Contemporary OB/GYN - Comtecmed - global … · Web viewNeonatal encephalopathy refers to “a clinical phenomena of compromised neurological function in the term or near-term infant,

Preterm Labor, Infection and Cerebral Palsy

Errol R. Norwitz, M.D., Ph.D.Associate Professor, Yale University School of MedicineAssociate Director, Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale-New Haven Hospital, New Haven, Connecticut, U.S.A.

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Cerebral palsy refers to a group of chronic conditions that are characterized by abnormal control of movement or posture. These conditions are all cerebral in origin, arise early in life, and are non-progressive [1-3]. These conditions are frequently accompanied by seizure disorders, sensory impairment, and/or cognitive limitation. Cerebral palsy is heterogeneous is both its clinical manifestations and its causation. It is now clear that no more than 10% of all cases of cerebral palsy occur as a result of an intrapartum event [1-5]. This review will summarize briefly our current understanding of the prevalence and etiology of cerebral palsy before focusing on two specific risk factors: preterm birth and intrauterine infection.

The diagnosis of cerebral palsy is typically made at age 2 to 3 years. However, few studies have been willing to wait this length of time for a definitive diagnosis to be made. For this reason, many investigators as well as consensus committees have chosen to focus on surrogate endpoints, namely neonatal encephalopathy or hypoxic-ischemic encephalopathy (HIE). Neonatal encephalopathy refers to “a clinical phenomena of compromised neurological function in the term or near-term infant, (which) manifests during the first few days after birth” [6]. HIE refers to a subset of the much broader category of neonatal encephalopathy, in which the etiology is felt to be intrapartum hypoxic-ischemic injury. Before intrapartum hypoxic acidemia can be considered as the cause of neurologic injury, a set of specific criteria defined by several recent national and international consensus panels – including, among others, the International Cerebral Palsy Task Force [2], the American College of Obstetricians and Gynecologists (ACOG) [7], and the American Academy of Pediatrics [8] – must be met. These are summarized in Table 1. Moreover, the only two forms of cerebral palsy that have been associated with HIE are spastic quadriplegia and dyskinetic cerebral palsy [1,6,9,10]. Many cases of newborn encephalopathy do not result in cerebral palsy. The bulk of evidence indicates that intrapartum HIE is an infrequent cause of cerebral palsy [1-5].

Table 1: Criteria to define an acute intrapartum hypoxic-ischemic event*

Profound metabolic or mixed acidemia (pH <7.00) in an umbilical cord arterial blood sample, if obtained

Persistent Apgar score of 0 to 3 for longer than 5 minutes Evidence of neonatal neurologic sequelae (seizures, coma, or hypotonia) Neonatal multiorgan system dysfunction.

* Data from (a) International Cerebral Palsy Task Force. International consensus statement. Br Med J

1999; 319:1054-9; (b) American College of Obstetricians and Gynecologists. Committee Opinion no. 137. Washington, DC: ACOG, 1994; and (c) American Academy of Pediatrics. Pediatrics 1986; 7:1148.

HISTORICAL PERSPECTIVEAlthough cerebral palsy has existed throughout history, it was not described in the medical literature until 1844 when W.J. Little, an orthopedic surgeon who specialized in operating on childhood contractures, outlined a sequence beginning with difficult labor (“asphyxia neonatorum”) followed by neonatal seizures and, eventually, spastic motor paralysis [11]. (Interestingly, Little’s disease – spastic diplegia – is no longer believed to result from intrapartum events [12].) The term “cerebral palsy” is attributed to Sir William Osler who, in 1889, associated the condition with asphyxia of the newborn following complicated deliveries [13]. The first to question the causal relationship between a difficult delivery and cerebral palsy was Sigmund Freud. Before turning his attention to psychiatry, Freud was a neurologist with a particular interest in handicapped children. An astute observer, Freud noted that children with cerebral palsy often had other manifestations of cerebral injury that suggested brain damage early in gestation rather that injury around the time of delivery. Unfortunately, the “intrapartum asphyxia theory” of cerebral palsy gained ascendance again in the late 1970s and has persisted. Whether by ignorance or convenience [4] and despite substantial epidemiologic evidence demonstrating that cerebral palsy is caused by entities other than intrapartum hypoxia in greater than 90% of cases [1-5], intrapartum mismanagement and resultant HIE remains uppermost in the minds of non-obstetric care providers as a major cause of cerebral palsy.

Fetal acidosis and cerebral palsy: Where did we go wrong?It seems clear that severe hypoxic ischemic injury to the fetus in its most extreme form, such as that seen after a complete placental abruption or uterine rupture, may lead to fetal demise or long-term neurologic handicap, including cerebral palsy. However, it remains highly controversial as to whether milder forms of fetal acidosis and/or hypoxemia can cause cerebral palsy. In rhesus monkeys, Myers et al [14] demonstrated that partial asphyxia may eventually lead to long-term cerebral lesions that resemble, but are not identical to, the lesions of cerebral palsy seen in the human infant. In a retrospective case-control study, Richmond et al [15] found that abnormal fetal heart rate recordings were identified more frequently in children that subsequent developed cerebral palsy. However, the authors themselves concluded that “optimal management of fetal distress” would be expected to decrease the prevalence of cerebral palsy “by only 16%” [15]. Other investigators have been unable to demonstrate any association between fetal heart rate patterns and subsequent neurologic development [16].

PREVALENCECerebral palsy is the most serious handicap of intrauterine and early neonatal life, and is the major cause of medicolegal disputes in obstetrics [17]. Cerebral palsy is the most common developmental disability in the United States, affecting approximately half a million residents. According to the statistics of the Centers for Disease Control (CDC) of the United States (1991-1994), the average annual prevalence rate is 2.8 per 1,000 children ages 3 to 10 [18]. Annually, at least 8,000 new cases are diagnosed in infants in the United States alone and a further 1,500 are identified in children of preschool age [19].

In 1986, Nelson and Ellenberg [20] observed that “despite earlier optimism that cerebral palsy was likely to disappear with the advent of improvements in obstetrical and neonatal care, there has

apparently been no consistent decrease in it frequency in the past decade or two.” These conclusions have been confirmed by other investigators (Figure 1) [21-23]. These observations likely speak to the fact that the causes of newborn encephalopathy and cerebral palsy are heterogeneous, and many causal pathways start either periconceptionally or in the early antepartum period.

Figure 1: Cerebral palsy rates per 1,000 live births, 1970 to 2000. Data from Clark SL, Hankins GDV. Am J Obstet Gynecol 2003; 188:628.

ETIOLOGYNew insights into the origins of cerebral palsy have recently transformed the old concept that most cases of cerebral palsy begin in labor. There are many causes, including developmental abnormalities, metabolic abnormalities, autoimmune and coagulation disorders, trauma, infection, and antepartum or intrapartum hypoxia in the fetus or newborn [1-5,7,18,19,21-25]. Efforts to identify possible causes of cerebral palsy require skills from many disciplines. In a given clinical scenario, however, it may be difficult to assess which features are causally related to the cerebral injury. In many instances, the etiology remains unknown. Risk factors for newborn encephalopathy are summarized in Table 2 and Figures 2 and 3. A discussion of all of these risk factors is beyond the scope of his monograph and has been reviewed in detail elsewhere [21,22,24-27]. The remainder of this monograph will therefore focus on two specific risk factors: prematurity and intrauterine infection.

Table 2. Risk factors for newborn encephalopathy*

Preconceptional factors Antepartum factors Intrapartum factors

Increased maternal age Primiparity Unemployed, unskilled laborer, or

housewife No private health insurance Infertility treatment Family history of seizures Family history of neurologic

disorders

Male fetus Maternal thyroid disease Severe preeclampsia/eclampsia Bleeding in pregnancy Viral illness during pregnancy Prematurity Postterm pregnancy Placental abnormalities Intrauterine growth restriction in

the fetus Structural anomalies in the fetus Twin pregnancy

Intrapartum fever Prolonged rupture of

membranes Thick meconium Malpresentation and

malposition Intrapartum hypoxia Acute intrapartum events

(including cord prolapse, abruptio placentae, uterine rupture, maternal seizures)

Forceps delivery Emergency cesarean delivery

* Data from Badawi N, et al. Br Med J 1998; 317:1549; Badawi N, et al. Br Med J 1998; 317:1554; Ellis M, et al. Br Med J 2000; 320:1229; and Adamson SJ, et al. Br Med J 1995; 311:598.

Figure 2: Risk factors for newborn encephalopathy. Figure 3: Distribution of risk factors forData from Badawi N, et al. Br Med J 1998; 317:1549 and newborn encephalopathy. Data from Badawi N, et al. Br Med J 1998; 317:1554. Badawi N, et al. Br Med J 1998; 317:1554.

PrematurityPreterm birth (defined as delivery before 37 weeks’ gestation) occurs in 7-10% of all deliveries, but accounts for over 85% of all perinatal morbidity and mortality [28.29]. Approximately 20% of preterm deliveries are iatrogenic and are performed for maternal or fetal indications, including intrauterine growth restriction, preeclampsia, placenta previa, and non-reassuring fetal testing [30]. Of the remaining cases of preterm birth, around 30% occur in the setting of preterm premature rupture of the membranes, 20-25% result from intra-amniotic infection, and the remaining 25-30% are due to spontaneous (unexplained) preterm labor [30,31]. Unfortunately, despite intense efforts, the ability of obstetric care providers to prevent preterm labor and birth is limited. Indeed, the incidence of preterm delivery continued to rise in 2002, reaching a high of 12.1% [32]. This observation has been attributed primarily to assisted reproductive technology and to an increase in multiple pregnancies.

Epidemiologic studies have clearly shown an association between premature birth and cerebral palsy. Williams et al, for example, found a cerebral palsy frequency of 3.2% among live births <29 weeks’ gestation, 2.8% at 29-32 weeks, 0.3% at 33-36 weeks, and 0.07% at 37 weeks [33].

Paradoxically, similar statisticsfrom developing countries often appear more favorable, because premature infants in such countries rarely survive long enough to manifest signs of cerebral palsy. In developed countries, on the other hand, improvements in neonatal care have led to vastly improved survival rates at the expense of an increased incidence of long-term neurologic injury.

Intrauterine exposure to infectionA diagnosis of intrauterine infection (chorioamnionitis) during pregnancy is associated with an increased risk of cerebral palsy in infants with a birth weight 2,500 g [24,34-37]. In very premature infants, the association between infection and cerebral palsy has been less consistent and, when present, less strong [24,38]. Intrauterine exposure to infections other than toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus (TORCH) is believed to account for approximately 12% of cases of otherwise unexplained spastic cerebral palsy in non-malformed singleton infants of normal birth weight [34]. Although the ‘gold standard’ for the diagnosis is often reported as a positive amniotic fluid culture, chorioamnionitis remains primarily a clinical diagnosis. Unfortunately, the clinical definition is imprecise and, for the same specimen, there is often disagreement between the histologic indicators and the clinical diagnosis [39]. Epidural analgesia in labor, for example, is associated with an increased risk of intrapartum fever resulting in more antibiotics being administered and more infants being evaluated for sepsis, but this does not appear to translate into higher rates of postpartum infection or neonatal infectious morbidity [40,41].

The association between intrauterine infection and fetal and newborn neurologic injury (including neonatal encephalopathy and cerebral palsy) is almost certainly causal. In a rabbit model, for example, Yoon et al [42] demonstrated that intrauterine infection leads to white matter lesions in the fetal brain that resemble the lesions of infection-associated cerebral palsy seen in the human infant. It is possible that the association with newborn encephalopathy may be mediated either directly by fetal infection, indirectly through inflammatory cytokines, or both [43-48]. In many patients with intrauterine infection, elevated levels of lipoxygenase and cyclooxygenase pathway products can be demonstrated in maternal serum, fetal serum, and amniotic fluid [44,46]. There are also increased concentrations of cytokines (including interleukin-1b, interleukin-6, and tumor necrosis factor-a) in the serum and amniotic fluid of such women [44,46,47], which may predate the development of clinical chorio-amnionitis by weeks or even months [48].

If infection is causally related to brain injury, can antibiotic therapy prevent the development of cerebral palsy? Existing randomized trials of the use of antibiotics during pregnancy were designed primarily to investigate short-term perinatal outcome measures and have not been large enough or willing to follow the children long enough to examine whether such therapy can reduce the risk of cerebral palsy. Because of the possibility of harmful consequences of the widespread administration of antibiotics during pregnancy, an evaluation of the safety and efficacy of such medications in pregnancy should require randomized clinical trials that include the evaluation of long-term neurologic outcomes. Such studies are still awaited.

CAN WE PREVENT CEREBRAL PALSY?Despite the severe clinical and socioeconomic significance, no effective clinical strategies have yet been developed to prevent or counteract this condition [3,25]. However, a few approaches are worthy of further comment:

(1) After adjustment for confounding variables, preeclampsia appears to be independently protective

against neurologic injury and possibly against the development of cerebral palsy [49,50]. The exact mechanism by which preeclampsia exerts its protective effect is not known. Antenatal corticosteroids may have a similar protective effect [51], and some authorities have suggested that preeclampsia may exert its effect by increasing production of endogenous steroids.

(2) There are recent data to suggest that antepartum magnesium sulfate administration may be associated with a decreased incidence of cerebral palsy [50,52-55]. This association was initially noted by Kuban et al [49] in very low birth weight infants born to women who were given magnesium for seizure prophylaxis in the setting of preeclampsia, but has more recently been confirmed in a number of other retrospective analyses [50,52-54] with a reported crude odds ratio of 0.11 (95% CI: 0.02-0.81) [54]. This effect appears to be independent of steroid therapy [54,55]. Moreover, the effect is also observed in infants born of pregnancies not complicated by preeclampsia [52]. The proposed mechanism of action is speculative, but magnesium may act to increase threshold and decrease excitability in membranes of neurons and muscle cells. Some investigators have suggested that magnesium may reduce the prevalence of cerebral palsy simply by increasing the death rate among susceptible fetuses and infants. Indeed, during the Magnesium and Neurologic Endpoints Trial (MagNET), a large randomized clinical trial designed to test the neuroprotective effect of magnesium sulfate in the setting of preterm labor (not preeclampsia), the occurrence of excess total pediatric mortality in the children exposed to magnesium (10 of 75 fetuses randomized to magnesium or saline control versus 1 of 75 infants randomized to “other” tocolytics or saline control; P=0.02) led to early termination of the trial [55,56]. The authors concluded that, despite the alarming findings in MagNET, it is conceivable that exposures to doses of magnesium sulfate less than those used for aggressive tocolysis may be neuroprotective without being lethal [56]. This conclusion may be supported by the recently published Magpie Trial [57], a clinical study of 10,141 women with preeclampsia randomized in 33 countries to receive either magnesium sulfate or placebo for seizure prophylaxis. This study showed no substantive short-term harmful effects of magnesium sulfate on the fetus. Because of the ongoing controversy, it is not currently standard of care to administer antenatal magnesium sulfate to women threatening to deliver extremely premature infants.

(3) There is some evidence to suggest that perinatal brain injury following an intrapartum hypoxic ischemic event may evolve, at least in part, over a period of hours or days, thereby providing a possible window of opportunity for early intervention. Preliminary studies on the use of neonatal hypothermia treatment suggest that such an approach may provide some neuroprotective effect [58,59]. Until further studies are available, however, such treatment should be regarded as investigational.

(4) Elective cesarean delivery prior to labor is protective against the development of cerebral palsy [22,26]. However, cesarean delivery after the onset of labor likely mitigates against this protective effect. Reviewing pooled data from nine industrialized countries, Clark and Hankins concluded that “despite a 5-fold increase in the rate of cesarean section based, in part, on the electronically derived diagnosis of ‘fetal distress’, cerebral palsy prevalence has remained stable” [23].

CONCLUSIONSCerebral palsy is a syndrome since the etiologies are varied. Considerable evidence suggests that no more than 10% of all cases of cerebral palsy occur as a result of an intrapartum event. A better understanding of the pathophysiologic mechanisms responsible for fetal and infant brain injury will further our knowledge about disorders of neurologic development, including cerebral palsy. There are

as yet no effective strategies available for the prevention and/or treatment of fetuses and newborns at risk for cerebral palsy.

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