Causative Factors in Cerebral Palsy

CLINICAL OBSTETRICS AND GYNECOLOGY Volume 51, Number 4, 749–762 r 2008, Lippincott Williams & Wilkins

KARIN B. NELSON, MD National Institute of Neurological Diseases and Stroke, Bethesda, MD and Department of Neurology, Children’s National Medical Center, Washington, DC

Abstract: Causative factors in cerebral palsy (CP) vary In 1955, obstetricians Eastman and to some degree according to gestational age group and DeLeon1 noted that, ‘‘whereas our obste- clinical CP subtype. Such catastrophes of birth as placental abruption, cord prolapse, and uterine rup- trical literature rarely mentions cerebral ture sharply heighten risk of CP. These conditions are palsy, the literature of cerebral palsy fortunately uncommon, and are sometimes not sur- abounds with statements that the etiology vived; individually and collectively they account for of the disease is chiefly obstetrical.’’ With only a small proportion of CP. Among other factors that introduction, Eastman and DeLeon associated with increased risk of CP are prematurity, intrauterine exposure to infection or maternal fever presented one of the first controlled stu- in labor, ischemic stroke, congenital malformations, dies of causative factors in cerebral palsy atypical intrauterine growth (restricted or excessive (CP), finding that: for gestational age), and complications of multiple Although preterm infants are at high indi- gestations. Although any 1 factor, if severe, may be vidual risk for CP, the majority of CP arises sufficient to cause CP, more often it is the presence of in infants born at term. multiple risk factors that overwhelms defense mechan- Placental abruption was more common in isms and leads to CP. The contribution of genetic vulnerabilities that interact with environmental stres- children with CP, but of the 96 children sors is an emerging aspect of our understanding of with CP they studied, only 2 were born after causative factors in CP. frank abruption. Abruptio placentae and Key words: cerebral palsy, prematurity, perinatal cord prolapse are dangerous to infants, but stroke, maternal fever in labor, placenta are uncommon and sometimes not sur- vived; these conditions do not contribute a major share of CP. Half of term infants who developed CP were in good condition in the delivery room, with none of the findings usually Correspondence: Karin B. Nelson, MD, National taken to indicate birth asphyxia, such as Institutes of Health, Building 31, Room 8A03, Bethes- da, MD 20892-2540. E-mail: [email protected]; respiratory depression, hypotonia, poor [email protected] color, or abnormal cry. (The Apgar score Supported in part by the Intramural Research Program was not described until 2 y later.) of the National Institute of Neurological Disorders and There were more congenital anomalies in Stroke. The content of this publication does not neces- infants who developed CP than in controls. sarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade Babies born to women who were febrile in names, commercial products, or organizations imply labor had 7 times more CP than infants of endorsement by the US government. women who were not febrile.

CLINICAL OBSTETRICS AND GYNECOLOGY / VOLUME 51 / NUMBER 4 / DECEMBER 2008

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These observations, published more and 1 group of studies was based on a than half a century ago, anticipated many large health maintenance organization. of the results of later controlled studies Most of the recent studies have been and made it clear that clinically defined analytically more sophisticated than their birth injury or birth asphyxia accounted predecessors. Recent investigations have for only a small minority of CP. In addi- incorporated neuroimaging information, tion, this study recognized several nonas- which has added importantly to our phyxial causal factors in CP. knowledge of underlying pathobiology From the earliest days of recognition of (see Inder, this volume). It is these large CP, in fact, it was known that a number of methodologically careful studies that causative factors, including prematurity, bring us to our current understanding of infection, and complications of multiple causes of CP, a better though still very gestations, could lead to CP. It was incomplete state of knowledge. known on the basis of neuropathologic Many papers have entered the litera- examination that ischemic arterial infarc- ture in which causes of CP were assigned tion of brain (stroke) was not rare in without controlled study, a subjective newborn infants. It was also recognized procedure that allows investigators to that many children with CP had experi- state causes according to their own expec- enced none of these causative factors, and tations and assumptions. In what follows, that many children with one or more uncontrolled studies and those employing causative factors did not turn out to have retrospective data ascertained after dis- CP. It required large controlled multivari- ability in the child was identified, which able studies, of which Eastman and entails the possibility of recall bias, are DeLeon presented the first impressive not included. example, to take us the next step. Controlled population-based studies This review will examine the evidence are necessary for the identification of concerning causative factors for CP, as major causes of clinical disorders, and these are known in early 2008 in studies of for studies of prognosis. Such studies do good medical quality of evidence. not, however, identify rare conditions whose recognition requires uncommon procedures or highly specialized knowledge, such as the Worster-Drought syndrome or DOPA-responsive dystonia, What Do We Know About although the latter is important to recog- Causes of CP and How Do nize because of its responsiveness to treat- We Know it? ment.2 There are trade-offs of large and After Eastman and DeLeon there were a generalizable samples versus specialized succession of studies using maternal and focus, and studies that optimize each birth information collected before out- are needed to provide a 3-dimensional come in the child was known. These picture. studies in representative samples, many of Several themes will emerge from this them population-based, first appeared in review: dominant causes of CP differ the 1980s, starting with those of Fiona somewhat according to gestational age Stanley and her colleagues in Western and clinical CP subtype. Although often Australia. Then followed the Collabora- discussed as if they were causes of later tive Perinatal Project and studies in Cali- disability, low Apgar scores and respira- fornia, Sweden, and Victoria and South tory depression and other signs of neuro- Australia. Many of these used large logic depression in the newborn infant are regional databases to ascertain outcome, results of their own antecedents, and if Causative Factors in Cerebral Palsy 751 adequate resuscitation is available are Attheheadofthelistofcausesof not causes in themselves. These signs are not hemiplegic CP, according to neuroimaging specific to asphyxial etiologies and do not studies,8 are perinatal stroke and congeni- serve to establish the cause of depression tal malformations. Hemiplegic CP is due to in the neonate. A single severe exposure a focal, or sometimes a multifocal, pathol- such as uterine rupture or massive abrup- ogy, and not the result of generalized hy- tion can be sufficient to cause CP, but poxia-ischemia. much more often it is not a single cause, Spastic diplegia, the CP subtype that is but rather multiple concurrent risk fac- most common in premature infants, can tors that precede CP. And multiple risk also occur in infants who were products of factors markedly increase risk. pregnancies that went to term. Causal Controlled studies, neuroimaging3 and factors for spastic diplegia include evi- clinical,4–6 based on populations provide dence of intrauterine infection, premature the best available estimates of the propor- rupture of membranes, and multiple tion of CP accounted for by each etiologic gestation.9 Several studies have found factor (Table 1). preeclampsia to be ‘‘protective’’ against CP. It is still unclear whether preeclampsia is just less toxic than inflammation as a factor leading to preterm birth, or there Causative Factors not Uniform really is some factor associated with pre- in Different CP Subtypes and eclampsia or its treatment that is benefi- Gestational Ages cial—such as perhaps magnesium sulfate Vulnerabilities to CP differ at different administered for preeclampsia.10 gestational ages, and a somewhat differ- Quadriplegic (4-limb) CP can be caused ent range of causative factors is apparent by any pathology that inflicts bilateral for different CP subtypes.7 In-term and and widespread damage to brain. Spastic near-term infants, hemiparetic (1-sided) quadriplegia, especially if accompanied and quadriparetic (4-limb) CP are the by movement disorder, is the form of CP most common clinical subtypes, whereas that results from global hypoxic-ischemic in preterm and very preterm infants events,11 although such events are not spastic diplegia (legs affected more than the only possible causes of this clinical arms) is the predominant form of spastic syndrome. involvement.

TABLE 1. Estimates of Proportion of Cerebral Palsy in Term and Birth Asphyxia: What it Does Near-term Infants Attributed and Does not Cause to Major Causes in Population- Birth asphyxia can cause CP. It has been based Studies demonstrated repeatedly in controlled Neuroimaging based3 population-based studies, however, that Perinatal ischemic stroke 22% interruption to oxygen supply to the fetus Congenital malformation 15 does not account for most CP. The term White matter disorder 12 Hypoxia-ischemia 5 ‘‘chronic hypoxia’’ is sometimes em- Clinical studies ployed but is vague and unverifiable; if it Intrauterine exposure to 11%-12% is used to indicate the presence of placen- inflammation3,4 tal vascular disease, such vasculopathy 5 Birth asphyxia 6 might interfere with oxygen transport, Complications of multiple birth6 5 but would be likely to interfere with 752 Nelson production and transport of many other and long-term neurologic disability.15 In- molecules in addition to oxygen. fants who have undergone acute asphyxia Over the decade of the 1990s, there was during birth, sufficient to produce irrever- a 90% decrease in diagnoses of birth sible brain injury, do not rapidly recover asphyxia as recorded on vital documents normal neurologic and systemic status. Of in California, where 1 in 9 American term infants with encephalopathy, only children is born.12 There was no change a minority had experienced recognized in CP rate in children born in a region of compromise to oxygen flow around the California in that period. The decline in time of birth. Some other candidate con- birth asphyxia diagnosis agrees with de- ditions have been identified, including cline in very low Apgar scores in Western maternal thyroid abnormalities and ma- Australia without a decrease in the CP ternal fever in labor.16 Thus, the clinical rate. Such observations should stimulate picture of respiratory and neurologic de- questioning of previous assumptions pression in the newborn is not specific as relating birth asphyxia and CP. to etiology. A low Apgar indicates that an More direct evidence of the contribu- infant is ill, and is not in itself informative tion of birth asphyxia to CP comes from as to the cause of that illness. Chorioam- large controlled studies in populations. In nionitis, for example, is known to increase agreement with Eastman and DeLeon, risk of low Apgar scores, meconium in the half or three-quarters of infants with amniotic fluid, and neonatal seizures,17,18 later-diagnosed CP were not markedly so these signs can be—often are—related depressed in the newborn period.13 to infectious or inflammatory rather than Furthermore, of those infants who were asphyxial conditions. depressed or manifested neonatal ence- The CP that birth asphyxia does cause phalopathy, a majority did not have a is spastic 4-limb involvement, spastic recognized asphyxial precursor to their quadriplegia11; there are other potential depression. In a population-based Amer- causes of that syndrome. Global hypoxia- ican study, only 6% of children with CP ischemia is not a likely cause of hemiplegic had had a recognized birth complication CP or spastic diplegia. Global hypoxia- capable of interrupting oxygen supply to ischemia is not a plausible cause of CP in the fetus.4 Among term-born children in an infant who did not manifest encepha- a well-planned study in a regional cohort lopathy in the newborn period. who had encephalopathy and seizures, Interventions based on the birth as- acidosis, and renal dysfunction in the phyxia hypothesis have not led to a de- neonatal period and later 4-limb CP, only crease in CP. An important example is the a third had recognized intrapartum as- repeated observation that electronic fetal phyxial events that seemed to account monitoring, introduced in the hope of for this clinical sequence.14 In the remain- recognizing and intervening early in a der of affected infants, despite the simi- developing asphyxial state, has not been larity of the clinical features, the cause or followed by a reduction in frequency of causes was not apparent. This study did CP.19 This disappointing SAGA is sum- not include placental pathology. Similar marized by the title of one review, ‘‘Birth findings are noted in several studies of can be a hazardous journey: electronic antecedents of severe depression in term fetal monitoring does not help.’’20 infants who were candidates for hypo- Unfortunately, although it would seem thermic therapy for ‘‘hypoxic-ischemic straightforward to prevent the small share encephalopathy.’’ of CP that is related by asphyxial events, Neonatal encephalopathy is an inevita- that has not proven to be so. This fact ble intermediary between asphyxial birth suggests that we have been operating, Causative Factors in Cerebral Palsy 753 clinically and experimentally, with too Prematurity simple a conceptual model. There is Birth too early in gestation is a very im- clinical and experimental evidence that portant causative factor for CP, risk per nonasphyxial factors can be sufficient infant being increased up to 100-fold. antecedents to CP. In addition, asphyx- Preterm and very preterm birth are rela- ia-ischemia can interact with other causal tively uncommon among all births, how- factors such as inflammation, the joint ever, so prematurity contributes half or occurrence of both further multiplying less of CP. The CP that arises in very risk. Other causative factors may also prematurely born infants is commonly interact with these. Thus, hypoxia-ische- spastic diplegia, and the underlying brain mia may arise at a cellular level down- pathology as explored by neuroimaging is stream in a pathobiologic process that white matter disorder. began with other instigators, and the clin- Intrauterine infection or inflammation ical features may not distinguish primary and prolonged rupture of membranes are from secondary or tertiary effects. important antecedents of preterm birth, The question is seldom asked, if there and also of CP in prematurely born chil- was asphyxial-ischemic injury as part or dren. A recent report indicates that fetal all of the pathogenesis of depression exposure to a variety of viruses may be in the neonate, when did that asphyxial associated with hypertensive disorders of injury occur? That question is critical to pregnancy, a risk factor for CP, and cyto- development of effective strategies for megalovirus was also associated with risk prevention, as an acute interruption of of birth before term,23 an example of a oxygen supply to the infant before or potential chain of causal links in which the during birth would probably require very cause of preterm delivery may also be a different action for primary prevention, cause, in addition to the prematurity it- as compared with a defect in perfusion or self, of brain injury in the early-born fetus. cellular response far down the causal In addition to infection or inflamma- chain. tion, risk factors for premature birth in- Abnormalities in the fetus can contri- clude previous preterm birth, black race, bute to an aberrant process of labor, as low maternal body mass index, vascular exemplified by the observation that chil- disease, and multiple gestation.24 Medical dren with cortical malformations much indications for preterm delivery include more frequently than others experienced preeclampsia or eclampsia and fetal ‘‘intrapartum complications, which could growth restriction. A genetic contribution lead to the misdiagnosis of hypoxic- to preterm birth is estimated to account ischemic encephalopathy.’’21 for 20% to 40%. An intriguing observation in a study of Wu et al22 raises questions about the assignment of asphyxial etiology based on Atypical Intrauterine Growth neuroimaging findings. Chorioamnionitis Babies who are small for dates at birth are was most tightly linked with CP risk in at increased risk for CP, a relationship infants whose neuroimaging studies were often cited. Equally striking, and much read as indicating ‘‘hypoxic-ischemic less often cited, is the fact that babies who brain injury.’’22 Perhaps the downstream are large for dates are also at increased consequences of insults of varying etiol- risk: there is a U-shaped curve, with ogy can produce similar imaging findings, heightened risk associated with growth that is, these imaging findings may, like abnormalities at both ends of the scale. the clinical signs of neonatal depression, A host of growth factors can influence not be etiologically specific. size at birth, some of them after only a 754 Nelson brief early exposure. Clinical characteris- associated with them, can cause CP with- tics of mother or child that are associ- out known invasion of the infant brain? ated with fetal growth restriction include It is more than half a century since chromosomal abnormalities (infections Eastman and DeLeon reported that wo- such as TORCH agents, malaria, HIV), men who were febrile in labor had babies preeclampsia, systemic maternal vascular with 7 times the rate of CP as women not disease, or thrombophilia. It is possible ex- febrile during delivery.1 In data of the perimentally to produce growth retarded National Institutes of Health Collabora- fetuses by clamping uterine arteries, but it tive Perinatal Project (NCPP), women is unknown whether this procedure models febrile during pregnancy with urinary- a mechanism that occurs with substantial tract infections had infants whose tested frequency in human fetal growth restriction. intelligence was lower, even after adjust- Size larger than the norm for gesta- ment for socioeconomic factors. Gilles tional age is also associated with risk of et al27 followed these findings with experi- CP. Some of this excess risk may be mental evidence of white matter abnorm- related to size per se leading to problems alities in the brains of kittens exposed in delivery. The classic risk factor prenatally to infection. for macrosomia is maternal diabetes, Also in NCPP data, routinely performed although in most studies diabetes itself examination of the placenta revealed that does not seem to increase risk for CP in moderate or severe inflammatory infiltrates the infant. Both excessively small and in umbilical cord, were associated with excessively large babies are at higher risk heightened risk of CP both in term and for perinatal stroke than infants near the preterm infants; in the years of the NCPP, mean of weight for dates.25 survival of preterm infants was chiefly Cloned animals sometimes die before limited to those not severely preterm. birth with a ‘‘too big syndrome’’ that Infants exposed in utero to inflammation includes a placenta of excessive size. As- had lower Apgar scores.28 This observa- sisted reproductive technologies seem to tion has been confirmed in many subse- be associated with a small but significant quent studies. increase in risk of imprinting disorders In a population-based study in north- such as Beckwith-Wiedemann syndrome, ern California, evidence of maternal in- which is associated with large fetal size, fection or fever during the admission for suggesting that epigenetic mechanisms delivery was associated with risk of CP in may sometimes be associated with exces- infants of normal birth weight, and with sive fetal growth.26 admission to a neonatal intensive care unit, neonatal seizures, and meconium aspiration. A recent paper agrees that meconium passage is commonly due to Infection, Inflammation, and inflammatory, not asphyxial, factors.18 Maternal Fever in Labor Most infants exposed to inflammation Congenital TORCH infections (toxoplas- or fever in utero did not experience pro- mosis, rubella, cytomegalovirus, herpes longed rupture of membranes or sepsis in virus, and other microorganisms includ- the newborn period. ing those of hepatitis B, syphilis, and There are now many other studies re- HIV) and streptococcus B can be trans- garding term and near-term infants, all mitted from mother to infant, affect the consistent in finding an association of brain of the infant, and produce congeni- maternal infection or fever with low Ap- tal motor disability, CP. What is the gar score, neonatal encephalopathy and evidence that microorganisms, or factors seizures, and with CP risk. The evidence is Causative Factors in Cerebral Palsy 755 less consistent, but also dominantly posi- ministration of a number of antibiotics tive, concerning the association of inflam- can affect cytokine, prostaglandins, nitric matory indicators with CP in very oxide, and other systems relevant to in- preterm infants. Study of this association fant brain development. The possibility of in very premature infants is plagued by unintended consequences is real, so that uncertainty about how best to deal with randomized trials of antibiotic interven- the important predictor, gestational age. tions that include observations of the Very premature babies often experience infant at least through the neonatal period postnatal episodes of sepsis or suspected are needed as the necessary basis for sepsis that complicate interpretation of responsible action. the relationship of intrauterine events with long-term outcome. There has been little systematic study of infectious or inflammatory maternal Perinatal Ischemic Stroke conditions that occur in pregnancy but Perinatal stroke is a cerebrovascular event before the admission for delivery as risk occurring during fetal or neonatal life factors for CP. before 28 days after birth. As used here Repeated observations, then, docu- the term excludes hemorrhagic stroke. ment that intrauterine exposure to indi- The separation between ischemic and cators of inflammation are linked with CP hemorrhagic lesions can be difficult as risk, and that this is a common cause of ischemic lesions can undergo secondary low Apgar scores, other signs of neonatal hemorrhage after reperfusion, and venous depression, and CP risk. Vulnerability of infarcts, also excluded by definition, are the very young brain to inflammatory often hemorrhagic. mediators is evidenced by the fact that Arterial ischemic stroke in the perinatal administration of interferon-a, an inflam- period has been recognized as a major matory cytokine given to shrink life- cause of CP only in recent years, as the threatening hemangiomas, has been fol- use of computed tomography and mag- lowed by development of spastic diplegia netic resonance imaging have been ap- in infants less than a year old, but not in plied with increased frequency to infants older children or adults.29 and young children. The diagnosis of As chorioamnionitis and perhaps other perinatal stroke can be suspected but not infections seem to be a common antece- established in surviving children without dent to encephalopathy in the neonate such imaging procedures because clinical and to later CP, should there be aggressive signs of stroke in the newborn period are efforts to detect and treat infection? variable, nonspecific, and often absent. Should antibiotic use be more widespread Cranial ultrasonography is not a sensitive in pregnancy? Willoughby and Nelson30 test for stroke. The frequency with which have discussed reasons for caution: iden- stroke is detected, and therefore the ob- tification of infecting agents is difficult served prevalence, are also related to the but necessary if treatment is to be effec- frequency of use of imaging procedures. tive. Placental infection frequently in- In a study in which magnetic resonance volves multiple organisms that would imaging was relatively often employed, require different therapeutic agents. Anti- unilateral strokes were identified in biotics are not necessarily free of neuro- 1:2300 term infants during the nursery logic risk; for example, metronidazole, a period.31 Not included in that study, radiation-sensitizing antibiotic used in a about a third of strokes are bilateral and number of trials for prevention of preterm many perinatal strokes are not recognized birth, can cause an encephalopathy. Ad- until after the newborn period. 756 Nelson

Newborn infants with stroke sel- ment have been observed in association dom display asymmetrical movement or with perinatal stroke.33 Maternal or strength, as would older children and family history of thromboembolic disease, adults. The most common finding to lead advanced maternal age, obesity, surgery to imaging, and thus to diagnosis, is neo- (including surgical delivery), dehydration natal seizures. There may be apnea, hy- or shock, and prolonged bed rest are risk potonia, or other nonspecific signs. Many factors for thrombosis in the mother, infants appear well between seizures, but as is a history of maternal migraine.34 some display neurologic depression and (Migraine and its treatment have not been encephalopathy and received diagnosis of examined as potential risk factors for ‘‘birth asphyxia’’ or ‘‘hypoxic-ischemic stroke in the infant, although headache encephalopathy.’’ Vasculopathy in the of migrainous sort is a common com- placenta has been linked with encephalo- plaint in children who have experienced pathic manifestations32 and may underlie perinatal stroke.) Infection and inflam- the fetal distress and neonatal depression mation are important triggers of throm- that sometimes is observed in infants with bosis. Preeclampsia, a maternal risk perinatal stroke. factor for stroke in the infant, is also Some infants who appeared neurologi- associated with risk of ischemic stroke in cally intact as newborns may be diag- young women at times remote from preg- nosed in later months or years when the nancy, and is a risk factor for stroke in the child learns to reach with one hand but child, and may be associated with throm- not the other, indicating a developing bophilia. hemiparesis, or fails to meet developmen- Both fetal growth restriction and ex- tal milestones, or experiences the onset of cessive size for gestational age are rela- a postneonatal seizure disorder. Retro- tively common in infants with strokes, spective diagnosis in such cases depends and a number of authors have observed on neuroimaging. There has been no test maternal complains of decreased fetal of consensus in the reading of the films on movements in infants who had perinatal which diagnosis is based, either with re- seizures. In the infant, the procoagulant spect to neonatally recognized or retros- and proinflammatory character of this pectively diagnosed stroke. period, and the high hemoglobin in fetus Stroke is much more common in the and neonate, traction on neck vessels, perinatal period than during childhood or inflammation, dehydration, hypotension, at any time until late middle life. Throm- use of intravascular catheters, and impor- boses at other sites are also relatively tantly the presence and nature of placen- common in the period immediately tal thrombotic lesions are associated with surrounding birth. It is unlikely to be a perinatal stroke. Thrombotic lesions are coincidence that maternal pregnancy- the most common finding in placentas of related stroke is also most common in infants with CP.35 Despite the probable the few days immediately before or after relevance of thrombotic and/or inflam- birth, a period during which coagulation matory vasculopathy in the placenta to status is maximally altered in both mother the occurrence of perinatal stroke, only a and infant. few studies have examined the association Known risk factors for perinatal stroke of specific findings in the placenta to risk include disorders of mother, placenta, of stroke in the infant. and infant. Normal pregnancy is, overall, About half of infants with stroke a prothrombotic and proinflammatory investigated for thrombophilias are state. Primiparity, preeclampsia, and a observed to have one or more such find- history of impaired fertility and its treat- ings. Thrombophilias are also common Causative Factors in Cerebral Palsy 757 in the unaffected population, however, co-twin death was similar for same-sex and so it is necessary to study and interpret for different-sex pairs (the surrogate for these thrombophilias with care. Unless zygosity in a large study in which zygosity thrombophilic factors are multiple or could not be determined reliably). accompanied by a family history of thro- Monozygotic twinning with conjoined mboembolic events, there is no consensus circulations in the placenta underlies that these provide information that much of the hazard to a twin or triplet should guide clinical management. when a co-twin or co-triplet dies in utero. Perinatal stroke has seldom been re- In that situation, the death of 1 twin is ported in more than 1 nontwin child in followed by vascular collapse in the sur- a sibship, so it seems likely that environ- vivor. If this sequence occurs early in mental factors play an important role. gestation, congenital anomalies can be Despite that, few studies focus on envi- the result in the survivor. There may be ronmental factors in perinatal stroke. other mechanisms of brain injury in the survivor of a co-twin death, in addition, and anything that harms 1 infant lethally Congenital Anomalies might harm the other sublethally. The consistent observation that children The ‘‘vanishing’’ of a twin is fairly with CP have more congenital anomalies common early in pregnancy. Some chil- than other children is an important part of dren who were twins early in gestation the evidence that prenatal factors contri- may be born as singletons, and bear the bute to CP. Recent studies linking popu- consequences of co-twin loss. lation-based registries for CP and for congenital malformations reinforce previous observations noting congenital mal- Placental Pathology formations of head, clefts of lip or palate, ‘‘The placenta remains a neglected source and gut atresias in CP.36 Other noncereb- of discovery.’’38 Examination of the pla- ral anomalies may also be more common. centa can help in the understanding of etiology and can influence workup and perhaps treatment decisions when out- Multiple Gestation come is adverse. Twins are at greater risk for CP than The relationship of chorioamnionitis singletons, and the risk in triplets is higher with CP risk has been indicated. In mate- still. Many factors have been considered rial assembled for medicolegal review, the in analysis of this heightened risk, includ- most common placental finding was ing birth sequence and mode of delivery, thrombotic lesions,35 and the relationship presentation, size, size discrepancy, con- was especially strong if evidence of in- genital anomalies (more common in flammation was also present.39 Gross monozygotic twins), and many others. findings indicative of disturbance of uter- The evidence is that 2 factors are predo- oplacental circulation, marked perivillous minant in contributing to CP risk in multi- fibrin deposition, and ischemic changes in ple gestation: the tendency of twins and placental villi were associated with pre- higher order multiple births to be born sence of white matter disorder, the lesion prematurely, and death of 1 infant. In a commonly underlying spastic diplegic study that included more than a million CP.40 births, the highest rates of CP were in Chronic villitis, a disorder affecting 5% surviving twins whose co-twin was still- to 15% of term placentas, is characterized born (4.5%), died soon after birth (6.3%), by focal areas of inflammation with or had CP (11.8%).37 CP risk after mononuclear cells and areas of fibrinoid 758 Nelson necrosis, and often recurs with subse- factors and their interaction with genetic quent pregnancies. When lesions are characteristics are important determi- widely distributed, it is associated with nants of disease occurrence. Only a begin- growth restriction, preterm birth, and ning has been made in studies to examine preeclampsia. The etiology is not well gene-gene and gene-environment interac- understood but is thought to be related tions, but much hope for further progress to autoimmune or alloimmune disease.41 depends on such studies in future. In the event of fetal or neonatal death and failure to obtain an autopsy, placental examination can be informative.42 Multiple Risk Factors Once placental tissue has been cut and In some cases a single overwhelming fac- put into preservative, it can be sectioned tor such as acute interruption of oxygen and made available to an experienced supply during birth is a sufficient cause of pathologist long after the delivery. It brain injury and subsequent CP. Much would be good policy for the placenta more often, however, multiple risk factors of every depressed term newborn to be converge to overwhelm natural defences. saved, preferably for immediate examina- Examples documented in clinical and ex- tion, but if not, as a resource for investi- perimental studies are the interaction of gation of etiology at a later time. intrauterine exposure to inflammation and asphyxial injury, and the interaction of multiple thrombophilias with one an- Genetics other and with environmental risk fac- Familial aggregation of CP has been re- tors. The prominence of multiplicity of ported in populations with high rates of risk factors in human CP is one reason consanguinity, and in a national Swedish why many animal experiments do not database an increased risk for CP was accurately model the clinical disorder. observed in families.43 Genetic factors The strong contribution of multiplicity can influence CP risk at a number of of risk factors to CP etiology means that a points along the causal pathway. A num- linear causal chain is often not evident. A ber of maternal and pregnancy conditions causal web is a more realistic model, and that are risk factors for CP have a genetic can mean that results of a given perturba- component, including preterm birth, tion may be difficult to predict. placental abruption, preeclampsia, and chorioamnionitis. Thrombophilias underlying perinatal strokes often have a genetic Neonatal Encephalopathy basis. Genetic variants of certain inflam- Neonatal encephalopathy is a necessary matory cytokines44 and an apolipopro- intermediary between birth asphyxia and tein E variant45 have been linked with CP in term and late preterm infants. All CP risk. Exploratory studies suggest that studies that have examined the issue find variants of nitric oxide synthase contri- that only a minority of cases, including bute to CP risk.46,47 The results of studies those meeting strict criteria for ‘‘hypoxic- to date are compatible with roles in CP ischemic encephalopathy’’ and having CP pathobiology for inflammation, coagula- as the later outcome,14 can account for tion, control of blood flow, and function only a minority of cases by such ‘‘sentinel of vascular endothelium in placenta and events’’ during birth as uterine rupture, brain. cord prolapse, or major placental abrup- Thus, CP can be seen as a common tion. What causes the majority of such complex disorder, in which many genes cases that look clinically identical during contribute to risk and environmental the newborn period? This is an important Causative Factors in Cerebral Palsy 759 unanswered question. The study of Badawi ciations would suggest potential thera- and others16 contain some hints, inclu- peutic interventions. ding maternal fever in labor, maternal The literature relating placental thyroid disorder, family history of neuro- pathology to maternal conditions, neona- logic disease, and other factors. Incor- tal status, and long-term outcome in the poration of broader maternal medical child is limited in amount and methodo- history and of examination of placental logically suboptimal, yet it contains hints pathology might advance knowledge in of important relationships that have gone this area, which remains, despite its largely unstudied to date. It seems importance, highly underresearched. that inflammatory and thrombotic lesions, especially when these occur together, are associated with high risk of CP. But there has been to date no study in a large and Clues not Pursued representative population that connects The literature contains a number of ob- the dots of maternal and family history, servations that have not, to date, been genetic and acquired thrombophilias, followed up to establish whether these maternal and pregnancy history, placental are dead ends or opportunities for new histology, and descriptors of neonatal and advances. For example, 3 large popula- later neurologic outcome. tion-based studies have found lengthy maternal menstrual interval to be associated with CP risk.48–50 What might this Where to From Here? mean? A major cause of aberrant men- The development of large CP registries strual spacing is polycystic ovary syn- and regional and national birth cohort drome (PCOS), which is also associated studies will make it possible to determine with reduced fertility, obesity, preeclamp- outcome in the child without the need for sia, a procoagulant and proinflammatory expensive, difficult, and potentially state, preterm birth, and need for special biased (by nonrandom missingness) fol- care for the infant, all of which are risk low-up studies. Linkage of these records factors for perinatal stroke or for CP for the child with maternal medical more generally. In a small randomized records will permit investigation of the trial, treatment of PCOS seemed to association of CP with such maternal improve pregnancy outcome, but CP conditions as PCOS, thyroid disease, was not among the outcomes studied. Is and lupus. PCOS, a common and treatable condi- Neonatal nurseries often care for ill tion, linked with CP? No study has sought infants, preterm and term, without to find out. knowledge of the placental histology or Maternal thyroid disease has been re- of maternal or delivery factors that can lated to neonatal encephalopathy in 3 strongly influence prognosis in the infant, studies (including Ref. 16) in term infants, such as presence of maternal fever during to CP,48 to decreased IQ,51 and to con- labor. More workup of ‘‘hypoxic- genital deafness.52 Antithyroid antibodies ischemic encephalopathy’’ babies would are present in 10% of pregnancies53 and probably be contributory, and more in- 10% of neonates.54 No study has sought teraction between obstetric and neonatal to examine further the possibility that caregivers to assemble the information thyroid hormone level or presence of an- needed would enable better differential tithyroid antibodies contributes impor- diagnosis and specific management. tantly to encephalopathy in term neonates For any term or near-term infant who or to CP, although if present these asso- is markedly depressed in the delivery 760 Nelson room, the placenta should be carefully References described and sent to the laboratory. 1. Eastman NJ, DeLeon M. The etiology of Blocks should be cut in every such case, cerebral palsy. Am J Obstet Gynecol. 1955; and the material reviewed by the local 69:950–961. pathologist if there is an interested and 2. Neville B. 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