Chorioamnionitis - - An Alternative Cause for
Cerebral Palsy
By Walter J. Price III
Introduction
Lawyers defending health-care providers have long recognized that many, many cases
arise from labor and delivery. Some of the more significant cases include claims involving
cerebral palsy. "Unexpected adverse outcomes" represent one of the most frequent
reasons for litigation. Baergen, The Placenta as Witness, 34 Clin. Perinatol. 393 (2007).
Generally, in cerebral palsy cases plaintiffs question predelivery monitoring and
treatment, especially in the face of "nonreassuring" fetal monitoring results. Plaintiffs
associate cerebral palsy with asphyxia allegedly demonstrated by fetal monitor strips.
However, emerging medical evidence points to infection and an associated inflammatory
process as an alternative, significant cause of cerebral palsy in infants.
Background
Cerebral palsy occurs in 1 to 2.4 cases per 1,000 live births. Muraskas, et al., A Proposed
Evidence-Based Neonatal Work-Up to Confirm or Refute Allegations of Intrapartum
Asphyxia, 116 Obstetrics and Gynecology 261 (2010); Wu, et al, Chorioamnionitis and
Cerebral Palsy in Term and Near-Term Infants, 290 JAMA 2677 (2003). Cerebral palsy is a
group of nonprogressive motor impairment syndromes characterized by spasticity,
movement disorders, muscle weakness, ataxia, and rigidity. Koman, et al. Cerebral Palsy,
363 The Lancet 1619 (2004). Birth asphyxia can cause cerebral palsy, though it does not
account for most cases. Nelson, Causative Factors in Cerebral Palsy, 51 Clinical Obstetrics
and Gynecology 751 (2008). Indeed, studies estimate the number of such cases as only 20
percent, or even as low as 8 to 10 percent. Yoon, Intrauteran Infection and the Development
of Cerebral Palsy, 110 (Suppl. 20) BJOG 124 (2003); Perlman, Intrapartum HypoxicIschemic Cerebral Injury and Subsequent Cerebral Palsy: Medicolegal Issues, 99 Pediatrics
851 (1997). A majority of cases of cerebral palsy occur in term infants. Nelson, supra, at
749.
As noted, in litigation plaintiffs generally claim that fetal heart-rate monitoring can
identify inutero asphyxia occurring in connection with delivery, and poor outcomes,
including cerebral palsy, resulting from the failure of the involved health-care providers to
recognize this condition and accelerate delivery. Fetal monitoring has become an accepted
part of predelivery care. Similarly, delivery by Cesarean section has continued to increase.
Nonetheless, researchers have noted that despite the use of fetal heart-rate monitoring, as
well as other improvements in care, the rate of cerebral palsy has not declined over the past
30 years. Id. A "five-fold" increase in delivery by Cesarean section accompanies this.
Muraskas, supra, at 261. This evidence calls into question the causal relationship between
birth asphyxia and the failure to recognize it during the delivery process and injury.
Notably some scientists have not only questioned this connection but also the use of
fetal heart-rate monitoring tracings and their interpretation as evidence supporting liability.
For example, the terms generally used to assess negative changes reflected by fetal
monitoring, such as "fetal distress" and "nonreassuring pattern," are vague and subjective.
Schifrin, et al. Medical Legal Issues in Fetal Monitoring, 34 Clin. Perinatol,330 (2007).
Moreover, the alleged injury mechanism, birth asphyxia, also involves an "imprecise"
definition. Perlman, Intrapartum Asphyxia and Cerebral Palsy: Is There a Link? 33 Clin
Perinatol. 336 (2006). In addition, the often poor quality of fetal heart tracings during the
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expulsive stage of labor further reduces the ability to assess poor oxygenation at that point.
Schifrin, supra, at 332. Thus, liability may rest upon opinions that rely on inexact concepts.
In fact, one study calls into question whether someone could assess and confirm that a poor
neurologic outcome was actually avoidable:
Thus, the inability to assess prospectively: a) the fetal
adaptive mechanisms to maintain cerebral perfusion and
metabolism, or b) the inherent tolerance or resistance of the
fetal brain to intrapartum asphyxia using current markers
render it almost impossible, with any degree of certainty, to
offer a legal opinion as to whether an alternative medical
strategy could have altered the neurologic outcome or
whether the outcome was an unavoidable act.
Perlman, Intrapartum Hypoxic-Ischemic Cerebral Injury in Subsequent Cerebral Palsy:
Medicolegal Issues, 99 Pediatrics 857 (1997).
As suggested above, questions also persist about the causal link between birth
asphyxia, as purportedly shown through fetal monitoring, and cerebral palsy. Emerging
research findings indicate that maternal infection and associated inflammation frequently
alternatively could cause cerebral palsy. Maternal infection may affect the placenta resulting
in inflammation of the inner two layers of the lining of the placenta, the chorion, and the
amnion. Research has linked the resulting infection-induced inflammation, chorioamnionitis,
with cerebral palsy. As discussed further below, the exact cause of injury remains unclear,
though researchers have identified a firm relationship between chorioamnionitis and cerebral
palsy. Not only does this cast doubt on the medical cause of injury that plaintiffs often assert,
chorioamnionitis frequently is clinically silent and requires a pathologic study of the placenta
to identify it, which challenges proof of liability.
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Involved Anatomy
A placenta is a temporary organ that attaches to the wall of a mother's uterus. It provides
oxygen and nutrients to a fetus, as well as removes waste products from the fetal blood. A
placenta also protects a fetus from infection, trauma, and toxins. Redline, Disorders of
Placental Circulation and the Fetal Brain, 36 Clin. Perinatol. 549 (2009). A placenta has
two internal layers, the chorion and the amnion; the amnion makes contact with the
amniotic fluid in which the fetus is maintained.
The umbilical cord attaches the placenta and the fetus. It is made up of three blood
vessels. These include two smaller arteries that carry blood from a fetus to the placenta and a
larger vein that returns blood from the mother to the fetus. Williams Obstetrics 107 (17th ed.
1985). In supplying oxygen and nutrients to a fetus, maternal blood leaves the mother's
arterial vessels and forms "lakes" near the chorionic plate where the exchange takes place. Id.
at 108.
Inflammation is the body's response to an insult. Chorioamnionitis is inflammation of
the chorion and the amnion. Acute chorioamnionitis is identifiable by the presence of
leukocytes, or white blood cells, in the amnion and the chorion. Baergen, Manual of
Pathology of the Human Placenta 284 (2d ed. 2011). Funisitis is inflammation of the
umbilical cord. It, too, represents an inflammatory response. It indicates a fetal response to a
maternal insult. The fetal response follows that of the mother in time. Redline, Infections and
Other Inflammatory Conditions, 24 Seminars in Diagnostic Pathology 8 (2007). Thus,
finding funisitis establishes that an infection and an inflammatory process have persisted for
a longer period of time, which originated before delivery and birth.
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Effects of Chorioamnionitis and Funisitis
Acute chorioamnionitis has been associated with preterm deliveries, as well as "lung
disease, poor long-term neurologic outcome, and cerebral palsy." Baergen, supra, at 282.
Researchers have noted that an infection "always" causes acute chorioamnionitis. Id.
Bacteria in the cervicovaginal tract usually initiates the infection. Reilly & FayePetersen, Chorioamnionitis and Funisitis: Their Implications for the Neonate, 9
NeoReviews 411 (2008). Interestingly, the infection "occurs most often in the presence of
intact fetal membranes." Baergen, supra, at 283. Thus, contrary to the beliefs that lay
persons generally hold, an infection may invade a placenta, and even the amniotic sac,
causing an inflammatory response, even before a mother's membranes have ruptured.
This, also, is significant to an inflammatory process' onset, which can even begin before a
health-care provider admits a mother to a hospital in anticipation of a delivery. Various
microorganisms may cause the infection. Baergen, supra, at 289.
Initially, a mother's body responds to an infection by releasing leukocytes. This
reaction begins in the intervillous space and the maternal vessels of the decidua. Baergen,
supra, at 287. However, these leukocytes "always" migrate toward the amniotic sac. Id.
Therefore, an inflammatory response, as reflected by the presence of leukocytes, can
directly affect a fetus. In addition, a fetus normally swallows and breathes the amniotic
fluid, exposing it to the organisms contained in the amniotic fluid. Id. However, studies
have shown that injury may occur even when a mother's infection hasn't directly infected
her fetus; instead, a fetal inflammatory response can trigger fetal inflammatory response
syndrome (FIRS). FIRS is a condition hypothesized to involve a "systemic fetal
inflammatory response" that can cause multiple organ dysfunction, septic shock, and
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death. Bashiri, et ah. Cerebral Palsy Fetal Inflammatory Response Syndrome: A Review,
34 J. Perinat. Med. 9 (2006).
Finding neutrophils, a type of white blood cells that attack invasive bacteria, in the
walls of the vein or arteries of an umbilical cord indicates that something has stimulated
this fetal response. Redline, Inflammatory Response in Acute Chorioamnionitis, 17
Seminars in Fetal and Neonatal Medicine 22 (2012). These neutrophils generally first
appear in the chorionic vessels and the umbilical vein. As discussed further below,
pathologic review identifies this as "Stage 1." The next stage, "Stage 2," finds neutrophils
in the wall of the umbilical artery. Later, "Stage 3" finds neutrophils in the Wharton's
jelly, which surrounds the umbilical vessels. Id.
Chorioamnionitis and funisitis stages are important because studies have associated more
severe responses with more severe injuries, and finding that a process has progressed as
time passed could suggest that the condition existed before labor or a mother or a child
received delivery care.
One study demonstrated that chorioamnionitis is "independently associated with a
four-fold increase of CP [cerebral palsy] in term infants." Wu, supra, at 2680-81. This
same study noted that often birth asphyxia was diagnosed despite finding
chorioamnionitis. Id. at 2681. Significantly, for purposes of birth injury litigation, studies
have
shown
that
conditions
traditionally
associated
with
hypoxic-ischemic
encephalopathy, such as low Apgar scores, meconium in amniotic fluid, and neonatal
seizures, may actually result from the infectious or the inflammatory process as opposed
to an hypoxic-ischemic event. Nelson, supra, at 752. In other words, the effects of
chorioamnionitis and funisitis may mirror those associated with birth asphyxia, which
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plaintiffs in litigation assert that poor fetal heart tracings demonstrate.
The exact cause of inflammatory process injury is not certain. Several noted theories
include:
1. Elevated levels of fetal cytokines in the presence of
maternal infection can cause direct injury to a fetal
brain by stimulating the fetal inflammatory response;
2. Inflammation of the placental membranes leads to
interruption of placental gas exchange and blood flow
resulting in hypoxic- ischemic brain injury in a fetus;
3. Maternal fever raises the core temperature of a fetus,
which, in turn, may harm the developing brain,
especially when accompanied by cerebral ischemia;
and
4. Maternal intrauterine infection leads to direct infection
of the fetal brain or meninges, although this is rarely
seen.
Wu, supra, at 2682.
Regarding the first theory, cytokines are proteins released by the immune system;
they regulate immune response. Studies have identified increased concentrations of
cytokines in children with cerebral palsy. Shalak, et ah, 110 Clinical Chorioamnionitis,
Elevated Cytokines, and Brain Injury in Term Infants, Pediatrics 673 (2002). These
cytokines may cross the blood-brain barrier that protects brain cells from insults from
invading organisms. Id. at 677. However, these same proteins may be "toxic" to the fetal
central nervous system. Holcroft, et ah. Are Histopathologic Chorioamnionitis and
Funisitis Associated with Metabolic Acidosis in the Preterm Fetus? 191 Am. J. Obstet.
Gynecol. 2011 (2004). The young fetal brain is particularly susceptible to injury by these
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inflammatory mediators. Nelson, supra, at 755. Complicating the effort to locate the
cause of injury is that brain injury resulting from the inflammatory process "mimics the
neuroradiological findings of hypoxic-ischemic brain injury in term infants." Wu, supra,
at 2682.
Regarding the second theory, some researchers suggest that the inflammatory
response may affect the placenta and cause hypoxic-ischemic brain injury. Others have
suggested that the fetal inflammatory response could alone cause hypotension with
decreased perfusion to the watershed regions of the brain. Id. Other potential causes of
reduced fetal perfusion associated with the inflammatory process include vasoconstriction
of the umbilical cord vessels and intravascular coagulation with cerebral arteriolar
obstruction. Id. In such a scenario, a child would actually receive a hypoxic-ischemic
injury, though the shock-like condition would cause it as opposed to asphyxia resulting
from some other insult. Of course, someone would expect that a plaintiffs counsel would
counter this theory by suggesting that the fetal monitor was, by exhibiting signs of
distress, reflecting the effects of the inflammatory process. Although, as alluded to
previously, a fetus may have experienced those effects for some time preceding the period
that the fetal monitor recorded.
One study has referred to a maternal fever; however, while fever may be associated
with acute chorioamnionitis, as noted, this condition mostly is "clinically silent" and
"diagnosed only after pathologic examination of the placenta." Reilly & Petersen, supra, at
411.
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Practical Considerations
Since doctors may not always discover chorioamnionitis before birth, a substantial issue to
explore when litigating involves whether the placenta has undergone pathologic review,
which is the sole means of confirming chorioamnionitis. Unfortunately, obstetricians do not
always send a placenta for a pathologic review. Muraskas, supra, at 262. Clinical issues also
can become relevant. For example, in most cases intrapartum asphyxia "deprives all other
organs of oxygenated blood before the flow of oxygen to the brain is diminished." Muraskas,
supra, at 266. As such, an attorney must closely review the clinical picture to look for
reduced urine output indicative of renal failure, the presence of liver enzymes, or cardiac
enzymes, among other things. In addition, meconium-stained amniotic fluid may not be an
indicator of hypoxic-ischemic encephalopathy. In the United States, 15 percent of births
annually involve meconium- stained amniotic fluid. Id. at 265. As such, finding it does not
settle the causal question.
Trained and experienced placental pathologists can, as indicated, categorize the
inflammatory response into "stages" by completing a pathologic examination. This assists in
defining the time of an event. A child may have suffered harmful effects of the inflammatory
process before the period purportedly identified by a fetal monitor record, and, indeed, it may
have happened before the mother's admission to the hospital. A child many have experienced
direct cellular damage for some time before he or she was born.
Chorioamnionitis and funisitis involve three stages, and the maternal response
precedes that of the fetus. Pathological examination pinpoints the stages by identifying the
number and the location of the neutrophils. Dr. Redline has opined that "Stage 1"
chorioamnionitis, noted as subchorionitis and chorionitis, may develop six to 12 hours after
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exposure to the infectious agent. Redline, Inflammatory Responses in the Placenta and
Umbilical Cord, 11 Seminars in Fetal & Neonatal Medicine 297 (2006). Chorioamnionitis,
or "Stage 2," can develop within 12 to 36 hours. Id. Necrotising chorioamnionitis signals
"Stage 3," which develops 36 hours or more after exposure. Id. Again, in terms of stages,
funisitis begins when neutrophils appear in the chorionic vessels and umbilical vein, then,
during the next stage they appear in the umbilical artery, and finally, they appear in the
Wharton's jelly. Severe fetal inflammatory response may even "develop as a consequence of
subacute processes beginning days before delivery." Redline, Placental Pathology and
Cerebral Palsy, 33 Clin. Perinatol. 569 (2006). Note, however, that these stages are not exact
and can overlap. Experienced placental pathologists can estimate the length of time that an
inflammatory process continued or how long a stage persisted by examining placental
samples in comparison with historical knowledge. More severe inflammation suggests not
only that more time has passed, but, also, it is associated with a poor outcome. The severity
of the fetal response is particularly relevant to the degree of injury. Redline, Infections and
Other Inflammatory Conditions, 24 Seminars on Diagnostic Pathology 9 (2007).
The medicine involved in these issues, especially regarding the means of injury, is
complex. Defense attorneys need to identify knowledgeable and experienced expert
witnesses to address the pathological confirmation of chorioamnionitis and funisitis, as well
as to discuss the effects of the inflammatory process. Only a few placental pathologists have
experience in this field, and a defense of a birth injury case involving cerebral palsy will
require a focused effort to obtain the appropriate assistance.
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Conclusion
Dr. Baergen's article, "The Placenta as Witness" is aptly titled. Pathologic review of a
placenta may yield information vital to a defense of a birth injury case involving cerebral
palsy. These claims create substantial exposure, and the health-care providers' conduct is
often judged based on nothing more than fetal monitoring records and an assertion that these
records depict fetal birth asphyxia. However, emerging science has revealed that cerebral
palsy is often associated with infection and inflammation initiated by bacteria or other
microorganisms affecting the placenta. Studies have firmly linked inflammation of the
placenta, chorioamnionitis, and inflammation of the umbilical cord, funisitis, to the
development of cerebral palsy, and confirming their existence with a pathologic review of a
placenta may provide an objective causation defense to claims of negligence in labor and
delivery care.
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