Neoreviews 1.11

Educational Perspectives: A Systematic Approach to Curriculum Development
Dara Brodsky and Lori R. Newman

NeoReviews 2011;12;e2-e7
DOI: 10.1542/neo.12-1-e2
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educational perspectives
A Systematic Approach to Curriculum

Development
Dara Brodsky, MD,* Lori R. Newman, MEd†
Abstract
This review presents a systematic approach to curriculum development,
divided into five steps: 1) perform a needs assessment, 2) define the goals
and learning objectives, 3) identify resources, 4) develop educational
strategies and implement the curriculum, and 5) evaluate and modify the
curriculum. Although the curriculum developmental stages are presented
in five ordered steps, curriculum development is actually a dynamic,
interactive process, in which development of one step naturally affects
other steps. Learners are central to this process, and with each step, the
instructor needs to be mindful of the learners’ needs and prior experiences,
using a variety of educational strategies to reach trainees with different
learning styles.
Objectives After completing this article, readers should be able to:

Author Disclosure 1. Identify key steps in developing a curriculum.
Drs Brodsky and Ms Newman have 2. Distinguish between goals and learning objectives.
disclosed no financial relationships 3. Select learner-centered teaching strategies.
relevant to this article. This 4. Recognize the importance of evaluating a curriculum.
commentary does not contain a
discussion of an unapproved/ Introduction framework for curriculum develop-
Medical school curricula receive sub- ment (modified from Kern and asso-
investigative use of a commercial
stantial attention and are largely stan- ciates). The learner is central to this
product/device.
dardized across the country, but process, and with each step, the in-
postgraduate curricula in most hos- structor should be mindful of the
pitals are inconsistent, depending on learner’s needs and prior experiences,
the ability, interest level, and avail- using a variety of educational strate-
ability of faculty. By using a system- gies to reach trainees with different
atic approach to curriculum develop- learning styles.
ment and standardizing teaching
practices, clinician educators can en- Definition of Curriculum
sure that their learners master the A curriculum is any planned educa-
knowledge and skills necessary to at- tional experience. Clinicians tend to
tain the next level of training. This think of curricula as teaching guide-
article describes one such systematic lines for clinical rotations or entire
approach: a five-step, easy-to-use training programs, but the term also
incorporates planned teaching ses-
sions at the bedside or in an outpa-
*Assistant Professor in Pediatrics, Harvard Medical
School, Beth Israel Deaconess Medical Center, tient clinic. Using this broader defi-
Boston, MA. nition, most neonatology fellows and
†
Director, Office of Faculty Education, Center for neonatologists have experience with
Education, Shapiro Institute for Education at
Harvard Medical School and Beth Israel Deaconess curriculum development activities.
Medical Center, Boston, MA. Within this definition of curricu-
e2 NeoReviews Vol.12 No.1 January 2011

lum are four categories. The official the amount of face-to-face contact municates the educational aim and
curriculum is generally a written set time they will have with the learners. purpose of the instruction. It also
of information and skills that learners For example, a clinician educator identifies the learner group and the
must master by the end of their train- developing a yearlong curriculum scope of the curricular content. Us-
ing experience. The operational cur- might need to use multiple assessing the scenario, the attending de-
riculum is that portion of the official ment methods, such as a knowledge cides that his primary learning goal
curriculum and any additional con- pretest, focus group input, and a is: To have the residents develop the
tent that actually is taught. The null written survey. On the other hand, if knowledge and skills necessary to care
curriculum category describes the a clinician is planning a single bedside for a hospitalized infant with respira-
knowledge and skills that are ne- teaching session, one method, such tory distress. In this example, “resi-
glected or intentionally not taught. as informally asking the trainees what dents” encompass the learner group,
Finally, the hidden curriculum cate- they want to learn, should suffice. “develop the knowledge and skills
gory is the set of values, attitudes, To demonstrate how this curricu- necessary” is the purpose of the in-
and beliefs embedded in the training lar design process works, we use a struction, and the “hospitalized in-
program’s cultural milieu, which is clinical scenario throughout this re- fant with respiratory distress” defines
conveyed through verbal and non- view: the scope.
verbal cues. An attending in the neonatal in- After defining the learning goal,
tensive care unit will be working with the attending needs to determine
Step 1: Needs Assessment three pediatric residents for a 2-week the learning objectives. The learning
The first step in curriculum develop- rotation. A few weeks before the rota- objectives describe what the learners
ment is for the instructor to assess the tion, the Department Chair tells the will be able to know, show, or do
learners’ educational needs, which attending that she has heard a lot of at the end of the teaching ses-
will help determine the breadth and criticism from the residents about the sion(s). The objectives can be cog-
depth of the curriculum. A needs as- curriculum this year. The trainees nitive (knowledge-based), psycho-
sessment is critical for effective cur- have complained that they are not motor (skill and performance-
riculum development, and although learning anything they really need to based), and affective (attitudinal).
it is a simple concept to understand, know. The Chair asks the attending to Objectives answer five questions:
it can be challenging to execute. Cur- design a new curriculum for the resi- ● Who?
riculum developers must determine dents. ● Will do?
what the learners already know, what The attending is already familiar ● How much?
they need to know to move to the with the Accreditation Council for ● Of what?
next training level, and what infor- Graduate Medical Education’s pedi- ● By when?
mation and skills need to be taught atric residency program requirements.
to fill knowledge gaps and meet edu- Because the rotation is fast approach- Thus, a learning objective for the
cational benchmarks. Methods for ing and there is no time for formal scenario might be: The pediatric resi-
assessing the learners’ current knowl- testing, the attending meets with the dents will intubate five infants who
edge and determining their prior ex- chief resident, a group of pediatric res- have respiratory distress by the end of
periences range from formal written idents, and other neonatologists to de- their 2-week rotation. This statement
tests to informal surveys. Curriculum termine what the residents typically answers the five questions:
developers should consider the local know at baseline. Based on this infor- ● Who?⫽The pediatric residents
and national expectations of their mation, the attending determines that ● Will do?⫽will intubate
training programs to help determine an important subject that the residents ● How much?⫽five
the educational standards for their need to know, but do not consistently ● Of what?⫽infants who have respi-
trainees. Once curriculum develop- learn, is how to manage a hospitalized
ratory distress
ers have identified what the trainees infant with respiratory distress. ● By when?⫽by the end of the 2-week
know and need to learn, they can
rotation
focus on the information they need Step 2: Goals and Learning
to teach. Objectives Ideally, the learning objectives
Developers should select a needs The second step of curriculum devel- should incorporate the acronym
assessment method based on the type opment is to define the learning goals “SMART”: Specific, Measurable,
of curriculum they are planning and and objectives. A learning goal com- Attainable, Relevant, and Targeted
NeoReviews Vol.12 No.1 January 2011 e3

to the learner. The example learning sion, application, analysis, synthesis, tify stakeholders and gain their sup-
objective fits these criteria. The fol- and evaluation. To engage the learn- port. Stakeholders are directly af-
lowing two learning objectives, on ers in higher-order thinking and fected by a curriculum, such as the
the other hand, are flawed: deep understanding of concepts, Department Chair in the scenario.
1. The pediatric residents will un- mastery of the lower levels is re- Additional stakeholders include cli-
derstand the causes of respiratory dis- quired. Figure 1 provides examples nicians who need to commit their
tress in an infant by the end of the of learning objectives for the scenario own time to help teach the curricu-
rotation. This learning objective is that target each cognitive domain. lum. Before approaching the stake-
not measurable because there is no holder, the instructor should know
observable indication of how to mea- Step 3: Resource how to respond to the often unspo-
sure the residents’ understanding. Identification ken question, “What’s in it for me?”
Because there are many causes of re- When developing a curriculum, in- In response, the curriculum devel-
spiratory distress in infants, this ob- structors need to identify the people, oper can reveal a well-developed
jective needs to be more specific and time, facilities, materials, and fund- needs assessment, well-crafted edu-
demonstrable. The objective might ing necessary to build, implement, cational objectives, and possibly an
be changed to: The pediatric residents and sustain the curriculum. Al- evaluation plan to show how the cur-
will summarize the five most common though this seems obvious, if curric- riculum will be an excellent return on
causes of respiratory distress in a hospi- ulum designers do not focus on this the stakeholder’s investment.
talized infant by the end of the rota- step in advance, they may find that
tion. This is measurable and demon- their curriculum is complete but Step 4: Development of
strable; at the end of the rotation, the lacks the critical resources to imple- Educational Strategies and
instructor can assess the residents’ ment it. For example, to teach resi- Implementation of the
acquired knowledge by having them dents how to intubate effectively, Curriculum
provide a written or verbal summary the curriculum should involve some Educational strategies are the teach-
of the causes of respiratory distress. type of simulation-based training. ing methods and activities used to
This objective is also specific, aimed Depending on the resources avail- engage learners actively and enable
at describing the five most common able, intubation training can range them to meet the learning objectives.
causes of respiratory distress in a hos- from use of a mannequin head to a These methods include:
pitalized infant. high-fidelity mannequin that has a
2. The pediatric residents will suc- cardiovascular monitor. ● Readings from textbooks or jour-
cessfully intubate an infant with a To obtain the necessary resources, nal articles
large neck mass obstructing the airway curriculum developers need to iden- ● Lectures
by the end of the rotation. Although
this objective is measurable (the res-
ident will be able to do it or not) and
specific, it is neither realistic nor
likely attainable. An improved objec-
tive would be: The pediatric residents
will successfully intubate three infants
by the end of the rotation.
To ensure that the learners are
actively engaged with the curricu-
lum, find the content meaningful,
and can apply and retain new knowl-
edge and skills, curriculum designers
should use Bloom’s taxonomy as a
guide when creating learning objec-
tives. This multi-tiered model classi- Figure 1. Bloom’s taxonomy. This multi-tiered model classifies educational objectives
fies educational objectives according according to six cognitive levels of increasing complexity: knowledge, comprehension,
to six cognitive levels of increasing application, analysis, synthesis, and evaluation. To the right of the model are examples
complexity: knowledge, comprehen- of learning objectives that target each cognitive domain.

● Small group or case-based discus- the instructor can implement the evaluation and program evaluation
sions curriculum. During this step, it is (Fig. 2). Learner evaluation asks the
● Simulations with patient-actor, easy to fall into a teacher-centered question, “Did the learners get it?”
family member-actor, or manne- approach with an overly rigid adher- and determines whether learners can
quins ence to the preplanned curriculum. provide evidence that they under-
● Bedside teaching sessions It is essential at this point for the stand what they were taught, can
curriculum designer to maintain his demonstrate new skills, and will be
In addition to connecting the or her commitment to learner- able to apply new learning when car-
teaching method with the specific centered learning. Teachers need to ing for their next patient. Program
curricular content, curriculum de- guide or facilitate learning and evaluation asks the question, “Does
signers also must think about the should consider the following tech- the curriculum work?” This is an-
learner when selecting educational niques: swered by quantitatively measuring
strategies. Some trainees prefer to the achievements of all learners, col-
● Avoid information overload and al-
learn by reading; others may learn lecting feedback about the quality of
low time for group discussion
best through discussions or active the teaching, and assessing the im-
● Ask higher-order questions, com-
practice. To appeal to all types of pact of the curriculum on future clin-
pelling learners to analyze and eval-
learners, curricula should include a ical care.
uate information
variety of teaching methods. In the There are many methods to eval-
● Encourage learner-to-learner dia-
scenario, the attending might use uate the learner. Some examples in-
logue
readings and small group discussions clude:
● Be flexible and allow the learners’
to help the learners summarize the
interests, experiences, and needs to ● Knows: Written examinations, pre-
five most common causes of respiratory
guide the direction of teaching and posttesting
distress in a hospitalized infant and
use simulation and bedside teaching ● Shows: Observation by a supervisor,
Step 5: Evaluation and simulation, objective structured
to have the residents apply knowledge
Modification clinical examination, standardized
of pharyngeal anatomy and intubate
Evaluation and modification com- patients
an infant.
pletes the curriculum development ● Does: Medical record audit, multi-
Each type of educational strategy
model. The process of evaluation al- source feedback, learner portfolio,
has its own strengths and weak-
lows the teacher to ask and answer clinical evaluation exercise
nesses. For example, readings are low
the critical question, “Was the curric-
cost, but learners need to be self-
ulum successful in achieving the In the scenario, if a learning ob-
motivated to complete their assign-
learning goals and objectives?” Eval- jective is to have the resident summa-
ments. Although lectures offer a
uation of a curriculum consists of rize the five most common causes of
great opportunity to teach to a large
two interconnected domains: learner respiratory distress in a hospitalized
number of learners simultaneously,
this approach can be passive, with
minimal interaction between the
learners and teachers. Small-group
discussions are ideal for problem-
solving and teaching clinical
decision-making, but success de-
pends on the learners’ interest, expe-
rience, and knowledge. Realism is a
tremendous benefit of simulation,
but the more realistic the simulation,
the higher the cost. Finally, bedside
teaching fosters learner motivation
and responsibility but requires inten- Figure 2. The questions that encompass the two interconnected domains of curricu-
sive faculty supervision. lum evaluation: learner evaluation and program evaluation. Adapted from Tess AV.
After determining the educational Introduction to curriculum development and instructional design. In: Principles of
strategies and curriculum content, Medical Education. Boston, MA: Beth Israel Deaconess Medical Center; 2009.

The learner is central to this process,

reflected within the star model. Dur-
ing each step of curriculum develop-
ment, clinical teachers need to be
mindful of their learners’ needs and
prior experiences and the educational
strategies to engage them. Curricu-
lum development is a dynamic, inter-
active process, in which development
of one step naturally affects other
steps. As clinicians move forward in
their own curriculum development
process, we encourage them to in-
corporate learner-centered instruc-
tion into their everyday interactions
with trainees, to reflect on what as-
pects of a curriculum works well and
what needs to be improved, to be
willing to modify the curriculum to
meet the needs of the learners, and to
have fun teaching.
Figure 3. Systematic approach to curriculum development.
American Board of Pediatrics

infant, the evaluation might include be shown by an increase in positive Neonatal-Perinatal Medicine
a written or verbal knowledge-based resident evaluations about the curric- Content Specifications
examination. If another learning ob- ulum meeting their learning needs
• Understand the
jective is to have the resident apply compared with precurriculum evalu- strengths and
knowledge of pharyngeal anatomy and ations. To determine if the curricu- weaknesses of
intubate an infant, the use of simu- lum had an impact on clinical care, various teaching
lation or observation of a resident’s the attending in the scenario can col- methods (eg,
intubation procedure is an excellent lect data to see if there are fewer lecture, small group discussion,
bedside teaching, simulation).
method of learner evaluation. resident-associated complications • Understand that individuals may learn
Program evaluation measures the from intubation after the curriculum more effectively with certain teaching
success of the curriculum by analyz- was introduced. methods (eg, reading, hearing, doing)
ing the quantity, quality, and impact After compiling the findings from than with others.
of the curriculum. Quantitative eval- learner and program evaluations, the • Understand the role of needs
assessment in educational planning.
uation of the curriculum can include attending can modify and improve • Distinguish between goals and
results of knowledge-based tests or the curriculum. By analyzing the learning objectives.
the number of learning objectives strengths and weaknesses of the cur- • Identify components of well-
that each resident attained. For ex- riculum and determining the needs formulated learning objectives.
ample, in the scenario, measuring the of the next set of learners, curriculum
resident’s success rate of intubation developers can engage in continuous
before and after the curriculum will quality improvement as they recon- Suggested Reading
help evaluate the program’s effec- sider and recalibrate each step of the Billings D, Halstead JA. Teaching in Nurs-
tiveness. Feedback from learners, at- model for the next clinical rotation. ing: A Guide for Faculty. St. Louis, MO:
Saunders, Elsevier Science Health Sci-
tendings, and clinical team members
ence; 1998
on the structure and content of the Conclusion Bloom B. Taxonomy of Educational Objec-
curriculum can help to assess the pro- The diagram in Figure 3 depicts the tives. Handbook I: Cognitive Domain.
gram qualitatively. In the scenario, systematic approach to curriculum New York, NY: David McKay Com-
improved quality of the program may development discussed in this article. pany, Inc; 1956

Brodsky D, Huang G. Principles of Teaching EB. Curriculum Development for Medi- Rodney JW, Peyton JW. Teaching & Learn-
and Learning. Computer-Based Mod- cal Education: A Six-step Approach. Bal- ing in Medical Practice. Rickmansworth,
ule. Boston, MA: 2010. Available at: timore, MD: Johns Hopkins University UK: Manticore Europe Ltd; 1998
http://tinyurl.com/brodsky1 Press; 1998 Prideaux D. ABC of learning and teaching:
Brodsky D, Martin C. Principles of teaching Lake FR, Hamdorf JM. Teaching on the curriculum design. BMJ. 2003;326:
and learning. In: Neonatology Review. run tips 6: determining competence. 268 –270
2nd ed. www.lulu.com; 2010 Med J Aust. 2004;181:502–503 Sheets KJ, Anderson WA, Alguire PC. Cur-
Chandran L, Gusic M, Baldwin C, et al. Ludmerer KM. Time to Heal: American riculum development and evaluation in
Evaluating the performance of medical Medical Education from the Turn of the medical education. J Gen Intern Med.
educators: a novel analysis tool to dem- Century to the Era of Managed Care.
1992;7:538 –543
onstrate the quality and impact of edu- Oxford, England: Oxford University
Thomas PA, Kern DE. Internet resources
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54 – 66 Mager RF. Preparing Instructional Objec-
education: an annotated bibliography.
Eisner E. The Educational Imagination: On tives. Belmont, CA: David S. Lake Pub-
the Design and Evaluation of School Pro- lishers; 1984 J Gen Intern Med. 2004;19:599 – 605
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Green ML. Identifying, appraising, and im- 1990;65:S63–S67 nity-based Preceptors. Accessed October
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Educational Perspectives: A Systematic Approach to Curriculum Development
Dara Brodsky and Lori R. Newman
DOI: 10.1542/neo.12-1-e2
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Core Concepts: The Biology of Hemoglobin
Robin K. Ohls
DOI: 10.1542/neo.12-1-e29
Article core concepts

Robin K. Ohls, MD*
Abstract
A consistent and organized transition from embryonic to fetal to adult hemoglobin
Author Disclosure (Hgb) occurs during human fetal development. Hgb concentrations gradually in-
Dr Ohls has disclosed crease, averaging 18 g/dL (180 g/L) by 40 weeks’ gestation. The ability to deliver
no financial oxygen to tissues in the fetus and neonate is primarily determined by the percentage of
fetal versus adult Hgb and the concentration of 2,3 diphosphoglycerate (2,3-DPG).
relationships relevant
Studies continue to evaluate the relationship between Hgb concentrations and oxygen
to this article. This
delivery in neonates to determine what Hgb concentrations best meet the needs of a
commentary does not wide variety of clinical situations from the critically ill extremely low-birthweight
contain a discussion infant to the stable growing preterm infant. Biochemical interactions between nitric
of an unapproved/ oxide (NO) and Hgb beyond the production of methemoglobin do occur and may be
investigative use of a a source of deliverable NO to the microcirculation under hypoxic conditions.
commercial
product/device.
Objectives After completing the article, readers should be able to:
1. Describe the development of globin gene synthesis and Hgb formation.

2. Explain fetal to neonatal transition of Hgb F to Hgb A.
3. Review the development and function of 2,3-DPG.
4. Describe the relationship between NO and Hgb.
Hemoglobin Concentration During Development

Red blood cell indices such as Hgb, hematocrit, mean cell volume, and red cell distribution
width change during gestation and continue to change through the first postnatal year. (1)
Hgb concentrations gradually rise during gestation. At 10 weeks’ gestation, the average
concentration is approximately 9 g/dL (90 g/L); (1)(2) by the start of the third trimester,
values in the developing fetus reach 11 to 12 g/dL (110 to 120 g/L); and by 30 weeks,
Hgb concentrations are 13 to 14 g/dL (130 to 140 g/L). (1) Jopling and associates (3)
have identified reference ranges based on approximately 25,000 preterm and term infants.
From 22 to 40 weeks’ gestation, there is a consistent increase in Hgb of 0.21 g/dL
(2.1 g/L) per week (Fig. 1). (3) In this large cross-sectional study, no sex differences were
noted in Hgb concentrations, but some studies have reported a slight difference in Hgb
concentrations between white and African American preterm infants. (4) At delivery, a 1-
to 2-g/dL (10- to 20-g/L) rise in Hgb may result from transfusion of placental blood into
the infant. In term and late preterm infants, Hgb concentrations increase by approximately
4% at 4 hours of postnatal age, resulting from a decrease in plasma volume. (5) By 8 to
12 hours of age, Hgb concentrations achieve a relatively constant level. In contrast, in an
evaluation of more than 20,000 preterm infants (29 to 34 weeks’ gestation), a decrease of
approximately 6% was measured at 4 hours of age. (3) This decrease might be due to a lack
of placental transfusion because the umbilical cord in preterm infants is rapidly clamped to
expedite resuscitation.
Red blood cell production decreases significantly after birth, primarily as a result of the
increased availability of oxygen, which greatly reduces erythropoietin (Epo) production
and endogenous erythropoiesis. By the end of the first postnatal week, Hgb concentrations
begin to decline (3) and continue to decrease over the next several weeks as a result of
decreased erythrocyte production, a shortened erythrocyte life span, and an increase in
*Professor of Pediatrics, University of New Mexico, Albuquerque, NM.

core concepts hemoglobin
count for the higher oxygen needs

and the compensatory increase in
erythropoiesis and Hgb concentra-
tion. (15)
Hemoglobin Synthesis
During fetal erythropoiesis, an or-
derly evolution of the production
of various Hgbs occurs. Eight glo-
bin genes direct the synthesis of six
different polypeptide chains, desig-
nated alpha (␣), beta (␤), gamma
(␥), delta (␦), epsilon (␧), and zeta
(␨). These globin chains combine
in the developing erythroblast to
form seven different Hgb tetramers:
Gower 1 (␨2-␧2), Gower 2 (␣2-␧2),
Portland (␨2-␥2), fetal hemoglobin
Figure 1. Reference ranges for blood hemoglobin concentrations at birth in 24,416 (Hgb F: ␣2-␥2), and two types of
patients at 22 to 42 weeks’ gestation. The solid line represents the mean value and the adult hemoglobin: ␣2-␤2, known as
dashed lines represent the 5% to 95% reference range. Reprinted with permission from Hgb A, and ␣2-␦2, known as Hgb
Jopling. (3) A2 (Table 1).
blood volume related to growth (Fig. 2). Term infants Globin Genes
reach their Hgb nadir at approximately 8 weeks, with The globin genes are organized into two clusters
an average Hgb concentration of 11.2 g/dL (112 g/L). (Fig. 3). The ␣-like genes are located along a 20-kb distal
(6) Hgb concentrations subsequently rise so that by segment of the short arm of chromosome 16. The cluster
6 months, the concentration averages 12.1 g/dL contains three functional genes (␣1, ␣2, and ␨2), three
(121 g/L). (7) pseudogenes (evolutionary remnants of genes that are
The decline in Hgb in very low-birthweight infants is not expressed because of inactivating mutations that
greater than that in term infants, in part because of prevent production of a functional globin protein), and
phlebotomy losses and in part because of the suppressive one gene of undetermined function (a globin-like gene
impact of transfusions on endogenous erythropoiesis. without inactivating mutations). The ␤-like gene cluster
Such infants reach the Hgb nadir of 8 g/dL (80 g/L) is located along a 60-kb segment of the short arm of
at 4 to 8 weeks of age. (8) Figure 2 demonstrates chromosome 11, and it contains five functional genes
relationships among birthweight, chronologic age, and (␤, ␦, A␥, G␥, and ␧) and one pseudogene. Within each
Hgb in term and preterm infants. (3) complex, the genes are all in the same 5⬘ to 3⬘ orienta-
Maternal conditions can influence fetal Hgb concen- tion, and they are arranged in the order in which they are
trations. Infants born small for gestational age can have expressed during development. (16)
higher Hgb concentrations due to placental insufficiency
and secondary polycythemia. (9)(10) Infants of dia- Timing of Globin Chain Synthesis
betic mothers, infants of smoking mothers, and infants Globin chain production has been determined at each
born at higher altitudes also tend to have higher Hgb stage of development, from initial yolk sac (primitive) to
concentrations at birth (11)(12)(13)(14) In all of these hepatic (definitive) and marrow erythropoiesis. It is not
conditions, accelerated erythropoiesis is believed to be clear why or how primitive erythroid progenitors pro-
part of a compensating mechanism designed to raise grammed to produce embryonic Hgb transition to de-
oxygen-carrying capacity to maintain an adequate oxy- finitive progenitors programmed to produce Hgb F.
gen supply to the fetus. In the case of the fetus of a Because quantification of globin gene expression using
mother who has diabetes, increased metabolic demands real time polymerase chain reaction methods reflects
of the fetus (as evidenced by a positive correlation be- production by a heterogeneous source of erythrocytes,
tween maternal Hgb A1c and neonatal Hgb) may ac- production of a specific Hgb is usually reported as a

During the sixth to seventh week of

gestation, primitive erythroblasts
continue to produce ␣, ␨, and ␧
chains, while definitive erythrocytes
produce ␣, ␧, G␥, and A␥ chains. By
the seventh to eighth week, ␧- and
␨-chain synthesis is no longer de-
tectable, and the primary globin
chains produced are ␣, G␥, and A␥.
␤-chain production is just barely
detectable at this time and gradu-
ally increases, comprising up to 10%
of total non–␣-chain production by
10 weeks of gestation. (18) Genetic
disorders associated with ␤-chain
synthetic or structural abnormali-
ties may be detected in utero as
soon as ␤-chain production occurs
but are often not clinically apparent
until after birth.
From 10 to 33 weeks of gesta-
tion, the primary globin chains syn-
thesized are ␣, G␥, A␥, and ␤. As-
sessment of the output of the two
linked ␣-globin genes by mRNA
analysis suggests that they are ex-
pressed in the ratio (␣2:␣1) rang-
ing from 1.5 to 3.0:1 throughout
fetal life, and this ratio continues
through normal adulthood. The
relative rates of G␥-chain and A␥-
chain production are also constant
throughout fetal life at a G␥:A␥ ratio
of approximately 3:1. (19) During
the transition from 32 to 36 weeks
of gestation, the relative rate of
␤-chain synthesis increases and that
of ␥-chain production declines, so
at birth, ␤-chain synthesis makes
Figure 2. Reference ranges for blood hemoglobin concentrations in 39,559 patients
during the 28 days after birth in late preterm and term infants 35 to 42 weeks’ gestation up approximately 50% of non–␣-
(panel A) and in preterm infants 29 to 34 weeks’ gestation (panel B). The solid line chain synthesis. There is consider-
represents the mean value and the dashed lines represent the 5% to 95% reference range. able variation among infants, how-
Reprinted with permission from Jopling. (3) ever, with many infants showing
prolonged dependence on Hgb F.
After birth, the level of ␤-chain pro-
percentage of the total Hgb measured. Studies measur- duction increases, while the level of ␥-chain production
ing Hgb production by erythroid colonies in culture steadily declines, so by the end of the first year, ␥-chain
show that individual cells in a colony produce predomi- synthesis reaches the low concentration that is character-
nantly one type of Hgb. (17) istic of adult life (⬍2%). Over the first few months after
During the fourth to fifth week of gestation, ␣, ␨, and birth, the G␥:A␥ ratio changes from 3:1 to 2:3, although
␧ chains are the primary globin chains produced (Fig. 4). this ratio varies in adults. (20)(21)(22)

Globin Chain Composition

Table 1. ing in the presence of ␧4. (23) Soon thereafter, ␣- and
␨-chain production begins, and Hgb Gower 1 (␨2-␧2),
of Common Hemoglobin Gower 2 (␣2-␧2), and Portland (␨2-␥2) are formed. (24)
By 5 to 6 weeks’ gestation, Hgb Gower 1 and Gower 2
Type of Hemoglobin Composition
constitute 42% and 24% of the total Hgb, respectively,
Embryonic Hemoglobin: with Hgb F (␣2-␥2) making up the remainder. By 14 to
Gower 1 ␨2-␧2 16 weeks, Hgb F constitutes 50% of the total Hgb, and
Gower 2 ␣2-␧2
Portland ␨2-␥2 by 20 weeks, it forms more than 90% of the Hgb. (25)
Fetal Hemoglobin: Small quantities of Hgb A (␣2-␤2) are found beginning
F ␣2-␥2 at 6 to 8 weeks’ gestation. The increase in ␤-chain
Adult Hemoglobin: production occurring between 12 and 20 weeks’ gesta-
A ␣2-␤2 tion accounts for the sudden rise in Hgb A found at
A2 ␣2-␦2
the end of the first trimester of pregnancy. Tetramers of
␥-chains (␥4 or Hgb Barts) and ␤-chains (␤4 or Hgb H)
Delta-chain production has been observed as early as can be found in conditions in which ␣-chain synthesis is
32 weeks’ gestation. Delta-gene production lags behind impaired or absent, such as ␣-thalassemia syndromes.
␤-gene production, so the adult ␤/␦ synthesis ratio is not Hgb F is easily distinguished immunologically and bio-
reached until 4 to 6 months after birth. chemically from Hgb A. The primary differentiating physi-
ologic characteristic of Hgb F is its decreased interaction
with 2,3-DPG (also known as 2, 3 bisphosphoglycerate).
Hemoglobin Production During Development 2,3-DPG binds to deoxyhemoglobin in a cavity between
Developmental changes in the production of Hgb can be the ␤-chains and stabilizes the deoxy form of Hgb, resulting
seen in Figure 5. Before the onset of other chain forma- in reduced Hgb-oxygen affinity. 2,3-DPG binds less effec-
tion, unpaired globin chains may form tetramers, result- tively to ␥-globin chains because of the differing amino acid
sequence in the non–␣-chain. Con-
sequently, 2,3-DPG does not reduce
the oxygen affinity of Hgb F as much
as that of Hgb A.
Fetal and adult Hgb also differ in
solubility. Hgb F is more soluble in
strong phosphate buffers than Hgb A
and is oxidized to methemoglobin
more easily than Hgb A. Hgb F has a
considerably greater affinity for oxy-
gen as a result of differences in bind-
ing to 2,3-DPG mentioned previ-
ously. Hgb F is resistant to acid
elution, which allows differentiation
of cells containing Hgb F from cells
containing Hgb A. (26) This prop-
erty forms the basis of differentiating
fetal from maternal red cells using the
Kleihauer Betke stain.
Figure 3. Organization of the globin genes. Transcription takes place from the 5ⴕ to the 3ⴕ G
␥-chains represent 70% to 80%
end; for both chromosomes, the genes are arranged in order of their developmental activation.
of the total ␥-chains in the blood of
The upper part of the figure represents the beta-like globin genes on the short arm of
the fetus and newborn. The percent
chromosome 11, and the lower part of the figure represents the alpha-like genes on the distal
short arm of chromosome 16. Regions of the gene that code for primary globin proteins are of ␥-chains made up of ␥ falls to
G
shown as shaded ovals. Regions that code for pseudogenes (y-nonexpressed remnants that about 40% by 5 months of age. This
have a number of inactivating mutations that prevent transcription and translation into unique difference in ␥-chain pro-
G
functional globin protein) are shown as open ovals. ␪-1 is a globin-like gene without duction found in the fetus helps to
inactivating mutations. The locus control region (LCR) is shown as a hatched segment. distinguish fetal hematopoiesis from

of diabetic mothers. (30)(31) Ele-

vated concentrations of Hgb F may
have protective effects in some dis-
ease states. For example, a high con-
centration of fetal Hgb F in patients
who have sickle cell disease may be a
predictor of increased adult life ex-
pectancy. (32)(33)
On a body weight basis, red blood
cell production during the latter
months of gestation is significantly
greater compared with that in adult
life. Immediately after birth, erythro-
poiesis is considerably reduced, asso-
ciated with a steady and linear decline
in ␥-chain synthesis during the pe-
riod of reduced neonatal erythropoi-
esis. Newly synthesized red blood cells
appearing in the circulation when
erythropoiesis resumes contain pre-
Figure 4. Production of globin chains during the fetal and neonatal period. dominantly Hgb A. The postpartum
decline of Hgb F production and of
that found in later life. Under stress, the older infant and the intercellular distribution of fetal and adult Hgb over
adult increase production of Hgb F. Increased Hgb F the first postnatal months has been extensively examined.
production often occurs in leukemic states and in other Immediately after birth, there is a brief rise in Hgb F,
conditions. (27)(28) The delay in the switch of Hgb F to followed by a steady decline. Studies of the intercellular
Hgb A has been noted in conditions of maternal hypoxia, in distribution of Hgb F (using an acid-elution technique)
infants who are small for gestational age, (29) and in infants have shown that the distribution of Hgb F is heterogeneous
over the first few months after birth.
At 3 months, the distribution of
Hgb F becomes bimodal, with pop-
ulations of cells that contain acid-
resistant Hgb F and populations of
cells containing Hgb A. These obser-
vations have suggested that Hgb
F-containing cells are replaced by a
population of cells containing Hgb A
during the early postnatal period.
Studies show that the type of
globin chains produced at different
stages of development are not closely
related to the site of erythropoiesis.
It appears that ␨- and ␧-chains are
synthesized in both primitive and
definitive cell lines. Moreover, dur-
ing the later stages of fetal develop-
ment, the switch from ␥- to ␤-chain
production occurs synchronously
throughout the liver and bone
marrow. The transition from ␥- to
Figure 5. Hemoglobin production during the fetal and neonatal period. ␤-chain synthesis is most closely re-

lated to postconceptional age and not chronologic age. Certain factors are known to alter the affinity of Hgb for
(27) Thus, infants born preterm continue to synthesize oxygen (Table 2). The most important of these are the Hgb
significant amounts of ␥-globin (and fetal Hgb) until F concentration and the red cell 2,3-DPG content. The
40 weeks’ gestation. concentration of red blood cell 2,3-DPG gradually in-
creases with gestation. At term, the concentration is similar
2,3-DPG Metabolism to that of adults. By the end of the first postnatal week, the
The affinity of Hgb for oxygen can be decreased by 2,3-DPG concentrations are considerably higher than they
interaction with certain organic phosphates, such as are at birth. After the first week, red blood cell 2,3-DPG
2,3-DPG and adenosine triphosphate. (34) The highly concentrations remain relatively unchanged for the next
charged anion 2,3-DPG binds to deoxyhemoglobin but 6 months. In term infants, the Hgb-oxygen dissociation
not to oxyhemoglobin. Deoxyhemoglobin F does not curve gradually shifts to the right, and by 4 to 6 months of
possess as great an affinity for 2,3-DPG as does deoxy- age, the P50 values approximate those of the adult.
hemoglobin A and, therefore, cannot bind 2,3-DPG to The situation is somewhat different in preterm in-
the same degree as Hgb A. Thus, the fetal leftward- fants. Because Hgb F synthesis is still active, increases in
shifted Hgb oxygen dissociation curve (Fig. 6) is not P50 seen in term infants as a result of the switch from
easily modulated in the presence of 2,3-DPG. Hgb F to Hgb A do not occur as rapidly. The red blood
The P50 (partial pressure of oxygen at which half of cell 2,3-DPG concentrations also are slightly lower in
Hgb is saturated) of fetal blood is 19 to 21 mm Hg, some preterm infants. (35) These concentrations are increased
6 to 8 mm Hg lower than that of adult blood. As Hgb F with the use of human recombinant Epo, which shifts the
concentration declines after birth, however, there is a oxygen dissociation curve to the right. (36)(37)
marked rightward shift in the postnatal Hgb oxygen
equilibrium curve. The percentage of Hgb A and the red Nitric Oxide-hemoglobin Interactions
cell 2,3-DPG content play the greatest roles in altering NO plays a significant role in vasoactive regulation.
the position of the Hgb oxygen dissociation curve. As a Under baseline conditions, NO is produced by endo-
result, preterm infants who have a greater proportion of thelial NO synthase and diffuses into surrounding smooth
Hgb A but less 2,3-DPG (which occurs following packed muscle cells, activating soluble guanylyl cyclase to produce
red blood cell transfusion) may have a similar P50 as those cyclic guanosine 5⬘-monophosphate, and regulates vascular
who have increased quantities of Hgb F. tone. NO reacts with oxyhemoglobin to form methemo-
globin, which is reversed by erythro-
cytic methemoglobin reductase. A
second reaction also can occur, in
which NO reacts with deoxyhemo-
globin to form nitrosyl hemoglobin
(NO-Hgb). There is some evidence
that erythrocytes containing NO-
Hgb may be able to release NO into
the circulation, thus causing vasodi-
latation in the microvasculature. A
third reaction has been studied that
involves the binding of NO to the
␤-chain cysteine amino acid to form
S-nitrosyl-hemoglobin (SNO-Hgb).
It has been postulated that nitrite
ions within erythrocytes can be re-
duced to NO by deoxyhemoglobin,
so NO is generated as erythrocytes
enter hypoxic regions. All of these
potential mechanisms result in NO
Figure 6. Hemoglobin-oxygen dissociation curve. The curve representing fetal hemoglo- controlling blood flow via hypoxic
bin is on the left, and the curve representing adult hemoglobin is on the right. The P50 is vasodilatation. These mechanisms
shown as a hatched line for each curve. are especially important in preterm

tissues may be greater in utero because of the character-

Factors Affecting
Table 2. istics of the Hgb-oxygen dissociation curve.
If pulmonary function is normal, the PO2 of pulmo-
Hemoglobin-Oxygen Affinity nary blood rises from the 40 mm Hg of pulmonary
Increased P50, increased red blood cell 2,3-DPG: arterial blood to the 100 mm Hg of pulmonary venous
blood. Because of the shape of the Hgb-oxygen dissoci-
● Adaptation to high altitude
● Hypoxemia associated with chronic pulmonary disease ation curve, these PO2 values permit 95% saturation of
● Hypoxemia associated with cyanotic heart disease Hgb by oxygen. Further increases in PO2 produce little
● Anemia additional increase in saturation. In the healthy adult,
● Decreased red blood cell mass approximately 50% of Hgb is saturated with oxygen
● Hyperthyroidism
when the PO2 falls to 27 mm Hg (P50⫽27 mm Hg). In
● Red cell pyruvate kinase deficiency
situations in which the Hgb-oxygen dissociation curve
Increased P50, no consistent alteration in red blood cell has shifted to the right, the affinity of Hgb for oxygen is
DPG:
reduced. Thus, at any given PO2, more oxygen is released
● Abnormal hemoglobins (Kansas, Seattle, to tissues. Conversely, if the curve is shifted to the left,
Hammersmith, Tacoma, E) the affinity of Hgb for oxygen is increased. Therefore, at
● Vigorous exercise
any given PO2, less oxygen is released to the tissues.
Decreased P50, decreased red blood cell 2,3-DPG: A precise relationship does not exist between the decline
● Septic shock in Hgb F and the decrease in oxygen affinity of a neonate’s
● Severe acidosis blood. (38) Rather, changes in P50 reflect the interaction
● Following massive transfusions of stored blood between red blood cell 2,3-DPG, the increase in Hgb A
● Neonatal respiratory distress syndrome
that occurs after birth, and the decline in Hgb F. Although
Decreased P50, no consistent alteration in red blood cell oxygen-carrying capacity (Hgb concentration ⫻ oxygen
DPG: saturation ⫻ 1.36 mL oxygen/g of Hgb) decreases over
● Abnormal hemoglobins (Kempsey, Chesapeake, the first few postnatal months as Hgb concentration de-
Capetown, Yakima, Rainier) clines, the amount of oxygen delivery can remain similar or
2,3-DPG⫽2,3 diphosphoglycerate, P50⫽partial pressure of oxygen at even increase. (35) For example, a preterm infant born with
which half of hemoglobin is saturated
a Hgb concentration of 15 g/dL (150 g/L) delivers 1 mL
of oxygen to the tissues for every 100 mL of circulating
infants because vulnerable vascular beds such as the splanch- blood (based on a P50 of 19 and a central venous PO2 of
nic system are at risk for hypoxic injury via shunting of 40 mm Hg). As the percent of Hgb A increases over time,
blood to the brain and heart. Blood that is collected for the P50 shifts to the right. The infant can now deliver
transfusion loses its SNO-Hgb within hours, so transfused 2.1 mL of oxygen per 100 mL of blood, despite a decrease
packed red blood cells (PRBCs) lack NO. Transfusing in total Hgb to 8 g/dL (80 g/L) (based on a P50 of 24 mm
PRBCs that cannot deliver NO to the microvasculature Hg and a central venous PO2 of 40 mm Hg). (35)
may, in fact, reduce local oxygen delivery to tissues through After intrauterine transfusion, infants have oxygen-
vasoconstriction. Studies are in progress to evaluate the unloading properties characteristic of adult blood. Despite
renitrosylization of Hgb before transfusion. the decrease in oxygen affinity that accompanies intrauter-
ine transfusion, no deleterious effects of this procedure with
Oxygen Transport respect to oxygen uptake by the fetus have been docu-
The mechanisms controlling oxygen transport in utero mented. (39) The physiologic significance of manipulating
and immediately postpartum are complex. During pre- the Hgb-oxygen affinity of extremely preterm infants via
natal life, the fetal arterial oxygen tension (PO2) is ap- PRBC transfusions continues to be studied. It is important
proximately 30 mm Hg, and the venous PO2 is approxi- to understand an infant’s ability to deliver oxygen to tissues
mately 15 mm Hg (Fig. 6). These low PO2s contribute to when determining whether to administer an erythrocyte
the development of relative polycythemia in the fetus. transfusion. The decision to transfuse should not be based
After birth, numerous factors affect oxygenation, includ- on Hgb concentration alone. Transfusions significantly af-
ing the inspired gas mixture, pulmonary function, the fect an infant’s endogenous erythropoiesis: for infants who
arterial oxygen dissociation curve, and the ability to undergo exchange transfusion or multiple transfusions,
extract oxygen at the tissue level. (38) It has been spec- both Epo concentrations and reticulocyte counts are lower
ulated that the actual amount of oxygen released to at any given Hgb concentration. (8)(40) The search con-

tinues for a specific marker that reflects the need for im- DG, eds. Hematology of Infancy and Childhood. Philadelphia, PA:
proved oxygen delivery to tissues (via red blood cell trans- WB Saunders; 1993:18 – 43
7. Kling PJ, Schmidt RL, Roberts RA, Widness JA. Serum eryth-
fusion). Currently, no ideal marker that is simple, requires
ropoietin levels during infancy: associations with erythropoiesis.
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rity: factors governing the erythropoietin response. N Engl J Med.
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The organized transition from embryonic to fetal to adult 9. Humbert JR, Abelson H, Hathaway WE, Battaglia FC. Poly-
Hgb has been extensively studied, providing significant cythemia in small for gestational age infants. J Pediatr. 1969;75:812
10. Hakanson DO, Oh W. Hyperviscosity in the small for gesta-
understanding of the molecular basis of Hgb development. tional age infant. Pediatr Res. 1977;11:472A
Studies continue to evaluate the relationship between Hgb 11. Moore LG, Newberry MA, Freeby GM, Crnic LS. Increased
concentrations and oxygen delivery in neonates to best incidence of neonatal hyperbilirubinemia at 3100 m in Colorado.
determine what Hgb concentrations best meet the needs of Am J Dis Child. 1984;138:158
a wide variety of clinical situations from the critically ill 12. Bureau MA, Shapcott D, Berthiaumey, et al. Maternal ciga-
rette smoking and fetal oxygen transport: a study of P50, 2,3-
extremely low-birthweight infant to the stable growing diphosphoglycerate, total hemoglobin, hematocrit, and type F he-
preterm infant. Studies are underway to explore the mech- moglobin in fetal blood. Pediatrics. 1983;2:22
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erythrocytes, and these studies have the potential to add cell parameters. Acta Paediatr Scand. 1971;60:317
greatly to the body of evidence regarding transfusion guide- 14. Gonzales GF, Steenland K, Tapia V. Maternal hemoglobin
level and fetal outcome at low and high altitudes. Am J Physiol Regul
lines in various neonatal populations.
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insulin critical determinants? Diabet Med. 2009;26:887– 892
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NeoReviews Quiz
9. Red blood cell production decreases after birth, primarily as a result of increased availability of oxygen,
which greatly reduces erythropoietin production and endogenous erythropoiesis. A decrease in hemoglobin
concentration follows this reduced red blood cell production. Of the following, the hemoglobin nadir in
healthy term infants is reached at a postnatal age closest to:
A. 8 weeks.
B. 12 weeks.
C. 16 weeks.
D. 20 weeks.
E. 24 weeks.
10. Hemoglobin consists of heme, an iron-containing protoporphyrin, and globin, a polypeptide. Eight globin
genes direct the synthesis of six different polypeptide chains, designated as alpha (␣), beta (␤), gamma
(␥), delta (␦), epsilon (␧), and zeta (␨). These globin chains combine in the developing erythroblast to
form seven different hemoglobin tetramers: Gower 1 (␨2-␧2), Gower 2 (␣2-␧2), Portland (␨2-␥2), fetal
hemoglobin (Hgb F: ␣2-␥2), adult hemoglobin (Hgb A: ␣2-␤2), and adult hemoglobin A2 (Hgb A2: ␣2-␦2).
Of the following, the most prevalent hemoglobin tetramer in the fetus at 18 weeks of gestational age is:
A. Gower 1.
B. Hgb A.
C. Hgb A2.
D. Hgb F.
E. Portland.
11. A term infant is born with severe anemia. A Kleihauer Betke test is performed on maternal blood to
determine whether fetomaternal hemorrhage is the cause. Of the following, the property of fetal
hemoglobin that best differentiates fetal from maternal red blood cells using the Kleihauer Betke test is
that the fetal hemoglobin, relative to adult hemoglobin, is/has:
A. Decreased interaction with 2,3-diphosphoglycerate.
B. Greater affinity for oxygen.
C. Greater solubility in strong phosphate buffer.
D. Readily oxidized to methemoglobin.
E. Resistant to acid elution.

Robin K. Ohls
DOI: 10.1542/neo.12-1-e29

s;12/1/e29
Legal Briefs: Neonatal Anemia at Birth
Maureen E. Sims
DOI: 10.1542/neo.12-1-e42
legal briefs
Neonatal Anemia at Birth

Maureen E. Sims, MD*
A Subacute Fetomaternal The woman said in her deposition

Hemorrhage that she shared with the nurses that
A 2,980-g 35-weeks’ gestation fe- fetal movement was reduced. The
male infant is delivered to a 30-year- plaintiff experts said this was the fe-
old woman whose pregnancy was tus’ attempt to conserve energy be-
complicated by chronic hyperten- cause of the anemia. The defense ex-
sion. Four days before delivery she perts said that the reduction in fetal
had a clinic visit, and fetal ultra- movement meant that the damage
sonography performed at that time already had occurred. The mother
was read as normal. Two days later was discharged.
(2 days before delivery), the woman Later that day, the woman visited
called the clinic because she began her obstetrician and had a repeat
Author Disclosure
experiencing chills, a “crampy feel- NST. The obstetrician read the NST
Dr Sims has disclosed no financial ing,” and loose stools. She reported as reactive, although he stated on his
relationships relevant to this good fetal movement. deposition that it took more than
discussion. This commentary does not Several hours later, she visited 60 minutes to become “somewhat
contain a discussion of an the emergency department because reactive.” The woman reported de-
unapproved/investigative use of a of additional symptoms of nausea, creased fetal movements during this
myalgia, back pain, and vomiting. visit. The plaintiff obstetric experts
commercial product/device.
During this visit, her temperature
said the NST was nonreactive and
was 38.9°C. The long-term variabil-
not only was the misinterpretation of
ity on a nonstress test (NST) was re-
the NST below the standard of care,
ported as fair, but one spontaneous
but an additional violation was not
deceleration was noted. The woman
to have pursued additional testing
reported that fetal movements de-
such as a BPP and a KB (in light of
creased from earlier in the day. (The
the hemoglobinuria on the previous
monitoring strip was missing and
day).
unavailable for review at the time of
The following day, the woman re-
litigation.) Complete blood count
turned to her obstetrician because of
findings were unremarkable, and uri-
nalysis showed 0 to 3 red blood cells continued decreased fetal move-
and a large amount of hemoglobin. ment. The NST was repeated and
The plaintiff experts said the physi- was interpreted by the treating obste-
cian caring for the woman should trician as nonreassuring. The first
have considered a transfusion reac- hour showed a flat baseline with a
tion from the fetus because of the he- spontaneous deceleration. By the
moglobinuria, the woman’s symp- next hour, a sinusoidal pattern ap-
toms, and the report of decreased peared. A BPP showed 2/10 (2 for
fetal movement. A more detailed amniotic fluid and 0 for tone, reac-
evaluation should have been per- tive heart rate, movement, and
formed, including a biophysical pro- breathing). The obstetrician was
file (BPP) and a Kleihauer-Betke concerned about a concealed abrup-
test (KB). The box on the paperwork tion or a fetomaternal hemorrhage.
for “fetal movement” was left blank. During the next hour, a KB showed
1% fetal cells and estimated a blood
*Professor of Pediatrics, UCLA School of Medicine, loss from the fetus of 50 mL. One
Los Angeles, CA. hour later, a cesarean section was per-

legal briefs
formed. The treating obstetrician rate supported her normalcy at birth. One hour later, a partial exchange
(defendant) said he saw no reason The plaintiff experts explained that transfusion was begun in which 80
for an emergency cesarean section. the baby was not hypovolemic at birth mL was transfused and 70 mL was
The plaintiff obstetric experts said because of the subacute nature of the removed. The plaintiff experts said
that much time was wasted and the transfusion that allowed fluid shifts that a sooner partial exchange and
cesarean section should have been in utero. They further explained that use of a higher volume would have
performed much sooner. Further- a saturation of 100% was not reflec- been ideal, but the action taken did
more, the lengthy evaluation kept the tive of the level of tissue oxygenation. not fall below standard of care or
fetus in a hostile environment un- The inadequate numbers of red blood contribute substantially to the ulti-
necessarily longer. Arterial and ve- cells produced tissue hypoxia. mate outcome. A posttransfusion Hct
nous cord gases showed pH values of Umbilical lines were inserted and was 20% (0.20). Repeat arterial
7.25 and 7.38, respectively. The de- completed by 37 minutes of age, and blood gas showed a pH of 7.07,
fense pointed out that the essential an arterial blood gas showed a pH of PCO2 of 23 mm Hg, PO2 of 69 mm
criteria to diagnose intrapartum 6.99, PCO2 of 36 mm Hg, PO2 of Hg, and base deficit of ⫺21 mEq/L.
hypoxia were not met because the ar- 50 mm Hg, and base deficit of A 45-mL blood transfusion was per-
terial cord blood gases were normal. ⫺20 mEq/L. The plaintiff experts formed 1 hour later that increased
(1) The plaintiff experts questioned pointed out that, considering the pro- the Hct to 34% (0.34).
the motives behind the conclusions in found paleness of this infant, a more On postnatal day 1, the infant de-
the American College of Obstetri- appropriate approach would have veloped seizures and oliguria. Elec-
cians and Gynecologists (ACOG) been to insert an umbilical venous troencephalography showed mark-
statements. The plaintiff experts fur- line emergently, obtain a venous gas edly abnormal results. On postnatal
ther explained that the placenta and hematocrit (Hct), and immedi- day 2, magnetic resonance imaging
cleared the lactic acid produced by ately start a partial exchange with (MRI) showed diffuse bilateral corti-
the fetal cells, which were undergo- emergency-release O-negative blood. cal laminar necrosis and loss of gray-
ing anaerobic metabolism due to The Hct was 11% (0.11), hemoglo- white differentiation. The infant’s
anemic hypoxia, and that the fetal bin was 3.7 g/dL (37 g/L), and creatinine values were elevated and
lactic acid was cleared by the moth- nucleated red blood cells (nRBCs) peaked on day 2 at 1.6 mg/dL
er’s liver. were 55/100 white blood cells. The (141.4 ␮mol/L), but her urine out-
A profoundly pale infant was born plaintiff experts pointed out that the put eventually normalized. Her ala-
with Apgar scores of 6 at 1 minute estimated blood volume of this baby nine aminotransferase peaked on day
and 8 at 5 minutes. The defense ex- was 253 mL (85% of her birth- 2 at 3,421 U/L, but liver function
perts pointed out that the baby was in weight). She must have lost a total of was never clinically compromised.
good clinical condition, as evidenced approximately 80% of her blood vol- The plaintiff experts pointed out that
by the good Apgar scores, and quoted ume for her Hct to be reduced to 11% despite the fluid adjustments that
the ACOG consensus criteria. (1) (0.11). The nRBC value was rela- prevented fetal death or neonatal
The plaintiff experts pointed out that tively low because of the subacute on- shock, a toll was paid at the cellular
in a subacute condition in which set of the anemia. The anemia was level. Eventually, the shift from oxy-
fluid adjustments are made, the Ap- not chronic because the nRBC would gen being used to nonoxygen path-
gar scores can be good because the have been much higher and the baby ways to support energy metabolism
cardiovascular system is still intact. did not have hydrops. The baby was became depleted. The liver and kid-
Blow-by oxygen was provided and crossed-matched for a transfusion. neys recovered; the brain did not. The
the infant was transported to the Her blood was A Rh-positive and the plaintiff experts explained that the
newborn intensive care unit. On ad- mother’s was O Rh-negative. The baby showed she could not tolerate the
mission, the infant’s temperature was plaintiff experts pointed out that the change from intrauterine to extra-
34.9°C, heart rate was 150 beats/ blood group incompatibility between uterine life. In utero, very little ef-
min, blood pressure was 57/34 mm the mother and the fetus created he- fort is expended by the fetus for blood
Hg (with a mean of 39 mm Hg), and molysis of the fetal cells in the moth- gas exchange. However, when the
oxygen saturation was 100% on 25% er’s circulation as the explanation baby is born, the left heart pumps
oxygen via hood. The defense experts for the underestimate of the fetal- against higher pressures than the
maintained that the baby’s normal maternal transfusion. (2) The di- placenta and the baby needs to
blood pressure, saturation, and heart rect Coombs test result was negative. breathe on its own, both of which

legal briefs
greatly increase the metabolic de- experts stated that the NRP does not are still in need of better oxygen-
mand and oxygen consumption. Al- set standards but serves merely as a ation from improved oxygen deliv-
though the baby was stable at birth, guideline. ery from the red cells.
the hypoxic anemia rapidly created a Cardiac compressions were given Ten minutes later, the pediatri-
huge ongoing base deficit until the intermittently when the heart rate cian ordered blood to be cross-
anemia was corrected. The conse- drifted to less than 60 beats/min, matched. The plaintiff contended
quences of this profound anemia in but most of the time during the first that blood loss should have been sus-
utero were manifested after birth in 20 minutes after birth, the heart rate pected immediately because of the in-
the kidney, liver, and brain. was more than 100 beats/min, al- fant’s pallor. Moreover, the infant
The infant subsequently devel- though the infant’s color remained was in shock, which necessitated im-
oped dystonic and spastic cerebral pale and his pulses were weak. Four- mediate blood administration. A
palsy and microcephaly. Her seizures teen minutes after birth the obstetri- peripheral intravenous line was
continued and were difficult to con- cian discovered on delivering the pla- placed at 28 minutes, followed im-
trol. She had developmental delays in centa that the umbilical cord was mediately by an infusion of 30 mL of
motor, speech, and social behavior. profusely bleeding near its velamen- normal saline. An umbilical venous
Her kidneys performed normally. tous insertion site. During the obste- line was placed at 31 minutes. The
The neonatologist was not sued. trician’s deposition, he stated that he plaintiff experts maintained that
Although the neonatologist did not immediately informed the pediatri- access should have been attempted
provide optimal intervention in cian and the nursing staff of this and immediately. The umbilical vein is
terms of correcting the profound included the finding in his delivery the most quickly accessible direct in-
anemia, the plaintiff experts be- note. The finding was validated by travenous route in the newborn. (3)
lieved that the damage occurred in the pathologist who examined the In addition to access, a blood gas
utero. The obstetrician and the fam- placenta. During the deposition, the from the umbilical vein should have
ily settled out of court. pediatrician denied hearing about been sent while waiting for
this. Nursing staff could not remem- emergency-release O-negative blood.
Acute Hemorrhage ber and did not document anything A baseline Hct should have been ob-
Immediately Before Delivery about it. The plaintiff experts said tained, although the value could
A 3,370-g 40-weeks’ gestation white that even without the knowledge of have been misleading because it
male infant was delivered by vacuum- the cord bleeding after birth, a pale would be fairly normal before equil-
assisted vaginal delivery. The preg- baby in cardiovascular collapse ibration occurs.
nancy was uncomplicated until needs volume and that volume re- The values for the cord gases
1 hour before delivery, when thick placement must be blood. Further- were available at 32 minutes. The
meconium was passed and a subse- more, the plaintiff experts main- arterial cord gas had a pH of 7.05,
quent fetal bradycardia to the 50s tained that the color of a baby is an PCO2 of 76 mm Hg, PO2 of 35 mm
occurred for several minutes, fol- important finding. Pallor, in con- Hg, bicarbonate of 20 mEq/L
lowed by a brief period of shoulder trast to a gray or dusky color, at birth (20 mmol/L), and base deficit of
dystocia. A profoundly pale, limp, points to anemia rather than pure ⫺12 mEq/L; the venous cord gas
and lifeless infant was handed to hypoxemia. Pale mucous membranes had a pH of 7.12, PCO2 of 60 mm
the pediatrician. The infant was can be evaluated as an additional or Hg, PO2 of 45 mm Hg, bicarbonate
intubated immediately and given substitute tool for neonates of pig- of 21 mEq/L (21 mmol/L), and
positive-pressure ventilation. Nalox- mented ethnic backgrounds, but this base deficit of ⫺9 mEq/L. Apgar
one was administered 2 minutes after infant was white and all clinicians scores were 1, 2, 4, 1, and 2 at 1, 5,
birth, two doses of endotracheal epi- admitted that the patient appeared 10, 15, and 20 minutes, respectively.
nephrine were administered at 5 and extremely white. In pure hypoxemic Another two boluses of normal saline
8 minutes, atropine was administered situations, as the heart rate improves were administered by 45 minutes of
at 7 minutes, and a dose of lidocaine with oxygenation and ventilation, so age. The plaintiff experts explained
followed. The plaintiff experts were does the color. In severe hypoxemic that normal saline was not the ap-
highly critical of the resuscitation. anemias, the heart rate may improve propriate volume expander in the
They stated that Neonatal Resuscita- (as it did in this situation), but the face of profound anemia, but it was
tion Program (NRP) guidelines color remains pale. Even in the face a good choice as long as emergency
were not followed. (3) The defense of an improved heart rate, the tissues blood was being processed. The de-

legal briefs
fense experts maintained that it was insufficiency. (4) The infant’s liver by only a moderate elevation of the
too risky to administer blood that was function tests were elevated into the nRBCs, the absence of hydrops, and
not cross-matched. They further 1,000s and his direct bilirubin the normal blood pressure at birth.
maintained that it was impossible to peaked at 14.9 mg/dL (254.8 The second baby with the ruptured
acquire emergency blood for the de- ␮mol/L), which was believed to be umbilical cord was born in hypovole-
livery room or a newborn intensive due to a postnecrotic hypoxic event mic shock because of the acute na-
care unit in 5 to 10 minutes. The resulting from the anemia. The liver ture of the hemorrhage. An appreci-
plaintiff pointed out that the hospi- function recovered. ation of pallor at birth and the need
tal needed to have had a process On long-term follow-up evalua- to move quickly with blood is vital
streamlined and even suggested to tion, the child has cerebral palsy, re- for appropriate intervention from the
the defense attorney that drills should nal insufficiency, a seizure disorder, damaging effects of hypoxic anemia
have been done at that center, espe- microcephaly, and significant devel- that have long-term devastating im-
cially because the need is not that opmental delays. pacts on the brain and kidneys.
common but crucial when it does The obstetrician was not sued.
occur. The family and the pediatrician set-
At approximately 1 hour of age, tled out of court. American Board of Pediatrics
an Hct measured 12% (0.12). An ar- Neonatal-Perinatal Medicine
terial blood gas at this time showed a Discussion Content Specifications
pH of 6.5, PCo2 of 158 mm Hg, PO2 Neonatal anemia at birth can be clas- • Know the causes of
of 47 mm Hg, and base deficit of sified according to the cause. (5) and diagnostic
⫺32 mEq/L. The plaintiff experts Anemia from hemorrhage is the most approach to an
pointed out that although the oxygen common cause. Mechanical trauma infant who is
anemic at birth.
concentration in the blood was satis- during delivery, uterine rupture or
• Know the causes and pathophysiology
factory, the oxygen concentration de- placental abruption, rupture of the of acute fetal and neonatal blood loss.
livered to the tissues because of the umbilical cord, and fetal-fetal or feto- • Know the clinical and laboratory
lack of red blood cells was profoundly maternal hemorrhage are the most findings and management of acute
reduced. The transport team arrived common causes of hemorrhagic ane- fetal and neonatal blood loss.
at the same time that the blood bank mia at birth. A less common cause
issued the cross-matched blood, and of anemia at birth is hemolysis, the
a transfusion was begun during causes of which include an immune References
transport. response between mother and baby 1. The American College of Obstetricians
and Gynecologists’ Task Force on Neonatal
At 1 day of age at the referral (Rh or ABO incompatibility) and
Encephalopathy and Cerebral Palsy, the
hospital, the patient developed sei- red blood cell membrane defects such American College of Obstetricians and Gy-
zures and electroencephalography as spherocytosis. Anemia at birth necologists, the American Academy of Pedi-
readings were very abnormal. MRI from hypoplasia of erythrocyte pro- atrics. Neonatal Encephalopathy and Cere-
showed cortical necrosis in the occip- duction is very rare, especially pre- bral Palsy: Defining the Pathogenesis and
Pathophysiology. Washington, DC: Ameri-
ital, temporal, and parietal lobes and senting at birth. The inherited causes
can College of Obstetricians and Gynecolo-
abnormal signals in the thalamic and (Diamond-Blackfan) must be differ- gists; 2003:1– 85
basal ganglia areas. The baby had entiated from infection with parvo- 2. Glasser L, West JH, Hagood RM. In-
anuria for 3 days, and his creatinine virus B19, which can cause a pure compatible fetomaternal transfusion with
peaked at 8.5 mg/dL (751.4 ␮mol/ red blood cell aplasia at birth. When maternal intravascular lysis. Transfusion.
1970;10:322–325
L). Renal ultrasonography suggested the anemia is chronic and severe, hy-
3. Neonatal Resuscitation Textbook. Elk
papillary necrosis. The renal function drops develops. In chronic anemia, Grove Village, IL; Dallas, TX: American
remained abnormal throughout the the fetus develops a microcytic, hy- Academy of Pediatrics; American Heart As-
hospitalization. The plaintiff experts pochromic anemia. After birth, the sociation; 2006
pointed out that hypoxia may pro- mean corpuscular volume and mean 4. Ringer SA. Acute renal failure in the
neonate. NeoReviews. 2010;11:e243– e251
duce acute tubular necrosis that usu- corpuscular hemoglobin are low.
5. Widness JA. Pathophysiology of anemia
ally is transitory. However, hypoxic In the first case discussed in this during the neonatal period, including ane-
anemia in the fetus or newborn has article, the fetomaternal hemorrhage mia of prematurity. NeoReviews. 2008;9:
been associated with chronic renal was subacute, which was supported e520 – e525

Legal Briefs: Neonatal Anemia at Birth
Maureen E. Sims
DOI: 10.1542/neo.12-1-e42

s;12/1/e42
Meta-analysis in Neonatal Perinatal Medicine
Roger F. Soll
DOI: 10.1542/neo.12-1-e8
Article research

Roger F. Soll, MD*
Abstract
Systematic overviews provide a comprehensive and thorough review of the available
Author Disclosure data from clinical trials. When these reviews include meta-analyses, clinicians can
Dr Soll has disclosed synthesize the results of related studies and gain greater precision in their estimates of
that he is president the effects of therapy. Even when inconclusive, meta-analyses allow for the exploration
of differences between studies and may point toward promising areas of future
of the Vermont
research (or steer clinicians away from further nonproductive areas). In the field of
Oxford Network and
neonatal-perinatal medicine, systematic overviews have provided the basis of several
editor of the major changes in guidelines with measurable impact on neonatal outcome.
Cochrane Neonatal
Review. This Objectives After completing this article, readers should be able to:
commentary does not
1. Describe the process of conducting a systematic review.
contain a discussion
2. Delineate biases inherent in meta-analyses.
of an unapproved/
3. Review how heterogeneity affects meta-analyses.
investigative use of a
commercial
product/device. Introduction
It is almost impossible to keep up with the scientific evidence on which clinicians base their
practice and policies. The simple exercise of searching a common bibliographic database
such as PubMed, using the word “neonate” and limiting the search to “all infants” and
“randomized, controlled trials” retrieves more than 7,000 citations. No clinician could
possibly keep up with this mass of literature. When multiple trials are available, clinicians
are confronted with a situation more like taking a Rorschach test than like interpreting the
evidence; what we see more reflects our biases than the evidence at hand.
A systematic approach to reviewing the literature is necessary to address this difficulty.
Systematic reviews identify, appraise, and synthesize research-based evidence and present it
in an accessible format. (1) Systematic overviews apply specific research strategies to data
from all relevant studies. If appropriate, these reviews can include meta-analyses, a
quantitative statistical method used to combine the results of similar randomized, con-
trolled trials (RCTs) to produce typical estimates of effect size. By combining information
from all relevant studies, meta-analysis can provide more precise estimates of the effect of
health care than those derived from the individual studies included within the review.
(2)(3) They also facilitate evaluation of the consistency of evidence across studies and the
exploration of differences between studies.
The following review discusses the approach to creating a systematic overview and
how to interpret the results of meta-analyses. A more detailed and technical discus-
sion of creating a systematic review and meta-analysis is given in “The Cochrane
Handbook.” (4)
How is a Systematic Review Conducted?

Systematic reviews are essentially “studies of studies.” They use rigorous scientific methods
similar to those used in any clinical trial. The specific objective of the review, framed as an
answerable question, provides the backbone of the analysis. Like a clinical trial, a protocol
for a systematic review should be developed that clearly states the objectives of the review,
the population and intervention of interest, and the methods used at each stage of the
review.
*H.W. Wallace Professor of Neonatology; Coordinating Editor, Cochrane Neonatal Review Group, Burlington, VT.

research meta-analysis
The next major step is selection of studies for inclu- Key Terminology for
Table.
sion. As noted previously, the criteria for study inclusion
must be specifically defined in the protocol. This includes Estimating the Size of the
the specifics regarding the intervention, the population, Treatment Effect
and the outcomes assessed. If appropriate, exclusion
criteria must be explicitly stated. Outcome
Positive Negative Risk of Outcome
Searching for trials for inclusion is much simpler in the
age of computer databases. Long gone are the days of Treated (Y) a b Yⴝa/(aⴙb)
sitting in the medical library pouring over volumes of Control (X) c d Xⴝc/(cⴙd)
Index Medicus. Today there are multiple resources for Relative Risk (RR) is the risk of the outcome in the treated group (Y)
compared to the risk in the control group. RR⫽Y/X
access to the general medical literature and some re- Relative Risk Reduction (RRR) is the percent reduction in risk in the
sources unique to the field of neonatal-perinatal medi- treated group (Y) compared to the control group (X). RRR⫽1-Y/
X⫻100% or 1-RR⫻100%
cine. Searching the medical literature is now widely Absolute Risk Reduction (ARR) is the difference in risk between the
available through the internet, including several biblio- control group (X) and the treatment group (Y). ARR⫽X-Y
Number Needed to Treat (NNT) is the number of patients that must
graphic databases. These include the Cochrane Library, be treated over a given period of time to prevent one adverse outcome.
MEDLINE, EMBASE, and CINAHL. NNT⫽1/(X-Y) or 1/ARR
Once studies are located, rigorous evaluation of
whether they meet the criteria for inclusion is necessary.
If included, the study must be assessed for the validity of
the methodology in study design, conduct, analysis, and
rate. The absolute risk reduction (ARR) indicates the
reporting. For the purpose of Cochrane reviews, only
absolute reduction in the event rate. If the overall inci-
randomized or quasi-randomized, controlled trials are
dence of the event is low, the ARR also will be low, even
included. (5)
if there is a relatively large difference in the relative risk.
Outcome data must be extracted and tabulated for
Understanding both the RR and ARR is essential to
each included trial. There are two distinct stages to the
making any clinical judgment. Also of use is the number
analysis. First, a clinically relevant standard statistic is
needed to treat (NNT), which is calculated by dividing
calculated for each study to describe the observed inter-
1 by the ARR. For example, if the ARR is 20%, then
vention effect. For example, the standard statistic may
the NNT is 5. In other words, five infants would need to
be the relative risk (RR), the RR reduction, the risk
be treated to prevent one theoretical event. In addition,
difference if the data are dichotomous, or a difference
confidence intervals (CIs) should be reported with each
between means if the data are continuous. Second, an of these statistics. A 95% CI reflects 95% certainty that the
estimate of the summary (pooled) intervention effect is true value of the measure lies within the bounds of the
calculated as a weighted average of the intervention interval.
effects estimated in the individual studies. The statistical A meta-analysis can be subject to many of its own
methods for pooling results are similar to the statistical biases. Any attempt at pooling results from various stud-
methods used in analyzing the data for multicenter trials. ies not only incorporates the biases of the primary studies
Pooling the results of similar RCTs increases the statisti- but adds further bias attributable to study selection and
cal power lacking in individual smaller trials and enables the inevitable heterogeneity of the selected studies. (7)
the clinician to have greater security in accepting or Publication bias, the tendency for investigators to choose
rejecting treatment differences demonstrated by the positive studies for publication, skews the medical litera-
trials. (2) ture toward favorable reports of treatment. Unless the
Once the analysis has been completed, it is important authors of the meta-analysis scrupulously research all
to assess the importance of the evidence. Clinical trials available resources, these studies are not located and the
may use a variety of statistical techniques in reporting the meta-analysis could report a false-positive finding. This
results. A “statistically significant” reported difference problem is compounded further by the greater chance
does not make the finding clinically relevant. (6) To that such a false-positive finding will be published. Meta-
assess whether the results of a trial are clinically relevant analysis can offer false-negative conclusions because of
requires calculation of some simple statistics from study inappropriate study selection. If the studies selected can-
findings (Table). The relative risk reduction (RRR) indi- not be grouped (heterogenous), the positive effects ob-
cates the relative, but not absolute, reduction in the event served with one specific treatment or in one specific

population may be lost. To minimize bias, the authors of man Development web site (http://www.nichd.nih.gov/
the meta–analysis and the readers of the review must cochrane/hallida3/hallida.htm) or in the Cochrane Library.
demand the same methodologic quality from these anal- Chronic lung disease remains a significant problem
yses that they would from individual RCTs. It is essential among very low-birthweight infants. It carries with it both
that all meta-analyses include a prospectively designed costs, in terms of longer hospital stay, and risks, in terms of
protocol, a comprehensive and extensive search strategy, later development. (9) Corticosteroids can reduce lung
strict criteria for inclusion of studies, standard definitions inflammation in newborns who have chronic lung disease,
of outcomes, and standard statistical techniques. but there are major short- and long-term adverse effects.
For the purposes of this review, the authors included
What is Heterogeneity? only RCTs of postnatal corticosteroid therapy. The
Invariably, studies brought together in a systematic re- “study participants” were defined as preterm infants be-
view have differences. Variability among studies in a lieved to be at risk of developing chronic lung disease
systematic review is termed “heterogeneity.” Clinical who were enrolled within the first 7 days of birth. Infants
heterogeneity refers to variability in the participants, were not required to be on ventilator support, which is an
interventions, and outcome included in the studies. important distinction. The authors could have limited
Methodologic heterogeneity refers to variability in the the population to very low-birthweight or extreme low-
study design. Clinical or methodologic heterogeneity birthweight infants and restricted the review only to
may contribute to measurable statistical heterogeneity. those receiving ventilator support. The authors chose to
Methods have been developed for quantifying inconsis- cast a wide net for studies, but this could potentially lead
tency across studies that move the focus away from to clinical heterogeneity.
testing whether heterogeneity is present (which is almost The authors chose to study intravenous or oral corti-
inevitable) to assessing the impact
of heterogeneity on the meta-
analysis. (4) The I-squared (I2) sta-
tistic can be used to evaluate
whether substantial heterogeneity
is present and may influence the
interpretation of the analysis. If
noted, heterogeneity can be ex-
plored using subgroup analyses.
Sample Meta-analysis:
Early Corticosteroids
for the Prevention of
Chronic Lung Disease
To understand a meta-analysis, it
may be useful to examine a system-
atic review and meta-analysis that
has influenced practice in neonatal
perinatal medicine, such as early
corticosteroids for the prevention
of chronic lung disease in preterm
infants. (8) This review examines
the relative benefits and adverse ef-
fects of postnatal corticosteroids
administered within the first 7 days
of birth to preterm infants at risk of
developing chronic lung disease. The Figure 1. Early (<8 days) postnatal corticosteroids for preventing chronic lung disease in
review can be found on the National preterm infants. Effect on chronic lung disease or death. Reprinted with permission from
Institute of Child Health and Hu- Halliday et al. (8)

For the studies of hydrocortisone,

little heterogeneity is noted (I2 24%).
For the studies exclusively using
dexamethasone, a moderate degree
of heterogeneity persists (I2 49%).
Close inspection of these studies
shows many differences in the dexa-
methasone studies, including patient
population, length of treatment, tim-
ing of treatment, and dosage.
Although the impact of cortico-
steroids on chronic lung disease
seems promising, the results regard-
ing cerebral palsy raise grave con-
cerns. Cerebral palsy was increased
with the use of corticosteroids (typi-
cal RR, 1.45; 95% CI, 1.06, 1.98 and
typical risk difference, 0.03; 95% CI,
0.00, 0.06 for 12 studies and 1,452
infants). Again, there was moderate
Figure 2. Early (<8 days) postnatal corticosteroids for preventing chronic lung dis-
heterogeneity (I2 66%) in the overall
ease in preterm infants. Effect on cerebral palsy. Reprinted with permission from Halliday
et al. (8)
analysis that was particularly notable
in the studies that used dexametha-
sone (I2 34%). The meta-analysis
costeroids (including dexamethasone and hydrocorti- provides a framework to examine individual studies com-
sone). Trials of inhaled corticosteroids were not in- pared with the other included studies. Of interest, Shinwell
cluded. The outcome measures included the important and associates (10) reported the greatest risk of cerebral
short-term measures related to neonatal intensive care palsy and yet represented some of the least exposure to
(eg, mortality, chronic lung disease) as well as longer- dexamethasone, suggesting to investigators that perhaps
term outcomes, including development at 18 to 24 timing of treatment is critical.
months. The search strategy was specifically detailed in The understanding of this meta-analysis led to strong
the review. In addition, a formal plan for data collection statements from the Committee on Fetus and Newborn of
and analysis was proposed. the American Academy of Pediatrics. (11) These statements
The authors identified 28 trials that qualified for recommend severe restriction in the use of postnatal corti-
inclusion in the review. This discussion is limited to the costeroids to prevent and treat chronic lung disease, noting
primary outcome measures of chronic lung disease or that “outside the context of a randomized, controlled trial,
death and cerebral palsy. Figures 1 and 2 are the “forest the use of corticosteroids should be limited to exceptional
plots” of the relative risk reported in each study and a clinical circumstances (eg, an infant on maximal ventilator
“summary” statistic showing the “pooled” relative risk support and oxygen support).”
estimated by the meta-analysis. In the review of all stud-
ies (using either dexamethasone or hydrocortisone), Conclusions
chronic lung disease (defined as oxygen requirement at Systematic overviews and meta-analysis are critical tools
36 weeks adjusted age) and death was significantly re- in efforts to practice evidence-based medicine. Although
duced (typical RR, 0.89; 95% CI, 0.84 to 0.95 and flawed by the deficiencies and limitations of the included
typical risk difference, 0.06; 95% CI, ⫺0.09 to ⫺0.02). studies as well as by biases created by the analysis itself,
Twenty-one studies were included in the analysis, in- meta-analysis provides a framework to inspect individual
volving more than 3,300 infants. For this outcome, the trials as well as a method to gain more precise estimates of
I2 is reported as 43%, which represents a moderate effects by analyzing the trials in aggregate. Analyses such
degree of heterogeneity. What might be the source for as the review of early postnatal corticosteroids have pro-
this heterogeneity? The primary analysis includes a sub- vided an improved perspective on the risks and benefits
group analysis of dexamethasone and hydrocortisone. of treatments and have changed practice. (12)

maintaining, and disseminating systematic reviews of the effects of

American Board of Pediatrics Neonatal-Perinatal health care. JAMA. 1995;274:1935–1938
Medicine Content Specifications 6. Laupacis A, Sackett DL, Roberts RS. An assessment of clinically
useful measures of the consequences of treatment. N Engl J Med.
• Understand the purpose of a systematic
1988;318:1728 –1733
review.
7. Bailar JC III. The promise and problems of meta-analysis.
• Understand the advantages of adding a
N Engl J Med. 1997;337:559 –561
meta-analysis to a systematic review.
• Interpret the results of a meta-analysis. 8. Halliday HL, Ehrenkranz RA, Doyle LW. Early (⬍ 8 days)
• Identify the limitations of a systematic review. postnatal corticosteroids for preventing chronic lung disease in
• Identify the limitations of a meta-analysis. preterm infants. Cochrane Database Syst Rev. 2010;1:CD001146
9. Schmidt B, Asztalos EV, Roberts RS, Robertson CM, Sauve
RS, Whitfield MF; Trial of Indomethacin Prophylaxis in Pre-
terms (TIPP) Investigators. Impact of bronchopulmonary dyspla-
References sia, brain injury, and severe retinopathy on the outcome of ex-
1. Cook DJ, Mulrow CD, Haynes RB. Systematic reviews: syn- tremely low-birth-weight infants at 18 months: results from the trial
thesis of best evidence for clinical decision. Ann Intern Med. 1997; of indomethacin prophylaxis in preterms. JAMA. 2003;289:
126:376 –380 1124 –1129
2. Sinclair JC, Bracken M, Horbar J. Introduction to neonatal 10. Shinwell ES, Karplus M, Reich D, et al. Early postnatal dexa-
systematic reviews. Pediatrics. 1997;100:892– 895 methasone treatment and increased incidence of cerebral palsy.
3. Oxman AD, Cook DJ, Guyatt GH. Users’ guides to the medical Arch Dis Child Fetal Neonatal Ed. 2000;83:F177–F181
literature: VI. How to use an overview. JAMA. 1994;272: 11. Committee on Fetus and Newborn. Postnatal corticosteroids
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NeoReviews Quiz
1. You are reviewing the results of a randomized trial to determine the effect of a drug (treatment group) in
preventing the occurrence of a specific disease (outcome) as compared with that of a placebo (control
group). The results are tabulated below:
Study Group Disease Present Disease Absent Risk of Disease

Treatment (nⴝ100) 41 59 0.41
Control (nⴝ100) 52 48 0.52
Of the following, the number needed to treat (number of infants needed to be treated to prevent the
occurrence of the disease in a single patient) in this trial is closest to:
A. 7.
B. 9.
C. 11.
D. 13.
E. 15.
2. A systematic review is designed to identify, appraise, and synthesize research-based evidence from all
relevant studies. Invariably, studies brought together in the systematic review differ in some aspects,
leading to heterogeneity in the clinical, methodological, and statistical domains. Of the following,
methodological heterogeneity is most likely to represent variability in the:
A. Data analysis.
B. Primary outcome.
C. Study design.
D. Study participants.
E. Treatment interventions.
Roger F. Soll
DOI: 10.1542/neo.12-1-e8

s;12/1/e8
Polycythemia in the Newborn
Juan I. Remon, Aarti Raghavan and Akhil Maheshwari
DOI: 10.1542/neo.12-1-e20
Article hematology

Juan I. Remon, MD,*
Aarti Raghavan, MD,* Abstract
Akhil Maheshwari, MD* Neonatal polycythemia, defined as a venous hematocrit ⱖ65% (0.65), is a common
problem in newborns. Infants born postterm or small for gestational age, infants of
diabetic mothers, recipient twins in twin-to-twin transfusion syndrome, and those
Author Disclosure who have chromosomal abnormalities are at higher risk. Although the cause of
polycythemia is often multifactorial, most cases can be classified as having active
Drs Remon, Raghavan,
(increased fetal erythropoiesis) or passive (erythrocyte transfusion) polycythemia. By
and Maheshwari have
increasing blood viscosity, polycythemia can impair microcirculatory flow in end
disclosed no financial organs and can present with neurologic, cardiopulmonary, gastrointestinal, and
relationships relevant metabolic symptoms. In this article, we review the pathophysiology, clinical presen-
to this article. This tation, diagnosis, and management of polycythemia in the newborn.
commentary does not
of an unapproved/ Objectives After completing this article, readers should be able to:
1. List the causes of polycythemia and hyperviscosity in the neonate.
commercial
2. Review the signs, symptoms, and diagnostic criteria for polycythemia and
product/device.
hyperviscosity.
3. Discuss the treatment of polycythemia and hyperviscosity in the neonate.
Introduction
Polycythemia (or more accurately, erythrocythemia), an abnormal elevation of the circu-
lating red blood cell (RBC) mass, is seen frequently in newborns. Although neonatal
polycythemia usually represents a normal fetal adaptation to hypoxemia rather than a true
hematopoietic defect, the abnormal increase in hematocrit increases the risk of hyper-
viscosity, microcirculatory hypoperfusion, and multisystem organ dysfunction. In this
article, we review the definition, pathophysiology, clinical presentation, and management
of polycythemia in the newborn.
Definition
In healthy term infants, the hematocrit and hemoglobin concentrations in venous blood
obtained at birth are 50.2⫾6.9% (0.5⫾0.07) (mean ⫾ standard deviation) and
15.9⫾1.86 g/dL (159⫾18.6 g/L), respectively. (1) Polycythemia is defined in newborns
as a venous hematocrit greater than 65% (0.65) or a hemoglobin value greater than
22 g/dL (220 g/L). (2)(3)(4) Based on this definition, the incidence of polycythemia in
healthy newborns has been reported to be 0.4% to 5%. (5)(6)(7) Increased incidence is
seen in certain high-risk groups such as postterm neonates, small-for-gestational age
infants, infants of diabetic mothers, identical twins who share the same placenta and
develop twin-to-twin transfusion, and infants who have chromosomal abnormalities.
(7)(8)(9)
Pathophysiology
Although the cause of polycythemia is often multifactorial, most patients can be classified
as having active (increased fetal erythropoiesis) or passive (erythrocyte transfusion) poly-
cythemia (Table 1). (5)(7)
*Department of Pediatrics, University of Illinois at Chicago, Chicago, IL.

hematology polycythemia
correlate with the severity of polycythemia, and current

Conditions Associated
Table 1. data do not support a causative role of leptin in this
process. (18)
With Neonatal Polycythemia ● Genetic disorders, such as trisomy 13, trisomy 18,
Increased Fetal Erythropoiesis trisomy 21, and Beckwith-Wiedemann syndrome. The
incidence of polycythemia in infants who have Down
● Placental insufficiency due to preeclampsia, maternal
chronic hypertension, chronic or recurrent placental syndrome is 15% to 33%. (19)(20)(21) Although the
abruption, maternal cyanotic congenital heart cause of polycythemia in Down syndrome is not
disease, postdate pregnancy, maternal smoking and known, high cord blood erythropoietin concentra-
heavy alcohol intake tions in affected infants has led to the speculation that
● Endocrine abnormalities such as congenital
intrauterine hypoxemia may play a role. (9) Among
thyrotoxicosis or maternal diabetes with poor
glycemic control neonates who have trisomy 13 and trisomy 18, the
● Genetic disorders such as trisomy 13, trisomy 18, prevalence of polycythemia has been estimated as 8%
trisomy 21, and Beckwith-Wiedemann syndrome and 17%, respectively. (22)
Erythrocyte Transfusion
Erythrocyte transfusion polycythemia can result from
● Placental-fetal transfusion with delayed cord placental-fetal transfusion. Delayed cord clamping allows
clamping, relative positioning of the delivered infant for delivery of an increased blood volume to the infant.
in relation to the maternal introitus before cord
clamping, perinatal asphyxia, oxytocin administration When cord clamping is delayed more than 3 minutes
● Twin-to-twin transfusion syndrome after birth, blood volume may increase by as much as
30%. (23) Hutton and Hassan (24) analyzed data from
seven randomized studies and showed that neonates in
Increased fetal erythropoiesis is frequently seen in the late-clamping group had a higher incidence of asymp-
conditions associated with hypoxia: tomatic polycythemia with a benign course (relative risk
● Placental insufficiency due to preeclampsia, primary (RR), 3.82; 95% confidence interval (CI), 1.11 to 13.21).
renovascular disease, chronic or recurrent placental However, a more recent meta-analysis showed that delayed
abruption, maternal cyanotic congenital heart disease, cord clamping did not cause a clinically significant change
postdate pregnancy, maternal smoking, and maternal in hematocrit at 1 and 4 hours of age. (25)
heavy alcohol intake. (10)(11)(12) The severity of Placental-fetal transfusion is likely influenced by grav-
hematopoietic dysfunction in these conditions appears ity and the relative position of the delivered infant in
to be proportional to the degree of placental insuffi- relation to the maternal introitus before cord clamping;
ciency and fetal growth restriction. (8) Whereas mild raising or lowering the baby by 15 to 20 cm or more with
placental dysfunction and consequent tissue hypoxia the cord intact appears to influence placental transfusion.
are associated with increased erythropoietin concen- (26) No randomized studies have examined this issue to
trations and polycythemia, more severe placental vas- date. Placental transfusion is augmented in infants who
culopathy may cause erythropoietin resistance and have perinatal asphyxia, which causes an active shift of
anemia. (13)(14) the blood volume from the placenta to the fetus. (27)
● Endocrine abnormalities associated with increased Oxytocin administration to the mother can also increase
fetal oxygen consumption, such as congenital thyro- the volume of placental transfusion to the newborn. (28)
toxicosis or maternal diabetes with poor glycemic Twin-to-twin transfusion syndrome due to a vascular
control. (13)(14) Thyrotoxicosis is presumed to in- communication occurs in approximately 10% of mono-
crease erythropoiesis through a direct effect on marrow zygotic twin pregnancies. (29)
progenitor cells, increased erythropoietin expression,
and the indirect effects of intrauterine growth restric- Polycythemia and Hyperviscosity
tion. (15)(16) In diabetic mothers who have poor Polycythemia remains an area of interest due to its po-
glycemic control, maternal hyperglycemia is proposed tential effects on the viscosity of blood and its flow
to increase fetal erythropoiesis through fetal hyper- properties in the microcirculation. (5)(7)(8) Viscosity is
insulinemia, tissue hypoxia, and increased erythro- a measure of the resistance of a fluid that is being de-
poietin concentrations. (17)(18) Although plasma lep- formed by either shear stress or tensile stress. (30) More
tin concentrations are frequently elevated in infants simply, viscosity refers to the “thickness” of a fluid and
of diabetic mothers, the actual concentrations do not is a measure of the fluid’s internal resistance to flow.

Hyperviscosity is arbitrarily defined as a viscosity mea- cosity, and only 24% of infants who have hyperviscosity
surement of greater than 14.6 centipoise detected in a have a diagnosis of polycythemia. (6)(7)(40) Whereas
viscometer at a shear rate of 11.5/sec. (5)(7)(30) Viscos- most patients who have polycythemia remain asymptom-
ity rises linearly with increasing hematocrit until the atic, characteristic clinical features may be recognized as
hematocrit reaches 60% (0.6) but increases exponentially early as 1 to 2 hours after birth as the hematocrit peaks
when hematocrit equals or exceeds 70% (0.7). with normal postnatal fluid shifts. (3) In some infants
(5)(31)(32) Although the terms polycythemia and hy- who have high borderline hematocrits, symptoms may be
perviscosity are often used interchangeably, they are not delayed until the second to third postnatal day, when
equivalent and show only modest concordance in clinical excessive depletion of the extracellular fluid may lead to
cohorts. (5)(30) Furthermore, blood viscosity can also hemoconcentration and hyperviscosity. Infants who have
rise with an increase in plasma proteins, platelets, leuko- no symptoms by 48 to 72 hours of age are likely to
cytes, and endothelial factors. (30)(32) remain asymptomatic. (3)(41)
Hyperviscosity occurs in polycythemia due to the Clinical features associated with neonatal polycythe-
presence of an abnormally large number of circulating mia are generally nonspecific and include ruddy com-
erythrocytes; the plasma viscosity in the newborn is al- plexion, irritability, jitteriness, tremors, feeding difficul-
most always normal. (5)(7) According to Poiseuille’s ties, lethargy, apnea, cyanosis, respiratory distress, and
law, flow velocities in the circulation are determined by seizures. (7) Neurologic symptoms occur in approxi-
the resistance to flow, which varies with the viscosity of mately 60% of affected patients. (5)(7)(42) The cause of
the blood and inversely with the fourth power of the these symptoms is uncertain, but reduced cerebral blood
radius of the blood vessel. This relationship can be ex- flow and altered tissue metabolism likely play important
pressed by the equation R⫽8hL/␲r4, where R repre- roles. Neurologic signs may also be related to metabolic
sents the resistance to blood flow, h is the viscosity, L is changes such as hypoglycemia and hypocalcemia. Hypo-
the length of the vessel, and r is the radius of the vessel. glycemia is the most common metabolic derangement
(33)(34) Because resistance is affected by viscosity as well and is observed in 12% to 40% of infants who have
as the caliber of the blood vessel, the effects of poly- polycythemia. Hypocalcemia is found in 1% to 11% of
cythemia on blood flow patterns are usually most pro- neonates who have polycythemia, possibly related to
nounced in the microcirculation. (34) In these small elevated concentrations of calcitonin gene-related pep-
vessels, non-newtonian mechanisms such as rouleaux tide (CGRP) in affected infants. (43) The pathophysiol-
formation and increased erythrocyte-endothelial interac- ogy of increased CGRP concentrations is not clear;
tion are also active and further contribute to the altered CGRP may play a role in the normal postnatal circulatory
flow. (32) adaptation to extrauterine life, and this process is pre-
Polycythemia and hyperviscosity are associated with sumed to be accentuated in infants who have polycythe-
decreased blood flow to the brain, heart, lung, intestines, mia. (44)
and carcass. (5)(7)(35)(36) Although renal blood flow is Polycythemia and hyperviscosity have been implicated
not affected, renal plasma flow and glomerular filtration as pathogenic factors in necrotizing enterocolitis (NEC),
rate are often diminished. (35) Hyperviscosity can also particularly in term or near-term neonates. (45)(46)(47)
reduce pulmonary blood flow that, in turn, can cause (48)(49) Historically, polycythemia has been identified
systemic hypoxia. (36) In contrast to the effects of poly- in up to half of all term infants who have NEC.
cythemia on the kidney and lungs, reduced cerebral (46)(47)(48) Although altered splanchnic perfusion is
blood flow in polycythemia likely represents a vascular widely considered to cause gut mucosal injury in affected
response to the increased arterial oxygen content (related infants, recent data indicate that attempts to reduce the
to increased hemoglobin concentrations) rather than hematocrit with partial exchange transfusions (PET) also
hyperviscosity. (7)(37) Changes in blood flow may also could contribute to the risk of NEC. (36)(42)(49)
alter the delivery of substrates (such as glucose) to organs Renal manifestations of polycythemia include de-
that are dependent on plasma flow. (7)(38)(39) creased glomerular filtration rates, oliguria, hematuria,
proteinuria, and renal vein thrombosis. (5)(7) Thrombo-
Clinical Findings ses can also be seen in other sites. Thrombocytopenia can
The symptom complex associated with polycythemia is be seen in up to one third of all cases, presumably due to
frequently described by the term “hyperviscosity syn- platelet consumption in the microvasculature. (50)(51)
drome,” although it is important to remember that only In neonates who have polycythemia due to increased
47% of infants who have polycythemia exhibit hypervis- erythropoiesis, thrombocytopenia may also be related to

“progenitor steal,” the diversion of hematopoietic pro- Treatment

genitors toward erythropoiesis at the expense of other The management of polycythemia is controversial be-
lineages. (8)(18) Overt disseminated intravascular coag- cause of the lack of evidence showing that aggressive
ulation is rare. (51) treatment improves long-term outcomes. Asymptomatic
infants whose central hematocrits are between 60%
Diagnosis (0.60) and 70% (0.70) can be monitored closely and
The diagnosis of polycythemia requires detection of a aggressively hydrated with adequate enteral intake or
venous hematocrit of at least 65% (0.65). (2)(3)(4) administration of intravenous fluids. The hematocrit
This cut-off finds its origins in studies on blood viscosity should be reassessed in 12 to 24 hours, and plasma
that show an exponential increase in viscosity above this glucose and bilirubin and cardiorespiratory status should
value. (3)(7) However, clinical evidence for this thresh- be monitored. If the hematocrit decreases or remains
old remains scant; studies have shown only modest stable and the patient remains asymptomatic, monitoring
concordance between a hematocrit greater than 65% can be continued for a further 24 to 48 hours. In asymp-
(0.65) and actual demonstration of hyperviscosity. (7) tomatic infants whose hematocrits are greater than 70%
Although blood viscosity could be a useful guide for (0.70), the treatment options are controversial. Al-
deciding appropriate management strategies in affected though traditional treatment has been PET, studies show
patients, hematocrits continue to be widely used surro- a lack of difference in outcomes with continued hydra-
gate markers of hyperviscosity due to limited availability tion and expectant management versus aggressive man-
of tools for direct measurement of blood viscosity. agement with PET. (36)(42) In the absence of a consen-
Detection of high hematocrits (ⱕ55% [0.55]) in cord sus, the decision to perform PET is usually taken on a
blood could help predict the risk of polycythemia at case-by-case basis, with a careful analysis of risks and
2 hours postnatal age, but such “screening” has not potential benefits.
gained acceptance because of the lack of data showing To perform PET, a precalculated volume of blood
that treatment of asymptomatic newborns who have (calculated to reduce the central hematocrit to 50%
elevated hematocrits alters outcomes. (3) The possibility [0.50] to 55% [0.55]) is replaced by an equivalent vol-
of polycythemia should be considered in any infant ex- ume of normal saline, 5% albumin, commercially avail-
hibiting signs of hyperviscosity. Detection of a high able solutions of human plasma protein fraction, or fresh
hematocrit in the first few hours after birth should trigger frozen plasma. Colloid solutions do not offer any thera-
a follow-up measurement in a few hours to identify any peutic advantages over normal saline and, at least in some
further rise with normal postnatal fluid shifts. (3) studies, have been associated with a higher incidence of
Close attention must be paid to the technique of NEC. (53) Because of its lower cost, ready availability,
sample collection while interpreting the test results. Cap- and absence of risk of transfusion-associated infection,
illary blood samples often show hematocrits that are 5% normal saline is generally accepted as the replacement
to 15% higher than venous samples, and, therefore, high fluid of choice for PET in infants who have polycythemia.
hematocrit measurements in samples obtained by heel- (54)(55)
sticks should be confirmed in a free-flowing venous sam- The total blood volume to be exchanged is deter-
ple. (3)(52) The technique of sample analyses should mined as follows:
also be taken into account during serial evaluation of
results because microcentrifuge hematocrit may be [Total blood volume ⫻ (patient’s hematocrit
slightly higher (due to trapped plasma of about 2%) than ⫺ desired hematocrit)]/(patient’s hematocrit)
that calculated from RBC volume and RBC count deter-
mined by hematology analyzer. (1) where total blood volume⫽the patient’s weight in kilo-
Neonates who have polycythemia should be evaluated grams multiplied by a presumed blood volume of
for underlying causes such as intrauterine growth restric- 90 mL/kg. PET can be performed through a single
tion, maternal diabetes, or birth asphyxia. Because clini- umbilical venous catheter using a pull-push technique
cal manifestations of hyperviscosity can overlap with (withdrawal of blood alternated with replacement of
other conditions, alternative causes for the symptoms fluid through a single catheter) or by withdrawing blood
should always be carefully excluded. Infants also should from an umbilical or peripheral arterial catheter and
be monitored for systemic complications of polycythe- administering replacement fluid simultaneously through
mia such as thromboses, NEC, hypoglycemia, hypocal- an umbilical or peripheral venous catheter. Regardless of
cemia, hyperbilirubinemia, and thrombocytopenia. the sites used, small aliquots of 5 mL/kg or less should

be used for removal or delivery, with each step carried there is no significant benefit of PET in asymptomatic
out over 2 to 3 minutes. patients or those who have mild symptoms.
Several randomized studies have evaluated the efficacy Patients who have polycythemia and show signs or
of PET in patients who have polycythemia (Table 2). symptoms that may be related to hyperviscosity are fre-
Malan and de V Heese (n⫽49), (56) Goldberg and quently treated with PET, even though the practice is
colleagues (n⫽20), (57) Black and coworkers (n⫽94), not supported by high-quality evidence. The arguments
(58) and Ratrisawadi and associates (n⫽42) (59) ran- in favor of PET are based on the pathophysiology of
domly assigned infants to receive either PET using hyperviscosity syndrome because most of the symptoms
plasma or supportive care. Bada and colleagues (n⫽28) are presumed to be related to altered microcirculatory
(60) compared PET using a commercially available perfusion and tissue hypoxia. (5)(7) By replacing some of
human plasma protein solution with supportive care. the circulating RBC mass with a crystalloid solution,
Kumar and Ramji (61) randomized 45 infants to periph- PET is believed to reduce blood viscosity and improve
eral PET using normal saline or to routine medical end-organ perfusion. However, no randomized clinical
management. None of these six studies documented a studies demonstrate a clear benefit of PET in the treat-
beneficial effect of PET on neurodevelopmental out- ment of symptomatic polycythemia. The groups led by
come. Dempsey and Barrington (42) systematically re- Bada, (60) Ratrisawadi, (59) and Kumar (61) random-
viewed five of these studies to investigate whether ized only asymptomatic polycythemic infants, while
PET was associated with improved short- and long-term those led by Black, (58) Goldberg, (57) and Malan (56)
outcomes in neonates who had polycythemia. They doc- made no distinction between symptomatic and asymp-
umented no improvement in long-term neurologic out- tomatic newborns. In nonrandomized clinical reports,
come (mental developmental index, incidence of devel- PET has been shown to lower pulmonary vascular resis-
opmental delay, and incidence of neurologic diagnoses) tance, improve cerebral blood flow velocity, (63)(64)
after PET in symptomatic or asymptomatic infants. and possibly normalize cerebral hemodynamics and im-
There was also no evidence of improvement in early prove the clinical status of infants who have polycythe-
neurobehavioral assessment scores (Brazelton neonatal mia. (65) However, the long-term benefits of PET re-
behavioral assessment scale). PET could have been asso- main unclear.
ciated with an earlier improvement in symptoms, but the Concerns remain about potential adverse events fol-
data were insufficient to calculate the size of the effect. lowing PET. PET was associated with an increased risk
Ozek and coworkers (36) reviewed six randomized of NEC in the systematic reviews performed by both
trials to determine the effect of PET on primary out- Dempsey (42) (RR, 8.68; 95% CI, 1.06 to 71.1) and
comes of mortality and neurodevelopmental outcomes at Ozek (36) (two studies: typical RR, 11.18; 95% CI, 1.49,
2 years and at school age. Secondary outcomes included 83.64 and typical risk difference, 0.14; 95% CI, 0.05,
seizures, cerebral infarction, NEC (Bell stage 2 or greater), 0.22). Malan and de V Heese (56) reported that 1 of
hypoglycemia, hyperbilirubinemia, and thrombocytope- their 24 patients in the exchanged group developed NEC
nia. Only one study reported data on mortality, and no within the first 24 hours after PET compared with none
significant increase was noted with PET (RR, 5.23; 95% of the control patients. Black and associates (58) re-
CI, 0.66, 41.26). Four studies reported neurodevelop- corded NEC in 8 of their 43 infants in the PET group
mental outcomes at 18 months or older, and no signifi- compared with none of the 50 control infants. PET also
cant delay was reported in the PET group (typical RR, did not alter the frequency of hypoglycemia (two studies)
1.45; 95% CI, 0.83 to 2.54 including all studies and or thrombocytopenia (one study). (36) Given the risks of
typical RR, 1.35; 95% CI, 0.68 to 2.69 when only PET for polycythemia in the newborn and the lack of
randomized, controlled trials were included). How- evidence indicating clear benefit, we are generally reluc-
ever, these results were based on data limited by poor tant to use PET in asymptomatic infants. We do offer
follow-up and did not account for patients who were lost PET for treatment of infants who have symptoms that
to follow-up. The authors performed a worst case/best could be ascribed to hyperviscosity, but this decision is
case scenario post hoc analysis, which showed a signifi- taken cautiously, with a careful review of all risk factors.
cant skewing toward or away from the association of Routine use of PET in neonatal polycythemia is not
PET with poor neurodevelopmental outcomes and was supported by current evidence, and further study is
considered to reflect the wide distribution of data points needed to identify patients who would be more likely to
rather than actual outcomes. The authors concluded that benefit from aggressive correction of polycythemia.

Table 2. Clinical Trials of Partial Exchange Transfusion in Neonatal Polycythemia
Randomization/ Hematocrit (Hct) Mode of Exchange/
Study Sample Size at Enrollment Replacement fluid Outcome Measurements
Malan and Not clearly stated; Hct >65% (0.65) UVC Brazelton neonatal scale
de V Heese nⴝ49 FFP Prechtl neurologic
(56) assessment at
10 days
Neurodevelopmental
assessment at
8 months
Goldberg et al Not clearly stated; Hct >64% (0.64) UVC Brazelton neonatal scale
(57) nⴝ20 and hyperviscosity FFP at 8 hours, 24 hours,
72 hours, and
2 weeks
BSID and neurologic
assessment at
8 months
Black et al (58) Randomized; Antecubital venous UVC Neonatal signs
nⴝ93 Hct >65% (0.65) FFP BSID and neurologic
and hyperviscosity assessment at 1 and
2 years
Cognitive testing at
7 years
Studies included in the meta-analysis by Ozek et al (36)

Bada et al (60) Not clearly stated; Radial artery Route not stated; Cerebral artery Doppler
nⴝ28 Hct >65% (0.65) Plasma protein measurement
solution BSID or cognitive
testing at 30 months
Ratrisawadi et al Randomized; Central venous Route not stated Gasel Development at
Studies included in the meta-analysis by Dempsey and Barrington (42)

(59) nⴝ105 Hct >65% (0.65) 1.5 to 2 years
Hakanson et al Not clearly stated; Hyperviscosity Not clearly stated; BSID at 8 months
(62)* nⴝ24 (undefined) FFP
Kumar and Randomized; Peripheral venous Peripheral; Normal Neurologic deficits at 3,
Ramji (61) nⴝ22 Hct >70% (0.70) saline 6, 9, 12, 18 months
hematology
FFP⫽fresh frozen plasma, BSID⫽Bayley Scale of Infant Development, UVC⫽umbilical venous line, * ⫽abstract only
polycythemia

19. Weinberger MM, Oleinick A. Congenital marrow dysfunction

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• Know the causes of neonatal polycythemia.
173–177
• Know the clinical manifestations, 21. Widness JA, Pueschel SM, Pezzullo JC, Clemons GK. Elevated
management, and outcomes of neonatal erythropoietin levels in cord blood of newborns with Down’s
polycythemia. syndrome. Biol Neonate. 1994;66:50 –55
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change transfusion improves cerebral hemodynamics in symptom-
Child. 1988;142:532–535
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Jr. Risk factors for necrotizing enterocolitis in infants weighing 61. Kumar A, Ramji S. Effect of partial exchange transfusion in
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49. Maayan-Metzger A, Itzchak A, Mazkereth R, Kuint J. Necro- 62. Hakanson DO. Neonatal hyperviscosity syndrome: long-term
tizing enterocolitis in full-term infants: case-control study and benefit of partial plasma exchange transfusion. [Abstract]. Pediatr
review of the literature. J Perinatol. 2004;24:494 – 499 Res. 1981;15:449A
50. Acunas B, Celtik C, Vatansever U, Karasalihoglu S. Thrombo- 63. Murphy DJ Jr, Reller MD, Meyer RA, Kaplan S. Effects of
cytopenia: an important indicator for the application of partial neonatal polycythemia and partial exchange transfusion on cardiac
exchange transfusion in polycythemic newborn infants? Pediatr Int. function: an echocardiographic study. Pediatrics. 1985;76:909 –913
2000;42:343–347 64. Maertzdorf WJ, Tangelder GJ, Slaaf DW, Blanco CE. Effects
51. Katz J, Rodriguez E, Mandani G, Branson HE. Normal coag- of partial plasma exchange transfusion on cerebral blood flow
ulation findings, thrombocytopenia, and peripheral hemoconcen- velocity in polycythaemic preterm, term and small for date newborn
tration in neonatal polycythemia. J Pediatr. 1982;101:99 –102 infants. Eur J Pediatr. 1989;148:774 –778
52. Rivera LM, Rudolph N. Postnatal persistence of capillary- 65. Bada HS, Korones SB, Pourcyrous M, et al. Asymptomatic
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birth-weight and term infants. Pediatrics. 1982;70:956 –957 exchange transfusion. J Pediatr. 1992;120:579 –585

NeoReviews Quiz
6. Polycythemia represents an abnormal elevation of the circulating red blood cell mass, which increases the
risk of hyperviscosity, microcirculatory hypoperfusion, and multisystem organ dysfunction. Of the following,
the hematocrit threshold that best defines polycythemia is:
A. 55% (0.50).
B. 60% (0.60).
C. 65% (0.65).
D. 70% (0.70).
E. 75% (0.75).
7. Polycythemia in neonates is often associated with metabolic complications. Of the following, the most
common metabolic abnormality associated with polycythemia in neonates is:
A. Hyperchloremia.
B. Hyperkalemia.
C. Hypernatremia.
D. Hypocalcemia.
E. Hypoglycemia.
8. The treatment of polycythemia includes partial exchange transfusion in which a precalculated volume of
blood is replaced by an equivalent volume of fluid. Of the following, the most accepted choice of fluid for
partial exchange transfusion is:
A. Albumin solution.
B. Fresh frozen plasma.
C. Lactated Ringer solution.
D. Normal saline.
E. Plasma protein fraction.

Juan I. Remon, Aarti Raghavan and Akhil Maheshwari
DOI: 10.1542/neo.12-1-e20

s;12/1/e20
Red Blood Cell Transfusions in the Neonate
Amélia Miyashiro Nunes dos Santos and Cleide Enoir Petean Trindade
DOI: 10.1542/neo.12-1-e13
Article hematology

Amélia Miyashiro Nunes
dos Santos, MD, PhD,* Abstract
Cleide Enoir Petean Despite recent trends to decrease allogeneic red blood cell (RBC) transfusion thresh-
† olds, such transfusions remain an important supportive and life-saving intervention for
Trindade, MD, PhD
neonatal intensive care patients. In neonates, apart from concerns about transfusion-
associated infections, many controversial questions regarding transfusion practices
remain unanswered. Moreover, neonates present specific clinical and immunologic
Author Disclosure
characteristics that require selected blood component products. This article addresses
Drs Nunes dos Santos
many of these issues from a medical perspective, with emphasis on the best blood
and Trindade have banking techniques to provide RBC products for neonatal transfusions.
disclosed no financial
relationships relevant Objectives After completing this article, readers should be able to:
to this article. This
1. Describe RBC products available for use in neonates.
commentary does not
2. Choose the best RBC products for use in preterm infants and in neonates who have
Rhesus hemolytic diseases or ABO incompatibility hemolytic diseases.
of an unapproved/
commercial Introduction
product/device. Transfusion therapy in the neonate poses specific challenges, requiring consideration of
issues not found in older patients. The transfer of maternal antibodies across the placenta,
the immature immune system, and the small blood volume of the fetus and neonate make
transfusion therapy a special issue in this group of patients.
Transfusion compatibility testing must take into account not only the mother’s blood
type but also blood group antibodies against the fetus or neonate’s blood type. The
immature immune system of fetuses and neonates makes them more susceptible to
transfusion-associated cytomegalovirus infections and transfusion-associated graft versus
host disease (TA-GVHD). Moreover, fetuses and neonates, especially those who are
extremely low birthweight (⬍1,000 g) may be at risk of hemodynamic instability if
volumes are not appropriately adjusted, hypothermia if blood is cold, and hyperkalemia if
large volumes of blood product that have high concentrations of potassium are infused
rapidly. Also, particular attention must be paid when transfusing blood group O to
neonates who have group A, B, or AB blood. The quantity of anti-A or anti-B antibodies
present in the type O RBC product can produce hemolysis in the neonate. All of these
issues should be considered when choosing the RBC product for transfusion in neonates.
RBC Products
Most RBC components available today are derived from the collection of 450 to 500 mL
of whole blood into sterile plastic bags containing citrate-phosphate-dextrose (CPD)
anticoagulant. Because RBCs, platelets, and plasma have different specific gravities, they
can be separated from each other by centrifugation. RBCs are separated from platelet-rich
plasma by performing centrifugation of the whole blood. RBCs are then collected into a
sterile satellite bag containing an anticoagulant solution, generally a nutrient additive
solution. A variety of additive solutions are used, containing a mix of glucose, adenine, and
in some cases, mannitol. These solutions prolong the shelf life of the RBC product from
21 days for packed RBCs in CPD to 35 days for RBCs in citrate-phosphate-dextrose-
*Associate Professor, Department of Pediatrics, Neonatal Division of Medicine, Federal University of São Paulo, São Paulo, SP,
Brazil.
†
Emeritus Professor of Pediatrics, Department of Pediatrics, Division of Neonatology, Botucatu School of Medicine, São Paulo
State University-UNESP, Botucatu, São Paulo, Brazil.

hematology red blood cell transfusions
adenine (CPDA-1) and to 42 days for RBCs in additive or fetuses requiring intrauterine transfusions are at in-
solutions. (1)(2) Transfusion of 10 mL/kg of RBCs is creased risk for posttransfusion CMV-related morbidity
expected to raise the patient’s hematocrit by 9% (0.9) to and mortality. (2)
10% (0.10) for CPDA-1 packed RBCs and by 7% (0.7) to CMV-seronegative blood is considered the gold stan-
8% (0.8) for RBCs preserved in additive solutions. (2)(3) dard for preventing transfusion-associated CMV infec-
Currently, an increasing proportion of blood compo- tions, but such products often are difficult to obtain in
nents are being collected by an automated apheresis areas where the prevalence of positive CMV antibodies is
instrument, which draws blood into an external circuit, high. Because CMV is harbored within WBCs, leukocyte
separates the components by centrifugation or filtration, reduction should decrease the risk of this infection.
collects the desired component, and returns the remain- Whether leukocyte reduction is as efficacious as CMV-
ing blood components to the donor. RBCs collected by seronegative blood is controversial. A meta-analysis of
apheresis contain additive solution. (3) the available controlled studies indicates that CMV-
RBC components for use in neonates are modified seronegative blood components are more efficacious
because of particular immunologic characteristics of this than WBC-reduced blood components in preventing
group of patients. Leukoreduced RBCs and irradiated transfusion-acquired CMV infection. (10) However, be-
RBCs are used in most countries for newborns, and cause use of WBC-reduced components may have other
washed RBCs are used for certain special conditions. (4) advantages in neonates, they should be used, regardless
of CMV serologic status.
Leukocyte-reduced RBC products

Most RBC products are modified soon after collection by Irradiated RBC Products
passing them through special filters that adsorb white Irradiation inactivates donor lymphocytes present in the
blood cells (WBCs), decreasing them from 109 per unit blood component, preventing them from proliferating
to 106 per unit. Currently, third-generation leukocyte and thereby reducing the risk of TA-GVHD. TA-GVHD
reduction filters consistently provide a 99.9% reduction can occur when viable donor lymphocytes are transfused
of WBCs, with a final product of 1 to 5⫻106 WBCs per into patients who have cellular immunodeficiency or
unit. (3) when donor and recipient share similar human leukocyte
Mukagatare and associates (5) reported that the im- antigens (HLAs), such as with blood donation from
plementation of universal leukocyte reduction signifi- family members. Neonates, especially preterm infants,
cantly decreased the rate of all transfusion reactions from are at high risk for TA-GVHD. Some neonatal centers
0.49% to 0.31% (P⬍0.001), the rates of febrile non- irradiate all cellular blood products for infants younger
hemolytic transfusion reactions from 0.35% to 0.24% than 4 months of age; others irradiate only blood prod-
(P⫽0.002), and the rate of allergic reactions from 0.05% ucts given to preterm infants whose birthweight is 1.2 kg
to 0.01% (P⬍0.001). However, the effect of leukocyte- or less. (4) TA-GVHD has been reported after intrauter-
reduced preparations on patient outcomes is still not ine transfusion in preterm infants and in term infants who
evidence-based, (6) except for some benefits in patients received exchange transfusion. (11)(12)
undergoing cardiac surgery. (7)(8) In preterm infants, Blood components are usually subjected to a mini-
leukocyte-depleted blood components have been used in mum of 25 Gy gamma irradiation. (13) Irradiation in-
many countries, (4) based on a possible cause-effect creases potassium leakage from RBCs during storage,
relationship between the implementation of universal and irradiated RBCs have a shortened shelf life. (14) The
WBC reduction and a lower incidence of bronchopul- United States Food and Drug Administration recom-
monary dysplasia (odds ratio [OR], 0.42; 95% con- mends a 28-day expiration for irradiated RBCs because
fidence interval [CI], 0.25 to 0.70), retinopathy of in vivo recovery of irradiated RBCs is decreased com-
prematurity (OR, 0.56; 95% CI, 0.33 to 0.93) and pared with nonirradiated RBCs at 42 days of storage.
necrotizing enterocolitis (OR, 0.39; 95% CI, 0.17 to (15) Therefore, it is preferable to use irradiated RBCs
0.93). (9) However, in neonatal settings, the primary close to the administration rather than prolonged refrig-
objective of leukocyte reduction is to reduce transfusion- erator storage products, especially for neonates, who may
associated cytomegalovirus (CMV) infection. Preterm not be able to tolerate a large potassium load. Irradiation
infants, seronegative neonates whose birthweights are of blood products has not been shown to prevent post-
less than 1,250 g and require blood component therapy, transfusion CMV infection. (14)(16)

Washed RBC Products group O, RhD-negative, CMV-reduced risk (CMV-

Saline washing can be used to remove plasma or additive negative antibody or leukocyte-reduced), and gamma-
solution from blood components or to reduce the po- irradiated to avoid TA-GVHD. The selected RBC units
tassium content in the supernatant of stored RBCs. for intrauterine transfusions must be compatible with
This process involves the addition of saline to cellular both the fetus and the mother. If mother and fetus have
blood components, followed by centrifugation, removal the same ABO group, then group-identical units may be
of supernatant, and resuspension of the cells in saline chosen. Fresh RBC product (usually within 72 hours
solution or plasma. Washed RBC products are used most after collection) can be used to maintain 2,3-diphos-
frequently in neonatal settings, for intrauterine trans- phoglycerate concentrations and avoid high potassium
fusions or exchange transfusions, or when transfusing concentrations. Group O RBCs should be saline-washed
more than 20 mL/kg of RBCs that have been stored for to eliminate plasma that contains anti-A and anti-B anti-
more than 14 days. (1)(3) Washed products must be bodies, if the fetal blood type is A, B, AB, or unknown.
used within 4 hours of processing if stored at room The RBC product can be resuspended in either normal
temperature or within 24 hours if stored in the refriger- saline or AB plasma at the desired hematocrit. The RBCs
ator because the washing process itself creates an open should be negative for blood group antigens to which the
system. (17) mother has made antibodies and crossmatch-compatible
with the mother’s plasma or serum because any blood
Selection of the RBC Products group antibodies in the fetal circulation will be derived
Intrauterine Transfusion from the mother. (21) RBCs used for exchange trans-
The primary indication for prenatal RBC transfusions is fusions or intrauterine transfusions should be negative
management of hemolytic disease of the fetus and new- for hemoglobin S screening to optimize oxygen-carrying
born. Maternal antibodies directed against the fetal capacity. Washed and irradiated maternal blood can be
RBCs are produced when fetal RBCs are positive for a used when there is no suitable blood donor. (22) Cells
certain antigen, usually Rhesus D (RhD), and pass into are packed to a hematocrit of 75% (0.75) to 85%
the blood circulation of a mother who is negative for that (0.85) to prevent volume overload. The volume of
particular antigen. Passage of maternal immunoglobulin RBCs to be transfused to achieve a hematocrit increment
G antibodies across the placenta into the fetal circulation of 10% (0.10) can be roughly calculated by multiplying
can cause mild-to-severe hemolytic anemia and fetal fetal weight (g) estimated on ultrasonography by a factor
hydrops. of 0.02. (23) Usually, a final target hematocrit of 40%
During the past few decades, prenatal care strategies (0.40) to 50% (0.50) is used. (18) The rate of RBC
for patients who have rhesus hemolytic diseases have infusion should be about 5 to 10 mL/min. (24)
evolved significantly, including the introduction of RhD
prophylaxis, the development of Doppler ultrasono- Exchange Transfusion After Birth
graphic techniques to detect fetal anemia, and treatment Currently, with the use of both intensive phototherapy
with intrauterine blood transfusions. Such developments management and immune globulin intravenous, ex-
have led to a dramatic decrease in perinatal mortality. change transfusion rarely is indicated in Rhesus or ABO
(18) hemolytic diseases. (25) Exchange transfusions, when
The first intrauterine transfusion was performed by indicated, (25) are performed with double-volume trans-
Liley in 1963 by the intraperitoneal route. (19) Donor fusion (160 mL/kg) using irradiated, leukocyte-reduced
RBCs administered by that route are absorbed into the erythrocytes (cross-matched against the mother and
circulation via the diaphragmatic lymphatics. This method compatible with the infant), usually via an umbilical vein
results in slower restoration of fetal hemoglobin than catheter.
observed with blood administered directly into the fetal For Rhesus hemolytic diseases, ABO-compatible
circulation and, as a result, is no longer the route of RhD-negative or group O RhD-negative RBCs resus-
choice for fetal therapy, except in cases requiring trans- pended in normal saline or neonate-compatible plasma
fusions before 18 to 20 weeks of gestation, when intra- are used for small-volume or exchange transfusion.
vascular access is not possible. (20) Type O Rh-compatible RBCs must be used for ex-
Depending on disease severity, either transfusions or change transfusions or RBC transfusions in neonates
exchange transfusions can be performed (in utero) via who have ABO hemolytic diseases because of the pres-
the umbilical vein. The RBCs chosen for intrauterine ence of maternal antibodies (anti-A or anti-B) against the
transfusions for Rhesus hemolytic disease are typically neonate’s RBCs in the neonatal circulation until 4 to

6 months of age. Therefore, type O Rh-compatible RBCs Improvements in prenatal and postnatal care have led
suspended in neonatal-compatible plasma are indicated to a decline in the number of exchange transfusions. As a
for exchange transfusion. For example, in a group A Rh- consequence, the most frequently transfused neonates
positive neonate who has ABO-incompatible hemolytic are preterm infants, especially those of very low birth-
disease, group O Rh-positive (or -negative) RBCs sus- weight (⬍1,500 g). In this group of patients, phlebot-
pended in plasma type A must be used for exchange omy blood losses and a slower rate of erythropoiesis due
transfusion. If type A RBCs are used, the anti-A anti- to low concentrations of erythropoietin result in progres-
body transferred from the maternal to fetal circulation sive anemia during the first few months after birth. (26)
will cause hemolysis of the transfused erythrocytes and a However, the optimal hemoglobin threshold for RBC
substantial increase in the bilirubin concentration, in- transfusions in preterm infants is unknown. (27) Restric-
creasing the risk of kernicterus. tive guidelines for RBC transfusions have been devel-
Although exchange transfusion for hemolytic diseases oped in an effort to limit transfusion-associated risks.
of the newborn is used rarely, it may be beneficial in some (28)(29)(30)(31)(32) Some studies showed the efficacy
cases of inborn errors of metabolism, especially ornithine of restrictive guidelines to reduce transfusion rates in
transcarbamylase deficiency. This disease is the most preterm infants without increasing the morbidity and
common urea cycle defect in which hyperammonemia mortality rate. (30)(32) However, scientifically based
and different nitrogenous precursors of urea accumulate, risk/benefit evidence for short-term clinical outcome
leading to coma and a high mortality rate. and long-term neurodevelopmental outcome of using
restrictive or liberal guidelines is still lacking. (27)(28)
Transfusion in the Neonate (29)(30)(33) Accordingly, varying transfusion practices
Before receiving any RBC transfusions, neonates must have been described in children and neonates between
be typed (ABO and Rh group) and screened for pas- institutions and countries. (4)(34)(35) The guidelines
sively transferred RBC antibody of maternal origin. If the for RBC transfusions in preterm neonates were published
antibody screen is negative, no further antibody screens in NeoReviews by Ohls. (36)
are required during the hospitalization until the child is To limit donor exposure, aliquots can be prepared
4 months old, and ABO/Rh-compatible RBCs may be from a single dedicated blood donor for small-volume
provided. If the antibody screen is positive, RBCs that transfusions. Pediatric bags or sterile connecting devices
are compatible with the maternally derived antibody can be used to make small aliquots from an adult blood
must be provided until the maternal antibody is no unit. Transfusions of small-volume RBCs stored in addi-
longer demonstrable. (1)(2) tive anticoagulant-preservative solutions (for 42 days) or
In many countries, leukocyte-reduced, gamma- CPDA-1 (for 35 days) decrease blood donor exposures
irradiated, and ABO-Rh-compatible RBC products are in newborns. (37)(38) Strauss and colleagues (37) no-
used for transfusions in neonates, especially those whose ticed a reduction from 6.5⫾3.7 to 1.9⫾0.6 (P⬍0.005)
birthweights are less than 1,200 g. When group O RBCs in the number of donors to which infants were exposed
are used for transfusing type A or B neonates, centrifu- for preterm infants transfused with RBCs stored for up to
gation before transfusion to remove the excess of plasma 42 days compared with neonates that received erythro-
that contains anti-A and anti-B antibodies can reduce the cytes preserved for up to 7 days. In this study, no major
risk of hemolysis in the neonate. clinical changes or significant differences in infants’ pH
Directed donations from family members, who often values and plasma sodium, potassium, lactate, and glu-
have never donated blood before, are not recommended. cose values were observed. Usually, the transfusion of a
This blood product presents a higher risk of infectious maximum of 20 mL/kg of RBCs, slowly infused over
disease and TA-GVHD than those provided by standard 4 hours, is not followed by acidosis or hyperkalemia
blood donors. unless the neonate already has impaired renal function
Mothers are not the ideal donors for their infants and a high potassium concentration. (1)(38) Fernandes
because maternal plasma frequently contains a variety of da Cunha and associates, (38) using a sterile connecting
antibodies against RBCs, leukocytes, platelets, and HLA device for transfusion of small aliquots of leukocyte-
antigens expressed by neonatal cells. When maternal reduced and gamma-irradiated RBCs preserved in
RBCs are used for transfusion in the neonate, washing CPDA-1 for up to 28 days after collection, noted a 70%
with saline solution can remove the excess of plasma with reduction of donor exposure in very low-birthweight
these antibodies. (1) Moreover, the product must be (⬍1,500 g) infants.
gamma-irradiated to prevent TA-GVHD. The use of restrictive guidelines and “dedicated” RBC

units for small-volume (10 to 20 mL/kg) RBC transfu- months. In this study, late cord clamping improved the
sions in very low-birthweight infants has progressively hematocrit and iron status and reduced the relative risk
decreased donor exposure and, therefore, the known and of anemia: 0.53 (95% CI, 0.40 to 0.70). Neonates who
unknown risks of allogeneic transfusions. However, after had late cord clamping were at increased relative risk of
an increased storage time, RBCs undergo numerous asymptomatic polycythemia: 3.91 (95% CI, 1.00 to
changes that may affect their functions. The primary 15.36).
hypothesis is that the longer blood is stored, the less In a randomized study of 72 infants from 24 to
effective is the oxygen delivery to tissues. Moreover, 31 weeks of gestation, Mercer and coworkers (44) showed
transfusion of older stored blood to critically ill infants that infants in the delayed cord clamping group (30 to
may trigger immunosuppressive or proinflammatory 45 seconds) had significantly less intraventricular hem-
effects, resulting in higher organ dysfunction and mor-
orrhage and late-onset sepsis compared with the early
bidity or mortality rates. (13) A multicenter, double-
cord clamping (⬍10 sec) group, with an advantage for
blind, randomized, controlled trial is in place to deter-
male infants for both outcomes. A follow-up evaluation
mine if RBCs stored for 7 days or less (fresh RBCs)
at 7 months of corrected age showed no differences in
compared with current standard transfusion practice de-
the Bayley Scales of Infant Development scores between
creases major nosocomial infection and organ dysfunc-
tion in neonates admitted to the neonatal intensive care delayed and early groups. However, in a subset analysis of
unit. (39) male neonates, regression model analysis adjusted for
gestational age, intraventricular hemorrhage, broncho-
pulmonary dysplasia, sepsis, and male sex showed that
Controversial Transfusion Practices infants in whom cord clamping was delayed had higher
in Neonates motor scores. (45)
Delayed Umbilical Cord Clamping Delayed cord clamping in preterm infants who are
The beneficial effects of delaying clamping of the umbil- well at birth seems to be safe and to confer some ben-
ical cord have been questioned. Early clamping of the efit. However, larger and longer term follow-up in-
cord (5 to 10 seconds after birth), compared with later vestigations are required to confirm the benefits before
clamping, can decrease the neonatal blood volume by the practice can be recommended for routine use. (46)
20 to 40 mL/kg. (40)
Strauss and colleagues (41) randomized 105 neonates
from 30 to 36 weeks of gestation to early cord clamping Autologous Cord Blood Transfusion
(maximum of 15 seconds) and delayed cord clamping Attempts have been made to collect, store, and transfuse
(1 minute). Circulating RBC volume/mass (P⫽0.04) blood from the placenta/umbilical cord, especially in
and weekly hematocrit values (P⬍0.005) were higher low-resource countries. However, several and significant
after delayed clamping, but the number of RBC transfu-
problems must be solved before this practice can be
sions was similar between groups (P⫽0.70). Require-
recommended routinely, including collection of insuffi-
ments for mechanical ventilation were similar. More
cient volumes of placental blood for meaningful transfu-
(P⫽0.03) neonates needed phototherapy after delayed
sions, clots forming during both collection and storage,
clamping, but initial bilirubin values and extent of pho-
and bacterial contamination. Volumes collected from the
totherapy did not differ.
Rabe and associates, (42) in a systematic review of placenta vary greatly among individual infants, averaging
delayed cord clamping based on 10 studies involving 454 about 20 mL/kg of whole blood, which is sufficient for
preterm infants, found that the major benefits of the only one to two transfusions. (47) A review article (47)
intervention were higher circulating blood volume dur- reported an analysis of 154 papers searched on the
ing the first 24 hours after birth, less need for blood PubMed and MEDLINE database related to the use of
transfusions (P⫽0.004), and lower incidence of intra- cord blood for transfusion purposes. The percentage of
ventricular hemorrhage (P⫽0.002). contaminated units of cord blood collections was less
Hutton and Hassan (43) published a meta-analysis of than 5%, but Ademokun and associates (48) reported a
15 controlled trials involving term infants that compared 12% incidence of bacterial contamination. These prob-
cord clamping delayed for at least 2 minutes (1,001 lems and the high costs have led authors to question
newborns) and early clamping immediately after birth whether, on balance, autologous/placental RBC trans-
(911 newborns) in terms of benefits over ages 2 to 6 fusions offer clinically significant benefits. (49)

18. Moise KJ Jr. Management of rhesus alloimmunization in preg-

American Board of Pediatrics Neonatal-Perinatal nancy. Obstet Gynecol. 2008;112:164 –176
Medicine Content Specification 19. Liley AW. Intrauterine transfusion of foetus in haemolytic
disease. Br Med J. 1963;2:1107–1109
• Know the clinical indications of potential 20. Fox C, Martin W, Somerset DA, Thompson PJ, Kilby MD.
complications, and their prevention, of Early intraperitoneal transfusion and adjuvant maternal immuno-
using blood products in neonatal globulin therapy in the treatment of severe red cell alloimmuniza-
transfusions, including transfusion tion prior to fetal intravascular transfusion. Fetal Diagn Ther. 2008;
reactions and graft-versus-host disease. 23:159 –163
21. Wu Y, Stack G. Blood product replacement in the perinatal
period. Semin Perinatol. 2007;31:262–271
22. Cassandra DJ, Strauss RG. Transfusion of Neonates and Pedi-
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2. Fasano R, Luban NL. Blood component therapy. Pediatr Clin estimate volume for fetal intravascular transfusions. Fetal Diagn
Ther. 1998;13:94 –97
North Am. 2008;55:421– 45
3. Galal SA. Therapeutic techniques. Selection of blood compo- 24. British Committee for Standards in Haematology. Transfusion
guidelines for neonates and older children. Br J Haematol. 2004;
nents for neonatal transfusion. NeoReviews. 2005;6:e351– e355
124:433– 453
4. New HV, Stanworth SJ, Engelfriet CP, et al. Neonatal transfu-
25. American Academy of Pediatrics Subcommittee on Hyper-
sions. Vox Sang. 2009;96:62– 85
bilirubinemia. Management of hyperbilirubinemia in the new-
5. Mukagatare I, Monfort M, de Marchin J, Gerard C. The effect of
born infant 35 or more weeks of gestation. Pediatrics. 2004;114:
leukocyte-reduction on the transfusion reactions to red blood cells
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concentrates [French]. Transfus Clin Biol. 2010;17:14 –19
26. Luban NL. Management of anemia in the newborn. Early
6. Vamvakas EC, Blajchman MA. Transfusion-related immuno- Hum Dev. 2008;84:493– 498
modulation (TRIM): an update. Blood Rev. 2007;21:327–348 27. Strauss RG. How I transfuse red blood cells and platelets to
7. Vamvakas EC, Blajchman MA. Transfusion-related mortality: infants with the anemia and thrombocytopenia of prematurity.
the ongoing risks of allogeneic blood transfusion and the available Transfusion. 2008;48:209 –217
strategies for their prevention. Blood. 2009;113:3406 –3417 28. Bell EF, Strauss RG, Widness JA, et al. Randomized trial of
8. van de Watering LM, Hermans J, Houbiers JG, et al. Beneficial liberal versus restrictive guidelines for red blood cell transfusion in
effects of leukocyte depletion of transfused blood on postoperative preterm infants. Pediatrics. 2005;115:1685–1691
complications in patients undergoing cardiac surgery: a randomized 29. Miyashiro AM, Santos N, Guinsburg R, et al. Strict red blood
clinical trial. Circulation. 1998;97:562–568 cell transfusion guideline reduces the need for transfusions in very-
9. Fergusson D, Hebert PC, Lee SK, et al. Clinical outcomes low-birthweight infants in the first 4 weeks of life: a multicentre
following institution of universal leukoreduction of blood transfu- trial. Vox Sang. 2005;88:107–113
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10. Vamvakas EC. Is white blood cell reduction equivalent to Infants in Need of Transfusion (PINT) study: a randomized, con-
antibody screening in preventing transmission of cytomegalovirus trolled trial of a restrictive (low) versus liberal (high) transfusion
by transfusion? A review of the literature and meta-analysis. Trans- threshold for extremely low birth weight infants. J Pediatr. 2006;
fus Med Rev. 2005;19:181–199 149:301–307
11. Flidel O, Barak Y, Lifschitz-Mercer B, Frumkin A, Moglilner 31. Venancio JP, Santos AM, Guinsburg R, Peres Cde A, Shinzato
BM. Graft versus host disease in extremely low birth weight neo- AR, Lora MI. Strict guideline reduces the need for RBC transfu-
nate. Pediatrics. 1992;89:689 – 690 sions in premature infants. J Trop Pediatr. 2007;53:78 – 82
12. Rühl H, Bein G, Sachs UJ. Transfusion-associated graft- 32. Mimica AF, dos Santos AM, da Cunha DH, et al. A very strict
versus-host disease. Transf Med Rev. 2009;23:62–71 guideline reduces the number of erythrocyte transfusions in pre-
13. Moroff G, Leitman SF, Luban NL. Principles of blood irradi- term infants. Vox Sang. 2008;95:106 –111
ation, dose validation, and quality control. Transfusion. 1997;37: 33. Bell EF. When to transfuse preterm babies. Arch Dis Child
1084 –1092 Fetal Neonatal Ed. 2008;93:F469 –F473
14. Zubair AC. Clinical impact of blood storage lesions. Am J 34. Slonim AD, Joseph JG, Turenne WM, Sharangpani A, Luban
Hematol. 2010;85:117–122 NL. Blood transfusions in children: a multi-institutional analysis of
15. Davey RJ, McCoy NC, Yu M, Sullivan JA, Spiegel DM, practices and complications. Transfusion. 2008;48:73– 80
Leitman SF. The effect of prestorage irradiation on posttransfusion 35. dos Santos AM, Guinsburg R, Procianoy RS, et al. Variability
red cell survival. Transfusion. 1992;32:525–528 in red blood cell transfusion practices among Brazilian neonatal
16. Wu Y, Zou S, Cable R, et al. Direct assessment of cytomega- intensive care units. Transfusion. 2010;50:150 –159
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Transfusion. 2010;50:776 –786 2007;8:e377– e386
17. Cambell-Lee SA. Packed RBCs and related products. In: 37. Strauss RG, Burmeister LF, Johnson K, Cress G, Cordle D.
Hillyer CD SL, Ness PM, Anderson KC, eds. Blood Banking and Feasibility and safety of AS-3 red blood cells for neonatal transfu-
Transfusion Medicine Basic Principles and Practice. Philadelphia, sions. J Pediatr. 2000;136:215–219
PA: Churchill Livingstone; 2003:145–152 38. Fernandes da Cunha DH, Nunes Dos Santos AM, Kopelman

BI, et al. Transfusions of CPDA-1 red blood cells stored for up to 44. Mercer JS, Vohr BR, McGrath MM, Padbury JF, Wallach M,
28 days decrease donor exposures in very low-birth-weight prema- Oh W. Delayed cord clamping in very preterm infants reduces the
ture infants. Transfus Med. 2005;15:467– 473 incidence of intraventricular hemorrhage and late-onset sepsis: a
39. Fergusson D, Hutton B, Hogan DL, et al. The Age of Red randomized, controlled trial. Pediatrics. 2006;117:1235–1242
Blood Cells in Premature Infants (ARIPI) randomized controlled 45. Mercer JS, Vohr BR, Erickson-Owens DA, Padbury JF, Oh W.
trial: study design. Transfus Med Rev. 2009;23:55– 61 Seven-month developmental outcomes of very low birth weight
40. Mercer JS. Current best evidence: a review of the literature on infants enrolled in a randomized controlled trial of delayed versus
umbilical cord clamping. J Midwif Womens Health. 2001;46: immediate cord clamping. J Perinatol. 2010;30:11–16
402– 414 46. Nicholl RM, Richards S, Ray S, Gowda R. Question 1. Is
41. Strauss RG, Mock DM, Johnson KJ, et al. A randomized delayed clamping of the umbilical cord in moderately preterm
clinical trial comparing immediate versus delayed clamping of the babies beneficial? Arch Dis Child. 2010;95:235–237
umbilical cord in preterm infants: short-term clinical and laboratory 47. Khodabux CM, Brand A. The use of cord blood for transfusion
endpoints. Transfusion. 2008;48:658 – 665 purposes: current status. Vox Sang. 2009;97:281–293
42. Rabe H, Reynolds G, Diaz-Rossello J. A systematic review and 48. Ademokun JA, Chapman C, Dunn J, et al. Umbilical cord
meta-analysis of a brief delay in clamping the umbilical cord of blood collection and separation for haematopoietic progenitor cell
preterm infants. Neonatology. 2008;93:138 –144 banking. Bone Marrow Transplant. 1997;19:1023–1028
43. Hutton EK, Hassan ES. Late vs early clamping of the umbilical 49. Strauss RG, Widness JA. Is there a role for autologous/
cord in full-term neonates: systematic review and meta-analysis of placental red blood cell transfusions in the anemia of prematurity?
controlled trials. JAMA. 2007;297:1241–1252 Transfus Med Rev. 2010;24:125–129
NeoReviews Quiz
3. Most red blood cell products are modified soon after collection by passing them through special filters that
adsorb white blood cells. Of the following, the primary objective of leukocyte reduction for transfusion in
preterm infants is to decrease the incidence of:
A. Bronchopulmonary dysplasia.
B. Cytomegalovirus infection.
C. Necrotizing enterocolitis.
D. Patent ductus arteriosus.
E. Retinopathy of prematurity.
4. Gamma irradiation of blood products inactivates donor lymphocytes, which reduces the risk of transfusion-
associated graft-versus-host disease. Of the following, gamma irradiation of blood products is most likely
to result in neonatal:
A. Hypercalcemia.
B. Hyperchloremia.
C. Hyperglycemia.
D. Hyperkalemia.
E. Hypernatremia.
5. Delayed clamping of the umbilical cord (>1 minute after birth), as compared with early clamping of the
umbilical cord (<15 seconds after birth), increases neonatal blood volume by 20 to 40 mL/kg bodyweight.
Of the following, based on a systematic review of controlled studies of delayed versus early clamping of the
umbilical cord, the major benefit of delayed clamping in preterm infants is reduced need for:
A. Antibiotic treatment.
B. Blood transfusions.
C. Intensive phototherapy.
D. Mechanical ventilation.
E. Vasopressor treatment.

Amélia Miyashiro Nunes dos Santos and Cleide Enoir Petean Trindade
DOI: 10.1542/neo.12-1-e13

s;12/1/e13
Something Old, Something New
Alistair G.S. Philip
NeoReviews 2011;12;e1
DOI: 10.1542/neo.12-1-e1
commentary
Commentary
sure that he will be a very positive With this first issue of 2011, we
Author Disclosure
influence on the journal. introduce a new section that we believe
Dr Philip has disclosed no financial
As we move into a new year, it is will be of interest to all who practice
relationships relevant to this article. perhaps worth reflecting on the current clinical neonatology. It is, unfortu-
This commentary does not contain a status of NeoReviews. During the past nately, a fact of life that most of us will
discussion of an unapproved/ year, in addition to the main articles, be accused of malpractice at some
investigative use of a commercial we have consistently provided learning point in our careers. Although many
opportunities in the form of Index of such accusations are unfounded, there
product/device.
Suspicion in the Nursery (IOSITN), Strip are other situations in which errors of
of the Month, and Visual Diagnosis. We judgment may be committed for a va-
In 2010, we commemorated our 10th also completed an initial series of arti- riety of reasons. One of the best ways to
anniversary of NeoReviews by collect- cles on neonatal informatics and plan avoid being sued is to communicate
ing previously published Historical Per- to publish more on this topic in the effectively with parents, but it is also
spectives into a book titled “Milestones coming months. In almost every month, worth being reminded of situations that
in Neonatal-Perinatal Medicine.” we have published a perspective piece resulted in a bad outcome that could
The past decade was one of sub- (Historical, Educational, or Interna- not be defended, so we can try to avoid
stantial growth for NeoReviews. At this tional). We have also published a num- doing the same thing ourselves.
time, I would like to acknowledge the ber of pieces under the heading “Core We have titled this new section
important contribution made by one of Concepts” and another of these (“The “Legal Briefs” because the messages are
the founding editors, Dr Bill Hay. We all Biology of Hemoglobin”) is published in derived from actual legal cases and
owe him a debt of gratitude. He was re- this issue. because the information concerning
sponsible for setting the tone of the Among the 20 major areas listed these cases will be presented in a brief
journal, maintaining that it should have for the American Board of Pediatrics (or concise) manner. In contrast to
a strong academic flavor and not be- Neonatal-Perinatal Medicine (NPM) Con- IOSITN, where the focus is on the pres-
come a chat room. Until the present tent Specifications is “Core Knowledge ence of findings that should lead to a
time, he has continued as coeditor, but in Scholarly Activities.” Because this diagnosis, Legal Briefs will emphasize
he now relinquishes this position. Join- area accounts for a sizeable percentage the absence of appropriate investiga-
of the questions (about 7%) on the tions or interpretation – at least from
ing the editorial staff as Associate Ed-
NPM sub-board examination, we will the lawyer’s perspective! Being re-
itor is Dr Joe Neu, who is currently on
pay specific attention to it in the com- minded of our collective deficiencies
the Editorial Board of NeoReviews. He
ing months. Previous issues have cov- should help to avoid repetition of such
is well known to many of our readers
ered some of the topics included under mistakes in the future and improve
and has been a frequent contributor
“Scholarly Activities,” but future con- patient care and outcomes.
of articles for the journal. Among many tributions will have a more definitive
other activities, he was recently the focus. This issue contains the first of
Chair of the Organization for Neonatol- these contributions, addressing “Meta- Alistair G.S. Philip, MD
ogy Training Program Directors. I feel analysis in Neonatal Perinatal Medicine.” Editor-in-Chief, NeoReviews

Alistair G.S. Philip
NeoReviews 2011;12;e1
DOI: 10.1542/neo.12-1-e1

s;12/1/e1
Index of Suspicion in the Nursery • Case: An Increased Number of Wet Diapers
Kamran Shahid, Kamakshya P. Patra, Amber Dawson and Eric Thomas
DOI: 10.1542/neo.12-1-e39
index of suspicion in the nursery
Case: An Increased Number of Wet Diapers

Case Presentation sounds and no murmur, and abdomi-
A 10-day-old term neonate has 8 to nal examination findings are unre-
10 diapers per day. She sucks vigor- markable. In addition to the blank
ously during feeding but vomits im- stare, the infant fails to close her eyes
mediately. She was born to a 17-year- appropriately.
old primigravida woman by cesarean Ophthalmologic examination re-
section and had no perinatal compli- veals severe bilateral optic nerve hypo-
cations. There are no findings of plasia. The metabolic profile reveals
note on the family history. The in- a serum sodium of 176 mEq/L
fant exhibits temperature instability, (176 mmol/L), serum potassium of
poor feeding, and abnormal facies. 4.2 mEq/L (4.2 mmol/L), blood urea
The reader is encouraged to write On physical examination, the baby nitrogen of 64 mg/dL (22.8 mmol/
possible diagnoses for each case has a blank stare and her temperature L), creatinine of 1.5 mg/dL (132.6
before turning to the discussion. is 36.7°C, heart rate is 178 beats/min, ␮mol/L), glucose of 104 mg/dL
We invite readers to contribute respiratory rate is 60 beats/min, blood (5.8 mmol/L), and calcium of
case presentations and discussions. pressure is 60/36 mm Hg, and oxy- 10 mg/dL (2.5 mmol/L). Complete
Please inquire first by contacting gen saturation is 97% on room air. blood count and C-reactive protein
Dr. Philip at [email protected]. Capillary refill is 4 seconds. She has a values are normal. Blood and urine
sunken anterior fontanelle and dry cultures yield no growth. Ultrasonog-
mucous membranes. Chest examina- raphy of kidneys shows normal find-
Author Disclosure tion reveals no abnormalities, cardiac ings. Further investigations reveal the
Drs Shahid, Patra, Dawson, and evaluation documents normal heart diagnosis.
Thomas have disclosed no financial
relationships relevant to this case.
This commentary does not contain a
discussion of an unapproved/
investigative use of a commercial
product/device.

Case Discussion mal results. Intranasal desmopressin Nephrogenic DI results from re-
Based on the polyuria and increased (DDAVP) therapy is initiated, as is nal tubular resistance to vasopressin.
serum osmolarity, the resident physi- breastfeeding. It arises from a vasopressin receptor
cian makes a tentative diagnosis of AQP2 water channel defect, which
diabetes insipidus (DI). Further labo- Differential Diagnosis is transmitted by X-linked or auto-
ratory investigations reveal a serum os- The differential diagnosis of polyuria somal recessive inheritance. Drugs
molality of 317 mOsm/kg and urine includes DI, diabetes mellitus, chronic (amphotericin B, lithium), electro-
osmolality of 813 mOsm/kg. Thyroid renal failure, urinary tract infection, lyte abnormalities, sickle cell disease
function test results and serum cortisol and solute (mannitol, glucose, saline) and trait, Fanconi syndrome, and re-
values are normal. Because of bilateral diuresis. Hyperglycemia, ketonuria, nal tubular acidosis are some of the
optic nerve hypoplasia and mid-facial and glucosuria differentiate diabetes causes of nephrogenic DI.
anomalies, central DI is suspected and mellitus from DI. In chronic renal fail-
Diagnosis
magnetic resonance imaging of the ure, in contrast to DI, azotemia does
DI should be considered in any de-
brain is obtained (Figure), which not reverse with hydration.
hydrated neonate who has polyuria,
shows absence of the septum pelluci-
increased serum osmolality, hyper-
dum and hypoplasia of the optic appa- The Condition/Pathophysiology
natremia, and a urinary concentration
ratus. Polydipsia, polyuria, hypernatremia
defect. Affected infants often present
An intravenous (IV) normal saline and dehydration are the hallmarks
with dehydration, fever, poor feeding,
bolus of 10 mL/kg is administered, of DI. DI results from deficiency of
failure to thrive, irritability, and sei-
followed by maintenance IV fluids. A antidiuretic hormone (ADH) or va-
zures. They are “hungry feeders” but
Foley catheter is placed to monitor the sopressin and can be either central or
vomit immediately.
urine output, and IV fluids are ad- nephrogenic. The hypothalamic os-
Septo-optic dysplasia (de Morsier
justed according to electrolyte results. moreceptors, the supraoptic or para-
syndrome) is a rare congenital malfor-
After receiving a dose of desmo- ventricular nuclei, and superior por-
mation involving partial or complete
pressin (synthetic form of vasopres- tion of the supraopticohypophyseal
absence of the septum pellucidum and
sin) subcutaneously, the infant’s tract are the sites for ADH secretion.
optic nerve hypoplasia. The malfor-
urine output decreases to 2.5 mL/kg Any condition affecting these sites
mation may manifest with seizures,
per hour, serum osmolality decreases, (infection, intracranial hemorrhage,
blindness, nystagmus, hypotonia, and
and urine osmolality and urine so- neurosurgery, primary or secondary
occasionally panhypopituitarism. Other
dium increase. Repeat serum sodium tumors or infiltrative diseases, and
neuroradiologic findings may include
measures 146 mEq/L (146 mmol/ idiopathic DI) results in central DI
schizencephaly and holoprosencephaly.
L). Coagulation studies yield nor- due to decreased ADH secretion.
Treatment
Intranasal DDAVP is the treatment
of choice for central DI. Aqueous
vasopressin or DDAVP also can be
administered IV or subcutaneously.
Chlorpropamide, clofibrate, and thi-
azide diuretics may be used in con-
junction with DDAVP but are rarely
administered in neonates. Breast-
feeding is preferred because of low
solute content. For acute episodes,
oral or parenteral hydration is needed
to reverse the hyperosmolality and
dehydration. Cerebral sinus throm-
bosis is a complication of hypernatre-
mic dehydration in DI, and aggressive
rehydration and neurologic monitor-
Figure. Brain MRI showing absence of the septum pellucidum (blue arrow) and ing are necessary in acute episodes.
hypoplasia of the optic apparatus (yellow arrow). Thiazide diuretic, amiloride, and indo-

methacin have been used in nephro- (Kamran Shahid, MD, Kamak- Suggested Reading
genic DI. Genetic counseling is impor- shya P. Patra, MD, Amber Dawson,
Alon U, Chan JCM. Hydrochlorothiazide-
tant because many of the cases are MD, Eric Thomas, MD, Louisiana amiloride in the treatment of nephro-
hereditary. The long-term prognosis State University, Shreveport, LA) genic diabetes insipidus. Am J Nephrol.
of DI depends on the cause. 1985;5:9 –13
DeVeber G, Andrew M, Adams C, et al.
Lessons for the Clinician American Board of Pediatrics Cerebral sino-venous thrombosis in chil-
● DI should be considered in any Neonatal-Perinatal Medicine dren. N Engl J Med. 2001;345:417– 423
dehydrated neonate who exhibits Content Specifications Leung AKC, Robson WLM, Halperin ML.
polyuria, hypernatremia, and uri- • Know the specific Polyuria in childhood. Clin Pediatr.
nary concentration defect. hormonal factors 1991;11:634 – 640
● Central DI results from deficiency of that influence water Sener RN. Septo-optic dysplasia associated
balance in newborn with cerebral cortical dysplasia. J Neuro-
vasopressin, and intranasal DDAVP is
infants. radiol. 1996;23:245–247
the treatment of choice. • Know the effects of arginine vasopressin Wang LC, Cohen ME, Duffner PK. Eti-
● Septo-optic dysplasia is character- (antidiuretic hormone) on sodium and ologies of central diabetes insipidus in
ized by hypoplasia of the optic nerve water balance. children: Pediatr Neurol 1994;11:273–
and agenesis of the corpus callosum. 277

Index of Suspicion in the Nursery • Case: An Increased Number of Wet Diapers
Kamran Shahid, Kamakshya P. Patra, Amber Dawson and Eric Thomas
DOI: 10.1542/neo.12-1-e39

s;12/1/e39
Strip of the Month: January 2011
Charlotte Clock and Leonardo Pereira
DOI: 10.1542/neo.12-1-e46
strip of the month

Charlotte Clock, MD,* Electronic Fetal Monitoring Case Review Series
Leonardo Pereira, MD, Electronic fetal monitoring (EFM) is a popular technology used to establish fetal well-
MCR* being. 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
Author Disclosure guidelines for interpretation of fetal tracings. This publication was the culmination of
2 years of work by a panel of experts in the field of fetal monitoring and was endorsed in
Dr Clock has disclosed
2005 by both the American College of Obstetricians and Gynecologists (ACOG) and the
no financial
Association of Women’s Health, Obstetric and Neonatal Nurses (AWHONN). In 2008,
relationships relevant ACOG, NICHD, and the Society for Maternal-Fetal Medicine reviewed and updated the
to this article. Dr definitions for fetal heart rate patterns, interpretation, and research recommendations.
Pereira has disclosed Following is a summary of the terminology definitions and assumptions found in the 2008
that he is the primary NICHD workshop report. Normal values for arterial umbilical cord gas values and
indications of acidosis are defined in Table 1.
investigator for a
research trial for
Assumptions from the NICHD Workshop
ProteoGenix, Inc,
Costa Mesa, Calif. ● Definitions are developed for visual interpretation, assuming that both the fetal heart rate
This commentary does (FHR) and uterine activity recordings are of adequate quality
● Definitions apply to tracings generated by internal or external monitoring devices
not contain a
● Periodic patterns are differentiated based on waveform, abrupt or gradual (eg, late
discussion of an
decelerations have a gradual onset and variable decelerations have an abrupt onset)
unapproved/ ● Long- and short-term variability are evaluated visually as a unit
investigative use of a ● Gestational age of the fetus is considered when evaluating patterns
commercial ● Components of fetal heart rate FHR do not occur alone and generally evolve over time
product/device.
Definitions
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 wave-like undulating pattern, with waves having
regular frequency and amplitude
Baseline Variability
● Fluctuations in the baseline FHR of two cycles per minute or greater, fluctuations are
irregular in amplitude and frequency, fluctuations are visually quantitated as the ampli-
tude of the peak to trough in beats per minute
● Classification of variability:
Absent: Amplitude range is 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
*Assistant Professor, Division of Maternal-Fetal Medicine, Oregon Health & Sciences University, Portland, Ore.

strip of the month
Table 1. Arterial Umbilical Cord Gas Values

pH PCO2 (mm Hg) PO2 (mm Hg) Base Excess
Normal* >7.20 <60 >20 <ⴚ10
(7.15 to 7.38) (35 to 70) (ⴚ2.0 to ⴚ9.0)
Respiratory Acidosis <7.20 >60 Variable <ⴚ10
Metabolic Acidosis <7.20 <60 Variable >ⴚ10
Mixed Acidosis <7.20 >60 Variable >ⴚ10
* Normal ranges from Obstet Gynecol Clin North Am. 1999;26:695
Accelerations Decelerations are tentatively called recurrent if they oc-

cur with ⱖ50% of uterine contractions in a 20-minute
● Abrupt increase in FHR above the most recently deter- period.
mined baseline
● Onset to peak of acceleration is ⬍30 seconds, acme is Decelerations occurring with ⬍50% of uterine contrac-
ⱖ15 beats/min above the most recently determined tions in a 20-minute segment are intermittent.
baseline and lasts ⱖ15 seconds but ⬍2 minutes
Sinusoidal Fetal Heart Rate Pattern
● Before 32 weeks’ gestation, accelerations are defined
by an acme ⱖ10 beats/min above the most recently ● Visually apparent, smooth sine wavelike undulating
determined baseline for ⱖ10 seconds pattern in the baseline with a cycle frequency of 3 to
● Prolonged acceleration lasts ⱖ2 minutes but ⬍10 min- 5/minute that persists for ⱖ20 minutes.
utes
Uterine Contractions
Late Decelerations
● Quantified as the number of contractions in a 10-
● Gradual decrease in FHR (onset to nadir ⱖ30 seconds) minute window, averaged over 30 minutes.
below the most recently determined baseline, with Normal: ⱕ5 contractions in 10 minutes
nadir occurring after the peak of uterine contractions Tachysystole: ⬎5 contractions in 10 minutes
● Considered a periodic pattern because it occurs with
uterine contractions
Interpretation
Early Decelerations A three-tier Fetal Heart Rate Interpretation system has
been recommended as follows:
● Gradual decrease in FHR (onset to nadir ⱖ30 seconds)
below the most recently determined baseline, with ● Category I FHR tracings: Normal, strongly predictive
nadir occurring coincident with uterine contraction of normal fetal acid-base status and require routine
● Also considered a periodic pattern care. These tracings include all of the following:
⫺Baseline rate: 110 to 160 beats/min
Variable Decelerations ⫺Baseline FHR variability: Moderate
⫺Late or variable decelerations: Absent
● Abrupt decrease in FHR (onset to nadir ⬍30 seconds) ⫺Early decelerations: Present or absent
● Decrease is ⱖ15 beats/min below the most recently ⫺Accelerations: Present or absent
determined baseline lasting ⱖ15 seconds but ⬍2 min- ● Category II FHR tracings: Indeterminate, require evalu-
utes ation and continued surveillance and reevaluation. Exam-
● May be episodic (occurs without a contraction) or ples of these tracings include any of the following:
periodic ⫺Bradycardia not accompanied by absent variability
Prolonged Decelerations ⫺Tachycardia
⫺Minimal or marked baseline variability
● Decrease in the FHR ⱖ15 beats/min below the most ⫺Absent variability without recurrent decelerations
recently determined baseline lasting ⱖ2 minutes but ⫺Absence of induced accelerations after fetal stimula-
⬍10 minutes from onset to return to baseline tion

strip of the month
⫺Recurrent variable decelerations with minimal y Recurrent variable decelerations

or moderate variability y Bradycardia
⫺Prolonged decelerations ⫺Sinusoidal pattern
⫺Recurrent late decelerations with moderate vari-
ability Data from Macones GA, Hankins GDV, Spong CY, Hauth
⫺Variable decelerations with other characteristics, J, Moore T. The 2008 National Institute of Child Health
such as slow return to baseline and Human Development workshop report on electronic
● Category III FHR tracings: Abnormal, predictive of fetal monitoring. Obstet Gynecol. 2008;112:661– 666.
abnormal fetal acid-base status and require prompt We encourage readers to examine each strip in the
intervention. These tracings include: case presentation and make a personal interpretation of
⫺Absent variability with any of the following: the findings before advancing to the expert interpreta-
y Recurrent late decelerations tion provided.

strip of the month
Case Presentation echocardiographic findings at 20 weeks’ gestation.

History The patient has no evidence of infection, so she re-
A 21-year-old primigravida at 32– 6/7 weeks’ gestation ceives nifedipine tocolysis, betamethasone for fetal
presents to labor and delivery with preterm labor. maturity, and penicillin for group B Streptococcus
Cervical examination reveals 3 cm dilation. Her preg- prophylaxis. The delivery plan is made for an assisted
nancy has been complicated by maternal repaired trans- second stage of labor due to maternal cardiac disease.
position of the great vessels with ventricular inver- A fetal heart tracing is obtained upon admission
sion and first-trimester bleeding. The fetus had normal (Fig. 1).
Figure 1. EFM Strip #1.

strip of the month
Findings on EFT Strip #1 are: maternal blood pressure that can be associated with
uteroplacental insufficiency. (1) In our institution, the
● Variability: Moderate
dose is held if the maternal blood pressure is less than
● Baseline Rate: 140 beats/min
● Episodic Pattern: Accelerations 90/60 mm Hg to avoid this complication.
● Periodic Pattern: None noted
● Uterine Contractions: Occurring every 2 minutes, last-
ing 45 seconds Progression of Labor
● Interpretation: Category I tracing Tocolysis is discontinued after 48 hours. The woman
● Differential Diagnosis: Normal tracing, with evidence remains stable for another 24 hours, when she begins
of fetal well-being indicated by moderate variability having increased contractions and variable decelerations.
and accelerations On physical examination, she is 6 cm dilated, completely
● Action: No intervention required for fetal status. Close effaced, and ⫺2 station. She is afebrile, and other exam-
monitoring will continue for the preterm labor and ination findings are within normal parameters. A fetal
blood pressure changes that can occur with the use of heart tracing is obtained as her contractions begin to
nifedipine. Nifedipine is associated with a decrease in increase (Fig. 2).

strip of the month
Findings on EFM Strip #2 are: ● Action: A plan is made to proceed with augmentation
of labor due to her advanced cervical dilation. The
● Variability: Moderate FHR tracing requires close surveillance and re-
● Baseline Rate: 140 beats/min evaluation.
● Episodic Pattern: None
● Periodic Pattern: Recurrent variable decelerations The decision is made to proceed with augmentation of
● Uterine Contractions: Occurring every 3 minutes, labor because she has completed her corticosteroid
lasting 45 seconds course, has advanced cervical dilation, and is having
● Interpretation: Category II tracing variable decelerations. Labor progresses rapidly after rup-
● Differential Diagnosis: Variable decelerations are usually ture of membranes and oxytocin augmentation, and her
associated with intermittent cord occlusion. They are cervix is 9 cm dilated. An intrauterine pressure catheter
normally well tolerated, but if they continue to be repet- (IUPC) is placed because of recurrent variable decelera-
itive or more severe, acidemia can develop and can occur tions, but blood returns through the catheter, and it is
more quickly in preterm or growth-restricted infants. removed. The fetal tracing is shown in Figure 3.

strip of the month
Findings on EFM Strip #3 are: which prompts consideration of IUPC placement and
amnioinfusion. Amnioinfusion has been associated
● Variability: Minimal to moderate with a decrease in variable decelerations, cesarean sec-
● Baseline Rate: 130 beats/min tion for fetal distress, and neonatal acidemia. (2) The
● Episodic Pattern: None return of blood in the catheter in this case most likely is
● Periodic Pattern: Recurrent variable decelerations due to placement behind the placenta. It is important
● Uterine Contractions: Occurring every 3 minutes, to recognize this complication, not start an amnioinfu-
lasting 45 seconds sion, and remove the catheter.
● Interpretation: Category II One hour later, the patient has a prolonged deceleration,
● Differential Diagnosis: Unchanged and the decision is made to move to the operating room
● Action: Overall, the tracing is reassuring due to mod- for further evaluation and possible operative delivery.
erate variability, but the variables are continuing, The fetal tracing is shown in Figure 4.

strip of the month
Findings on EFM Strip #4 are: ● Action: Cervical examination shows no evidence of

cord prolapse. Resuscitative measures should be un-
● Variability: Moderate dertaken, including administration of intravenous
● Baseline Rate: 120 beats/min fluids and oxygen, position changes, and possibly
● Episodic Pattern: Prolonged bradycardia discontinuation of oxytocin. The patient is transferred
● Periodic Pattern: Recurrent variable decelerations to the operative room for further evaluation and pos-
● Uterine Contractions: Occurring every 2 minutes sible cesarean delivery if the bradycardia does not re-
● Interpretation: Category II, based on recurrent vari- solve.
able decelerations with periods of moderate variability,
followed by a prolonged bradycardia In the operating room, the bradycardia resolves, but
● Differential Diagnosis: Prolonged cord occlusion, variable decelerations continue. Thirty minutes later, the
uteroplacental underperfusion, or uteroplacental dys- patient is examined, and her cervix is still 9 cm dilated.
function resulting in fetal hypoxia A final fetal heart tracing is obtained (Fig. 5).

strip of the month
Findings on EFM Strip #5 are: taken to the neonatal intensive care unit, where he has a
normal course for a preterm infant.
● Variability: Moderate
This infant’s FHR tracing could be explained by the
● Baseline Rate: 130 beats/min
● Episodic Pattern: None presence of a nuchal cord. Single nuchal cords are seen in up
● Periodic Pattern: Recurrent variable decelerations with to 30% of normal pregnancies. They are rarely associated
slow return to baseline with significant neonatal morbidity or mortality. Results are
● Uterine Contractions: Occurring every 2 minutes mixed on their association with abnormal FHR patterns,
● Interpretation: Category II low birthweight, and umbilical artery pH of 7.10 or less.
● Differential Diagnosis: The slow return to baseline is The poor sensitivity of ultrasonography in diagnosing nu-
concerning for the development of fetal acidosis chal cord and poor predictive value of adverse outcomes do
● Action: The decision is made to proceed with cesarean not justify routine screening for its presence. (3)(4)
delivery due to the repetitive variable decelerations
with late return because vaginal delivery is not immi- References
nent, with no cervical change over the past 90 minutes. 1. Nassar AH, Aoun J, Usta IM. Calcium channel blockers for the
management of preterm birth: a review. Am J Perinatol. 2010 Jul
Fifteen minutes later, a primary cesarean delivery is per- 16. Epub ahead of print
formed. There is a single nuchal cord. 2. Regi A, Alexander N, Jose R, Lionel J, Varghese L, Peedicavil A.
Amnioinfusion for relief of recurrent severe and moderate variable
Outcome decelerations in labor. J Reprod Med. 2009;54:295–302
A viable male infant is delivered by cesarean section. He 3. Larson JD, Rayburn WF, Crosby S, Thurnau GR. Multiple
nuchal cord entanglements and intrapartum complications. Am J
weighs 4 lbs 4 oz and has Apgar scores of 5 at 1 minute
Obstet Gynecol. 1995;173:1228 –1231
and 7 at 5 minutes. The arterial blood gas findings are 4. Peregrine E, O’Brien P, Jauniaux E. Ultrasound detection of
consistent with respiratory acidosis (Table 2). The baby nuchal cord prior to labor induction and the risk of cesarean section.
receives continuous positive airway pressure. He is then Ultrasound Obstet Gynecol. 2005; 25:160 –164
Table 2. Arterial Umbilical Cord Gas Values

pH PCO2 (mm Hg) PO2 (mm Hg) Base Excess
Normal* >7.20 <60 >20 <ⴚ10
(7.15 to 7.38) (35 to 70) (ⴚ2.0 to ⴚ9.0)
Respiratory Acidosis <7.20 >60 Variable <ⴚ10
Metabolic Acidosis <7.20 <60 Variable >ⴚ10
Mixed Acidosis <7.20 >60 Variable >ⴚ10
Patient 7.10 81 17 ⴚ8.7
* Normal ranges from Obstet Gynecol Clin North Am. 1999;26:695

Charlotte Clock and Leonardo Pereira
DOI: 10.1542/neo.12-1-e46

s;12/1/e46
A newborn male born at 35 weeks’ gestation displays respiratory distress, flaccid
abdominal musculature, and undescended testes.
fig. 1

Prenatal History:

29-‐year-‐old G3 P1011à2 woman who has a healthy 8-‐year-‐old son
Rubella-‐nonimmune, group B Streptococcus-‐positive
Social history negative for medications, alcohol, tobacco
Family history negative for renal or genitourinary anomalies
Antenatal diagnosis of bladder outlet obstruction with posterior urethral valves, left
cystic kidney, possible right talipes equinovarus, and oligohydramnios
Amniocentesis revealed normal 46XY karyotype
Placement of a fetal vesicoamniotic shunt at 23 weeks’ gestation
Repeat ultrasonography performed at 31 weeks’ gestation revealed a decompressed
bladder, left kidney with mild dilation and multiple small cysts, irregular abdominal
musculature, and normal amniotic fluid volume
Repeat ultrasonography at 33 weeks’ gestation showed decreased amniotic fluid
volume, prompting hospitalization of the mother for intravenous fluid hydration
and corticosteroid administration.

Birth History and Presentation:

Due to concerns for recurrent, self-‐resolved fetal heart rate decelerations, the infant
was delivered via cesarean section at 35 weeks’ gestation
Apgar scores were 6 and 8 at 1 and 5 minutes, respectively
Infant developed increased work of breathing in the delivery room and was
intubated
Birthweight: 2,590 g (50th percentile)
Length: 47.5 cm (50th to 90th percentile)
Occipitofrontal circumference: 27 cm (<3rd percentile)
Vital Signs:

Temperature: 36.8°C
Heart rate: 152 beats/min
Respiratory rate: 40 breaths/min
Blood pressure: 68/37 mm Hg

Physical Examination:
Intubated, pink, and well perfused
Relatively small chest, with subcostal retractions, fair aeration bilaterally
Regular heart rate and rhythm without murmur, normal pulses
Bulging abdomen, poor abdominal musculature that is flaccid to palpation and
nontender, palpable loops of bowel
Palpable left flank mass
Vesicoamniotic tube to the right of umbilicus draining urine
Normal penis with bilateral undescended testes
Right talipes equinovarus

Radiologic Findings:
Bilateral cystic dysplastic kidneys with echogenic cortex and multiple small cortical
cysts, bilateral dilation of the renal pelvis and ureters, decompressed urinary
bladder

Differential Diagnosis:

Respiratory Distress, Flaccid Abdominal Musculature, and Cryptorchidism:
Megacystis megaureter
Megacystis-‐microcolon-‐intestinal hypoperistalsis syndrome
Neurogenic bladder
Posterior urethral valves
Prune belly syndrome
Severe primary vesicoureteral reflux
Ureteropelvic junction obstruction
Urethral obstruction

Actual Diagnosis:

Prune belly syndrome

Prune belly syndrome (PBS), also known as Eagle-‐Barrett Syndrome, is a rare
condition characterized by the triad of absent or incomplete abdominal
musculature, undescended testes, and urinary tract abnormalities. The incidence is
estimated at approximately 3.8 cases per 100,000 live births, with a marked male
predominance. (1) Recent epidemiologic data obtained from the Kids Inpatient
Database found 50% of PBS patients were white, 31% black, and 10% Hispanic. (1)
Affected patients are often born preterm (43% of infants), and prematurity is
associated with higher inpatient mortality. (1)

Although the exact inheritance pattern is unknown, PBS is most likely transmitted in
a sex-‐influenced, autosomal recessive pattern,,with some familial cases reported. (2)
Of note, affected females are seen more commonly in the familial (28%) than the
nonfamilial (5%) forms of PBS. (2) PBS has been observed in association with
trisomy 13, 18, and 21. (3-‐5) In addition, one affected infant had a large deletion of
the long arm of chromosome 6. (6)

The two primary theories regarding the pathogenesis of PBS are: aberrant
mesodermal development (7,8) and early urethral obstruction (9,10). The
mesodermal defect theory proposes that the constellation of anomalies is due to a
defect in the intermediate and lateral plate mesoderm, which affects the
development of the mesonephric and paramesonephric ducts as well as the
abdominal musculature and urinary tract (8). The urethral obstruction theory
proposes that distal obstruction in early gestation results in distension of the
bladder and ureters, urinary ascites, and degeneration of the abdominal muscles.
(11,12)

Patients who have PBS can present with a variety of renal and urologic
complications, including cystic renal disease, renal dysplasia, renal insufficiency,
hypospadias, micropenis, urachal anomalies, and ureterocele. (1) Anomalies of the
urinary tract can lead to impaired voiding, vesicoureteral reflux, repeat urinary tract
infections, pyelonephritis, and renal scarring during childhood. (13) Among the
extrarenal manifestations are pulmonary hypoplasia due to oligohydramnios and
skeletal deformities (45%) such as talipes equinovarus, hip dysplasia,
kyphoscoliosis, torticollis, and pectus excavatum. (13) In addition to pulmonary
hypoplasia, many patients who have PBS develop chronic respiratory dysfunction
due to associated skeletal anomalies and abdominal weakness; they are prone to
recurrent respiratory infections and are at increased risk of respiratory
complications after exposure to general anesthesia. (14) Cardiac abnormalities are
seen in 10% of patients and include ventricular septal defects, tetralogy of Fallot,
patent ductus arteriosus, and atrial septal defects. (13) Gastrointestinal
complications are seen in up to 30% of patients and include malrotation, intestinal
atresias (often colonic) or stenoses, volvulus, and chronic constipation. (12,15,16)
Although central nervous system anomalies are rare (5%), (1) many patients exhibit
developmental delay and growth retardation as children. (17)

PBS is often diagnosed by prenatal ultrasonography as early as 13 weeks’ gestation
or upon physical examination at birth. (18,19) The severity of PBS is classified as
grade I: oligohydramnios, lung hypoplasia, and Potter facies; grade 2: moderate-‐to-‐
severe involvement of the fetal urinary system without lung hypoplasia and without
Potter facies; and grade 3: mild renal impairment. (19) The prognosis varies
primarily according to the severity of renal impairment. Approximately 30% of
patients who survive the neonatal period develop chronic renal insufficiency
necessitating dialysis or transplantation during childhood or adolescence.
(13,20,21) The overall mortality is estimated at 36% to 60% (1,22), with most
deaths occurring during the initial hospitalization or neonatal period.

Promising treatments include in utero placement of a vesicoamniotic shunt, which
has been successful in restoring amniotic fluid volume and reducing neonatal
mortality, although long-‐term outcomes in terms of chronic renal insufficiency are
not yet available. (23) Postnatal treatment includes orchiopexy, abdominoplasty,
renal transplant, and relief of bladder outlet obstruction (vesicostomy early and
later Mitrofanoff). (24)

In conclusion, PBS is a rare disease primarily affecting males that is characterized by
a triad of congenital anomalies (deficient abdominal musculature, cryptorchidism,
and urinary tract abnormalities) and related complications. Early diagnosis and
treatment can lead to improved perinatal outcomes, although long-‐term data
regarding chronic renal disease are not yet available.

References:

1. Routh JC, Huang L, Retik AB, Nelson CP. Contemporary epidemiology and
characterization of newborn males with prune belly syndrome. Urology.
2010;76:44-‐48
2. Ramasamy R, Haviland M, Woodard JR, Barone JG. Patterns of inheritance in
familial prune belly syndrome. Urology. 2005;65:1227
3. Beckmann H, Rehder H, Rauskolb R. Prune belly sequence associated with
trisomy 13. Am J Med Genet. 1984;19:603-‐604
4. Nivelon-‐Chevallier A, Feldman JP, Justrabo E, Turc-‐Carel C. Trisomy 18 and
prune belly syndrome [in French]. J Genet Hum. 1985;33:469-‐474
5. Baird PA, Sadovnick AD. Prune belly anomaly in Down syndrome. Am J Med
Genet. 1987;26:747-‐748
6. Fryns JP, Vandenberghe K, Van den Berghe H. Prune-‐belly anomaly and large
interstitial deletion of the long arm of chromosome 6. Ann Genet. 1991;34:127
7. Barnhouse DH. Prune belly syndrome. Br J Urol. 1972;44:356-‐360
8. Stephens FD, Gupta D. Pathogenesis of the prune belly syndrome. J Urol.
1994;152:2328-‐2331
9. Hoagland MH, Hutchins GM. Obstructive lesions of the lower urinary tract in
the prune belly syndrome. Arch Pathol Lab Med. 1987;111:154-‐156.
10. Moerman P, Fryns JP, Goddeeris P, Lauweryns JM. Pathogenesis of the prune-‐
belly syndrome: a functional urethral obstruction caused by prostatic hypoplasia.
Pediatrics. 1984;73:470-‐475
11. Wheatley JM, Stephens FD, Hutson JM. Prune-‐belly syndrome: ongoing
controversies regarding pathogenesis and management. Semin Pediatr Surg.
1996;5:95-‐106.
12. Herman TE, Siegel MJ. Prune belly syndrome. J Perinatol. 2009;29:69-‐71
13. Bogart MM, Arnold HE, Greer KE. Prune-‐belly syndrome in two children and
review of the literature. Pediatr Dermatol. 2006;23:342-‐345
14. Crompton CH, MacLusky IB, Geary DF. Respiratory function in the prune-‐belly
syndrome. Arch Dis Child. 1993;68:505-‐506
15. Wright JR Jr, Barth RF, Neff JC, Poe ET, Sucheston ME, Stempel LE.
Gastrointestinal malformations associated with prune belly syndrome: three cases
and a review of the literature. Pediatr Pathol. 1986;5:421-‐448
16. Smythe AR 2nd. Ultrasonic detection of fetal ascites and bladder dilation with
resulting prune belly. J Pediatr. 1981;98:978-‐980
17. Crankson S, Ahmed S. The prune belly syndrome. Aust N Z J Surg.
1992;62:916-‐921
18. Woods AG, Brandon DH. Prune belly syndrome. A focused physical
assessment. Adv Neonatal Care. 2007;7:132-‐143
19. Papantoniou N, Papoutsis D, Daskalakis G, et al. Prenatal diagnosis of prune-‐
belly syndrome at 13 weeks of gestation: case report and review of literature. J
Matern Fetal Neonatal Med. 2010;23:1263-‐1267
20. Fischbach M. Ask the expert. Is peritoneal dialysis (CAPD or APD) appropriate
for small children with prune belly syndrome and terminal renal failure? Pediatr
Nephrol. 2001;16:936-‐937
21. Gonzalez R, Reinberg Y, Burke B, Wells T, Vernier RL. Early bladder outlet
obstruction in fetal lambs induces renal dysplasia and the prune-‐belly syndrome. J
Pediatr Surg. 1990;25:342-‐345
22. Druschel CM. A descriptive study of prune belly in New York State, 1983 to
1989. Arch Pediatr Adolesc Med. 1995;149:70-‐76
23. Biard JM, Johnson MP, Carr MC, et al. Long-‐term outcomes in children treated
by prenatal vesicoamniotic shunting for lower urinary tract obstruction. Obstet
Gynecol. 2005;106:503-‐508.
24. Strand WR. Initial management of complex pediatric disorders: prunebelly
syndrome, posterior urethral valves. Urol Clin North Am. 2004;31:399-‐415

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