NEO REVIEW FEBRERO 2013
Pain and Sedation in the NICU
1. Dennis E. Mayock, MD, and
2. Christine A. Gleason, MD
+ Author Affiliations
1. Division of Neonatology, Department of Pediatrics, University of Washington
School of Medicine, Seattle, WA.
Next Section
Abstract
Recognition and treatment of procedural pain and discomfort in the neonate remain a
challenge. Procedural sedation and control of pain and discomfort are frequently
managed together, often by using the same intervention. Therefore, although this article
focuses on sedation, separating sedation from pain control is not always possible or
wise. Despite significant progress in the understanding of human neurodevelopment,
pharmacology, and more careful attention to how we care for sick infants, we still have
much to learn. Protecting and comforting our fragile patients requires us to use poorly
validated tools to assess and intervene to minimize distress, often applying data derived
from adult patients to infants. Our first priority should be to minimize pain and distress.
Further exploration of nonpharmacologic methods of procedural pain and distress
control are needed. When pharmacologic intervention is necessary for procedural pain
control and sedation, we need to use the least amount of drug that controls the pain and
distress for the shortest period of time. As newer techniques and medications are
introduced to clinical practice, we must demonstrate that such additions achieve their
goal of sedation or pain control, and are safe over the lifetimes of our patients.
Clinicians should identify appropriately the need for and use of sedatives and analgesics
in the neonate.
Previous SectionNext Section
Practice Gaps
1. Many neonates do not receive adequate sedation for procedures in the NICU.
2. There is no evidence to guide appropriate sedation during extracorporeal life
support.
3. The risks of some sedatives may outweigh their potential benefits.
4. Nonpharmacologic methods of sedation need further evaluation.
Previous SectionNext Section
Objectives
After completing this article, readers should be able to:
1. Understand the challenges of using “pain scores” to assess the need for, and
response to, neonatal sedation.
2. Describe the uses of sedation for facilitation of neonatal procedures.
3. Discuss pharmacologic approaches to neonatal sedation.
4. Discuss nonpharmacologic approaches to neonatal comfort care.
Previous SectionNext Section
Introduction
Advances in neonatology have significantly improved morbidity and mortality, but
pain, discomfort, and stress remain sad realities for infants in the NICU. Assessing,
managing, and trying to limit these clinical realities while providing optimal care for
critically ill neonates is challenging and increasingly controversial. Fortunately, there
has been considerable research and much clinical dialogue aimed at developing best
clinical practices in this problematic area.
Sedation can be defined as the reduction of irritability or agitation, usually by
administration of sedative drugs. In the NICU, sedation is used both to facilitate care
(by limiting movement/agitation) and to minimize pain, discomfort, and stress during
procedures and intensive care. Appropriate identification of the need for and use of
sedatives and analgesics, based on the best available evidence, should be clinicians'
objective.
Previous SectionNext Section
Assessment of Neonatal Sedation: “Pain Scores”
More than 40 infant pain scales have been developed, most often for use in clinical trials
to assess treatment efficacy; few have been validated for general clinical use for acute
pain assessment. These pain scores are also frequently used to assess adequacy of
sedation, even though they were not developed for this purpose nor were they designed
or validated for assessment of chronic pain or discomfort associated with mechanical
ventilatory support, or for use in paralyzed or neurologically compromised infants. The
American Academy of Pediatrics (AAP) and the American Academy of Pediatric
Dentistry have recently published an update on pediatric sedation, which recommends
using a carefully staged process to plan for and carry out sedation for diagnostic and
therapeutic procedures (Coté et al, 2006).
Sedation can be categorized according to the level of consciousness, effect on protective
airway reflexes, patency of the airway, and response to stimulation. The level of
sedation can progress from conscious sedation to deep sedation to general anesthesia
(Table 1).
View this table:


In this window
In a new window
Table 1.
Levels of Sedation According to the American Academy of Pediatrics
The optimal approach to sedation management should include reducing the frequency of
painful procedures and environmental stressors, facilitating developmentally appropriate
care, determining the best technique to minimize the pain and stress associated with
procedures, delegating responsibility for pain/sedation assessment and treatment to the
bedside nursing staff, and using a balanced multimodal approach to procedural sedation
(Allegaert et al, 2009).
Previous SectionNext Section
Sedation for Mechanical Ventilation
Use of mechanical ventilation in neonates who have respiratory failure is a common
practice. In the past, sedation (most often with opiates) was frequently used in pediatric
and adult ICU patients who required mechanical ventilation. Extrapolation of evidence
from early studies in nonneonatal patients led to frequent use of opiate sedation in
neonates during mechanical ventilation, with limited information as to safety and
efficacy. However, in the past decade, use of pharmacologic sedation in the adult ICU
has been significantly reduced because of concerns regarding adverse cognitive
outcomes and longer duration of ventilator support. These concerns have led to a
rethinking of this practice in both pediatric and neonatal ICUs. The following discussion
is a historical review of this issue.
Mechanical ventilation in neonates is associated with an increase in hormonal stress
responses, including increased cortisol and catecholamine levels. In the past, infants
who appeared uncomfortable while on ventilatory support demonstrated asynchronous
respiratory effort (“fighting the ventilator”), compromised gas exchange, and altered
stress responses. Clinical studies from the 1990s demonstrated that opiate treatment
prevented these adverse effects and reversed the previously described hormonal stress
changes. Opiate sedation decreased stress scores in ventilated newborns. In ventilated
term infants, the severity of respiratory failure as assessed by using the oxygenation
index directly correlated with the need for analgesia and sedation. More recently, with
the introduction of surfactant replacement therapy and synchronized ventilatory
technology, many of these previous problems with infants “fighting the ventilator” have
been eliminated. Furthermore, clinical trials have shown that preemptive narcotic use in
ventilated infants may actually have detrimental effects. A small randomized trial of
routine morphine infusion in ventilated preterm infants concluded that morphine lacked
a “measurable analgesic effect” and there was “absence of a beneficial effect on poor
neurological outcome.” The larger clinical trial which followed (NEOPAIN, published
in 2004) reported no beneficial effect of preemptive morphine infusions in ventilated
preterm infants and an increased incidence of severe intraventricular hemorrhage in 27-
to 29-week gestational age preterm infants. Indeed, additional bolus doses of morphine
resulted in worse respiratory outcomes and longer requirement for ventilatory support.
These controlled clinical trials provide no evidence that routine narcotic sedation during
mechanical ventilatory support in neonates is beneficial. One approach to this dilemma
has been to minimize the use of ventilatory support as much as possible.
A recent Cochrane Reviews article evaluated the effects of preemptive opioid sedation
on pain scales, duration of mechanical ventilation, mortality, growth, and development
in neonates requiring mechanical ventilation (Bellù et al, 2008). The authors found no
differences in mortality, duration of mechanical ventilation, or short- and long-term
neurodevelopmental outcomes. However, very preterm infants given morphine took
longer to achieve full enteral feeding. If morphine sedation prolongs time to full enteral
feeds, we should expect an increase in the risk of complications related to the use of
venous lines (bloodstream infections) and parenteral nutrition (cholestasis). Indeed, the
duration of morphine use was a strong predictor for development of severe necrotizing
enterocolitis. The overall conclusion of the Cochrane Reviews article regarding use of
sedation during mechanical ventilation was that “there is insufficient evidence to
recommend routine use of opioids in mechanically ventilated newborns.”
Previous SectionNext Section
Sedation for Procedures
Infants undergoing intensive care endure many painful procedures, often several times
each day. Although new pharmacologic and nonpharmacologic treatment strategies
have been developed to decrease or eliminate some of this pain and stress, we have a
long way to go in developing evidence-based “best practices.”
Blood Sampling and Monitoring
Heel sticks are routinely performed to obtain blood samples in neonates. The most
appropriate method for relieving pain from a heel stick has yet to be determined. EMLA
(eutectic mixture of local anesthetics; 2.5% lidocaine and 2.5% prilocaine) does not
relieve the pain of a heel lance. Neonates experiencing venipuncture had lower pain
scores than those who underwent heel stick. In neonates, venipuncture should be used
preferentially over heel stick.
The pain of arterial puncture can be decreased by infiltrating the site with 0.1 to 0.2 mL
of 0.5% or 1% lidocaine using the smallest-gauge needle possible. Buffering the
lidocaine with sodium bicarbonate is recommended to decrease the burning caused by
lidocaine. EMLA may reduce the pain of arterial puncture.
Endotracheal Intubation
The use of premedication to minimize the pain and stress of endotracheal intubation
benefits the neonate. However, concerns about rapid medication availability, ability to
maintain the airway, and the ability to provide ongoing ventilatory support have caused
controversy. Premedications typically include atropine, narcotics for sedation, and
muscle relaxants. Atropine abolishes vagal bradycardia. Narcotics attenuate the
increases in arterial blood pressure. Muscle relaxants attenuate the increases in
intracranial pressure. Combination treatment decreases time and number of attempts
needed to intubate the infant.
When one is considering the use of medications for intubation, several questions need to
be asked:





Does the infant have adequate vascular access?
What is the urgency of intubation need?
Is the infant known to have a “difficult airway”?
When was the last feeding?
Can the infant be preoxygenated while avoiding gastric distension?
If the decision is made to use medications for intubation, typical dosages include:



Atropine 0.02 mg/kg fast intravenous (IV) push
Fentanyl 2 μg/kg slow IV push (over at least 5 minutes)
Vecuronium 0.1 mg/kg IV push
Alternative muscle relaxants may include succinylcholine 1 to 2 mg/kg IV push or
rocuronium 1 mg/kg IV push.
Propofol has been used as a premedication for intubation. As a single agent, it is easier
and faster to prepare compared with a preparation of three separate drugs. Propofol is a
hypnotic agent without anesthetic properties. However, propofol is painful when
injected into small veins, and extremely painful if it extravasates. A major advantage is
continued spontaneous breathing during the intubation procedure. The dose is 2.5 mg/kg
intravenously; this dose might need to be repeated. Concerns with the use of propofol
for intubation in neonates include minimal published experience in neonates, uncertain
pharmacokinetics and duration of action, restricted availability in some institutions, and
incompatibility with peripherally inserted central catheter lines.
Circumcision
The 2012 AAP Technical Report on Male Circumcision recommends that analgesia be
provided to infants undergoing circumcision. EMLA cream, dorsal penile nerve block,
and subcutaneous ring block are all possible options. The AAP reports that
subcutaneous ring block may provide the best analgesia and has published a videotape
demonstrating the use of local anesthesia for this procedure. Subcutaneous ring block is
more effective than EMLA or dorsal penile nerve block. Dorsal penile nerve block is
more effective than EMLA.
EMLA is superior to placebo for pain relief during circumcision. An effective method
for applying EMLA in preparation for circumcision is to apply one third of the dose to
the lower abdomen, extend the penis upward gently, pressing it against the abdomen,
and then apply the remainder of the dose to an occlusive dressing placed over the penis.
The dressing is taped to the abdomen so the cream surrounds the penis and is left on for
60 to 90 minutes. Another method is to apply the cream and then place plastic wrap
around the penis in a tube-like fashion to help direct the urine stream out and away from
the cream.
Acetaminophen is ineffective for the management of acute pain associated with the
circumcision procedure but may provide some analgesia in the postoperative period.
Previous SectionNext Section
Other Invasive Procedures
Placement of a central venous catheter requires topical anesthesia with EMLA or
infiltration of the skin with lidocaine. In addition, a parenteral opioid such as morphine
or fentanyl is typically used. Consideration should also be given to regional blocks for
central line placement if anesthesia expertise is available for this method.
The pain of a lumbar puncture is compounded by both the needle puncture and the
distress caused by the body position required for the procedure. EMLA has been shown
to decrease the pain of lumbar puncture in children. Sedatives are generally not
recommended.
Chest tube insertion is painful and requires an intravenous opioid, adequate local
analgesia (lidocaine), or both.
Previous SectionNext Section
Sedation for Imaging Procedures
Imaging of neonates in the NICU typically includes routine diagnostic radiographs and
ultrasound examinations, including echocardiograms. Sedation is rarely required for
these procedures. More detailed imaging requires specialized scanning such as
computed tomography or magnetic resonance imaging. Although they provide more
specific diagnostic and predictive information, such imaging usually requires
transportation of the infant from the NICU to distant facilities. For high-quality
computed tomography and magnetic resonance imaging, sedation is often considered to
minimize artifacts from patient movement. Sedation in these circumstances can add
substantial risk and cost to the procedure. Various approaches to avoid the use of
sedation have been employed. Sleep promotion is often used, with scanning scheduled
soon after a feeding (30 minutes), use of immobilization (swaddling) and restraint
devices, and administration of sucrose drops before and during the scanning. Use of
pacifiers during magnetic resonance imaging scanning, while often calming to the
infant, can add motion artifact.
Previous SectionNext Section
Sedation During Therapeutic Hypothermia
Therapeutic hypothermia is used increasingly for neuroprotection in newborns who
have neonatal encephalopathy. Shivering is an uncommon finding in neonates, but it has
been described frequently in infants undergoing therapeutic hypothermia and is an
adverse effect that counteracts the physiologic intent of this intervention. Morphine
sedation is usually adequate to minimize shivering. Dexmedetomidine, clonidine,
meperidine, and propofol have been used for this purpose in adults. Benzodiazepines
should be avoided because they can mask seizure activity. Pharmacologic
neuromuscular blocking agents are not used unless the patient has uncontrollable
shivering or generalized clonus that cannot be controlled with other sedatives or
anticonvulsants.
Previous SectionNext Section
Sedation During Extracorporeal Life Support
Sedation and analgesia are frequently needed during extracorporeal life support (also
known as extracorporeal membrane oxygenation [ECMO]) to prevent cannula
displacement with body movement. Muscle relaxants are also often used. No controlled
trials have been published to provide guidance. It is important to understand that
multiple factors influence drug pharmacokinetics during ECMO and that prediction of
appropriate dosing is not possible.
Factors leading to need for increased drug doses:



Increased volume of distribution from ECMO circuit priming volume
Binding/sequestration of drugs in oxygenator/other circuit components
Hemofiltration of small molecules
Factors leading to need for decreased drug doses:



Renal and hepatic injury decreasing drug clearance
Immature organ function in neonates
Active drug metabolites
Sedatives such as midazolam and opiates such as fentanyl are commonly used.
However, achieving the desired effect of these medications frequently results in
substantial dose escalation, requiring prolonged periods of slow drug weaning to avoid
abstinence symptoms. Dexmedetomidine may be useful as a short-term adjunct for
ECMO sedation.
Previous SectionNext Section
Pharmacologic Sedative Interventions
The expected severity of the discomfort, its etiology, available administration routes,
and potential adverse effects should all be considered when selecting a sedative for a
planned procedure. Once medication administration has begun, careful monitoring for
these effects can decrease potential adverse events. A key component of effective
sedation management is ongoing assessment during and after an intervention or
procedure. It is important to be prepared to rescue the infant if needed from a deeper
level of sedation than originally planned.
Nonopioid Analgesics
Nonsteroidal anti-inflammatory drugs
Nonsteroidal anti-inflammatory drugs (eg, indomethacin, ibuprofen) inhibit
prostaglandin synthesis by inhibiting the action of cyclooxygenase enzymes. These
agents have many physiologic effects, including sleep cycle disruption, increased risk of
pulmonary hypertension, cerebral blood flow alterations, decreased glomerular filtration
rate, alteration in thermoregulatory control, and changes in platelet function. Moreover,
development of the central nervous, cardiovascular, and renal systems are all dependent
on prostaglandins. These drugs have been used frequently in the NICU for
pharmacologic closure of a patent ductus arteriosus, and aside from effects on renal and
perhaps mesenteric circulation (which are difficult to separate from the patent ductus
arteriosus), no clear-cut adverse effects have been reported. However, there is no robust
evidence that they have analgesic efficacy in infants aged less than 3 months, thus
limiting their use in neonates.
Acetaminophen
Acetaminophen is the most widely administered analgesic in patients of all ages despite
little evidence of efficacy in infants less than 3 months of age. Acetaminophen inhibits
the activity of cyclooxygenase in the central nervous system, decreasing the production
of prostaglandins and peripherally blocking pain impulse generation. Neonates are able
to form the metabolite that results in hepatocellular damage; however, it is inappropriate
to withhold acetaminophen in newborns because of concerns of liver toxicity. The
immaturity of the newborn’s cytochrome P-450 system may actually decrease the
potential for toxicity by reducing production of toxic metabolites.
Current recommendations call for less frequent oral dosing (every 8 to 12 hours in
preterm and term neonates) because of slower clearance times and for higher rectal
dosing due to decreased absorption. Oral dosages for acetaminophen are 10 mg/kg per
dose every 6 to 8 hours for preterm neonates and 12.5 mg/kg per dose every 4 to 6 hours
for term infants. The maximum recommended daily dose is 75 mg/kg for infants, 60
mg/kg for term and preterm neonates greater than 32 to 34 weeks’ postconceptual age,
and 40 mg/kg per day for preterm neonates 28 to 32 weeks’ postconceptual age.
Rectally administered acetaminophen has a longer half-life, but absorption is highly
variable because it is dependent on the individual infant and placement of the
suppository. It should also be noted that the drug may not be uniformly distributed
throughout the suppository and therefore should be divided lengthwise if a partial dose
is desired. The analgesic effect of acetaminophen may be additive when the agent is
administered with opioids; coadministration may enable a decrease in the opioid dose
and in corresponding opioid adverse effects. However, demonstration of this potential
benefit awaits further study.
Opioid Analgesics
Opioids are believed to be the most effective sedative and analgesic for control of
moderate to severe pain in patients of all ages. There is a wide range of interpatient
pharmacokinetic variability. Opioid dosing depends on the severity of the anticipated
procedural pain as well as the age and clinical condition of the infant. Opioids should be
used in infants younger than age 2 months in a monitored setting only. Some clinicians
propose a more conservative recommendation, restricting use of opioids to monitored
settings for any infant younger than age 6 months.
Morphine
Morphine remains the gold standard for procedural pain management in neonates
despite lack of proven efficacy in many circumstances. Morphine is metabolized in the
liver by uridine diphosphate glucuronyltransferase into two active metabolites:
morphine-6-glucuronide (M6G), a potent opiate receptor agonist, and a second
metabolite, morphine-3-glucuronide (M3G), a potent opiate receptor antagonist. Both
metabolites and some unchanged morphine are excreted in the urine. The predominant
metabolite in preterm and term neonates is M3G. Because of slow renal excretion, the
metabolites can accumulate substantially over time. There is a potential for late
respiratory depression due to a delayed release of morphine from less well-perfused
tissues and the sedating properties of the M6G metabolite.
Because the predominant metabolite of morphine in infants is M3G, a potent opiate
receptor antagonist, one should consider using the lowest dose possible to achieve the
needed sedation. As we escalate the morphine doses, we are also increasing the levels of
M3G and potentially interfering with our goal of adequate sedation. Doses as low as 1
to 5 μg/kg per hour can provide adequate sedation/analgesia, minimizing the risk of
accumulation of high M3G levels with that metabolite’s prolonged half-life.
Clearance or elimination of morphine and other opioids is prolonged in infants because
of the immaturity of the cytochrome P-450 system. The rate of elimination and
clearance of morphine in infants aged 6 months and older approaches that of adults.
Chronologic age seems to be a better indicator of opioid metabolism in infants than
gestational age.
Infants are at greater risk for opioid-associated respiratory depression because of their
immature respiratory center responses to hypoxia and hypercarbia. Furthermore, there is
an increase in unbound or free morphine and M6G available to reach the brain as a
result of the reduced concentration of albumin and α1-acid glycoproteins.
Dosing recommendations currently reflect the wide range of interpatient
pharmacokinetic variability. Previously, a 0.03 mg/kg bolus of IV morphine was
suggested as a starting dose in nonventilated infants (Acute Pain Management Guideline
Panel, 1992) whereas 0.05 to 0.1 mg/kg of IV morphine was recommended as an
appropriate starting dose in ventilated infants. Recently, much lower doses have been
recommended (0.025–0.05 mg/kg as a bolus dose or 1–5 μg/kg per hour as a continuous
infusion). Titration to the desired clinical effect is required in adjusting both the dose
and the frequency of administration. Furthermore, it is important to continually assess
need and responses. As we further explore the use of morphine for analgesia and
sedation in neonates, it is becoming concerning that some of the risks may outweigh any
potential benefits.
Fentanyl
Fentanyl is 80 to 100 times more potent than morphine and causes less histamine
release, making it a more appropriate analgesic/anesthetic choice for infants who have
hypovolemia, hemodynamic instability, or congenital heart disease. Another potential
clinical advantage of fentanyl is its ability to reduce pulmonary vascular resistance,
which can be of benefit for infants who have undergone cardiac surgery, have persistent
pulmonary hypertension, or need ECMO. Bolus doses of fentanyl must be administered
slowly over a minimum of 5 minutes to avoid chest wall rigidity, a serious adverse
effect observed after rapid infusion. Chest wall rigidity, which can result in difficulty or
inability to ventilate, can be treated with naloxone or a muscle relaxant such as
pancuronium or vecuronium. Recommended bolus doses are 1 to 2 μg/kg by slow IV
infusion. Continuous infusion dosing should start at low levels (1–2 μg/kg per hour) and
titrate to effect.
Fentanyl is highly lipophilic. It has a quick onset and relative short duration of action.
Because of this short duration of action, fentanyl is typically used as a continuous
infusion for sedation and postoperative pain control. In infants age 3 to 12 months, total
body clearance of fentanyl is greater than that of older children, and the elimination
half-life is longer owing to its increased volume of distribution. Fentanyl has a
prolonged elimination half-life in infants who have increased abdominal pressure. Due
to tachyphylaxis, continuous infusions of fentanyl are frequently increased to maintain
constant levels of sedation and pain management. Infusion dosing can reach substantial
levels requiring prolonged withdrawal.
A rebound transient increase in plasma fentanyl levels is a phenomenon known to occur
after discontinuation of therapy in neonates. It is a result of fentanyl’s accumulation in
fatty tissues, which may prolong its effects after continued use. Therefore, caution must
be exercised in the use of repeated doses or a continuous infusion.
Oral Opioids
Oral methadone can be used to wean infants from long-term opioid use, although there
are limited data on its efficacy and pharmacokinetics in this population. The respiratory
depressant effect of methadone is longer than its analgesic effect. Methadone is
metabolized very slowly via hepatic N-methylation resulting in accumulation in the
body, and its half-life is very long (16 to 25 hours) in neonates.
Codeine has been prescribed at 0.5 to 1 mg/kg orally every 4 hours as needed. Scarce
data are available to recommend use of codeine in neonates. Most pharmacies supply
acetaminophen and codeine in a set formula consisting of acetaminophen 120 mg and
codeine phosphate 12 mg per 5 mL with 7% ethanol. The dose prescribed is limited by
both the appropriate dose of codeine and the safe dose of acetaminophen. This
combination is not recommended in neonates.
Oxycodone is not recommended in neonates because no data are available for dosing
guidelines. The liquid form is not universally available.
Benzodiazepines
Benzodiazepines such as lorezapam and midzaolam are sedatives that activate γaminobutyric acid receptors and should not be used in place of an appropriate pain
medication because this class of medication has no analgesic effect. Benzodiazepines
can be administered to decrease irritability and agitation in infants and to provide
sedation for procedures. In ventilated infants, benzodiazepines can help avoid hypoxia
and hypercarbia from breathing out of “sync” with the ventilator, although, as noted
previously, this is not as much of a problem today as it was in the past. When given as
continuous infusions, dosing often escalates rapidly to maintain apparent sedation,
resulting in the need for prolonged weaning. These medications have been associated
with abnormal neurologic movements in both preterm and term infants. In rats, prenatal
exposure to diazepam results in long-term functional deficits and atypical behaviors,
and exposure of 7-day-old mice to diazepam induces widespread cortical and
subcortical apoptosis. Midazolam potentiates pain behavior, sensitizes cutaneous
reflexes, and has no sedative effect in newborn rats. Whether these data can be
extrapolated to human infants is unknown, but clinicians have reason to be concerned
and should use these drugs with caution in the NICU.
Dexmedetomidine
Dexmedetomidine is a potent relatively selective α2-adrenergic receptor agonist
indicated for the short-term sedation of patients in ICU settings, especially those
receiving mechanical ventilatory support. It is administered by either bolus doses for
short procedural sedation (1–3 μg/kg) or by continuous IV infusion (0.25–0.6 μg/kg per
hour). Because dexmedetomidine does not produce significant respiratory depression, it
has been used for procedural interventions in spontaneously breathing infants. As
neonatologists become more familiar with dexmedetomidine, its use may increase.
However, short- and long-term safety and effectiveness need to be assessed in human
infants because preliminary work in a neonatal rodent model suggests that it may alter
brain development.
Topical Anesthetics
EMLA cream reduces the pain of circumcision. It must be applied 60 to 90 minutes
before the procedure; longer application times provide deeper local anesthetic
penetration but may lead to toxicity. There is a slight risk of methemoglobinemia with
the use of EMLA cream in infants and patients who are G6PD-deficient. This rare
occurrence (methemoglobinemia) occurs when hemoglobin is oxidized by exposure to
prilocaine. EMLA should not be used in patients who have methemoglobinemia or
infants younger than age 12 months who are also receiving methemoglobinemiainducing drugs, such as acetaminophen, sulfonamides, nitrates, phenytoin, and class I
antiarrhythmic agents. A study of 30 preterm infants found that a single 0.5-g dose of
EMLA applied for 1 hour did not lead to a measurable change in methemoglobin levels.
A systematic review concluded that EMLA diminishes the pain during circumcision.
Limited efficacy was noted with pain from venipuncture, arterial puncture, and
percutaneous venous line placement. EMLA did not diminish pain from heel lancing.
Oral sucrose or glucose may be as effective as EMLA for venipuncture.
Previous SectionNext Section
Nonpharmacologic Analgesic Interventions
There are numerous nonpharmacologic interventions available for prevention and/or
relief of neonatal procedural pain and stress, either as the sole method of pain control or
in combination with pharmacologic interventions. Because pharmacologic analgesia and
sedation have not been proven effective and may be harmful, these alternative methods
of pain and stress relief need to be assessed for their efficacy and safety. As clearly
stated by Golianu et al (2007), “These therapies may optimize the homeostatic
mechanisms of the infant, thereby mitigating some of the adverse consequences of
untreated pain, as well as facilitating healthy physiologic adaptions to stress.” However,
widespread adoption of specific interventions is not consistent. Following are
summaries of currently available information on selected interventions:








Breastfeeding reduces the physiologic and behavioral responses to acute
procedural pain and stress in neonates and has been recommended as the first
line of treatment.
Nonnutritive sucking using pacifiers reduces pain responses to heel prick,
injections, venipuncture, and circumcision procedures.
Infant massage decreases plasma cortisol and catecholamine levels in preterm
infants during painful procedures.
Maternal skin-to-skin contact (kangaroo care) is associated with greater
physiologic stability and reduced responses to acute procedural pain. Kangaroo
care can decrease pain scores after vitamin K injections.
Maternal rocking has been shown to diminish neonatal distress.
Multisensory stimulation (simultaneous gentle massage, soothing vocalizations,
eye contact, smelling a perfume, and sucking on a pacifier) has been associated
with analgesia and calming of the infants in several reports from one unit.
Music therapy may reduce the behavioral and physiological responses to acute
procedural pain.
Oral sucrose reduces pain behavior in preterm and term infants. The mechanism
of oral sucrose analgesia is not known but may be related to stimulation of
endogenous opioid release. Of all these methods and techniques, oral sucrose
has been the most widely studied and used.
As more data regarding the limitations of pharmacologic treatment are published,
consideration of nonpharmacologic interventions will likely become more important
and commonplace.
Previous SectionNext Section
Long-term Consequences of Neonatal Opioid Exposure
Experimental Animal Studies
Perinatal and neonatal opioid exposure in experimental animals is associated with both
short- and long-term adverse neurologic effects. These effects should make clinicians
wonder whether the use of such medications, with questionable benefits, should
continue. Perinatal narcotic exposure restricts brain growth, induces neuronal apoptosis,
and alters behavioral pain responses later in life. One area of particular concern to
clinicians is the developing cerebral circulation, which is extremely vulnerable to
physiologic perturbations and drug effects. Cerebrovascular effects of drug exposure
early in development may have lifelong consequences, including increased risk for
stroke. The acute effects of exogenous narcotics, including morphine, on the developing
cerebral circulation have been described in piglets and include modulation of
prostaglandin-induced pial artery dilation during hypoxia, alteration in endothelin
production, and increases in endothelin A receptor messenger RNA expression.
Endogenous opioids are important regulators of cerebrovascular tone and angiogenesis.
Exposure to morphine in fetal sheep and neonatal rats permanently alters
cerebrovascular control mechanisms. Permanent neurobehavioral and neuropathologic
changes have reportedly been found in a rodent model of neonatal stress and morphine
exposure. These animal studies demonstrated short- and long-term effects of neonatal
morphine exposure, which is not surprising because opioid receptor–mediated signaling
likely plays a role in several aspects of early brain development. However, the clinical
relevance of these animal studies regarding the long-term effects of neonatal opioids is
difficult due to species differences in timing of brain development, the development of
opiate receptors and major neurotransmitter systems, and the pharmacokinetics of
administered opioids.
Clinical Studies
Clinical studies addressing the short- and long-term effects of prolonged opiate use in
human neonates are limited. The few that exist are contradictory and confounded by
illness severity. Reversible “encephalopathic” changes in neonates receiving long-term
sedative and narcotic infusions have been described. One study demonstrated no
adverse neurodevelopmental outcomes in a small group of newborns who received
morphine for a median of 5 days. A second study presented 5-year neurodevelopmental
outcomes in very low birthweight infants exposed to prolonged sedation and/or
analgesia (defined as >7 days of sedative and/or opioid drugs). Exposed very low
birthweight infants had more severe or moderate disability at 5 years (42%) compared
with those not exposed (26%). Preterm infants (23–32 weeks’ gestation at birth)
evaluated at 36 weeks’ postconceptual age in the NEOPAIN study demonstrated
neurobehavioral abnormalities if exposed to morphine during ventilatory support.
Previous SectionNext Section
Summary
Recognition and treatment of procedural pain and discomfort in the neonate remain a
challenge. There is still much to learn about human neurodevelopment, pharmacology,
and how to best care for sick infants. Because we try to protect and comfort our fragile
patients, and because external regulatory forces have required us to document
discomfort by using poorly validated tools and to intervene to minimize distress, we
often apply what is known from data in adult patients to infants. Our care should
minimize the risks of adverse effects of both drugs and pain/stress on
neurodevelopment. Further exploration of nonpharmacologic methods of procedural
pain and distress control is needed. As newer techniques and medications are introduced
to clinical practice, we must demonstrate that such additions achieve their goal of
sedation or pain control, and also establish their safety over the lifetime of our patients.
Escalation of drug doses may, in fact, be adding to our problem. Better tools are needed
to help us optimize the outcomes of infants.
American Board of Pediatrics Neonatal–Perinatal Content Specifications

For therapeutic drugs commonly used in the neonate (eg, opiates,
methylxanthines, barbiturates), know indications for their use, clinical effects,
pharmacokinetics, adverse effects, and toxicity.
Previous SectionNext Section
Footnotes

Author Disclosure
Drs Mayock and Gleason have disclosed no financial relationships relevant to
this article. This commentary does contain a discussion of an
unapproved/investigative use of a commercial product/device.
Abbreviations:
EMCO;
extracorporeal membrane oxygenation
EMLA;
eutectic mixture of local anesthetics
M3G;
morphine-3-glucuronide
M6G;
morphine-6-glucuronide

Copyright © 2013 by the American Academy of Pediatrics
Previous Section
Suggested Reading
1.
1. Allegaert K,
2. Veyckemans F,
3. Tibboel D
. Clinical practice: analgesia in neonates. Eur J Pediatr. 2009;168(7):765–770
CrossRefMedlineWeb of Science
2.
1.
2.
3.
4.
Anand KJ,
Hall RW,
Desai N,
et al
; NEOPAIN Trial Investigators Group. Effects of morphine analgesia in ventilated
preterm neonates: primary outcomes from the NEOPAIN randomised trial. Lancet.
2004;363(9422):1673–1682
CrossRefMedlineWeb of Science
3.
1.
2.
3.
4.
Anand KJS,
Anderson BJ,
Holford NHG,
et al
; NEOPAIN Trial Investigators Group. Morphine pharmacokinetics and
pharmacodynamics in preterm and term neonates: secondary results from the
NEOPAIN trial. Br J Anaesth. 2008;101(5):680–689
Abstract/FREE Full Text
4.
1. Bellù R,
2. de Waal KA,
3. Zanini R
. Opioids for neonates receiving mechanical ventilation. Cochrane Database Syst Rev.
2008;(1):CD004212
Search Google Scholar
5. American Academy of Pediatrics; American Academy of Pediatric Dentistry; Coté CJ,
Wilson S; Work Group on Sedation. Guidelines for monitoring and management of
pediatric patients during and after sedation for diagnostic and therapeutic procedures:
an update. Pediatrics. 2006;118(6):2587–2602
Abstract/FREE Full Text
6.
1.
2.
3.
4.
5.
Golianu B,
Krane E,
Seybold J,
Almgren C,
Anand KJ
. Non-pharmacological techniques for pain management in neonates. Semin Perinatol.
2007;31(5):318–322
CrossRefMedlineWeb of Science
7.
1. Mayock DE,
2. Gleason CA
. Neonatal pain and stress: assessment and management. In: Gleason CA, Devaskar SU,
eds. Avery’s Diseases of the Newborn. 9th ed. Philadelphia, PA: Elsevier; 2012:429–444
Search Google Scholar
8.
1. Walden M,
2. Carrier CT
. Sleeping beauties: the impact of sedation on neonatal development. J Obstet Gynecol
Neonatal Nurs. 2003;32(3):393–401
CrossRefMedline
Neonatal Thrombocytopenia
1. Karen S. Fernández, MD*, and
2. Pedro de Alarcón, MD†
+ Author Affiliations
1.
*
Assistant Professor of Pediatrics, University of Illinois College of Medicine at
Peoria and Children’s Hospital of Illinois, Peoria, IL.
2. †William H. Albers Professor and Chair Department of Pediatrics, University of
Illinois College of Medicine at Peoria and Children’s Hospital of Illinois,
Peoria, IL.
Next Section
Abstract
Thrombocytopenia is one of the most common hematologic problems in the neonate. It
affects up to 30% of all patients admitted to the neonatal intensive care unit (NICU).
The causes of thrombocytopenia in neonates are diverse and include immune, inherited,
and acquired disorders. The evaluation of the neonate with thrombocytopenia may be
challenging. Developing a diagnostic strategy to evaluate the neonate with
thrombocytopenia is key for the practicing clinician. Here, we provide a practical
approach to the evaluation of the neonate with thrombocytopenia and an overview of its
most common etiologies.
Previous SectionNext Section
Educational Gaps
1. Knowing the differential diagnosis and most likely etiologies of
thrombocytopenia in the neonate will lead to more appropriate diagnostic
evaluations and treatments.
2. Thrombocytopenia may be a symptom of a variety of congenital or acquired
conditions in the neonatal period and prompt further diagnostic evaluations.
Previous SectionNext Section
Objectives
1. Describe the differences between neonatal and adult thrombopoiesis.
2. Provide a differential diagnosis of neonatal thrombocytopenia.
3. Describe the clinical presentation and management of the most common forms
of thrombocytopenia during the neonatal period.
4. Explain and contrast the pathophysiology of neonatal autoimmune
thrombocytopenia and alloimmune thrombocytopenia.
5. Describe the most common inherited causes of thrombocytopenia in the
newborn.
6. Discuss the approach to treatment for the neonate with thrombocytopenia
according to the etiology.
Previous SectionNext Section
Definition and Incidence
Thrombocytopenia is defined as a platelet count under 150,000/μL. However, healthy
neonates tend to have platelet counts in the range of 100 to 150,000/μL.
Thrombocytopenia occurs in less than 1% of all neonates, but is one of the most
common hematological problems in neonates, affecting 25% to 30% of all admissions
to the neonatal intensive care unit (NICU). The evaluation and management of
thrombocytopenia is a challenge for the neonatologist and hematologist, because it can
be caused by multiple disease processes. Therefore, a review of the differential
diagnosis, the pathophysiology, and the management of the newborn with
thrombocytopenia is important.
Previous SectionNext Section
Platelets Production in the Newborn
Platelets are tiny cellular fragments produced by megakaryocytes. Platelet production,
or thrombopoiesis, is a complex process that consists of four main steps:
1. Production of thrombopoietin (Tpo) as the thrombopoietic stimulus.
2. Generation and proliferation of megakaryocyte progenitors.
3. Maturation of megakaryocytes characterized by a progressive increase in nuclear
ploidy (the number of sets of chromosomes in a given cell) and cytoplasmic
maturity that leads to the generation of large polyploid (8N–64N)
megakaryocytes.
4. Platelet formation and release of new platelets into the circulation.
These mechanisms are significantly different between neonates and adults with
thrombocytopenia. In neonates Tpo levels are not as high in thrombocytopenic
neonates, particularly in the small for gestational age infants, as those found in children
or adults. The number of megakaryocyte progenitors circulating in the peripheral blood
of neonates is higher than in children and adults. They give rise to colonies with a
greater number of megakaryocytes, and may be more sensitive to Tpo stimulation in
comparison with those of children or adults. Megakaryocytes in the neonate are smaller
and have lower ploidy, but their cytoplasm reflects that of a mature cell. Last, Tpo effect
inhibits megakaryocyte polyploidization in the neonate. Neonates maintain normal
platelet counts on the basis of the increased proliferative potential of their
megakaryocyte progenitors.
Most cases of thrombocytopenia encountered in the NICU are nonimmune and
associated with several common neonatal conditions, such as chronic intrauterine
hypoxia, sepsis, necrotizing enterocolitis (NEC), and viral infections. Although an indepth review of the particular mechanism underlying the etiology of these nonimmune
causes of thrombocytopenia in the neonate is beyond the scope of this review,
understanding the differences between neonatal and adult megakaryopoiesis helps us
see what predisposes the neonate to develop thrombocytopenia and the potential utility
of thrombopoietic growth factors as potential therapeutic interventions in selected
neonates.
Previous SectionNext Section
Platelet Count and Risk of Bleeding
Circulating platelets are about one fifth of the diameter of a red blood cell, with a mean
volume between 7 and 9 fL. Platelets live for a very short time in the circulation with a
half-life of 7 to 10 days. Their primary function is to maintain the integrity of the
vascular endothelium and to control hemorrhage from small-vessel injury through the
formation of small aggregates or plugs in the microcirculation. Bleeding tendency
results when platelets are deficient in number or function.
The normal platelet count in newborns and infants is considered to be between 150,000
and 450,000/μL. However, this range of platelet count comes from a limited number of
small sample studies of healthy newborns. A study from 18 hospitals in the United
States using data from more than 47,000 neonates reported lower limit of platelet ranges
from neonates at various gestational ages during their first 90 days after birth of
123,000/μL in late preterm and term neonates and 104,000/μL in infants of less than 32
weeks’ gestation. Whether or not a platelet count below 150,000/μL is considered
abnormal, it should always be interpreted within the context of the clinical situation.
The tendency to bleed is proportional to the number of platelets within the circulation.
As such, there is no risk of bleeding with platelet counts greater than 100,000/μL,
minimal or mild risk of bleeding occurs with platelet counts between 20,000 and
100,000/μL, the risk is moderate with platelet counts below 20,000/μL, and the risk is
severe and/or there is spontaneous bleeding with platelets below 5,000/μL. In the
neonate, the correlation of platelet count with bleeding has not been established. The
trauma and the stress of birth can precipitate, although rarely, intracranial or internal
bleeding when platelets are below 30,000/μL, and, therefore, clinicians act upon this
platelet count to prevent bleeding in the NICU setting. This threshold seems to be
higher for preterm infants. Many centers will use a platelet count of 50,000/μL to
transfuse preterm infants. However, there is little evidence that this approach will
prevent intracranial hemorrhage (ICH). Prospective studies are warranted to establish
the most safe and cost-effective threshold at which to transfuse premature infants.
The bleeding pattern in the presence of moderate to severe thrombocytopenia is
mucocutaneous. The presence of petechiae, bruises, or bleeding from the mucous
membranes is characteristic of low platelet counts. In the neonate, intraventricular
hemorrhage or intracranial bleed are also possible in the setting of thrombocytopenia.
Previous SectionNext Section
Diagnostic Approach to Neonatal Thrombocytopenia
Multiple disease processes can cause thrombocytopenia. A practical approach to the
diagnosis and management of thrombocytopenia in the neonate can be based on the time
of onset of thrombocytopenia (early ≤72 hours after birth or late ≥72 hours after birth),
gestational age of the patient (term versus preterm), on the underlying mechanism
(consumption, increased destruction, decreased production), or on whether the
thrombocytopenia is due to maternal or infant factors or individualized to the particular
infant. Critical parameters that are common to all these approaches include the severity
of thrombocytopenia, the maternal history, the health status of the infant, and the
presence or absence of congenital malformations.
A simplified approach to the diagnosis of thrombocytopenia in the newborn is presented
here. It is based on an algorithm (see Figure) and a table (see Table) that takes the above
factors into account, especially the severity of thrombocytopenia and the level of illness
of the neonate.
View larger version:


In this page
In a new window

Download as PowerPoint Slide
Figure.
Diagnostic approach to an infant with thrombocytopenia. NAIT=Neonatal alloimmune
thrombocytopenia.
View this table:


In this window
In a new window
Table.
Specific Illnesses and Patterns Associated With Neonatal Thrombocytopenia
The sick newborn may become thrombocytopenic from a variety of neonatal
complications such as infection, asphyxia, meconium aspiration, respiratory distress
syndrome, polycythemia, NEC, and the presence of an indwelling umbilical catheter. In
the sick newborn who has severe thrombocytopenia, specific treatment for the
underlying condition should be provided and the thrombocytopenia treated
symptomatically.
In general, mild to moderate thrombocytopenia with a platelet count between 50,000
and 149,000/μL in a healthy newborn that occurs in the first 72 hours after birth is
associated with a maternal history of placental insufficiency. These infants will recover
a normal platelet count within 10 days and require only close observation. In sick
newborns without evidence of placental insufficiency, evaluation for sepsis is warranted
in addition to initiation of broad spectrum antibiotics.
When the newborn’s underlying condition improves, the thrombocytopenia should also
improve, usually within 5 to 7 days. Persistent thrombocytopenia should alert the
physician to look for other causes.
Patients with severe thrombocytopenia or a platelet count lower than 50,000/mL should
be evaluated for sepsis, disseminated intravascular coagulation (DIC), or neonatal
alloimmune thrombocytopenia (NAIT). If any of those are present no additional
evaluation is required.
In newborns without signs of sepsis, additional evaluation must be pursued and must
include: (1) maternal history of thrombocytopenia, (2) detailed familial history of
thrombocytopenia, (3) detailed physical examination with special attention to the upper
extremities, dysmorphic features suggestive of a congenital anomaly or a particular
syndrome, such as thrombocytopenia-absent radii syndrome, Fanconi anemia, trisomy
13, 18, 21, or Turner syndrome.
In newborns with a negative maternal or familial history and an unrevealing physical
examination, other infections, such as toxoplasmosis, other viruses and syphilis, rubella,
cytomegalovirus, and human immunodeficiency virus complex; human
immunodeficiency virus infection; or enteroviruses, should be considered. In addition,
catheter-related thrombosis, chromosomal anomalies, and inborn errors of metabolism,
especially propionic acidemia and methylmalonic acidemia, should be considered.
The most common etiology of severe thrombocytopenia in an otherwise healthy-looking
newborn is immune-mediated thrombocytopenia in which there is passage of maternal
antibodies from the mother to the fetus. Other rarer disorders, such as vascular tumors
or hemangiomas with Kasabach-Merritt phenomenon and renal vein thrombosis, should
be investigated.
When thrombocytopenia occurs more than 72 hours after birth, it is more likely to be
due to bacterial or fungal sepsis and/or NEC. For patients in whom a bacterial or fungal
process is excluded as etiology of thrombocytopenia, viral infections such as herpes
simplex virus and cytomegalovirus, DIC, catheter-related thrombosis, drug-induced
thrombocytopenia, heparin-induced thrombocytopenia, or other inherited disorders
should be considered. This group of patients constitutes the most common reason for
consultation to the hematology team. Immune-mediated thrombocytopenias should also
be considered in this group, in particular, because they tend to worsen in the first few
days after birth. The differential diagnosis of immune-mediated thrombocytopenias is
between NAIT, maternal autoimmune disorders, or, rarely, maternal drug-induced
immune thrombocytopenia.
In the following sections we will highlight some of the features of the most common
causes of thrombocytopenia in newborns in the three major categories of destruction of
platelets by immune mediated process, decreased or abnormal production of platelets
owing to inherited disorders, and consumption of platelets related to some acquired
disorders.
Previous SectionNext Section
Immune-Mediated Causes of Neonatal
Thrombocytopenia
Neonatal Alloimmune Thrombocytopenia
NAIT is a rare disorder that presents in an otherwise well-appearing newborn with
moderate to severe thrombocytopenia. NAIT occurs when fetal platelets contain an
antigen inherited from the father, a human platelet antigen (HPA) that the mother lacks.
Fetal platelets that cross the placenta into the maternal circulation trigger the production
of maternal antiplatelet antibodies against the foreign antigen. These antibodies cross
the placenta into the fetal circulation and destroy platelets resulting in fetal and neonatal
thrombocytopenia. There are sixteen HPAs identified but only three cause 95% of the
NAIT cases (HPA-1a, HPA-5b, and HPA-15b). Feto-maternal incompatibility for HPA1a is responsible for 75% of cases in whites. HPA-1a incompatibility occurs in 1:350
pregnancies, although thrombocytopenia develops in only 1:1,000 to 1,500 pregnancies.
Infants with NAIT will have symptoms of mucocutaneous bleeding but will look
otherwise healthy. Typically, platelet count falls below 50,000 in the first few days after
birth, but then rises as the alloantibody concentration declines, which usually happens in
1 to 4 weeks, the expected half-life of immunoglobulin G. This immune-mediated
platelet disorder is the equivalent to Rh sensitization of red blood cells with the only
difference that NAIT often develops in the first pregnancy of an at-risk couple. The
most serious complication of NAIT is ICH. This may occur in as many as 10% of the
cases, and up to 50% of the time it happens before birth. All infants with severe
thrombocytopenia due to NAIT should have a cranial ultrasound to look for evidence of
ICH.
If available, the best alternative to treat these patients is the use of HPA-1a–negative
platelets from the blood bank. Random donor platelets, even though they are likely to
have the target antigen, are effective in treating the infant with severe
thrombocytopenia. Platelets obtained from the mother are also effective, but these
platelets need to be washed to minimize the presence of the circulating anti-HPA-1a
antibodies. Specific platelet antigen and antibody testing are not readily available at all
centers but can be requested at major referral laboratories. The administration of
intravenous immunoglobulin (IVIG) may be helpful and represents another alternative
treatment but less effective than platelet transfusions. Once an infant is diagnosed with
NAIT, it is important to carry out a complete diagnostic plan with genotyping of mother
and father to be able to provide genetic counseling. In subsequent pregnancies, if the
father is a homozygote for the affected antigen, therapy should be started as early as the
13th week of pregnancy with weekly IVIG with or without prednisone, depending on
the severity of the previously affected infant or if there was a history of ICH. If the
father is a heterozygote for the antigen, the risk of the infant must be determined by
molecular analysis of fetal cells circulating in the maternal blood, if available, or by
invasive procedures: chorionic villi biopsy or amniocentesis, which both carry
significant risks to the pregnancies, to establish if the fetus is affected.
Neonatal Autoimmune Thrombocytopenia
Neonatal autoimmune thrombocytopenia, in contrast to NAIT, is caused by the passage
of maternal antibodies that react with both maternal and infant platelets, and therefore
both mother and infant are affected. This disorder occurs in maternal autoimmune
disorders such as immune thrombocytopenic purpura or systemic lupus erythematosus.
It occurs in 1 to 2:1,000 pregnancies. The diagnosis becomes obvious from a maternal
history of thrombocytopenia. Transplacental passage of maternal autoantibodies in this
setting is much less of a clinical problem than NAIT. It is important to note that the
maternal history is not always positive, because there are many thrombocytopenic
mothers who would be asymptomatic and therefore unaware of their own disorder. All
neonates of mothers with autoimmune diseases should have their platelet count
determined at birth. In most cases, the platelet count rises spontaneously by day 7. In
cases of severe thrombocytopenia, treatment with IVIG is recommended. The presence
of unexplained thrombocytopenia in a newborn that is suggestive of autoimmune
destruction and in whom NAIT has been excluded should trigger evaluation for the
presence of an autoimmune disorder in the mother, because neonatal thrombocytopenia
can sometimes be the presenting sign of maternal disease.
Previous SectionNext Section
Inherited Thrombocytopenias
Aneuploidies
Thrombocytopenia is seen in neonates with trisomy 13, 18, and 21, and also with Turner
syndrome. The exact mechanism of thrombocytopenia is unknown, but may be due to
reduced platelet production and the pathogenesis may be similar to that seen in chronic
fetal hypoxia.
Bernard-Soulier Syndrome
Bernard-Soulier syndrome (BSS) is a moderate to severe platelet function defect
characterized by mild thrombocytopenia, giant platelets, and mucosal type bleeding. It
is a very rare disorder with an incidence of 1:1,000,000. It may present in the neonatal
period, although bleeding is not usually severe. It is a qualitative platelet disorder with a
defect in the von Willebrand factor receptor, the glycoprotein (GP) complex GP Ib–IX–
V.
The defect in BSS is in the GPIbα gene, and also in the GPIbβ and GPIX genes, mapped
to chromosome 17, chromosome 22, and chromosome 3, respectively. Defect in
chromosome 22 and abnormality in GPIbβ explains why infants with DiGeorge
syndrome and cardiac disease may develop severe bleeding due to a coexisting BSS.
The diagnosis of BSS is confirmed by the absence of CD41a or PGPIb–IX–V by flow
cytometry. Treatment for BSS is mostly supportive and with platelet transfusion for lifethreatening bleeding. Mothers with BSS may develop alloantibodies against GPIb–IX–
V that can cross the placenta, and, therefore, their offspring can develop NAIT due to
the passage of alloantibodies against GPIb–IX–V antigens.
Wiskott-Aldrich Syndrome
Small platelets on peripheral blood film and/or a low mean platelet volume may indicate
Wiskott–Aldrich syndrome (WAS). WAS is due to mutations in the WAS protein gene
on the short arm of the X chromosome. Mutations in this gene have been isolated to
Xp11.23. WAS is characterized by microthrombocytopenia, eczema, and recurrent
bacterial and viral infections. Most cases will not present during the neonatal period
unless there is a known family history. The disorder usually presents in the first year
after birth with bleeding symptoms. Bleeding is due to abnormal platelet function,
reduced platelet survival, and thrombocytopenia. X-linked thrombocytopenia is a part of
the spectrum of WAS. These patients have thrombocytopenia and small platelets as the
major manifestations of their disease. However, the difference is in the variable and less
severe degrees of eczema and immunodeficiency.
Fanconi Anemia
Fanconi anemia (FA) can present in the newborn with persistent thrombocytopenia. It
is, in most cases, an autosomal recessive disorder. The infant may present with
thrombocytopenia alone, pancytopenia, or with dysmorphic features only. The
associated congenital abnormalities of hypopigmented and hyperpigmented skin lesions,
microcephaly, small size, urinary-tract abnormalities, and upper-extremity radial-side
abnormalities involving the thumb, should alert the physician to the possibility of FA.
The cross-linking agent diepoxybutane has been used effectively to diagnose FA and is
the standard diagnostic test. Treatment is rarely necessary in the neonatal period.
Thrombocytopenia Absent Radii Syndrome
This syndrome is characterized by the bilateral absence of the radii and
thrombocytopenia. The inheritance pattern of the thrombocytopenia absent radii (TAR)
syndrome is autosomal recessive. Both boys and girls are affected, but there is a
predominance of girls. The onset of symptoms usually occurs very early in life. Half of
the patients have onset of hemorrhagic manifestations in the first week after birth, and
most develop thrombocytopenia by 4 months of age. In contrast to infants with FA, in
patients with TAR syndrome both thumbs are present. The prognosis in the TAR
syndrome is dependent on the severity of the hemorrhagic manifestations. If the patient
survives the first year after birth, the hemorrhagic manifestations resolve, because the
platelet count spontaneously improves to low normal levels which are then maintained.
Treatment is supportive with platelet transfusions indicated only in the event of active
bleeding.
Congenital Amegakaryocytic Thrombocytopenia
Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare recessive autosomal
disorder presenting during the neonatal period with thrombocytopenia. Most affected
infants have petechiae or other evidence of bleeding. Physical anomalies are present in
approximately 50% of the patients. CAMT typically presents with isolated
thrombocytopenia; however, 50% of the patients will later progress to aplastic anemia
during infancy or early childhood. The bone marrow shows decreased to absent
megakaryocytes with normal erythroid and myeloid precursors. Bleeding episodes in
neonates with CAMT are treated by platelets transfusions, but stem cell transplantation
is the definitive form of therapy for this disorder. There is another variant of
amegakaryocytic thrombocytopenia with radioulnar synostosis. Patients with
amegakaryocytic thrombocytopenia with radioulnar synostosis have a mutation in the
HOXA11 gene that distinguishes them from TAR syndrome, and from CAMT in which
the mutation is located in the cMPL gene.
Giant Platelet Syndromes
Giant platelet syndromes may present in the neonatal period. The characteristic of these
disorders is not only a reduced platelet count, but the appearance of large platelets on
the peripheral smear. Several of the rare giant platelet syndromes present in the fetus,
including the May-Hegglin anomaly, which is characterized by the presence of
leukocyte Dohle-like inclusion bodies. This could be a rare cause of fetal or neonatal
ICH. The defect in May-Hegglin anomaly is in the MY-H9 gene on chromosome 22q.
This mutation is also found in other giant platelet syndromes such as Fletcher
syndrome, where leukocyte inclusions are absent and there is association of sensorial
hearing loss, nephritis and cataracts, and Epstein syndrome, in which there are no
leukocyte inclusions but there is association to hearing loss and nephritis without
cataracts. Other macrothrombocytopenias are a group of heterogeneous disorders that
include functional platelet disorders like Bernard-Soulier syndrome that was previously
described, gray platelet syndrome in which there is lack of platelet granules, and
Jacobsen-Paris-Trousseau syndrome that is associated with psychiatric problems or
mental retardation.
Previous SectionNext Section
Consumptive Causes of Thrombocytopenia in the
Neonatal Period
Kasabach-Merritt Phenomenon
This is an important cause of thrombocytopenia in the newborn. It typically presents
with profound thrombocytopenia, microangiopathic anemia, and DIC in association
with a vascular malformation. The diagnosis is obvious when the vascular anomaly is
cutaneous, but it may be more challenging with the presence of vascular anomalies with
visceral involvement. The thrombocytopenia is due to the trapping and consumption of
platelets in the endothelium of the abnormal blood vessels. The treatment of these
lesions requires supportive treatment with plasma and platelet transfusion if DIC is
present. Some of these vascular malformations with aggressive behavior may need
treatment with steroids, interferon, vincristine, and other chemotherapy agents. More
recently, the use of the angiogenesis inhibitor bevacizumab and the use of the mTOR
inhibitor, rapamycin, have shown some activity; however, further studies are necessary
before recommending therapy with these agents.
Thrombotic Disorders
Acquired thrombotic events in the NICU have increased over the past several years,
mainly because of the high complexity of the patients cared for in the NICU requiring
indwelling catheters and being at risk for several factors that predispose them to
secondary thrombotic events. The use of heparin flushes to maintain the patency of
indwelling catheters is also a risk for the development of heparin-induced
thrombocytopenia that is associated with arterial thrombosis. Inherited deficiency of
ADAMTS13, the cleaving protease of von Willebrand factor, that causes thrombotic
thrombocytopenic purpura may present in the newborn period. Renal vein thrombosis
should also be considered in the differential diagnosis of patients with
thrombocytopenia and renal failure. Thrombocytopenia is part of the clinical
presentation of anticoagulant factor deficiencies, and these deficiencies should be
considered in the differential diagnosis of thrombocytopenia. However, the severe form
of these deficiencies presents with purpura fulminans and diffuse thromboses and not
just isolated thrombocytopenia.
Previous SectionNext Section
Conclusions
Thrombocytopenia is a common problem in the newborn. The differential diagnosis of
thrombocytopenia in the neonate can be simplified when taking into account the
severity of the thrombocytopenia and the clinical appearance of the neonate. Most
episodes of thrombocytopenia in the newborn occur after the first 72 hours after birth
and are most commonly caused by infectious process. Persistent thrombocytopenia, or
thrombocytopenia that does not respond to adequate treatment of the presumed etiology
of the low platelet count, deserves further investigation to look for some of the rare
causes of thrombocytopenia in neonates including immune-related disorders, inherited
thrombocytopathies and other acquired causes of platelet consumption.
American Board of Pediatrics Neonatal–Perinatal Content Specifications



Know the normal pattern of platelet production and maturation.
Know the causes and pathophysiology of neonatal thrombocytopenia and
thrombocytosis.
Know the clinical and laboratory manifestations and management of neonatal
thrombocytopenia and thrombocytosis.
Previous SectionNext Section
Footnotes

Author Disclosure
Drs Fernández and de Alarcón have disclosed no financial relationships relevant
to this article. This commentary does contain a discussion of an
unapproved/investigative use of a commercial product/device.
Abbreviations:
BSS;
Bernard Soulier syndrome
CAMT;
congenital amegakaryocytic thrombocytopenia
DIC;
disseminated intravascular coagulation
FA;
Fanconi anemia
GP;
glycoprotein
HPA;
human platelet antigen
ICH;
intracranial hemorrhage
IVIG;
intravenous immunoglobulin
NAIT;
neonatal alloimmune thrombocytopenia
NEC;
necrotizing enterocolitis
NICU;
neonatal intensive care unit
TAR;
thrombocytopenia absent radii
Tpo;
thrombopoietin
WAS;
Wiskott-Aldrich syndrome

Copyright © 2013 by the American Academy of Pediatrics
Previous Section
Suggested Reading
1.
1. Chakravorty S,
2. Roberts I
. How I manage neonatal thrombocytopenia. Br J Haematol. 2012;156(2):155–
162
CrossRefMedline
2.
1. Drachman JG
. Inherited thrombocytopenia: when a low platelet count does not mean ITP.
Blood. 2004;103(2):390–398
Abstract/FREE Full Text
3.
1.
2.
3.
4.
Ferrer-Marin F,
Liu ZJ,
Gutti R,
Sola-Visner M
. Neonatal thrombocytopenia and megakaryocytopoiesis. Semin Hematol.
2010;47(3):281–288
CrossRefMedline
4.
1.
2.
3.
4.
Hammill AM,
Wentzel M,
Gupta A,
et al
. Sirolimus for the treatment of complicated vascular anomalies in children.
Pediatr Blood Cancer. 2011;57(6):1018–1024
CrossRefMedlineWeb of Science
5.
1. Nurden P,
2. Nurden AT
. Congenital disorders associated with platelet dysfunctions. Thromb Haemost.
2008;99(2):253–263
MedlineWeb of Science
6.
1. Risson DC,
2. Davies MW,
3. Williams BA
. Review of neonatal alloimmune thrombocytopenia. J Paediatr Child Health.
2012;48(9):816–822
CrossRefMedline
7.
1. Sola-Visner M,
2. Sallmon H,
3. Brown R
. New insights into the mechanisms of nonimmune thrombocytopenia in
neonates. Semin Perinatol. 2009;33(1):43–51
CrossRefMedlineWeb of Science
Hemolytic Disease of the Fetus and
Newborn
1. Mary Beth Ross, MD*, and
2. Pedro de Alarcón, MD†
+ Author Affiliations
1.
*
Assistant Professor of Pediatrics, University of Illinois College of Medicine at
Peoria and Children’s Hospital of Illinois, Peoria, IL.
2. †William H. Albers Professor and Chair, Department of Pediatrics, University of
Illinois College of Medicine at Peoria and Children’s Hospital of Illinois,
Peoria, IL.
Next Section
Abstract
Hemolytic disease of the fetus and newborn (HDFN) is the result of immune-mediated
destruction of fetal or newborn red blood cells when such cells contain antigens that are
not present in the maternal blood. HDFN is now the preferred term that replaces the
historic term erythroblastosis fetalis. Sensitization of the mother to fetal-newborn red
blood cells requires fetomaternal hemorrhage in most cases except in ABO
incompatibility where naturally occurring antibodies against A and B antigens are
present in mothers with O blood type. The most common antigen involved in HDFN is
Rhesus D. Kell 1 HDFN is rare but commonly associated with severe anemia and lower
titers of anti-Kell antibodies in maternal serum in severely affected infants. Prevention
of Rhesus D HDFN with anti-D immunoglobulin during pregnancy, delivery, and fetalmaternal events that predispose to fetomaternal hemorrhage, have markedly decreased
the incidence of the disorder but may not be available in low-income countries. An
algorithm is available to manage affected pregnancies by using antibody titers, fetal
middle cerebral artery velocities, intrauterine transfusions, and timed delivery. Infants
who have mild to moderate anemia may tolerate normal labor, but severely affected
infants may require transfusion or exchange transfusions at birth, and the delivery team
needs to be prepared. Delayed anemia in the transfused infants is still a concern, and the
infants need to be closely followed after delivery. Phototherapy has largely replaced
exchange transfusion in the management of hyperbilirubinemia. With appropriate early
detection and multidisciplinary planning, infants who have HDFN can be delivered in a
timely manner with appropriate planning for postnatal resuscitation and postnatal
therapy resulting in good neonatal outcomes.
Previous SectionNext Section
Objectives
After completing this article, readers should be able to:
1. Recognize the symptoms and signs associated with hemolytic disease of the
fetus and newborn (HDFN).
2. Understand the pathophysiology of HDFN.
3. List the red blood cell antigens most commonly associated with HDFN.
4. Identify the fetus at risk for HDFN.
5. Discuss the clinical management of fetus/newborn affected by HDFN.
Previous SectionNext Section
Introduction
Advances in prevention and detection have markedly decreased the incidence of
hemolytic disease of the fetus and newborn (HDFN). The disorder, caused by red blood
cell (RBC) incompatibility between infant and mother, and its multiple clinical
manifestations were first brought together in 1932 in the landmark article by Dr Louis
K. Diamond, where he coined the term erythroblastosis fetalis, based on the
morphology of the peripheral blood smear seen in infants who have severe diseases.
HDFN is now the preferred term encompassing all infants who have alloimmune
hemolysis, whether or not erythroblasts are present. The work of Landsteiner and other
investigators defined RBC antigens and their role in transfusion reaction by 1940, and
Levine et al in 1941 gathered enough cases to document that HDFN was indeed caused
by blood group incompatibility between a mother and her infant. HDFN is the result of
immune destruction of fetal or newborn RBCs. Maternal antibodies develop when fetal
RBCs express cell surface antigens that are not present on the maternal RBCs. For this
process to occur, fetal RBCs must enter the maternal circulation secondary to
fetomaternal hemorrhage (FMH). The exception to this rule is ABO incompatibility
because type O mothers have naturally occurring anti-A and anti-B antibodies. HDFN
should be considered in the differential diagnosis of postnatal early, severe, or
prolonged jaundice. It also should be considered in the differential diagnosis of neonatal
anemia, in particular, if it is severe or associated with hydrops fetalis. The presence of
maternal RBC antibodies and/or a positive direct antibody testing in the infant are
diagnostic for HDFN.
A comprehensive maternal history is essential for the proper diagnosis of HDFN.
Particular emphasis should be placed on uncovering maternal events that predispose to
FMH. A maternal history of a previous pregnancy, particularly a complicated
pregnancy, history of hydrops fetalis, a miscarriage, early termination of pregnancy,
blood transfusion, or clinical documentation of FMH, should alert the clinician to the
possibility of HDFN in an infant with anemia and/or jaundice.
The greatest advances in this disorder have been the introduction of very effective
prevention strategies, the aggressive use of phototherapy for jaundice, and the
introduction of noninvasive techniques to monitor the affected fetus.
Previous SectionNext Section
Differential Diagnosis
The two main signs of HDFN are anemia and hyperbilirubinemia. The anemia is
hemolytic and the bone marrow is reactive with reticulocytosis and often presents
immature RBCs, erythroblasts, in the peripheral blood; hence, the original term
erythroblastosis fetalis was given to the disorder. Other types of non–immune-mediated
hemolysis can result in anemia and hyperbilirubinemia. These include RBC membrane
defects such as hereditary spherocytosis and hereditary elliptocytosis. Although these
disorders are hereditary, their phenotype is variable, and the RBC defects may go
undiagnosed well into adulthood. Clues that can be suggestive of undiagnosed RBC
membrane defects include family members who are intermittently jaundiced,
intermittently have scleral icterus, or intermittently have dark urine. These episodes
generally occur in association with acute illness. Family members who have a history of
splenectomy unrelated to trauma or early gallbladder disease may suggest an
undiagnosed inherited RBC membrane defect.
Hemoglobinopathies also may contribute to neonatal hemolysis. Hemoglobinopathy
screening in the United States has been available in most states for over a generation,
and today all 50 states screen for these disorders and they are diagnosed at birth.
Nonetheless, recent immigrants to the United States may have previously undiagnosed
hemoglobinopathies. Review of the blood smear, newborn screening, confirmatory
hemoglobin electrophoresis, and potentially maternal and paternal hemoglobin
electrophoresis should clarify this diagnosis.
RBC enzyme defects such as glucose-6-phophate dehydrogenase can lead to hemolysis
and anemia. Significant and prolonged hyperbilirubinemia and even kernicterus have
been described in infants who have glucose-6-phophate dehydrogenase deficiencies,
particularly in the Philippines, Africa, and Greece. Hemolysis can occur from disorders
of glycolysis such as pyruvate kinase deficiency. Here too, family history and ethnic
background can be key factors in identifying the risk for RBC enzyme defects.
Previous SectionNext Section
Mechanisms of Maternal Exposure
All individuals with blood type O naturally express antibodies to A and B RBC surface
antigens. No previous exposure to blood group antigens is necessary for antibody
development. These antibodies are immunoglobulin G type and cross the placenta.
Individuals who have blood type A have antibodies against type B and vice versa.
However, these antibodies are predominantly immunoglobulin M class and do not cross
the placental barrier.
For all other blood group antigens, maternal exposure to blood group antigens is
necessary for the development of antibodies. The most frequent cause of maternal
sensitization is FMH. FMH can occur in the first trimester, but is most common in the
third trimester. Numerous fetal events or procedures may be associated with previously
underappreciated risk for FMH. See the Table for a listing of events that may be
associated with FMH.
View this table:


In this window
In a new window
Table.
Mechanisms of Maternal Exposure to Red Blood Cell Antigens
Women who have a known history of transfusion represent only a small proportion of
all pregnant women. However, women who have a previous transfusion history
represent half of the pregnancies affected by non-Rhesus D (RhD) HDFN. Routine
blood typing and cross-match screen for ABO and RhD blood types, but none of the
other blood types involve HDFN. As more children survive previously serious
childhood illnesses such as cancer and congenital heart disease, we are likely to see an
increase in HDFN from maternal transfusion. In fact, the mother may be unaware of her
own blood product exposure, because treatment may have occurred during her early
childhood. See the Table for a listing of maternal history elements that raise concern for
unappreciated exposure to RBC antigens.
The ever expanding utilization of reproductive technologies leads to unexpected risks
for HDFN. The battle with infertility is highly personal in nature. That, combined with
our fragmented health-care system and highly mobile society, leads to significant
opportunity for utilization of egg donor, sperm donor, or embryo adoption to go
undisclosed to the health-care team at the time of delivery. Even when a family is
willing to disclose use of egg donor, sperm donor, or embryo adoption, ABO blood type
of the donors may or may not be known to the pregnant woman. This circumstance can
set up otherwise uninheritable combinations of RBC antigens. For example, an O−
(negative) mother with an O− (negative) husband could deliver an AB+(positive) infant
who is at risk for HDFN from ABO and Rh mismatch.
Previous SectionNext Section
Red Blood Cell Antigens Most Frequently Involved in
Hemolytic Disease of the Fetus and Newborn
Rhesus (RhD) incompatibility is the best described cause of HDFN. Despite
international efforts aimed at prevention of HDFN in infants of Rh-negative mothers,
Rh remains the most commonly identified RBC antigen causing HDFN.
RhD-negative denotes the lack of D antigen on the RBC surface. Eleven percent to 35%
of white populations are RhD-negative because of gene deletion. In contrast, most East
Asian and African populations that lack RBC surface expression of RhD have a grossly
intact gene. In Africans, a 37-bp insertion results in the insertion of a stop codon leading
to a prematurely shortened protein product.
A special circumstance exists with an RhD variant called weak D. There is both an
altered protein sequence and decreased cell surface protein expression. Serologic testing
will identify this person as RhD-negative. Although more sensitive testing can
demonstrate the presence of the protein on the cell surface, importantly, these
apparently RhD-negative mothers will not form anti-D antibodies even if they are
transfused with RhD-positive blood.
The second most common RBC antigen associated with HDFN is the ABO blood
group. HDFN due to an ABO blood group mismatch occurs almost exclusively in
infants with mothers of blood type O. Hemolysis is more common with anti-A than with
anti-B. The clinical presentation for HDFN due to ABO blood group is predominantly
hyperbilirubinemia without severe anemia. Phototherapy is generally sufficient for most
of these infants.
Another major cause of HDFN is Kel1 antigen of the Kell antigen system. Kell is a
glycoprotein containing 15 antigens and their antithetical variants. It is the first
erythroid-specific antigen known to be expressed during erythroid development.
Clinically, anti-Kel1 HDFN is manifest by more severe anemia and reticulocytopenia.
Hyperbilirubinemia is less severe than with other RBC antigens. Anti-Kel1 antibody is
rare and is only found in 0.1% of pregnant women. However, most of these women
have developed antibody because of previous transfusion exposure. Fortunately, only
9% of people of European descent and 2% of people of African descent express Kel1.
Because of the early erythroid lineage expression of Kell when Kel1 is present, antiKel1 is associated with a lower critical antibody titer (1:8) than anti-RhD or antibodies
to other RBC antigens.
A variety of other RBC antigens have been described as causing HDFN. For a detailed
listing of RBC antigens, the severity of HDFN associated with each antigen, and
reference citation, see Table 6.1 in de Alarcon, Werner, and Christensen’s Neonatal
Hematology.
Previous SectionNext Section
Clinical Management: Prevention of Hemolytic Disease
of the Fetus and Newborn Due to Rhesus D
The first approach to prevention of HDFN due to an RhD-positive fetus born to an
RhD-negative mother is administration of one postnatal dose of anti-RhD. Between
1968 and 1983, both maternal immunization and perinatal infant deaths were reduced
by 90%. Subsequently, clinical trials were performed demonstrating that the
administration anti-RhD at 28 weeks’ gestation in addition to the postnatal dose could
further decrease the frequency of immunization from the remaining 2% down to 0.2%.
Similarly, an appreciation rose for other events that led to FMH effectively immunizing
the mother further against RhD. We now know that fetal and pregnancy events such as
ectopic pregnancy, spontaneous or induced abortion, fetal demise, and maternal
abdominal trauma can result in maternal immunization from FMH. Invasive medical
procedures such as amniocentesis, cordocentesis, and chorionic villus sampling are
associated with an increased risk of immunization to RhD. Recommendations are now
in place for immune prophylaxis in the event of planned or unscheduled events that may
increase FMH and therefore increase maternal exposure to RhD. For a listing of such
events, see the Table.
Anti-RhD prophylaxis policies vary slightly between developed countries (such as the
United States, England, Mexico, Canada, and Australia). In third world countries,
access to anti-RhD may still be extremely limited both owing to medical infrastructure
reasons as well as socioeconomic reasons such as minimal prenatal care and delivery at
home.
In the United States, the Preventative Services Task Force current consensus
recommendations are available at http://www.uspreventiveservicestaskforce.org (then
search the site for “Rh incompatibility”). Current US recommendations include the
proposal that all pregnant women should have antibody screening and RBC antigen
typing for ABO and RhD at the first prenatal visit. RhD-negative mothers with no
antibody present at the first screen should have repeat screening at 24 to 28 weeks. If
they remain negative, they should receive 1,500 IUs (= 300 μg) anti-RhD
immunoglobulin at 28 weeks’ gestation unless the father of the infant is also known be
RhD-negative. Second, women at high risk for FMH, such as previous transfusion,
obstetrical complications in which anti-RhD was not administered, or the woman had
sustained injuries, should continue to be screened for antibody development into the
second and third trimesters. An additional dose of anti-RhD is recommended for women
experiencing obstetrical complications with a risk for FMH or undergoing diagnostic
testing that can increase FMH. This anti-RhD dose is trimester-dependent. For events in
the first trimester, the recommended dose is 250 IUs (= 50 μg). For events in the second
or third trimester, the recommended dose is 1,500 IUs (= 300 μg). Last, the postnatal
dose of 1,500 IUs is administered to all RhD-negative mothers. This dose should
prevent immunization when as much as 15 mL of newborn blood enters the maternal
circulation. Women experiencing high-risk problems or maneuvers, such as abruption,
manual removal of the placenta, or multiple infant gestations may be at risk for higher
volume FMH. An effort should be made to quantitate the FMH and administer
additional anti-RhD, if necessary (when estimated to be >15 mL).
Previous SectionNext Section
Clinical Management: Identifying Pregnancies at Risk
for Hemolytic Disease of the Fetus and Newborn
Monitoring is dependent upon previous pregnancy history, whether the infant from a
previous pregnancy was clinically affected, which RBC antigen is involved, what is the
father’s genotype and phenotype, how high is maternal antibody, and whether there is
clinical evidence of fetal anemia. The first level of monitoring is phlebotomy for serial
determination of anti–RBC antigen antibodies or indirect antiglobulin testing (IAT).
An algorithm has been developed by Moise for monitoring of pregnancy in an RhDnegative woman with an RhD-positive fetus or RhD-positive father. This algorithm can
also be applied to assessing risk for fetal anemia due to other RBC antigens.
A first pregnancy of an RhD-negative mother is monitored by repeated anti–RBC
antibody titers. If the titer remains low, serial monitoring continues and the infant is
delivered at term. If the titer crosses above a critical threshold, then infants are
monitored by serial fetal middle cerebral artery (MCA) velocities. An increased MCA
velocity correlates well with fetal anemia.
For pregnancies with previously affected infants, the current fetus is monitored with
serial MCA velocities by using Doppler ultrasound to monitor for development of fetal
anemia.
Previous SectionNext Section
Clinical Management: Intrauterine
Once a pregnancy is identified as being at risk because of positive or rising IAT, serial
Doppler ultrasound MCA velocities are utilized to monitor for fetal anemia. If mild
anemia is detected, serial monitoring by ultrasound continues until there is adequate
lung maturity or term delivery.
Where severe anemia is suspected, cordocentesis may be utilized to confirm severe
anemia (hematocrit <30% or hemoglobin <10 g/dL). In the event of severe anemia, an
intrauterine transfusion may prevent progression to a severely ill, hydropic infant.
Packed red blood cells (pRBCs) that are negative for the RBC antigen involved in the
HDFN are used for transfusion. Additional pRBC specifications include leukodepletion,
cytomegalovirus-negative donor, and irradiated products to prevent transfusionassociated graft versus host disease.
Previous SectionNext Section
Clinical Management: Postnatal
Delivery, either preterm or term, should be scheduled in a perinatal level 3 center with
interdisciplinary obstetric, maternal-fetal, and pediatric services available. Assessment
of fetal lung maturity and risk for subsequent respiratory distress must be taken into
account in preparation for delivery. This includes consideration of glucocorticoids to
accelerate lung maturity, when appropriate, and planning for personnel and equipment
for resuscitation of the infant experiencing respiratory distress.
A mildly or moderately anemic fetus will often tolerate labor adequately. A severely
anemic fetus may not. ABO matched (if ABO typing has been done with previous
cordocentesis) or O-type blood that is also negative for the antigen responsible for
HDFN should be available to the resuscitating team in the delivery room. This pRBC
product should be leukodepleted, cytomegalovirus-negative, and irradiated.
The most severely ill infants may require an exchange transfusion, which involves
replacing the native infant RBCs with appropriately antigen-negative RBCs to prevent
further hemolysis. This is accomplished by replacing a total of 25 to 50 mL/kg pRBCs.
Once vascular access has been established, 5 mL/kg aliquots can be removed and
replaced over several minutes. This cycle is repeated until the targeted volume is
replaced.
Many anemic but more stable infants may be transfused with ABO-matched pRBCs that
are negative for the antigen contributing to the HDFN at 10 mL/kg over a 2- to 3-hour
period; 3 mL/kg pRBCs are needed to increase the hemoglobin 1 gm/dL (hematocrit
3%).
Exchange transfusion was the mainstay of therapy early in management of RhD HDFN
to minimize kernicterus from hyperbilirubinemic infants. Now, many
hyperbilirubinemic infants who have HDFN will respond adequately to early
phototherapy with blue light “bilirubin lights,” often in combination with “bilirubin
blankets.” These infants may only require early phototherapy in combination with
transfusion to address mild to moderate anemia.
HDFN from some RBC antigens may result in delayed or prolonged postnatal anemia.
Therefore a pediatric hematologist should be consulted to help monitor for the need for
delayed or repeated pRBC transfusion.
Previous SectionNext Section
Conclusions
RhD remains the most significant antigen contributing to HDFN. However, prenatal
anti-D prophylaxis has significantly decreased the incidence of severe HDFN. At this
time, antibody prophylaxis is only available for HDFN due to RhD. Appropriate
prenatal screening with IAT and Doppler ultrasound has greatly improved infant
outcomes by allowing early identification of pregnancies at risk for HDFN. With
appropriate early detection and multidisciplinary planning, these infants can be
delivered in a timely manner with appropriate planning for postnatal resuscitation and
postnatal therapy resulting in good neonatal outcomes.
American Board of Pediatrics Neonatal–Perinatal Content Specifications




Know the diagnostic evaluation and perinatal management of fetal-maternal
blood group incompatibility.
Know the etiology and pathophysiology of hemolytic anemias in the neonate.
Know the clinical and laboratory features of hemolytic anemia in the neonate.
Know the management of hemolytic anemia in the neonate.
Previous SectionNext Section
Footnotes

Author Disclosure
Drs Ross and de Alarcón have disclosed no financial relationships relevant to
this article. This commentary does not contain a discussion of an
unapproved/investigative use of a commercial product/device.
Abbreviations:
FMH;
fetomaternal hemorrhage
HDFN;
hemolytic disease of the fetus and newborn
IAT;
indirect antiglobulin testing
MCA;
middle cerebral artery
pRBC;
packed red blood cell
RBC;
red blood cell
RhD;
Rhesus D

Copyright © 2013 by the American Academy of Pediatrics
Previous Section
Suggested Reading
1.
1. Basu S,
2. Kaur R,
3. Kaur G
. Hemolytic disease of the fetus and newborn: Current trends and perspectives.
Asian J Transfus Sci. 2011;5(1):3–7
CrossRefMedline
2.
1. Brinc D,
2. Lazarus AH
. Mechanisms of anti-D action in the prevention of hemolytic disease of the fetus
and newborn. Hematology (Am Soc Hematol Educ Program). 2009:185–191
Search Google Scholar
3.
1. Diamond LK,
2. Blackfan KD,
3. Baty JM
. Erythroblastosis fetalis and its association with universal edema of the fetus,
icterus gravis neonatorum and anemia of the newborn. J Pediatr.
1932;1(3):269–309
CrossRef
4.
1. Illanes S,
2. Soothill P
. Noninvasive approach for the management of hemolytic disease of the fetus.
Expert Rev Hematol. 2009;2(5):577–582
CrossRefMedline
5.
1. Moise KJ Jr
. Management of rhesus alloimmunization in pregnancy. Obstet Gynecol.
2008;112(1):164–176
CrossRefMedlineWeb of Science
6.
1. Osaro E,
2. Charles AT
. Rh isoimmunization in Sub-Saharan Africa indicates need for universal access
to anti-RhD immunoglobulin and effective management of D-negative
pregnancies. Int J Womens Health (Larchmt). 2010;2:429–437
Search Google Scholar
7.
1.
2.
3.
4.
Ross ME,
Waldron PE,
Cashore WJ,
de Alarcon PA
. Hemolytic disease of the fetus and newborn. In: de Alarcon PA, Werner EJ,
Christensen RD, eds. Neonatal Hematology, Pathogenesis, Diagnosis, and
Management of Hematologic Problems. 2nd ed. Cambridge, UK; Cambridge
University Press; 2013
Search Google Scholar
8.
1. Stockman JA III
. Overview of the state of the art of Rh disease: history, current clinical
management, and recent progress. J Pediatr Hematol Oncol. 2001;23(6):385–
393
CrossRefMedlineWeb of Science
Preeclampsia: Pathophysiology,
Management, and Maternal and Fetal
Sequelae
1. Mollie McDonnold, MD, and
2. Gayle Olson, MD
+ Author Affiliations
1. University of Texas Medical Branch, Department of Obstetrics and Gynecology,
Division of Maternal Fetal Medicine, Galveston, TX.
Next Section
Abstract
Preeclampsia is a unique, complicated problem of pregnancy that is prevalent
worldwide. The maternal effects of severe disease may involve multiple organ systems.
Consequences of disease for the infant include possible prematurity, fetal growth
restriction, placental abruption, or intrauterine fetal demise. In addition, long-term
effects of disease have been studied in both mothers and children. Although the exact
cause of preeclampsia is not fully understood, increasing evidence points to abnormal
placentation and an imbalance of antiangiogenic factors. Specifically, soluble Fms-like
tyrosine kinase-1 has been investigated as the link between poor placental invasion and
maternal disease. Clinically, maternal disease is defined as the presence of elevated
blood pressure after 20 weeks’ gestation and proteinuria. The presence of severe
symptoms or abnormal laboratory test results separate mild and severe disease. Studies
have shown that delivery should occur at 37 weeks’ gestation with mild disease and 34
weeks’ gestation with severe disease. In early-onset severe disease, expectant
management with close monitoring is possible if maternal and fetal status remain stable.
Pathophysiology, diagnosis criteria, management, and possible maternal and fetal
complications are reviewed.
Previous SectionNext Section
Practice Gaps
1. The timing of delivery and supportive treatments for mothers with preeclampsia
can help to reduce both maternal and neonatal morbidity.
2. Neonates born to mothers who have preeclampsia are at risk not only for
morbidities in the newborn period but also for diseases later in life.
Previous SectionNext Section
Objectives
After completing this article, readers should be able to:
1.
2.
3.
4.
Review the underlying pathophysiology of preeclampsia.
Understand the criteria for the diagnosis of the spectrum of preeclampsia.
Review indications and timing for delivery.
List short- and long-term neonatal consequences of maternal preeclampsia.
Previous SectionNext Section
Introduction
Preeclampsia is the most common medical complication of pregnancy worldwide,
occurring in 3% to 5% of all pregnancies and carrying a perinatal and neonatal mortality
rate of 10%. (1) Severe preeclampsia occurs in 0.6% to 1.2% of pregnancies in Western
countries, whereas preeclampsia less than 37 weeks’ gestation and severe disease less
than 34 weeks’ gestation occur in 0.6% to 1.5% and 0.3% of pregnancies, respectively.
(2) Preeclampsia is a multisystem disorder with variable effects on the maternal brain,
lungs, kidney, liver, coagulation cascade, and the fetus. It is a disease spectrum whose
clinical manifestations vary by gestational age at onset and by severity of symptoms.
Mild disease is primarily associated with good outcomes. Conversely, severe disease,
especially if early onset, is associated with increased complications of eclampsia;
cerebral hemorrhage; renal failure; hepatic failure; HELLP (hemolysis, elevated liver
enzymes, and low platelet count syndrome); prematurity; fetal growth restriction;
oligohydramnios; placental abruption; and intrauterine fetal demise. The only treatment
that has proved effective is timely delivery of the neonate; thus, avoidance of poor
maternal outcome often means the burden of morbidity and mortality is placed on the
neonate. This review focuses on the pathophysiology, diagnosis, management, and
maternal and neonatal outcomes of severe preeclampsia.
Previous SectionNext Section
Pathophysiology
Although the pathophysiology of preeclampsia is not fully understood, it is generally
regarded as a two-stage disorder. The first stage consists of reduced placental perfusion,
likely due to abnormal implantation and abnormal development of the placental
vasculature. (3)(4) Early normal placental development is characterized by invasion of
the uterine spiral arteries of the decidua and myometrium by extravillous
cytotrophoblasts. These transform the uterine vessels from small and resistant to
compliant with high-caliber capacitance. This change allows for the increase in uterine
blood flow needed to sustain the fetus in the second half of pregnancy. (4)(5)(6)(7) In
addition, there is a rise in oxygen tension, stimulating cytotrophoblasts to downregulate
the expression of adhesion molecules characteristic of their epithelial origin and adopt
an endothelial surface adhesion phenotype. (5)
Figure 1 shows the abnormal events occurring in preeclampsia. The invasion of the
arteries is limited to the superficial decidua, leaving the myometrial segments narrow
and undilated. (1)(4) This action contributes to a deficient blood supply from the
maternal side, resulting in prolonged fetal hypoxia and aberrant formation of the
placental vasculature. (4) Without changes in oxygen tension, endothelialization fails to
occur. (5) Evidence of placental hypoperfusion and ischemia may be seen on
pathological specimens, including acute atherosis, intimal thickening, necrosis,
atherosclerosis, endothelial damage, and placental infarction. Although these findings
are not universal, they do correlate with disease severity. (1)(7)
View larger version:


In this page
In a new window

Download as PowerPoint Slide
Figure 1.
Abnormal events occurring in preeclampsia.
Angiogenic factors (vascular endothelial growth factor [VEGF] and placental growth
factor) are highly expressed by invading cytotrophoblasts and are important in the
regulation of placental vasculogenesis. (1)(5) An imbalance between these factors and
antiangiogenic factors, specifically soluble Fms-like tyrosine kinase-1 (sFlt-1) and
soluble endoglin, leads to an antiangiogenic state and endothelial dysfunction.
(1)(4)(5)(6) Levels of sFlt-1 messenger RNA are upregulated in placentas of
preeclamptic patients, both at the time of clinical disease and 2 to 5 weeks before onset,
with higher elevations noted in severe preeclampsia, early-onset preeclampsia, and
preeclampsia complicated by intrauterine growth restriction. (5) Hypoxia has been
shown to increase the expression of sFlt-1 in primary trophoblast cultures of firsttrimester placentas. (5)
It is this imbalance in angiogenic factors that seems to be the link between abnormal
placentation and the second stage of preeclampsia, the maternal response, which is
manifested by widespread inflammation and maternal endothelial cell dysfunction,
increased markers of oxidative stress, insulin resistance, reduced immune function, and
dyslipidemia. (3)(4)(7) In addition, sFlt-1 antagonizes VEGF, preventing it from
stabilizing endothelial cells. Clinically, this action is seen as elevated blood pressure
and proteinuria, along with multiorgan system involvement. (1) Fetal complications are
also evident at this stage and include prematurity, oligohydramnios, intrauterine growth
restriction, placental abruption, and intrauterine demise. It is likely that impaired
uteroplacental blood flow or placental infarction plays a role in determining this fetal
morbidity.
Previous SectionNext Section
Screening And Diagnosis
Maternal risk factors for preeclampsia include primiparity, multifetal gestations,
extremes of maternal age, history of preeclampsia, and medical comorbidities such as
obesity, hypercoagulability, chronic hypertension, renal disease, lupus, and diabetes
mellitus. (1)(2) Although there is evidence of an imbalance in angiogenic markers, there
are currently no clinically available biomarkers for use in screening for preeclampsia. In
women with pre-existing hypertension or proteinuria, the diagnosis can be difficult, but
worsening symptoms, or the development of other clinical or laboratory findings of
severe disease, are suggestive. Therefore, it is standard practice to obtain baseline
studies, including 24-hour urine for protein quantification, in women with diabetes,
chronic hypertension, or underlying renal disease.
Blood pressure is obtained during each prenatal visit. These measurements occur
monthly until the end of the third trimester, at which time weekly visits are planned.
Additional visits are tailored to pre-existing maternal conditions. Hypertension in
pregnancy represents a spectrum of disorders, and criteria for the diagnosis of these
disorders are listed in Table 1. Critical to the diagnosis is the gestational age of the
pregnancy. Preeclampsia occurs after 20 weeks’ gestation; therefore, increased blood
pressure at less than 20 weeks warrants investigation for other disorders. When elevated
blood pressure (>140/90 mm Hg) or patient symptoms are noted, additional observation
and laboratory studies as listed in Table 1 will be needed. (2)(8)
View this table:


In this window
In a new window
Table 1.
Diagnostic Criteria
Previous SectionNext Section
Management
The management of preeclampsia consists of reducing maternal and neonatal morbidity
by controlling blood pressure levels, preventing eclampsia, and timing delivery
appropriately.
For those women who have nonsevere disease, treatment of blood pressure is usually
not required. Once the diagnosis is made, increased observation begins, the location of
which is practitioner dependent. Whether as an inpatient or outpatient, the woman’s
blood pressure, laboratory data, fetal growth, and amniotic fluid levels are monitored to
look for signs of worsening disease. If findings of severe disease do not develop,
expectant management may be undertaken until 37 weeks’ gestation. (9) Delivery by
this gestational age has been shown to improve outcomes in women who have
nonsevere disease. In the Hypertension and Preeclampsia Intervention Trial At Term
(HYPITAT), a randomized controlled study of 756 women presenting with gestational
hypertension or preeclampsia between 36 and 41 weeks’ gestation, those who were
induced within 24 hours of presentation had a 0.71 relative risk (RR) of experiencing
poor maternal outcomes (confidence interval [CI]: 0.59–0.86), defined as maternal
mortality; eclampsia; hemolysis, elevated liver enzymes, low platelet count syndrome;
pulmonary edema; thromboembolic disease; placental abruption; progression to severe
disease; and major postpartum hemorrhage. (10) These patients were compared with
those who were expectantly managed until the onset of labor. In the two groups, there
was no difference in neonatal morbidity. No fetal deaths were recorded in either group.
There were similar rates of Apgar scores less than 7 at 5 minutes, admission to intensive
care, and arterial pH less than 7.05.
For women who have severe hypertension, obtaining control of maternal blood pressure
is necessary to decrease the consequences of acute hypertension, including
cerebrovascular accident or myocardial ischemia, but blood pressure should not be
reduced so dramatically as to impair uteroplacental perfusion. Persistently severe
ranging blood pressures are treated to achieve a target range of systolic blood pressure
of 140 to 155 mm Hg and a diastolic blood pressure of 90 to 105 mm Hg. (11)
Commonly used agents for acute and chronic control include nicardipine, labetalol,
hydralazine, and nifedipine.
Magnesium sulfate is a mainstay in the treatment of preeclamptic disorders. The Magpie
trial, a double-blind, placebo-controlled study of 10,141 women worldwide,
demonstrated a 58% lower risk of eclampsia in women who received magnesium sulfate
as opposed to placebo. (12) There was also a 0.67 RR of placental abruption (CI: 0.45–
0.89) associated with magnesium sulfate administration. No differences in maternal
morbidity, including respiratory depression or arrest, pneumonia, cardiac arrest,
coagulopathy, renal failure, liver failure, pulmonary edema, cerebral hemorrhage,
toxicity, induction and length of labor, cesarean delivery rate, retained placenta, blood
loss, or transfusion were seen. Subsequently, the use of magnesium sulfate has become
standard in cases of severe preeclampsia, both during labor and in the initial postpartum
period. The use in nonsevere disease is practice dependent. However, studies have
shown that the signs considered to be prognostic for seizures, including headache,
epigastric pain, or hyperreflexia, are not reliable, and when the use of magnesium
sulfate was limited to only severe cases, the incidence of eclampsia increased by 50%.
(8) In the Magpie trial, there was no difference in neonatal morbidity for those fetuses
whose mothers received magnesium, including Apgar scores less than 7 at 5 minutes,
need for intubation at time of delivery, need for ventilation, abnormal cerebral
ultrasound, convulsions, or admission to the NICU. (12)
Eclampsia is most likely to occur during intrapartum or immediate postpartum periods
when the disease accelerates and is diagnosed when the patient experiences generalized
tonic-clonic seizures that cannot be attributed to other causes. (8) It is not uncommon to
observe prolonged fetal bradycardia during eclamptic seizures, but fetal status generally
improves with maternal stabilization and oxygenation. Thus, it is generally not advised
to perform an urgent cesarean delivery during an acute seizure.
In women who have severe disease, delivery by 34 weeks’ gestation seems to maximize
maternal and neonatal outcomes. When the diagnosis is made remote from this
gestational age, management becomes more complex. The administration of
corticosteroids for fetal lung maturity is considered if presentation is between 24 and 34
weeks’ gestation for any degree of preeclampsia. At minimum, the goal is to continue
observation for 48 hours after the steroids are administered to achieve benefit for the
infant. The maximum length of observation is dependent on the severity of the course of
preeclampsia. The median latency from time of diagnosis of severe, early-onset disease
to delivery is 7 to 14 days. (2) However, in cases of worsening disease, even a 48-hour
window of observation may not be attainable. If the disease is ameliorated, observation
could continue until 34 weeks’ gestation for those who have severe but stable
preeclampsia or 37 weeks’ gestation with nonsevere disease. Timing and indications for
delivery are shown in Table 2. (2)(11) Two randomized trials have compared expectant
management of severe disease until at most 34 weeks' gestation to delivery immediately
following corticosteroid benefit. Immediate delivery was associated with higher rates of
respiratory distress (RR: 2.3 [CI: 1.39–3.81]), necrotizing enterocolitis (RR: 5.54 [CI:
1.04–29.56]), and NICU admission (RR: 1.32 [CI: 1.13–1.55]). (2)(11)(13) The results
of a systematic review of the frequency of complications observed in 39 cohorts of
patients who underwent expectant management of severe preeclampsia remote from
term are displayed in Table 3. (13)
View this table:


In this window
In a new window
Table 2.
Timing of Delivery
View this table:


In this window
In a new window
Table 3.
Complications of Expectant Management of Severe Preeclampsia Remote From Term
When delivery is indicated, it is possible to achieve a vaginal delivery. However, this
option becomes less likely with decreasing gestational age. When labor is induced at
less than 28 weeks’ gestation, the cesarean delivery rate approaches 93% to 97%. In
comparison, only 31% to 38% of women induced at 32 to 34 weeks’ gestation will
require a cesarean delivery. (2)
Previous SectionNext Section
Maternal Complications
Complications, especially in severe, early-onset disease, have been seen in every organ
system. Preeclampsia is characterized by a constricted plasma volume compartment as
well as by alterations in vasculature; thus, decreased arterial and venous compliance
occurs, which can contribute to myocardial dysfunction, stroke, acute respiratory
distress, coaguloapathy, renal or hepatic failure, and retinal injury. (14)
In addition to eclampsia, other central nervous system complications include stroke and
posterior reversible encephalopathy syndrome (PRES). PRES is characterized by
vasogenic cerebral edema and infarctions in the subcortical white matter, predominantly
in the parieto-occipital lobe. Clinical signs include headache, seizures, altered mental
status, and hypertension. The edema associated with PRES seems to be due to
endothelial damage and not a direct result of acutely elevated blood pressures. Evidence
that PRES is caused by antiangiogenic factors is supported by the fact that it has also
been seen in patients who have malignancies treated with antiangiogenic agents. (1)
Figure 2 displays the classic magnetic resonance imaging findings of PRES.
View larger version:


In this page
In a new window

Download as PowerPoint Slide
Figure 2.
Classic magnetic resonance imaging findings of posterior reversible encephalopathy
syndrome (PRES). Extensive areas of subcortical increased T2 signal with enhanced
diffusivity involving bilateral posterior parietal and occipital white matter. Obstetric
Triage and Emergency Care Protocols, Angelini & Fontaine, 2012, Courtesy of
Springer Publishing Company, LLC.
Cardiac abnormalities include asymptomatic left ventricular dysfunction and
hypertrophy. In a study of women who had early-onset severe preeclampsia, 20% had
severe hypertrophy, 52% had global diastolic dysfunction, and 26% had global systolic
dysfunction. Although the women were usually asymptomatic at the time,
epidemiologic studies have shown a high prevalence of essential hypertension and an
increased cardiovascular risk status within a few years postpartum in what seems to be a
dose-dependent relationship between preeclampsia and long-term morbidity. (14)
Previous SectionNext Section
Neonatal Complications
Preeclampsia is the leading cause of iatrogenic premature delivery, and prematurity
therefore leads to much of the observed neonatal morbidity. (15)(16) Several studies
have compared infants born prematurely to healthy mothers versus those born to
mothers with severe preeclampsia. Although some studies have shown no difference in
outcomes, including respiratory distress syndrome, intraventricular hemorrhage, and
periventricular leukomalacia, this is not a consistent finding. (17) In a study comparing
the two populations, the incidence of a composite outcome (need for respiratory
support, intraventricular hemorrhage, necrotizing enterocolitis, seizures, or neonatal
mortality) was significantly higher in infants born after spontaneous labor to healthy
mothers at 24 to 27 weeks and 6 days (100% vs 71%; P = .008). However, the opposite
relationship was observed in infants 32 to 33 weeks and 6 days, suggesting the fetus
receives some degree of protection when delivered very early but develops potential
compromise when exposed to placental insufficiency for a prolonged period of time.
(15)
The reduced placental perfusion of preeclampsia also leads to neonatal complications,
including growth restriction and fetal death. In the Magpie trial, the risk of fetal death in
severe disease was 11.5%, twice as high as the rate of 5.4% seen in patients who had
nonsevere disease. (12) Severe preeclampsia is the most common cause for intrauterine
growth restriction in the nonanomalous infant. In a study of 307 infants born to mothers
with preeclampsia compared with infants born to healthy mothers, birthweight was
reduced 5% overall and 12% in early-onset disease. (18) In a separate review, the
incidence of growth restriction in women who had severe preeclampsia remote from
term was 28%, but after 32 weeks, this risk decreased to 9%, probably reflecting a more
benign process. (15)
The antiangiogenic state of the mother is also shared by the fetus, as cord blood VEFG
and placental growth factor levels are decreased, whereas sFlt-1 levels are increased.
This may contribute to the increased risk for bronchopulmonary dysplasia. An
angiogenic state is required for normal pulmonary vascular development and airway
branching, and adequate VEGF signaling is needed to maintain the alveolar structure of
the lungs. A prospective cohort of 107 infants born between 23 and 32 weeks’ gestation
showed an odds ratio of 2.96 for developing bronchopulmonary dysplasia if the mother
had preeclampsia. (16)(19)
Hematologic abnormalities may also be seen immediately after birth. The severity of
dysfunction is proportional to the degree of growth restriction and placental dysfunction
and not related to maternal hematologic abnormalities. Neutropenia is observed in 40%
to 50% of neonates who are growth restricted and is potentially due to decreased
production secondary to placental inhibitors. (15)(16) In a study of 520 hypertensive
mothers, the rate of neonatal thrombocytopenia was 9.2% compared with 2.2% in
controls. (20) However, term infants of hypertensive mothers were no more likely to be
thrombocytopenic than control infants. This finding may be secondary to decreased
production and microangiopathic sequestration of the platelets in the placental thrombi.
These abnormalities are rarely severe and resolve in 1 to 3 days. (15)(16)(20)
It has been hypothesized that an abnormal intrauterine environment causes long-term
effects in adult life. Known as “the developmental origin of adult diseases,” this theory
implies that chronic adult disease such as diabetes, hypertension, and cardiovascular
disease have their origin in utero due to insults during critical periods of development.
(21) A growing body of evidence in both laboratory and epidemiologic science supports
this theory. In a study of 12-year-old children, those born to preeclamptic mothers had
significantly higher systolic and diastolic blood pressure even after adjusting for weight
and height. (22) In addition, after subdividing into children who were small for
gestational age, children of mothers with preeclampsia who were small for gestational
age had the highest levels of total cholesterol, low-density lipoprotein cholesterol,
triglycerides, insulin, and plasma epinephrine. Another population-based study of over
one million children showed an increased risk of endocrine, nutritional, and metabolic
derangements in adolescence and early adulthood among the cohort exposed to
preeclampsia in utero, risk factors that remained even after adjusting for differences in
lifestyle. (23)
The chronic placental insufficiency present in preeclampsia has the potential to
influence fetal brain perfusion and lead to long-term effects on brain development and
intelligence. Multiple studies have shown that children born to mothers who have
preeclampsia may have various degrees of neurodevelopmental delay. (24)(25) In a
study of 78 very low birthweight infants born before 32 weeks’ gestation, assessments
at 2 years of corrected age (using the Bayley Scales of Infant Development), infants of
mothers who had preeclampsia had significantly lower scores compared with infants
born to healthy mothers. (25) In a retrospective study of 5,460 mothers with
preeclampsia, a significant 1.46 increased risk of epilepsy was noted in their offspring
compared with women who did not have preeclampsia. (26) This finding is supported
by a separate study in the Danish population noting increased risks of epilepsy in the
offspring of mothers with preeclampsia compared with offspring of healthy women.
(27)
Previous SectionNext Section
Conclusions
Preeclampsia, especially early-onset severe disease, is a complex disorder capable of
leading to significant short- and long-term maternal and neonatal morbidity. Clinical
manifestations of preeclampsia are a common end point for a number of complex
pathophysiologic changes that seem to be a result of abnormal placentation. Because the
only definitive therapy remains delivery, management of the disorder, especially when
presenting in early gestation, continues to pose a challenge and focuses on minimizing
significant maternal morbidity while achieving maximal benefit for the neonate. Infants
born to mothers who have preeclampsia are at risk for both immediate and long-term
health consequences of their abnormal uterine environment.
American Board of Pediatrics Neonatal-Perinatal Content Specifications


Know the normal morphologic development of the placenta.
Know the effects on the fetus and/or newborn infant of mild preeclampsia and
its management.

Know the effects on the fetus and/or newborn infant of severe preeclampsia,
including hemolysis, elevated liver enzymes, low platelet count syndrome, and
its management.
Previous SectionNext Section
Footnotes

Author Disclosure
Drs McDonnold and Olson have disclosed no financial relationships relevant to
this article. This commentary does not contain a discussion of an
unapproved/investigative use of a commercial product/device.
Abbreviations:
CI;
confidence interval
PRES;
posterior reversible encephalopathy syndrome
RR;
relative risk
sFlt-1;
soluble Fms-like tyrosine kinase-1
VEGF;
vascular endothelial growth factor

Copyright © 2013 by the American Academy of Pediatrics
Previous Section
References
1. 1.↵
1. Maynard SE,
2. Karumanchi SA
. Angiogenic factors and preeclampsia. Semin Nephrol. 2011;31(1):33–46
CrossRefMedline
2. 2.↵
1. Sibai BM
; Publications Committee, Society for Maternal-Fetal Medicine. Evaluation and
management of severe preeclampsia before 34 weeks’ gestation. Am J Obstet
Gynecol. 2011;205(3):191–198
CrossRefMedline
3. 3.↵
1. Zavalza-Gómez AB
. Obesity and oxidative stress: a direct link to preeclampsia? Arch Gynecol
Obstet. 2011;283(3):415–422
CrossRefMedline
4. 4.↵
1. George EM,
2. Granger JP
. Endothelin: key mediator of hypertension in preeclampsia. Am J Hypertens.
2011;24(9):964–969
CrossRefMedline
5. 5.↵
1.
2.
3.
4.
Silasi M,
Cohen B,
Karumanchi S,
Rana S
. Abnormal placentation, angiogenic factors, and the pathogenesis of
preeclampsia. Obstet Gynecol Clin N Am. 2010;37(2):239–253
CrossRefMedline
6. 6.↵
1.
2.
3.
4.
5.
6.
Gilbert JS,
Ryan MJ,
LaMarca BB,
Sedeek M,
Murphy SR,
Granger JP
. Pathophysiology of hypertension during preeclampsia: linking placental
ischemia with endothelial dysfunction. Am J Physiol Heart Circ Physiol.
2008;294(2):H541–H550
Abstract/FREE Full Text
7. 7.↵
1. Redman C,
2. Sargent I
. Preeclampsia, the placenta, and the maternal systemic inflammatory response
– a review. Placenta. 2003;24(suppl A):S21–S27
Search Google Scholar
8. 8.↵
1. Roberts J,
2. Funai E
. Pregnancy related hypertension. In: Creasy RK, ed. Creasy and Resnik’s
Maternal Fetal Medicine: Principles and Practice. 6th ed. Philadelphia, PA:
Saunders Elsevier; 2009:651–688
Search Google Scholar
9. 9.↵
1.
2.
3.
4.
5.
6.
Spong CY,
Mercer BM,
D’alton M,
Kilpatrick S,
Blackwell S,
Saade G
. Timing of indicated late-preterm and early-term birth. Obstet Gynecol.
2011;118(2 pt 1):323–333
CrossRefMedline
10. 10.↵
1.
2.
3.
4.
Koopmans CM,
Bijlenga D,
Groen H,
et al
; HYPITAT study group. Induction of labour versus expectant monitoring for
gestational hypertension or mild pre-eclampsia after 36 weeks’ gestation
(HYPITAT): a multicentre, open-label randomised controlled trial. Lancet.
2009;374(9694):979–988
CrossRefMedlineWeb of Science
11. 11.↵
1. Sibai B,
2. Barton J
. Expectant management of severe preeclampsia remote from term: patient
selection, treatment, and delivery indications. Am J Obstet Gynecol.
2007;196(6):514.e1–514.e9
Search Google Scholar
12. 12.↵
1.
2.
3.
4.
Altman D,
Carroli G,
Duley L,
et al
; Magpie Trial Collaboration Group. Do women with pre-eclampsia, and their
babies, benefit from magnesium sulphate? The Magpie Trial: a randomised
placebo-controlled trial. Lancet. 2002;359(9321):1877–1890
CrossRefMedlineWeb of Science
13. 13.↵
1.
2.
3.
4.
5.
6.
Magee LA,
Yong PJ,
Espinosa V,
Côté AM,
Chen I,
von Dadelszen P
. Expectant management of severe preeclampsia remote from term: a structured
systematic review. Hypertens Pregnancy. 2009;28(3):312–347
CrossRefMedline
14. 14.↵
1. Melchiorre K,
2. Thilaganathan B
. Maternal cardiac function in preeclampsia. Curr Opin Obstet Gynecol.
2011;23(6):440–447
CrossRefMedline
15. 15.↵
1. Gruslin A,
2. Lemyre B
. Pre-eclampsia: fetal assessment and neonatal outcomes. Best Pract Res Clin
Obstet Gynaecol. 2011;25(4):491–507
CrossRefMedline
16. 16.↵
1.
2.
3.
4.
Backes C,
Markham K,
Moorehead P,
Cordero L,
5. Nankervis C,
6. Giannone P
. Maternal preeclampsia and neonatal outcomes. J Pregnancy.
2011;2011:214365
Search Google Scholar
17. 17.↵
1.
2.
3.
4.
Kimberlin DF,
Hauth JC,
Owen J,
et al
. Indicated versus spontaneous preterm delivery: An evaluation of neonatal
morbidity among infants weighing </=1000 grams at birth. Am J Obstet
Gynecol. 1999;180(3 Pt 1):683–689
CrossRefMedlineWeb of Science
18. 18.↵
1.
2.
3.
4.
5.
Odegård RA,
Vatten LJ,
Nilsen ST,
Salvesen KA,
Austgulen R
. Preeclampsia and fetal growth. Obstet Gynecol. 2000;96(6):950–955
CrossRefMedlineWeb of Science
19. 19.↵
1.
2.
3.
4.
Hansen AR,
Barnés CM,
Folkman J,
McElrath TF
. Maternal preeclampsia predicts the development of bronchopulmonary
dysplasia. J Pediatr. 2010;156(4):532–536
CrossRefMedlineWeb of Science
20. 20.↵
1. Burrows RF,
2. Andrew M
. Neonatal thrombocytopenia in the hypertensive disorders of pregnancy. Obstet
Gynecol. 1990;76(2):234–238
MedlineWeb of Science
21. 21.↵
1.
2.
3.
4.
5.
Barker DJ,
Osmond C,
Golding J,
Kuh D,
Wadsworth ME
. Growth in utero, blood pressure in childhood and adult life, and mortality from
cardiovascular disease. BMJ. 1989;298(6673):564–567
Abstract/FREE Full Text
22. 22.↵
1.
2.
3.
4.
5.
Tenhola S,
Rahiala E,
Martikainen A,
Halonen P,
Voutilainen R
. Blood pressure, serum lipids, fasting insulin, and adrenal hormones in 12year-old children born with maternal preeclampsia. J Clin Endocrinol Metab.
2003;88(3):1217–1222
Abstract/FREE Full Text
23. 23.↵
1.
2.
3.
4.
5.
6.
Wu C,
Nohr E,
Bech B,
Vestergaard M,
Catov J,
Olsen J
. Health of children born to mothers who had preeclampsia: a population-based
cohort study. Am J Obstet Gynecol. 2009;201(3):269.e1–269.e10
Search Google Scholar
24. 24.↵
1.
2.
3.
4.
5.
Silveira RC,
Procianoy RS,
Koch MS,
Benjamin AC,
Schlindwein CF
. Growth and neurodevelopment outcome of very low birth weight infants
delivered by preeclamptic mothers. Acta Paediatr. 2007;96(12):1738–1742
CrossRefMedline
25. 25.↵
1.
2.
3.
4.
5.
Cheng SW,
Chou HC,
Tsou KI,
Fang LJ,
Tsao PN
. Delivery before 32 weeks of gestation for maternal pre-eclampsia: neonatal
outcome and 2-year developmental outcome. Early Hum Dev. 2004;76(1):39–46
CrossRefMedlineWeb of Science
26. 26.↵
1. Mann JR,
2. McDermott S
. Maternal pre-eclampsia is associated with childhood epilepsy in South
Carolina children insured by Medicaid. Epilepsy Behav. 2011;20(3):506–511
CrossRefMedline
27. 27.↵
1.
2.
3.
4.
Wu CS,
Sun Y,
Vestergaard M,
et al
. Preeclampsia and risk for epilepsy in offspring. Pediatrics. 2008;122(5):1072–
1078
Abstract/FREE Full Text
Intrapartum Asphyxia, Neonatal
Encephalopathy, Cerebral Palsy, and
Obstetric Interventions in the Term and
Near-Term Infant
1. Shannon M. Clark, MD,
2. Sanmaan K. Basraon, MD, and
3. Gary D.V. Hankins, MD
+ Author Affiliations
1. University of Texas Medical Branch, Galveston, TX.
Next Section
Abstract
Intrapartum asphyxia (IA) as a cause of neonatal encephalopathy (NE) and cerebral
palsy (CP) is a concern for obstetric providers due to the significant neonatal sequelae
that ensue. CP is a nonprogressive static neuromuscular disorder appearing early after
birth that occurs in 2 per 1,000 births. NE is a clinical syndrome of disturbed neurologic
function in the first week after birth, and it occurs in 6 per 1,000 live births. Only ∼6%
of all term infants diagnosed with CP have a history of NE, and without the
development of NE, IA cannot be considered as the sole cause of CP. There are various
preconceptional, antepartum, and intrapartum risk factors associated with CP. Obstetric
interventions, including various modalities of fetal monitoring and cesarean delivery,
have not led to improvement in outcomes or a reduction in the incidence of CP. The
goal of this review was to discuss the association of IA with NE and CP in term and
near-term infants, with a focus on the diagnosis and risk factors for IA and potential
obstetric interventions.
Previous SectionNext Section
Objectives
After completing this article, readers should be able to:
1. Differentiate between cerebral palsy, neonatal encephalopathy, and intrapartum
asphyxia.
2. Define the criteria required to diagnose intrapartum asphyxia as a cause of
moderate to severe neonatal encephalopathy.
3. Identify preconceptional, antepartum, and intrapartum risk factors for the
development of neonatal encephalopathy and/or cerebral palsy.
4. Recognize potential obstetric interventions.
Previous SectionNext Section
Introduction
In the majority of the cases of cerebral palsy (CP), the timing of insult is largely
unknown, and an isolated intrapartum event causing asphyxia is rarely the cause of
neurologic damage. It is prudent to understand the risk factors associated with the
development of intrapartum asphyxia (IA) and the pathophysiology behind the
development of neonatal encephalopathy (NE) and CP. Currently, there is a dearth of
obstetric interventions that decrease the incidence of these disorders; thus, further
research is needed to develop preventive strategies and targeted interventions aimed at
improving neonatal outcomes. The goal of this review was to discuss the association of
IA with NE and CP in term and near-term infants, with a focus on the diagnosis and risk
factors for IA and potential obstetric interventions.
Previous SectionNext Section
The Connection
Definition and Incidence
CP is defined as a nonprogressive static neuromuscular disorder characterized by an
abnormal control of movement or posture appearing early in life. (1) The onset occurs
no later than age 1 year, and the definitive diagnosis is typically reserved until age 4 to
5 years. The prevalence of CP is ∼2 per 1,000 live births. Although term infants are at
relatively low risk for CP, approximately one half of all births with CP are term and
near-term infants (2) as term births constitute about 92% of all births. Whereas CP has
many causes that may or may not be recognized at birth, NE is recognizable at birth.
NE is a clinically defined syndrome of disturbed neurologic function manifested by
difficulty with initiating and maintaining respirations, depression of tone and reflexes,
altered level of consciousness, and often seizures in the first week after birth in the nearterm and term infant. (3)(4)(5)(6) Such acute neonatal neurologic dysfunction is the
earliest and best indicator of neurologic injury and increased risk for later
neurodevelopmental sequelae. (7) NE occurs in 1 to 6 per 1,000 live term births, (2)
with 15% to 20% of affected newborns dying in the postnatal period and an additional
25% sustaining childhood disabilities. (8)
IA is a known cause of NE. A key feature in the consideration of IA as a cause of CP in
an individual infant is the concomitant presence of symptoms of moderate to severe NE.
However, only 6% of all term infants diagnosed with CP have a history of NE; (9)
therefore, the great majority of term CP cannot be considered to be the result of an
intrapartum injury. (10) The reported incidence of IA in term or near-term infants is 1 to
8 neonates per 1,000 live term births, with 0.5 to 1.6 per 1,000 subsequently developing
NE. (11) Of those with NE due to IA, between 10% and 60% will die, and ∼25% of the
survivors will have long-term neurodevelopmental sequelae. (4) Other investigators
(6)(7)(8)(9)(10)(11)(12) have reported that only 8% to 15% of term infants with NE,
and even fewer with early neonatal seizures, (13) have evidence of asphyxia
immediately before birth. Finally, IA as a cause of CP occurs in only a minority of cases
and has been cited as low as 10% and as high as 20%. (14)(15)
Timing of Injury
Even though guidelines for diagnosing IA as a cause of NE have been established,
determining if asphyxia was present before the onset of labor or developed during labor
and delivery is difficult to ascertain. In addition, intrapartum adverse events could be
the result of an antepartum predisposition or antepartum onset of brain injury or brain
dysfunction that results in a negative response of the fetus to the stresses incurred
during labor and delivery. (16)(17) As such, difficulties during the course of labor and
delivery could be secondary to fetal compromise predating labor, and subsequent poor
oxygenation or fetal hypotension during labor are merely contributors to the
development of NE. (17) However, even if antenatal factors are identified, it is still
difficult to prove that subsequent injury did not occur during the intrapartum period.
The Western Australian case-control study by Badawi et al (4) in 1998 compared 164
term infants exhibiting moderate to severe NE (broadly defined) with 400 randomly
selected controls. They found no evidence of intrapartum hypoxia in more than 70% of
NE cases, and isolated IA accounted for only 4% of moderate to severe NE.
Furthermore, they noted that most causes of NE were heterogeneous and most
commenced in the antenatal period. These findings were in agreement with an
international consensus statement, which noted that epidemiologic studies suggest that
∼90% of cases of CP have no history of IA. (18) In the remaining 10%, intrapartum
signs compatible with damaging hypoxia may have had either antenatal or intrapartum
origins. However, there are conflicting reports that suggest otherwise. In 2003, Cowan
et al (19) used neonatal brain magnetic resonance imaging or postmortem examination
in 351 term infants with NE, early seizures, or both to distinguish between lesions
acquired antenatally and those that developed in the intrapartum and early postpartum
period. They found that greater than 90% of term infants with NE, seizures, or both, but
without specific syndromes or major congenital defects, had evidence of perinatally
acquired insults, and there was a very low rate of established brain injury acquired
before birth. However, their data could not exclude the possibility that antenatal factors
might contribute to perinatal brain injury and, in addition to genetic predispositions to
hypoxic-ischemic injury, may render the fetus more susceptible to the stresses of labor
and delivery.
Previous SectionNext Section
Clinical Criteria for Diagnosing Intrapartum Asphyxia
Pathophysiology of Intrapartum Asphyxia
The diagnosis of IA (fetal hypoxia and/or ischemia) includes impaired respiratory gas
exchange and development of fetal metabolic acidosis (20) during labor and delivery
with oxygen deprivation in fetal brain either through hypoxia and/or ischemia.
Hypoxemia results from diminished oxygen in the fetal blood supply, and cerebral
ischemia occurs due to impaired blood supply to the fetal brain, with the latter resulting
in deprivation of glucose, which further contributes to the development of neuronal
injury. (21) When an intrapartum insult occurs as a result of various events, the
placental blood flow and gas exchange is impaired, leading to a cycle of ischemia and
reperfusion of the fetal brain that results in necrosis and cell death. (22)(23) After such
insult, the fetal cardiac output is redistributed, with decreased blood flow to the lungs,
kidney, and intestine with preservation of circulation to the brain, heart, and adrenals.
(24)
Of utmost importance is the maintenance of the integrity of the central nervous system
(CNS), especially the brain, during the compensatory phase of an asphyxial exposure
that is accomplished by a combination of increased cerebral blood flow and oxygen
extraction. (24) Damage is greatest when the asphyxial exposure persists and
cardiovascular decompensation occurs. A severe metabolic acidosis then develops, and
the combination of asphyxia and ischemia due to hypotension and hypoperfusion results
in a decrease in cerebral oxygen consumption and ultimately brain injury and end-organ
damage. (24) A fetus can usually compensate and recover after an asphyxial exposure
with correction of respiratory acidosis. (25) However, recurrent, intermittent, or
continuous asphyxial insults causing metabolic acidosis for a prolonged period of time
can result in varying degrees of brain injury depending on the gestational age of the
fetus. Ultimately, these events can lead to short-term sequelae, as represented by NE, or
long-term sequelae, as seen with CP.
Clinical Diagnosis of Intrapartum Asphyxia
Currently, the standard for defining an acute intrapartum hypoxic-ischemic event as
sufficient to cause moderate to severe NE in term and near-term neonates that
subsequently results in CP uses the four essential criteria put forth by the American
College of Obstetricians and Gynecologists and American Academy of Pediatrics Task
Force on Neonatal Encephalopathy and Cerebral Palsy (Table 1). (26) If all of these
criteria are met, it is likely that the pathology causing CP occurred during labor. The
task force also presented five criteria that suggest an intrapartum timing of a hypoxic
event within 48 hours of delivery when present collectively but are nonspecific to
asphyxial insults. These criteria are weakly associated with an acute IA event, with the
exception of the first one (a sentinel or hypoxic event occurring immediately before or
after the onset of labor). (3)
View this table:


In this window
In a new window
Table 1.
Criteria for Defining an Acute Intrapartum Hypoxic-Ischemic Event as a Cause of CP
(26)
Even when all four essential criteria are met, the timing of the insult cannot be definitely
determined. Hypoxia could be intermittent, chronic, or acute during labor in a
previously healthy fetus. However, if an ischemic cerebral injury occurred in the
intrapartum period, results of the neurologic examination of the neonate will be
abnormal within the first 24 hours of birth. Abnormalities can be observed in the
following: 1) cortical function (lethargy, stupor, coma with or without seizures); 2)
brainstem function (pupillary and cranial nerve abnormalities); 3) tone (hypotonia); and
4) reflexes (absent, hyporeflexia). (7(21) If the NE that develops after an IA event is
severe enough to cause CP, it is of the spastic quadriplegic or dyskinetic type.
(3)(27)(28) Unilateral brain lesions, hemiparetic CP, (29)(30) hemiplegic CP, spastic
diplegia, and ataxia have not been associated with acute IA. (30) Finally, any
progressive neurologic disability is not CP and thus not a result of an acute IA event. (3)
When considering fetal tracings, abnormal patterns most frequently found to be
associated with the development of CP include multiple late decelerations and
decreased beat-to-beat variability. (3) Of note, the presence of such tracings may be the
first sign of a pre-existing fetal neurologic abnormality, (31) severe antenatal neurologic
injury, (32)(33) or an acute intrapartum injury. However, there is a high false-positive
rate when predicting CP. (34) Nelson et al (34) found that intrapartum fetal heart rate
tracing abnormalities as a marker for IA had poor predictive value for the development
of NE; the presence of multiple late decelerations and/or persistent decreased beat-tobeat variability had a false-positive predictive rate for subsequent development of CP of
99.8%. Similarly, it is known that 1- or 5-minute Apgar scores alone are poor predictors
of long-term neurologic outcome, with 75% of children with CP obtaining normal
Apgar scores at birth. (35) Finally, extremely low Apgar scores at 15 and 20 minutes
only have been shown to strongly correlate with subsequent neurologic dysfunction. (3)
The best indicator for IA is metabolic acidosis (pH <7 and base deficit ≥12 mmol/L) in
umbilical arterial blood at the time of delivery. (18)(36) This finding allows for an
accurate diagnosis of asphyxia via umbilical cord blood gas and acid base assessment.
(24) It is recommended that both arterial and venous cord blood be obtained because
arterial blood reflects fetal status more directly and venous blood reflects whether the
uteroplacental oxygen exchange is optimal; (37) however, this testing is not always
feasible. If there is significant metabolic acidosis at the time of sampling, it is likely that
IA has occurred. However, it does not indicate the duration of exposure or whether it
was continuous or intermittent. (24) The diagnosis of IA is based on the presence of
metabolic acidosis; the severity of the asphyxia is based on the degree of NE and the
presence of other organ system complications. (24)
Multisystem organ involvement, once thought to be a requirement for the diagnosis of
IA, was included on the list of nonspecific criteria for hypoxic-ischemic encephalopathy
(HIE) by the American College of Obstetricians and Gynecologists/American Academy
of Pediatrics Task Force. (26) As previously mentioned, during an IA event, an attempt
is made to preserve perfusion to the vital organs by shunting blood away from other
organ systems. (11) As a result, elevation in liver enzyme levels, impaired renal
function and acute tubular necrosis, and heart injury may be observed in the neonate.
Laboratory assessment should occur as soon as possible after delivery if IA is believed
to be present, and followed over the next several days to weeks because some markers
do not immediately appear as abnormal.
In a 2002 study by Hankins et al, (38) 46 cases of acute peripartum asphyxia sufficient
to result in the diagnosis of NE were identified through a prospectively maintained
database. Using criteria to define an acute IA event that are slightly different from what
is used today, the authors identified how often various organ systems reflected injury
patterns by using commonly available laboratory tests and/or imaging technologies.
They included patients with an obvious acute intrapartum event of recent onset, such as
a placental abruption, umbilical cord prolapse, or deterioration in a previously normal
fetal heart rate pattern in gestations greater than 32 weeks. They found that in cases with
clinical CNS injury resulting in encephalopathy, 49% had abnormal results on
electroencephalogram and 40% had imaging studies that were diagnostic of acute
injury. In addition, liver injury, based on elevated transaminase levels, occurred in 80%;
heart injury, as defined by pressor or volume support beyond 2 hours after birth or
elevated cardiac enzyme levels, occurred in 78%; and renal injury, defined by an
elevation of serum creatinine to greater than 1.0 mg/dL, persistent hematuria, persistent
proteinuria, or clinical oliguria, occurred in 72%. Finally, when combining results of
laboratory and imaging studies, involvement of the renal, hepatic, CNS, and cardiac
systems was observed in greater than 70% of cases. Hankins et al concluded that
multiple organs suffer damage during an acute IA event sufficient to result in NE, and
absence of injury does not correlate with the diagnosis of IA.
Previous SectionNext Section
Risk Factors
Preconceptional and Antepartum Risk Factors
There is a higher incidence of maternal illness, antenatal complications, and adverse
social factors in infants with NE, seizures, or both,
(2)(3)(5)(30)(39)(40)(41)(42)(43)(44) most occurring occur well before birth, which
must be excluded before the diagnosis of IA is made. (19)(26) As previously discussed,
the presence of antepartum risk factors may render the fetus more susceptible to the
stresses of labor and delivery, and further increase the risk of IA. In this scenario, it is
impossible to determine whether the antepartum risk factor(s) or an intrapartum insult
played the key role in the development of NE and/or CP. Conversely, the presence of
antepartum risk factors does not mean that an acute intrapartum event cannot occur.
In addition to intrapartum insults, Badawi et al, (5) in their population-based unmatched
case-control study of term infants, found various preconceptional and antenatal factors
that increase the risk of NE and/or CP as summarized in Tables 2 and 3. Various social
factors, family and personal history, and infertility treatment were strongly associated
with risk of development of NE and/or CP. In addition, various antenatal factors, most
importantly maternal thyroid disease, severe preeclampsia, and intrauterine growth
restriction (less than the third percentile for birthweight), had a strong association with
NE. They concluded that there are numerous causes of NE, many of which start before
labor and delivery. In 2011, Maisonneuve et al (45) identified risk factors of severe
acidosis in a case-control study of term pregnancies with severe neonatal acidosis
(umbilical artery pH < 7.0) and found severe acidosis in 0.63% of 39,321 live term
births. They did not use all criteria for the diagnosis of IA for the purposes of this study.
Maternal age greater than 35 years, previous neonatal death and previous cesarean
delivery (CD), were independent risk factors for severe neonatal acidosis (Tables 2 and
3).
View this table:


In this window
In a new window
Table 2.
Preconceptional Risk Factors for NE and/or CP
View this table:


In this window
In a new window
Table 3.
Antepartum Risk Factors for NE and/or CP
Chorioamnionitis (intrapartum maternal and/or fetal tachycardia and maternal
temperature elevation) increase the risk of NE and CP. (2) Although chorioamnionitis is
readily identifiable during the course of labor and delivery, other antepartum infections
are variable in their sequelae and ease of diagnosis. It is well known that rubella and
cytomegalovirus are viral teratogens; however, there are other viruses that may play a
role in fetal neurologic damage in the antepartum period. (46) In addition, maternal
hyperthermia, inflammatory mediators, and other pathophysiologic sequelae observed
with any maternal infection may contribute to the development of IA and NE. (47) In
the event that antenatal or intrapartum exposure to infection occurs, neonates should be
evaluated by using proper laboratory assessments and examination, and, ideally, the
placenta should be sent for pathologic evaluation.
Intrapartum Risk Factors
A sentinel event (SE) is an acute intrapartum pathologic event that causes neurologic
damage to a previously intact fetus through compromised blood or oxygen supply. (3)
Although the task force considers it as a criterion suggestive of an IA event as a cause
of NE, an SE is more strongly associated with acute IA than other criteria. (26)
Examples of SEs and intrapartum risk factors are shown in Table 4. (2)(3)
View this table:


In this window
In a new window
Table 4.
Intrapartum Risk Factors and Sentinal Events (*) for NE and/or CP
A retrospective population-based study by Gilbert et al (48) in 2010 examined adverse
intrapartum events in children with spastic quadriplegic or dyskinetic type CP. These
events included abruption, uterine rupture, fetal distress, birth trauma, prolapsed cord,
and mild to severe birth asphyxia. The frequency of CP within the study population was
1.4 per 1,000 deliveries. Overall, 31.3% of these children had one or more of the six
adverse intrapartum events compared with 12.9% of controls. Fifty-nine percent (4,274
of 7,242) of children identified with CP in this study were term births; 28.3% had one or
more adverse events compared with 12.7% in controls. The authors noted that these
findings could show that birth-related events are a more significant cause of the
development of CP than previously thought. However, overall, the majority of children
who had CP did not have an adverse intrapartum event related to their development of
CP.
In a 2012 retrospective double cohort study of three groups of infants at greater than 35
weeks’ gestation exposed to different risk factors for IA, Martinez-Biarge et al (49)
examined perinatal morbidity and the rate of HIE in infants exposed to intrapartum SE.
These groups included the following: (1) infants with an intrapartum SE; (2) infants
delivered by emergency CD or operative vaginal delivery due to abnormal fetal heart
rate tracing; and (3) infants delivered by elective CD before the onset of labor. SE
included uterine rupture, placental abruption, cord prolapse, and amniotic fluid
embolism. Diagnosis of HIE was made when the infant met the criteria for neonatal
depression/cord arterial pH ≤7.00 or Apgar score ≤3 at 1 minute and/or ≤5 at 5 minutes
or need for advanced resuscitation; and NE as presented by Leviton and Nelson. (6)
They found that perinatal mortality was 6% in the SE group and 0.3% in the
nonreassuring fetal status group (relative risk [RR]: 2.4 [95% confidence interval (CI):
1.95–2.94]) with perinatal morbidity increased two to six times in infants exposed to
SE. The incidence of HIE was 10% in the SE group compared with 2.5% in the
nonreassuring fetal status group (RR: 1.93 [95% CI: 1.49–2.52]). When considering SE,
uterine rupture was associated with the highest incidence of HIE (32%), followed by
placental abruption (11%). Finally, no infant in the elective cesarean group died, had
perinatal morbidity, or developed encephalopathy. The authors concluded that
intrapartum SE are a significant cause of perinatal morbidity and the development of
HIE. (49)
The 1998 Australian study of Badawi et al (4) also examined various intrapartum
predictors for NE in term infants (Table 4). They found that the prevalence of moderate
or severe NE was 3.8 per 1,000 term live births with a neonatal mortality rate of 9.1%.
When considering risk factors, 69% of case infants had only antepartum risk factors for
NE, 24% had antepartum and intrapartum factors, 5% had only intrapartum factors, and
2% had no identifiable risk factors. They concluded that IA accounts for a small
proportion of cases of NE, and elective CD has an inverse association with NE.
Previous SectionNext Section
Obstetric Interventions
Electronic Fetal Monitoring
For the term and near-term infant, the most obvious tool that the obstetrician can use to
identify fetuses at risk for IA and decrease the risk of intrapartum fetal death or neonatal
seizures is electronic fetal monitoring (EFM) during labor and delivery. (50) Although
some studies report that EFM correlates with the onset of metabolic acidosis and
subsequent neurologic injury, (50)(51) there is no consensus on this subject, and
investigators disagree on what is the most ominous fetal heart rate pattern that signifies
potential metabolic acidosis. In general, prolonged decreased variability with repetitive,
prolonged late or variable decelerations and sustained bradycardia are all potential signs
of impending neonatal metabolic acidosis. In general, however, the predictive power of
EFM for the development of NE and CP is low, (25) and to date, the use of EFM has
not decreased the incidence of CP. (52) This is likely due to the fact that most cases of
CP are a result of events that occurred before the onset of labor, and a very small
percentage of cases are a result of IA. (3)(5) Overall, EFM has led to an increase in
obstetric interventions in the form of cesarean and operative vaginal deliveries,
especially during active labor. (53) This affords the potential for increased
complications for both the mother and fetus. Despite this risk, EFM is the best tool
obstetricians can use in labor in an effort to identify fetal metabolic acidosis.
ST waveform analysis includes the addition of the fetal electrocardiogram to standard
cardiotocography for intrapartum fetal monitoring in an attempt to reduce neonatal and
fetal asphyxia. (54)(55) A meta-analysis of randomized controlled trials by Becker et al
(56) in 2012 compared the effects on ST waveform analysis with standard continuous
cardiotocography in singleton pregnancies in cephalic presentation at ≥34 weeks’
gestation. They evaluated various abnormalities in metabolic acidosis, umbilical cord
pH, Apgar scores, admittance to the NICU, need for intubation, presence of HIE,
perinatal death, operative delivery, and number of fetal blood samplings. They found
that ST waveform analysis did not reduce the occurrence of metabolic acidosis (RR:
0.72 [95% CI: 0.43–1.19]). However, ST waveform analysis did significantly reduce the
incidence of additional fetal blood sampling (RR: 0.59 [95% CI: 0.44–0.79]), operative
vaginal deliveries (RR: 0.88 [95% CI: 0.80–0.97]), and total operative deliveries (RR:
0.94 [95% CI: 0.89–0.99]). (56) Although fetal blood sampling is not standard practice
in most institutions, continuous cardiotocography for intrapartum fetal monitoring is
still used. Trials are underway to determine if ST waveform analysis is effective in
reducing the occurrence of neonatal metabolic acidosis.
Cesarean Delivery
CD has well-known surgical risk to the mother, especially with subsequent repeat CD.
When considering the term infant and CD, the risk of respiratory complications is
greater, especially in the case of elective CD in the absence of labor. There is evidence
that CD for the breech fetus reduces perinatal mortality, neonatal mortality, and serious
neonatal morbidity with a planned CD. (57) Although it seems reasonable that elective
CD may decrease the incidence of IA, any benefit may indeed be due to avoidance of
certain intrapartum risk factors rather than bypassing the potential for adverse
intrapartum events. (4) Currently, there is no recommendation for the performance of
elective CD for the prevention of IA and the subsequent development of NE and CP.
Other Interventions
One of the most obvious interventions obstetricians have is antenatal screening for the
detection of risk factors for adverse antepartum and intrapartum outcomes. (25) Early
detection allows earlier intervention and informed decision-making regarding mode and
timing of delivery. Identification of maternal and fetal disease is of utmost importance.
When considering labor and delivery, there are several interventions that obstetricians
use when faced with a nonreassuring fetal heart tracing. These interventions include
maternal oxygen supplementation and position change, tocolytic agents (ie, β2adrenergic agonist), and amnioinfusion. In some of these cases, these measures allow
resuscitation before the decision is made to proceed with CD.
American Board of Pediatrics Neonatal–Perinatal Content Specifications








Know the clinical features, diagnosis, and management of perinatal hypoxicischemic encephalopathy.
Differentiate asphyxia from other causes of depression at birth, including drug
effects and hypovolemia.
Understand the significance, limitations, and causes of low Apgar scores.
Know the interpretation of fetal scalp and umbilical cord blood gas and pH
values.
Know the approximate risk of cerebral palsy in very low birthweight,
moderately low birthweight, and normal birthweight infants.
Know the relationship between Apgar scores and later development of cerebral
palsy in preterm and term infants.
Know the prenatal, perinatal, and neonatal risk factors for the development of
cerebral palsy.
Know that the majority of children with cerebral palsy have no identifiable
cause.
Previous SectionNext Section
Footnotes

Author Disclosure
Drs Clark, Basraon, and Hankins have disclosed no financial relationships
relevant to this article. This commentary does contain a discussion of an
unapproved/investigative use of a commercial product/device.
Abbreviations:
CD;
cesarean delivery
CNS;
central nervous system
CP;
cerebral palsy
EFM;
electronic fetal monitoring
HIE;
hypoxic-ischemic encephalopathy
IA;
intrapartum asphyxia
NE;
neonatal encephalopathy
SE;
sentinel event

Copyright © 2013 by the American Academy of Pediatrics
Previous Section
References
1. 1.↵
1.
2.
3.
4.
Aisen ML,
Kerkovich D,
Mast J,
et al
. Cerebral palsy: clinical care and neurological rehabilitation. Lancet Neurol.
2011;10(9):844–852
CrossRefMedline
2. 2.↵
1. Shankaran S
. Prevention, diagnosis, and treatment of cerebral palsy in near-term and term
infants. Clin Obstet Gynecol. 2008;51(4):829–839
CrossRefMedline
3. 3.↵
1. Hankins GD,
2. Speer M
. Defining the pathogenesis and pathophysiology of neonatal encephalopathy
and cerebral palsy. Obstet Gynecol. 2003;102(3):628–636
CrossRefMedlineWeb of Science
4. 4.↵
1.
2.
3.
4.
Badawi N,
Kurinczuk JJ,
Keogh JM,
et al
. Intrapartum risk factors for newborn encephalopathy: the Western Australian
case-control study. BMJ. 1998;317(7172):1554–1558
Abstract/FREE Full Text
5. 5.↵
1.
2.
3.
4.
Badawi N,
Kurinczuk JJ,
Keogh JM,
et al
. Antepartum risk factors for newborn encephalopathy: the Western Australian
case-control study. BMJ. 1998;317(7172):1549–1553
Abstract/FREE Full Text
6. 6.↵
1. Leviton A,
2. Nelson KB
. Problems with definitions and classifications of newborn encephalopathy.
Pediatr Neurol. 1992;8(2):85–90
CrossRefMedlineWeb of Science
7. 7.↵
1. Sarnat HB,
2. Sarnat MS
. Neonatal encephalopathy following fetal distress. A clinical and
electroencephalographic study. Arch Neurol. 1976;33(10):696–705
CrossRefMedlineWeb of Science
8. 8.↵
1.
2.
3.
4.
Badawi N,
Felix JF,
Kurinczuk JJ,
et al
. Cerebral palsy following term newborn encephalopathy: a population-based
study. Dev Med Child Neurol. 2005;47(5):293–298
CrossRefMedlineWeb of Science
9. 9.↵
1. Nelson KB
. The epidemiology of cerebral palsy in term infants. Ment Retard Dev Disabil
Res Rev. 2002;8(3):146–150
CrossRefMedlineWeb of Science
10. 10.↵
1. Johnson SL,
2. Blair E,
3. Stanley FJ
. Obstetric malpractice litigation and cerebral palsy in term infants. J Forensic
Leg Med. 2011;18(3):97–100
CrossRefMedline
11. 11.↵
1. Flidel-Rimon O,
2. Shinwell ES
. Neonatal aspects of the relationship between intrapartum events and cerebral
palsy. Clin Perinatol. 2007;34(3):439–449
CrossRefMedline
12. 12.↵
1. Blair E,
2. Stanley FJ
. Intrapartum asphyxia: a rare cause of cerebral palsy. J Pediatr.
1988;112(4):515–519
CrossRefMedlineWeb of Science
13. 13.↵
1.
2.
3.
4.
5.
6.
Mercuri E,
Cowan F,
Rutherford M,
Acolet D,
Pennock J,
Dubowitz L
. Ischaemic and haemorrhagic brain lesions in newborns with seizures and
normal Apgar scores. Arch Dis Child Fetal Neonatal Ed. 1995;73(2):F67–F74
Abstract/FREE Full Text
14. 14.↵
1. Shevell MI,
2. Majnemer A,
3. Morin I
. Etiologic yield of cerebral palsy: a contemporary case series. Pediatr Neurol.
2003;28(5):352–359
CrossRefMedlineWeb of Science
15. 15.↵
1.
2.
3.
4.
Yudkin PL,
Johnson A,
Clover LM,
Murphy KW
. Assessing the contribution of birth asphyxia to cerebral palsy in term
singletons. Paediatr Perinat Epidemiol. 1995;9(2):156–170
MedlineWeb of Science
16. 16.↵
1.
2.
3.
4.
5.
6.
Low JA,
Galbraith RS,
Muir DW,
Killen HL,
Pater EA,
Karchmar EJ
. Motor and cognitive deficits after intrapartum asphyxia in the mature fetus. Am
J Obstet Gynecol. 1988;158(2):356–361
MedlineWeb of Science
17. 17.↵
1. de Vries LS,
2. Cowan FM
. Evolving understanding of hypoxic-ischemic encephalopathy in the term infant.
Semin Pediatr Neurol. 2009;16(4):216–225
CrossRefMedline
18. 18.↵
1. MacLennan A
. A template for defining a causal relation between acute intrapartum events and
cerebral palsy: international consensus statement. BMJ. 1999;319(7216):1054–
1059
FREE Full Text
19. 19.↵
1.
2.
3.
4.
Cowan F,
Rutherford M,
Groenendaal F,
et al
. Origin and timing of brain lesions in term infants with neonatal
encephalopathy. Lancet. 2003;361(9359):736–742
CrossRefMedlineWeb of Science
20. 20.↵
1. Shevell MI
. The “Bermuda triangle” of neonatal neurology: cerebral palsy, neonatal
encephalopathy, and intrapartum asphyxia. Semin Pediatr Neurol.
2004;11(1):24–30
CrossRefMedline
21. 21.↵
1. Volpe JJ
. Neurology of the Newborn. 4th ed. Philadelphia, PA: WB Saunders Company;
2001
Search Google Scholar
22. 22.↵
1. Perlman JM
. Intrapartum hypoxic-ischemic cerebral injury and subsequent cerebral palsy:
medicolegal issues. Pediatrics. 1997;99(6):851–859
FREE Full Text
23. 23.↵
1.
2.
3.
4.
Lorek A,
Takei Y,
Cady EB,
et al
. Delayed (“secondary”) cerebral energy failure after acute hypoxia-ischemia in
the newborn piglet: continuous 48-hour studies by phosphorus magnetic
resonance spectroscopy. Pediatr Res. 1994;36(6):699–706
MedlineWeb of Science
24. 24.↵
1. Low JA
. Determining the contribution of asphyxia to brain damage in the neonate. J
Obstet Gynaecol Res. 2004;30(4):276–286
CrossRefMedlineWeb of Science
25. 25.↵
1. Kumar S,
2. Paterson-Brown S
. Obstetric aspects of hypoxic ischemic encephalopathy. Early Hum Dev.
2010;86(6):339–344
CrossRefMedlineWeb of Science
26. 26.↵
American College of Obstetricians and Gynecologists. The American College of
Obstetricians and Gynecologists' Task Force on Neonatal Encephalopathy and
Cerebral Palsy, the American College of Obstetricians and Gynecologists, the
American Academy of Pediatrics. Neonatal Encephalopathy and Cerebral
Palsy: Defining the Pathogenesis and Pathophysiology. Washington, DC: the
American College of Obstetricians and Gynecologists; 2003
27. 27.↵
1. Rosenbloom L
. Dyskinetic cerebral palsy and birth asphyxia. Dev Med Child Neurol.
1994;36(4):285–289
Medline
28. 28.↵
1. Stanley FJ,
2.
3.
4.
5.
Blair E,
Hockey A,
Petterson B,
Watson L
. Spastic quadriplegia in Western Australia: a genetic epidemiological study. I:
Case population and perinatal risk factors. Dev Med Child Neurol.
1993;35(3):191–201
MedlineWeb of Science
29. 29.↵
1. Michaelis R,
2. Rooschüz B,
3. Dopper R
. Prenatal origin of congenital spastic hemiparesis. Early Hum Dev.
1980;4(3):243–255
CrossRefMedline
30. 30.↵
1. Nelson KB,
2. Grether JK
. Potentially asphyxiating conditions and spastic cerebral palsy in infants of
normal birth weight. Am J Obstet Gynecol. 1998;179(2):507–513
CrossRefMedlineWeb of Science
31. 31.↵
1.
2.
3.
4.
5.
6.
Adamson SJ,
Alessandri LM,
Badawi N,
Burton PR,
Pemberton PJ,
Stanley F
. Predictors of neonatal encephalopathy in full-term infants. BMJ.
1995;311(7005):598–602
Abstract/FREE Full Text
32. 32.↵
1. Phelan JP,
2. Ahn MO
. Perinatal observations in forty-eight neurologically impaired term infants. Am
J Obstet Gynecol. 1994;171(2):424–431
MedlineWeb of Science
33. 33.↵
1. Schifrin BS,
2. Hamilton-Rubinstein T,
3. Shields JR
. Fetal heart rate patterns and the timing of fetal injury. J Perinatol.
1994;14(3):174–181
Medline
34. 34.↵
1.
2.
3.
4.
Nelson KB,
Dambrosia JM,
Ting TY,
Grether JK
. Uncertain value of electronic fetal monitoring in predicting cerebral palsy. N
Engl J Med. 1996;334(10):613–618
CrossRefMedlineWeb of Science
35. 35.↵
1. Nelson KB,
2. Ellenberg JH
. Apgar scores as predictors of chronic neurologic disability. Pediatrics.
1981;68(1):36–44
Abstract/FREE Full Text
36. 36.↵
American College of Obstetricians and Gynecologists. ACOG committee
opinion. Use and abuse of the Apgar score. Number 174-July 1996 (replaces
No. 49, November 1986). Committee on Obstetric Practice and American
Academy of Pediatrics: Committee on Fetus and Newborn. Int J Gynaecol
Obstet. 1996;54(3):303–305
CrossRefMedline
37. 37.↵
1. Muraskas JK,
2. Morrison JC
. A proposed evidence-based neonatal work-up to confirm or refute allegations
of intrapartum asphyxia. Obstet Gynecol. 2010;116(2 pt 1):261–268
CrossRefMedline
38. 38.↵
1.
2.
3.
4.
5.
6.
Hankins GD,
Koen S,
Gei AF,
Lopez SM,
Van Hook JW,
Anderson GD
. Neonatal organ system injury in acute birth asphyxia sufficient to result in
neonatal encephalopathy. Obstet Gynecol. 2002;99(5 pt 1):688–691
CrossRefMedlineWeb of Science
39. 39.↵
1. Blair E,
2. Stanley F
. Intrauterine growth and spastic cerebral palsy. I. Association with birth weight
for gestational age. Am J Obstet Gynecol. 1990;162(1):229–237
MedlineWeb of Science
40. 40.↵
1. Foley J
. Birth-weight ratio and cerebral palsy. Early Hum Dev. 1995;40(2):145–156
CrossRefMedline
41. 41.↵
1. Keogh JM,
2. Badawi N
. The origins of cerebral palsy. Curr Opin Neurol. 2006;19(2):129–134
MedlineWeb of Science
42. 42.↵
1. Nelson KB,
2. Ellenberg JH
. Antecedents of cerebral palsy. I. Univariate analysis of risks. Am J Dis Child.
1985;139(10):1031–1038
CrossRefMedline
43. 43.↵
1. Nuñez JL,
2. McCarthy MM
. Sex differences and hormonal effects in a model of preterm infant brain injury.
Ann N Y Acad Sci. 2003;1008:281–284
CrossRefMedlineWeb of Science
44. 44.↵
1. Uvebrant P,
2. Hagberg G
. Intrauterine growth in children with cerebral palsy. Acta Paediatr.
1992;81(5):407–412
MedlineWeb of Science
45. 45.↵
1.
2.
3.
4.
Maisonneuve E,
Audibert F,
Guilbaud L,
et al
. Risk factors for severe neonatal acidosis. Obstet Gynecol. 2011;118(4):818–
823
CrossRefMedline
46. 46.↵
1. Halperin LR,
2. Wilroy RS Jr
. Maternal hyperthermia and neural-tube defects. Lancet. 1978;2(8082):212–
213
Medline
47. 47.↵
1. Adlinolfi M
. Infectious diseases in pregnancy, cytokines and neurological impairment: an
hypothesis. Dev Med Child Neurol. 1993;35(6):549–553
MedlineWeb of Science
48. 48.↵
1.
2.
3.
4.
5.
Gilbert WM,
Jacoby BN,
Xing G,
Danielsen B,
Smith LH
. Adverse obstetric events are associated with significant risk of cerebral palsy.
Am J Obstet Gynecol. 2010;203(4):328.e1–328.e 5
Search Google Scholar
49. 49.↵
1.
2.
3.
4.
5.
Martinez-Biarge M,
Madero R,
Gonzalez A,
Quero J,
Garcia-Alix A
. Perinatal morbidity and risk of hypoxic-ischemic encephalopathy associated
with intrapartum sentinel events. Am J Obstet Gynecol. 2012;206(2):148.e1–
148.e7
Medline
50. 50.↵
American College of Obstetricians and Gynecologists. Intrapartum Fetal Heart
Rate Monitoring: Nomenclature, Interpretation, and General Management
Principles. Washington, DC: the American College of Obstetricians and
Gynecologists; 2009. ACOG Practice Bulletin Number 106
51. 51.↵
1. Williams KP,
2. Galerneau F
. Intrapartum fetal heart rate patterns in the prediction of neonatal acidemia.
Am J Obstet Gynecol. 2003;188(3):820–823
CrossRefMedlineWeb of Science
52. 52.↵
1. Clark SM,
2. Ghulmiyyah LM,
3. Hankins GD
. Antenatal antecedents and the impact of obstetric care in the etiology of
cerebral palsy. Clin Obstet Gynecol. 2008;51(4):775–786
CrossRefMedlineWeb of Science
53. 53.↵
1. Nelson KB,
2. Chang T
. Is cerebral palsy preventable? Curr Opin Neurol. 2008;21(2):129–135
CrossRefMedlineWeb of Science
54. 54.↵
1.
2.
3.
4.
Amer-Wåhlin I,
Hellsten C,
Norén H,
et al
. Cardiotocography only versus cardiotocography plus ST analysis of fetal
electrocardiogram for intrapartum fetal monitoring: a Swedish randomised
controlled trial. Lancet. 2001;358(9281):534–538
CrossRefMedlineWeb of Science
55. 55.↵
1.
2.
3.
4.
5.
Ojala K,
Vääräsmäki M,
Mäkikallio K,
Valkama M,
Tekay A
. A comparison of intrapartum automated fetal electrocardiography and
conventional cardiotocography—a randomised controlled study. BJOG.
2006;113(4):419–423
CrossRefMedline
56. 56.↵
1.
2.
3.
4.
Becker JH,
Bax L,
Amer-Wåhlin I,
et al
. ST analysis of the fetal electrocardiogram in intrapartum fetal monitoring: a
meta-analysis. Obstet Gynecol. 2012;119(1):145–154
CrossRefMedline
57. 57.↵
1.
2.
3.
4.
5.
6.
Hannah ME,
Hannah WJ,
Hewson SA,
Hodnett ED,
Saigal S,
Willan AR
; Term Breech Trial Collaborative Group. Planned caesarean section versus
planned vaginal birth for breech presentation at term: a randomised multicentre
trial. Lancet. 2000;356(9239):1375–1383
CrossRefMedlineWeb of Science