical manifestations, diagnosis, and treatment of congenital malabsorption syndromes in newborn infants, including the congenital mineral and electrolyte malabsorption syndromes.
Index of Suspicion in The Nursery Case 1: A 4-day-old Who Has Decreased Activity and Poor Feeding Case 2: Profuse Diarrhea in a 4-day-old Term Male Marilisa Elrod, John C. Arnold, Resmy P. Gopi, S. Khanna and B. K. Rajrgowda NeoReviews 2011;12;e721-e726 DOI: 10.1542/neo.12-12-e721
Reprints
Legal Briefs: KernicterusStill Preventable Maureen E. Sims NeoReviews 2011;12;e727-e730 DOI: 10.1542/neo.12-12-e727
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KernicterusStill Preventable
Maureen E. Sims, MD*
Introduction
A 3,760-g 38 weeks gestation African American male was vaginally delivered to an 18-year-old woman whose pregnancy was normal. Apgar scores were 8 and 9, at 1 and 5 minutes, respectively. The mothers blood type was O Rh-positive. The Direct Coombs was negative. He was gavaged once and put to breast twice, but data on latching or audible swallow were not documented. The mother and infant were discharged at 31 hours after delivery. The nurses noted that there was no jaundice when the infant left the hospital. No bilirubin assessments were made. At the time of discharge the mother was told to call the pediatricians ofce after a week to obtain an appointment. A phone number was provided. She was told to call sooner if there were problems. Before the delivery, the mother had been living in a group foster home for many years. Because she had just turned 18 years old, she was not allowed to return to the group home, but was told to go an apartment that had been set up for her through social services. The plaintiff experts were critical of the hospital for early discharge because 1) feeding issues existed, 2) the mother was a teenager and had no support structure, and 3) an immediate follow-up appointment either by a visiting nurse or a pediatrician was not scheduled. The mother stated in her deposition that she did not feel that her infant ever fed well, in the hospital or at home. She said she felt scared staying in her new apartment and tried staying with her sister. How*Professor of Pediatrics, University of California Los Angeles, Los Angeles, CA.
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.
ever, because of overcrowding at her sisters, she returned to her apartment. She called her mother for feeding advice and was told to keep trying, that every infant is different, and there was probably no problem. The defense experts pointed out that the infants mother never called the pediatrician after being discharged for problems. They said she did not take responsibility for her child. The plaintiff experts pointed out that she herself was very young and needed a safety net at the time of discharge with either a follow-up appointment the next day or a visiting nurse. At 72 hours, the mother brought the infant to the emergency department (ED) because he became very sleepy, had some choking with feeds, and eventually stopped sucking entirely. An ED physician was at his beside 41 minutes after the infant entered the hospital. The plaintiff experts pointed out that a newborn has very little reserve and that he needed to be examined sooner. He presented with a history of poor feeding, choking, and being very sleepy. The ED physician found a lethargic infant with poor tone and suck. No mention was made of the color of the sclera. The infants weight was 3,150 g, a decrease of 16% from birthweight. The plaintiff experts pointed out that this was an excessive weight loss and represented how poorly the infant was feeding. His respiratory rate was 40 breaths/min, his heart rate was 107 beats/min, and his mean blood pressure was 48 mm Hg. The result of the bedside glucose check was 61 mg/dL. The ED physician ordered a complete blood count (CBC) and a chemistry panel. These tests were drawn 1 hour
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later. Urine and blood cultures, and a urine analysis were done as well. A chest radiograph was ordered, and when the infant was returned from the radiology department his temperature was 34.4C. At this point a lumbar puncture was performed and the cerebral spinal uid was unremarkable. Three and one-half hours later, the results of the CBC and chemistry panel were available. The white blood cell count was 15.8 103/uL, the hematocrit was 43% (0.43), and the platelet count was 317 103/uL. Electrolyte concentrations were normal except for the serum sodium being slightly elevated at 146 mEq/L. A serum albumin was not evaluated. The total bilirubin was 44.7 mg/dL, and the direct fraction was 2.1 mg/dL. The urine analysis results were negative. A course of antibiotics was started for presumed infection. When the laboratory technician was questioned in the deposition why it required more than 1 hour for the bilirubin results to be available to the physician, he said he had to keep diluting the serum to obtain a precise value because the bilirubin level was so high. Thirty minutes after the bilirubin results were available, the ED physician contacted the neonatologist, who requested that the infant be cross-matched for blood. Four and one-half hours after admission to the ED, the infant was admitted to the newborn intensive care unit where phototherapy was begun. The plaintiff experts were critical of the excessive time lag before starting phototherapy. The ED physician said he did not have phototherapy lights in the ED. The plaintiff experts said that was an unacceptable situation. Either somebody should have obtained phototherapy lights and brought them to the ED or a set should have been kept in the ED. The ED physician also stated that he
called the pediatrician on-call shortly after nding out the results of the bilirubin but was told to call the neonatologist on-call, causing a further delay in the consult. By the time all the communication was accomplished, much time had elapsed. The plaintiff experts pointed out that bilirubin encephalopathy should have been included in the differential. Because jaundice is more difcult to discern on an African American infant, one cannot count on seeing yellow skin. It also was pointed out that 10% of African American males are glucose-6-phosphate (G6PD) decient, thereby placing them at a higher risk for a hemolytic jaundice. The plaintiff experts pointed out that the ED physician did not embrace the sense of urgency that this level of bilirubin was in a dangerous zone. The defense stated that because the infant was already encephalopathic, it was too late. The plaintiff experts pointed out that duration of the dangerous levels of hyperbilirubinemia as well as the peak were important in causing the brain damage. One hour after phototherapy began, the bilirubin level was 33.9 mg/ dL. At this point, the physician attempted to locate blood for an exchange transfusion. The plaintiff experts pointed out that the level of initial bilirubin was so dangerously high that emergency release blood should have been used for an immediate exchange transfusion as soon as the high level of bilirubin was initially reported. The plaintiff experts pointed out that the blood bank should have been alerted immediately so that a double volume exchange would be done as soon as vascular access was achieved. The treating neonatologist said that it was dangerous to exchange with blood that was not specically crossmatched for the infant. The plaintiff
pointed out that group O blood with AB serum should have been recognized as the appropriate emergency blood for the urgent situation. Because the blood bank was not alerted to the critical situation, timely and emergency release blood was not requested and blood from other sources only began being sought many hours later than was appropriate. Five and one-half hours after being admitted to the neonatal intensive care unit (10 h after admission to the ED), the neonatologist attempted to place an umbilical venous catheter. The plaintiff experts pointed out that the neonatologist should have been trying to achieve vascular access immediately and not waited for blood to do so. The treating neonatologist said he did not try access because he was waiting for cross-matched blood. The attempt to cannulate the umbilical vein was unsuccessful. Therefore, a pediatric surgeon was paged. Many delays in communication occurred, but eventually a cut-down for vascular access was achieved and a double volume exchange transfusion was completed 18 hours after the infant arrived in the ED. A pre-exchange bilirubin was 24.9 mg/dL. And the postexchange bilirubin was 18.8 mg/dL. Screening for G6PD deciency was not done at the time of birth because the state did not mandate it at this time. A G6PD evaluation was done in the hospital and it was positive. Nothing could be identied as a stress for provoking the G6PD hemolysis. After a few more days of phototherapy, the infant was discharged from the hospital with the mother. On follow-up examinations, the infant developed athetoid cerebral palsy and mental retardation. The birthing hospital, the pediatrician who discharged the infant at 31 hours, the hospital where the in-
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fant was admitted at 72 hours, the ED physician, and the neonatologist were sued. A settlement agreement was reached.
Discussion
Kernicterus is preventable. It should be a never disease. In 2001 the National Quality Forum, an agency for healthcare research and quality, listed kernicterus as a never-event and equated its occurrence to egregious, nonreversible, iatrogenic catastrophe that should be viewed as an irreproachable medical error. Over the last two decades, national healthcare organizations including the Academy of Pediatrics, Centers for Disease Control and Prevention (CDC), and the Joint Commission on Accreditation of Healthcare Organizations have alerted practitioners and hospitals about the reemergence of this devastating disorder and need for vigilance and a systematic approach. They have underscored that there is a biologic certainty that kernicterus will occur in some infants if the pattern of hyperbilirubinemias progression is inadequately monitored or if intervention with phototherapy or exchange transfusion is not timely. An incremental relationship of increasing levels of total serum bilirubin 19 mg/dL to kernicterus is apparent. Most nurseries in the United States discharge infants without screening for hemolysis other than Rh disease. In the Pilot Kernicterus Registry the causes of kernicterus were attributed to three equivalent categories: 1) hemolytic disorders (mostly ABO isoimmunization), 2) G6PD deciency (associated with both hemolysis and bilirubin conjugation disorder), and 3) idiopathic causes presumed to be secondary to delayed or impaired function of the glucuronyl transferase enzyme system coupled with
breastfeeding and inadequate nutritional intake. This infant probably had a combination of breastfeeding with inadequate nutritional intake as well as the G6PD deciency. G6PD deciency is one of the commonest enzyme deciencies in humans. It occurs in 10% of African American males. Hemolysis with this disorder has been associated with a number of stressors: bacterial and viral infections, certain analgesics, sulfonamides, antimalarial drugs, and exposure to maternal ingestion of fava beans. None of these factors was identied. Functional severe mutations may cause hemolysis in the absence of stress. It is possible that as yet unidentiable chemical offenders may be included in the vast array of cleaning and other household materials available. Multiple initial missteps occurred in the care of this infant. An evaluation of the infants poor feeding after birth was not done. Lactation support was not provided. The mother was a teenager without an appropriate support structure. A timely follow-up system for this infant was not provided. No education about jaundice was provided at the time of discharge. Neither a serum nor transcutaneous bilirubin assessment was done, and therefore a risk assessment to determine the chance for a signicant hyperbilirubinemia was not made. Perhaps the severe dehydration stress triggered the hemolysis. Undoubtedly, the severe hyperbilirubinemia could have been avoided if appropriate care had been provided. The subsequent missteps involved physicians who did not appreciate the time-sensitive nature of this infants condition, thereby creating major delays in the initiation of phototherapy and his exchange transfusion. The lack of the physicians vigilance, the early discharge, failure to
provide a safety net for this teenage mother, subsequent long delay in the evaluation of this encephalopathic infant, and prolonged time before intervention caused the infants adverse outcome.

Know the pathologic ndings of kernicterus. Know the factors that increase the risk of the development of kernicterus Know the clinical features of acute bilirubin encephalopathy in newborn infants Know the clinical features of kernicterus.
Suggested Reading
American Academy of Pediatrics. Hospital stay for healthy term newborns. Pediatrics. 1995;96:788 790 Bhutani VK, Johnson L. Predictive ability of a predischarge hour-specic serum bilirubin for subsequent signicant hyperbilirubinemia in healthy term and nearterm newborns. Pediatrics. 1999;103: 6 14 Bhutani V, Johnson LH. Lessons for the future from a current tragedy. NeoReviews. 2003;4:e30 e32 Brown AK, Johnson L. Loss of concern about jaundice and the reemergence of kernicterus in full-term infants in the era of managed care. In: Fanaroff AA, Klaus MH, eds. The Year Book of Neonatal and Perinatal Medicine. Philadelphia, PA: Mosby Yearbook;1996:1728 Brown AR. Kernicterus: past, present, and future. NeoReviews. 2003;4:e33 e40 Joint Commission on Accreditation of Healthcare Organizations. Revised guidance to help prevent kernicterus. Sentinel Event Alert. 2004;31:12 Johnson LH, Brown AK, Bhutani VK. System-based approach to management of neonatal jaundice and prevention
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of kernicterus. J Pediatr. 2002;140: 396 403 Maisels MJ, Baltz RD, Bhutani VK, et al; American Academy of Pediatrics, Subcommittee on Hyperbilirubinemia. Clinical practice guideline: management of hyperbilirubinemia in the newborn
infant 35 or more weeks of gestation. Pediatrics. 2004;114:297316 Robertson WO, Almquist JR, Light IJ, et al; American Academy of Pediatrics, Provisional Committee for Quality Committee for Quality Improvement. Practice parameter: management of hyperbiliru-
binemia in the healthy term newborn. Pediatrics. 1994;94:558 565 Soorani-Lunsing I, Woltil H, HaddersAlgra M. Are moderate degrees of hyperbilirubinemia in healthy term neonates really safe for the brain? Pediatr Res. 2001;50:701705
Legal Briefs: KernicterusStill Preventable Maureen E. Sims NeoReviews 2011;12;e727-e730 DOI: 10.1542/neo.12-12-e727
Reprints
Strip of the Month: December 2011 Maurice L. Druzin and Nancy Peterson NeoReviews 2011;12;e731-e740 DOI: 10.1542/neo.12-12-e731
strip of the month
Strip of the Month: December 2011

Maurice L. Druzin, MD,* Nancy Peterson, RNC, PNNP, MSN, IBLC
Electronic Fetal Monitoring Case Review Series

Electronic fetal monitoring (EFM) is a popular technology used to establish fetal wellbeing. Despite its widespread use, terminology used to describe patterns seen on the monitor has not been consistent until recently. In 1997, the National Institute of Child Health and Human Development (NICHD) Research Planning Workshop published guidelines for interpretation of fetal tracings. This publication was the culmination of 2 years of work by a panel of experts in the eld of fetal monitoring and was endorsed in 2005 by both the American College of Obstetricians and Gynecologists (ACOG) and the Association of Womens Health, Obstetric and Neonatal Nurses (AWHONN). In 2008, ACOG, NICHD, and the Society for Maternal-Fetal Medicine reviewed and updated the denitions for fetal heart rate patterns, interpretation, and research recommendations. Following is a summary of the terminology denitions and assumptions found in the 2008 NICHD workshop report. Normal values for arterial umbilical cord gas values and indications of acidosis are dened in Table 1.
Author Disclosure Dr Druzin and Ms Peterson have disclosed no nancial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/device.
Assumptions From the NICHD Workshop
Denitions are developed for visual interpretation, assuming that both the fetal heart rate (FHR) and uterine activity recordings are of adequate quality Denitions 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
Denitions
Baseline Fetal Heart Rate
Approximate mean FHR rounded to increments of 5 beats/min in a 10-minute segment of tracing, excluding accelerations and decelerations, periods of marked variability, and segments 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 having regular frequency and amplitude
Baseline Variability
Fluctuations in the baseline FHR of two cycles per minute or greater, uctuations are irregular in amplitude and frequency, uctuations are visually quantitated as the amplitude of the peak to trough in beats per minute Classication of variability: Absent: Amplitude range is undetectable Minimal: Amplitude range is greater than undetectable to 5 beats/min Moderate: Amplitude range is 6 to 25 beats/min Marked: Amplitude range is 25 beats/min
*Charles B. and Ann L. Johnson Professor of Obstetrics; Chief, Division of Maternal-Fetal Medicine; Co-Medical Director, MidCoastal California Perinatal Outreach Program, Stanford University School of Medicine, Palo Alto, CA. Director of Perinatal Outreach, Stanford University, Palo Alto, CA. NeoReviews Vol.12 No.12 December 2011 e731
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Table 1.
Arterial Umbilical Cord Gas Values

pH Pco2 (mm Hg) <60 (3570) >60 <60 >60 Po2 (mm Hg) >20 Variable Variable Variable Base Excess < 10 ( 2.0 to < 10 > 10 > 10 9.0) >7.20 (7.157.38) <7.20 <7.20 <7.20
Normal* Respiratory Acidosis Metabolic Acidosis Mixed Acidosis
*Normal ranges from Obstet Gynecol Clin North Am. 1999;26:695.
Accelerations
Abrupt increase in FHR above the most recently determined baseline Onset to peak of acceleration is 30 seconds, acme is 15 beats/min above the most recently determined baseline and lasts 15 seconds but 2 minutes Before 32 weeks gestation, accelerations are dened by an acme 10 beats/min above the most recently determined baseline for 10 seconds Prolonged acceleration lasts 2 minutes but 10 minutes
Decelerations are tentatively called recurrent if they occur with 50% of uterine contractions in a 20-minute period. Decelerations occurring with 50% of uterine contractions in a 20-minute segment are intermittent. Sinusoidal Fetal Heart Rate Pattern
Visually apparent, smooth sine wavelike undulating pattern in the baseline with a cycle frequency of 3 to 5/minute that persists for 20 minutes.
Uterine Contractions
Late Decelerations
Gradual decrease in FHR (onset to nadir 30 seconds) below the most recently determined baseline, with nadir occurring after the peak of uterine contractions Considered a periodic pattern because it occurs with uterine contractions
Quantied as the number of contractions in a 10minute window, averaged over 30 minutes. Normal: 5 contractions in 10 minutes Tachysystole: 5 contractions in 10 minutes
Interpretation
A three-tier Fetal Heart Rate Interpretation system has been recommended as follows:
Early Decelerations
Gradual decrease in FHR (onset to nadir 30 seconds) below the most recently determined baseline, with nadir occurring coincident with uterine contraction Also considered a periodic pattern
Variable Decelerations

Abrupt decrease in FHR (onset to nadir 30 seconds) Decrease is 15 beats/min below the most recently determined baseline lasting 15 seconds but 2 minutes May be episodic (occurs without a contraction) or periodic
Prolonged Decelerations
Decrease in the FHR 15 beats/min below the most recently determined baseline lasting 2 minutes but 10 minutes from onset to return to baseline
Category I FHR tracings: Normal, strongly predictive of normal fetal acid-base status and require routine care. 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 evaluation and continued surveillance and reevaluation. Examples of these tracings include any of the following: Bradycardia not accompanied by absent variability Tachycardia Minimal or marked baseline variability Absent variability without recurrent decelerations Absence of induced accelerations after fetal stimulation
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Recurrent variable decelerations with minimal or moderate variability Prolonged decelerations Recurrent late decelerations with moderate variability Variable decelerations with other characteristics, such as slow return to baseline Category III FHR tracings: Abnormal, predictive of abnormal fetal acid-base status and require prompt intervention. These tracings include: Absent variability with any of the following: y Recurrent late decelerations y Recurrent variable decelerations y Bradycardia Sinusoidal pattern
Data from Macones GA, Hankins GDV, Spong CY, Hauth J, Moore T. The 2008 National Institute of Child Health and Human Development workshop report on electronic fetal monitoring. Obstet Gynecol. 2008;112: 661 666 and American College of Obstetricians and Gynecologists. Intrapartum fetal heart rate monitoring: nomenclature, interpretation, and general management principles. ACOG Practice Bulletin No. 106. Washington, DC: American College of Obstetricians and Gynecologists; 2009. We encourage readers to examine each strip in the case presentation and make a personal interpretation of the ndings before advancing to the expert interpretation provided.
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Case Presentation
History
A 30-year-old, G 1, P0 woman at 3637 weeks gestation is sent to labor and delivery from the perinatal diagnostic center for extended fetal monitoring after a nonreactive nonstress test (NST), a biophysical prole (BPP) of 8/10 with vibroacoustic stimulation, and an amniotic uid index of 10.4. This is the second admission for similar symptoms of decreased fetal movement in 2 days. Her history is signicant for type 1 diabetes mellitus, hypothyroidism, and nonproliferative retinopathy. During her prenatal care, the patient was controlled on an insulin
pump; however, her blood sugars were difcult to control and required frequent adjustments of her insulin regimen. Her glycosylated hemoglobin (HbAIc) has ranged from 6.9 to 7.5 throughout pregnancy and is a reection of glucose control over the previous 4 to 6 weeks. HbAIc levels above 6 indicate elevated glucose levels. She has also been on levothyroxine 25 mcg daily for her hypothyroid condition. Her vital signs are a blood pressure of 126/84 mm Hg, 80, temperature and respirations not documented. A FHR admission tracing is obtained shortly after admission to labor and delivery (Fig. 1).
Figure 1. EFM Strip #1.
strip of the month
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 amniotic uid volume despite a nonreactive NST for the past 2 days and minimal variability is considered a normal nding, and is a reliable predictor of fetal well-being. The false-negative rate of a BPP is superior to that of the NST alone and is comparable to the false-negative rate of a contraction stress test. The BPP assesses ve components:
fetal breathing movement, gross body movement, fetal tone, amniotic uid volume, and FHR reactivity (NST). The plan at this point is to continue with continuous fetal monitoring overnight in labor and delivery, and repeat BPP in the morning if FHR tracing does not improve. However, if there is a recurrent deceleration pattern, fetal bradycardia or BPP score of 6, an immediate delivery will be considered.
Case Progression
Eight hours later, the patient denies feeling irregular contractions that are seen on the tracing. Her temperature is 36.6C; heart rate, 79 beats/min; and blood pressure, 121/77 mm Hg. Her nger stick blood glucose (FSBG) is 158. A cervical exam reveals a closed, long, posterior cervix and the following tracing is obtained (Fig. 2).

strip of the month

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 uid 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 addition, Category II tracings warrant close observation and may benet from various therapeutic interventions to optimize fetal oxygenation such as, maternal position change, O2 per rebreather mask, and intravenous (IV) hydration. It is important to inform the patient and family, however, of the possibility of induction of labor or cesarean section if the fetal or maternal status worsens. Seven hours later, the patient is still not feeling any contractions and her vital signs remain stable with a FSBG of 125. A repeat BPP is still reassuring with a score of 8/10. The associated tracing is seen in Figure 3.

strip of the month

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 all pregnancies. They can usually be resolved with maternal lateral positioning and IV hydration. Will continue with expectant management as there is no indication to expedite the delivery at this time. Eight hours later, a cervical exam reveals no change in the cervix; it is still long and closed; see Figure 4 for the fetal 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 palpation Interpretation: Category II evolving to a Category III Action: The tracing shown is quickly evolving to a Category III tracing, which reects a fetus that is decompensating and becoming increasingly hypoxic and possibly acidotic. A consultation with a perinata-
logist was obtained and given the persistent minimal variability in addition to decelerations as well as an unfavorable cervix, a decision was made to proceed to delivery by cesarean section for nonreassuring FHR. Immediate interventions should focus on optimizing fetal oxygenation by lateral maternal positioning, O2 per rebreather mask, and IV hydration. Clear communication with the charge nurse, anesthesia, neonatal intensive care unit (NICU) staff, and operating room team is imperative to ensure a timely, safe delivery. The nal tracing (Fig. 5) was obtained approximately 60 minutes later.

strip of the month

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 throughout the pregnancy, the possibility of nonhyperglycemic diabetic ketoacidosis (DKA) should be entertained. DKA is an important etiology of nonreassuring fetal status as manifested by a Category III tracing with decreased variability and late decelerations. This pattern was apparent in this patient. The simplest diagnostic tool for a diagnosis of DKA in pregnancy is to evaluate the anion gap, which is easily calculated from a metabolic panel and is often calculated by the laboratory. Anion gap of less than 12 essentially rules out DKA, and one of greater than 12 should raise the
possibility of this condition. Correction of DKA will often result in improvement of a Category III tracing. Continue with interventions to improve blood ow and oxygenation to the fetus (ie, maternal position change, IV hydration, O2 per nonrebreather mask). Proceed with plans to deliver the fetus by cesarean.
Outcome
The patient was prepped and transported to the OR where spinal anesthesia was administered. Approximately 30 minutes later, a viable male infant weighing 3,420 kg is delivered by cesarean section with Apgars of 5 and 7. There was a nuchal cord X 1 that was reduced easily without incident. The infant was handed off to the NICU team, and responded quickly to stimulation and O2, and was transported to the NICU for further evaluation. Cord gases were obtained and the placenta was sent to pathology. The nal pathology report revealed changes of acute and chronic ischemia of the decidua capsularis and extensive compensatory chorangiosis.
Table 2.
Arterial Umbilical Cord Gas Values

pH Pco2 (mm Hg) <60 (3570) >60 <60 >60 118.2 Po2 (mm Hg) >20 Variable Variable Variable <5 Base Excess < 10 ( 2.0 to < 10 > 10 > 10 10 9.0) >7.20 (7.157.38) <7.20 <7.20 <7.20 6.89
Normal* Respiratory Acidosis Metabolic Acidosis Mixed Acidosis Patient
*Normal ranges from Obstet Gynecol Clin North Am. 1999;26:695.
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Cord gases revealed a mixed respiratory metabolic acidosis (Table 2), which correlates with a Category II tracing that is evolving to a Category III tracing. This case is an excellent example of the importance of utilizing adjunct antepartum testing such as BPP to conrm fetal well-
being. In this case, close observation with continuous fetal monitoring and recognition of evolving fetal compromise, allowed a few more days for fetal lung maturity and a good outcome. Both mother and infant were discharged 4 days later in stable condition.
Strip of the Month: December 2011 Maurice L. Druzin and Nancy Peterson NeoReviews 2011;12;e731-e740 DOI: 10.1542/neo.12-12-e731
Reprints
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, 98.6F (37C)
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,
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.....

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
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;9:321327 Chervenak FA, Isaacson G, Blakemore KJ, et al. Fetal cystic hygroma: cause and natural history. N Engl J Med. 1983;309:822825 Edwards MJ, Graham Jr JM. Posterior nuchal cystic hygroma. Clin Perinatol. 1990;17:611640
Geifman-Holtzman O, Drury HE, Holmes LB. Increased detection of cystic hygroma: a technology-induced phenomenon. Teratology. 1996;54:298302 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; 1997:163181 Marchese C, Savin E, Dragone E, et al. Cystic hygroma: prenatal diagnosis and genetic counselling. Prenat Diagn. 1985;5:221227 Siegel MJ, Glazer HS, St Amour TS, et al. Lymphangiomas in children: MR
imaging. Radiology. 1989;170:467470 Tanigawa N, Shimomatsuya T, Takahashi K, et al. Treatment of cystic hygroma and lymphangioma with the use of bleomycin fat emulsion. Cancer. 1987;60:741749
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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