Maternal and Infant Characteristics Associated with Perinatal Arterial Stroke in the Infant

ORIGINAL CONTRIBUTION

Maternal and Infant Characteristics Associated With Perinatal Arterial Stroke in the Infant

Janet Lee, MS Context Perinatal arterial ischemic stroke (PAS) is a common cause of hemiplegic Lisa A. Croen, PhD cerebral palsy. Risk factors for this condition have not been clearly defined. Kendall H. Backstrand, BA Objective To determine maternal and infant characteristics associated with PAS. Cathleen K. Yoshida, MS Design, Setting, and Patients Case-control study nested within the cohort of all 199176 infants born from 1997 through 2002 in the Kaiser Permanente Medical Care Louis H. Henning, BA Program, a managed care organization providing care for more than 3 million resi- Camilla Lindan, MD dents of northern California. Case patients were confirmed by review of brain imag- Donna M. Ferriero, MD ing and medical records (n=40). Three controls per case were randomly selected from the study population. Heather J. Fullerton, MD Main Outcome Measure Association of maternal and infant complications with A. J. Barkovich, MD risk of PAS. Yvonne W. Wu, MD, MPH Results The population prevalence of PAS was 20 per 100000 live births. The majority (85%) of infants with PAS were delivered at term. The following prepartum ERINATAL ARTERIAL ISCHEMIC and intrapartum factors were more common among case than control infants: primi- stroke (PAS) is an important parity (73% vs 44%, P=.002), fetal heart rate abnormality (46% vs 14%, PϽ.001), cause of cerebral palsy and emergency cesarean delivery (35% vs 13%, P=.002), chorioamnionitis (27% vs other neurologic disabilities, 11%, P=.03), prolonged rupture of membranes (26% vs 7%, P=.002), prolonged Pincluding epilepsy and cognitive im- second stage of labor (25% vs 4%, PϽ.001), vacuum extraction (24% vs 11%, pairment.1-7 Arterial ischemic stroke is P=.04), cord abnormality (22% vs 6%, P=.01), preeclampsia (19% vs 5%, P=.01), diagnosed primarily in neonates born and oligohydramnios (14% vs 3%, P=.01). Risk factors independently associated at term8,9 and is responsible for 50% to with PAS on multivariate analysis were history of infertility (odds ratio [OR], 7.5; 95% 70% of congenital hemiplegic cerebral confidence interval [CI], 1.3-45.0), preeclampsia (OR, 5.3; 95% CI, 1.3-22.0), pro- 10,11 longed rupture of membranes (OR, 3.8; 95% CI, 1.1-12.8), and chorioamnionitis palsy in this population. (OR, 3.4; 95% CI, 1.1-10.5). The rate of PAS increased dramatically when multiple The cause of PAS is poorly under- risk factors were present. stood. Investigators have reported a Conclusions Perinatal arterial ischemic stroke in infants is associated with several number of obstetric and neonatal independent maternal risk factors. How these complications, along with their poten- complications in the setting of PAS, tial effects on the placenta and fetus, may play a role in causing perinatal stroke de- including birth asphyxia, preeclamp- serves further study. sia, chorioamnionitis, cardiac anoma- JAMA. 2005;293:723-729 www.jama.com lies, polycythemia, and systemic infection.7,12-15 Others have failed to Author Affiliations: Departments of Neurology (Ms find a significant difference in the Previous studies of PAS are subject to Lee, Mssrs Backstrand and Henning, and Drs Ferri- frequency of perinatal complications a number of important limitations. Most ero, Fullerton, Barkovich, and Wu), Pediatrics (Drs Fer- riero, Fullerton, Barkovich, and Wu), and Radiology between infants with PAS and con- describe only a small number of chil- (Dr Barkovich), University of California, San Fran- trols.16 Hematologic disorders, dren7,12,16,20-22 or lack an adequate com- cisco; and Kaiser Permanente Division of Research (Dr 8,14,23 Croen and Ms Yoshida) and Department of Radiol- including factor V Leiden mutation parison group. We found previ- ogy (Dr Lindan), Oakland, Calif. and hyperhomocysteinemia, may ously that preeclampsia and intrauterine Corresponding Author: Yvonne W. Wu, MD, MPH, UCSF Department of Child Neurology, Box 0137, 350 also play a role in the pathogenesis growth restriction are independent risk Parnassus Ave, Suite 609, San Francisco, CA 94117 of PAS.14,17-19 factors for PAS.15 However, our earlier ([email protected]).

Downloaded from www.jama.com at McGill University Libraries, on January 15, 2007 CHARACTERISTICS ASSOCIATED WITH NEWBORN STROKE study included only children with PAS tify potential cases of PAS. They ex- Data Abstraction who developed long-term motor impair- cluded neuroimaging studies that re- Two study investigators blinded to ment, and we did not confirm the diag- vealed (1) no mention of possible case status reviewed prenatal (J.L.), nosis of PAS with review of brain imag- stroke; (2) an acute infarction occur- obstetric (J.L.), and neonatal (L.H.H.) ing. Therefore, we set out to determine ring after 28 days of life; (3) isolated medical records by using a standard- pregnancy complications associated with hemorrhagic lesions; (4) venous in- ized protocol. An infant born at or radiologically confirmed PAS in a de- farction; or (5) infarctions limited to the later than 41 weeks of gestation was fined population of infants. arterial watershed zones.1 A study neu- considered postdates. Maternal body roradiologist (C.L.) then reviewed 141 mass index was calculated from METHODS head MRI or CT scans to confirm the prepregnancy height and weight mea- This case-control study was nested presence of an arterial-distribution is- surements, if available, or from the within the cohort of all 199176 infants chemic infarction. When the presence first prenatal visit. To evaluate the born from January 1, 1997, to Decem- of an arterial infarction was not obvi- effect of ethnicity on risk of PAS, we ab- ber 31, 2002, in the Northern Califor- ous, the imaging studies were re- stracted maternal ethnicity according nia Kaiser Permanente Medical Care Pro- viewed by a second neuroradiologist to self-report as noted in the medical gram (KPMCP). The KPMCP is a large (A.J.B.), and a consensus about the fi- records. Intrauterine growth restric- managed care organization that pro- nal neuroimaging diagnosis was tion was defined as birth weight less vides care for more than 30% of the reached through discussion. One child than the 10th percentile for gesta- population in northern California. The whose MRI scan could not be located tional age according to race- and sex- members of KPMCP are demographi- was included because his MRI report specific normative data compiled cally similar to the California popula- described an unambiguous large pos- from California births.26 The mother tion, except that the very poor and very terior cerebral artery infarction. was considered to have a history of wealthy are underrepresented.24 All study Two investigators (K.H.B., J.L.) re- infertility if this was documented in a procedures were approved by the insti- viewed the medical records of chil- prenatal, obstetric, or neonatal record. tutional review boards at KPMCP and at dren with radiologically confirmed ar- Information about the use of infertil- the University of California, San Fran- terial infarction to determine whether ity drugs for the index pregnancy was cisco, which waived requirement for the stroke was perinatal. We defined a also abstracted from these records. informed consent. perinatal event as one that occurred in Preeclampsia was defined as a phy- utero or up to 28 days after birth.25 If sician diagnosis of either preeclampsia Case Ascertainment the infant presented within the first 28 or pregnancy-induced hypertension. We searched electronically all head days after delivery, the stroke was con- We used the term chorioamnionitis to magnetic resonance imaging (MRI) and sidered to be acute. If an infant had been indicate a maternal temperature of at computed tomographic (CT) reports considered neurologically normal be- least 37.8°C or a physician diagnosis generated from January 1, 1997, fore 1 month of age but was later diag- of chorioamnionitis according to clini- through July 1, 2003 (all study infants nosed with an old arterial infarction, the cal symptoms alone. The term cord were all at least 6 months of age when stroke was considered to be presumed abnormalities included tight nuchal records were searched), and retrieved perinatal.3 cord, umbilical cord knot, and body neuroimaging reports containing any of Three infants with PAS caused by a cord. We used the term birth asphyxia the following text strings: stroke, in- known neonatal event were excluded to indicate a diagnosis made by a treat- farct, thrombo, ischemi, middle cerebral from the risk factor analysis but in- ing physician of either birth asphyxia artery, MCA, posterior cerebral artery, cluded in the prevalence calculation. or hypoxic-ischemic encephalopathy. PCA, anterior cerebral artery, ACA, vas- One infant had an iatrogenic PAS after The second stage of labor was coded cular insult, vascular injury, vascular surgical evacuation of an intracranial as prolonged if it lasted more than 2 event, porencephal,orhydranencephal. hematoma, and 2 had acute arterial hours. Fetal heart rate abnormalities We also retrieved all head MRI and CT strokes in the setting of severe menin- were considered present if a treating reports generated for newborns admit- gitis after 2 weeks of age. physician noted repetitive or pro- ted to the neonatal intensive care unit longed late decelerations, fetal brady- with seizures and for children who were Control Selection cardia, nonreassuring fetal heart trac- given an inpatient or outpatient phy- We randomly selected 3 controls per ing, or fetal distress according to sician diagnosis of stroke, developmen- case from the study population. Con- electronic fetal heart rate monitoring. tal delay, hemiparesis, or cerebral palsy trol infants were frequency matched to Decreased fetal movement referred to before November 2003. the infants with PAS on birth year, fa- a maternal report of decreased fetal Two study investigators (K.H.B., J.L.) cility of birth, and gestational age stra- movement before labor or decreased independently reviewed the head MRI tum (Ͻ32 weeks, 32-35 weeks, and fetal movement noted during a non- and CT reports of 1970 patients to iden- Ն36 weeks of gestation). stress test.

Downloaded from www.jama.com at McGill University Libraries, on January 15, 2007 CHARACTERISTICS ASSOCIATED WITH NEWBORN STROKE

Data Analysis Figure. Selection of Study Cases We compared dichotomous variables by ␹2 using or Fisher exact test and con- 199 176 Infants in Study Population tinuous variables by using the t test. We calculated univariate odds ratios (ORs) and 95% confidence intervals (CIs) with 1970 Whose Head MRI or CT Reports Were 197 206 Excluded (No Clinical Diagnosis of the Cornfield or exact method, as appro- Reviewed∗ Stroke, No Head MRI or CT With Stroke Diagnosis, or No Head priate, and multivariate ORs with back- Imaging Performed) ward stepwise logistic regression, with 1829 Excluded PϽ.10 used as the cutoff for retention in 11 Acute Childhood Stroke 120 Control Infants 27 the model. To determine whether risk 1818 No Evidence of factors differed for the acute-presenta- Arterial Stroke tion group compared with the delayed- 141 Whose Head MRI or CT Scans presentation group, we performed a Were Reviewed by a Neuroradiologist polytomous logistic regression.27 Odds ratios closely approximate the relative 100 Excluded (No Evidence risk because the outcome of PAS is rare. of Arterial Stroke) The multivariate model included maternal (primiparity and infertility), 41 Chart Review to Confirm Perinatal prepartum (preeclampsia, oligohydram- Arterial Stroke nios), and intrapartum (chorioamnionitis, prolonged rupture of mem- 1 Excluded (Hypoglycemic branes, cord abnormality, and use of Brain Injury) oxytocin) characteristics associated Ͻ 40 Case Infants With Perinatal with PAS at a level of P .15 in univari- Arterial Stroke ate analyses that were considered un- likely to be a result of the stroke. In- CT indicates computed tomography; MRI, magnetic resonance imaging. fant characteristics such as neonatal *Patients with a neuroimaging report containing a keyword suggestive of stroke, or who carried a physician diagnosis of stroke, cerebral palsy, neonatal seizures, or a related diagnosis. seizures and low Apgar scores, as well as decreased fetal movement, were not included in the model because they RESULTS tally when a routine head ultrasound most likely result from perinatal brain Among 1970 children who had either showing intraventricular hemorrhage injury and do not play a causal role. a head-imaging report or a clinical di- or white-matter abnormalities led to a It is impossible to know where some agnosis suggesting possible PAS, 141 head CT that diagnosed an arterial variables lie on the causal pathway. For patients had a head MRI or CT scan that stroke. All children with presumed peri- instance, fetal heart rate abnormalities was reviewed by a neuroradiologist natal stroke presented after 2 months may (1) play a primary causal role in (FIGURE). A total of 40 cases of PAS of age, with pathologic handedness PAS; (2) be on the causal pathway be- were confirmed, providing a popula- (hand preference earlier than 1 year of tween a preceding risk factor and PAS; tion prevalence of 20 per 100000 live age) as the most common presenting (3) be merely an adverse effect of an un- births. Infants with PAS were all single- symptom, which was consistent with derlying causal factor without direct im- ton gestation, and the majority (85%) previous reports.3 pact on PAS; (4) be a direct conse- were delivered at term (mean [SD], Previously described causes of PAS quence of the stroke event; or (5) be a 39.9[1.0] weeks). The 6 preterm in- were uncommon in our cohort. Al- combination of the above. For this rea- fants with PAS were born between 30 though cardiac echocardiography was son, intrapartum complications asso- and 35 weeks of gestation, with the ex- not performed routinely, none of the ciated with PAS, including fetal heart ception of 1 infant who was delivered children with PAS were diagnosed with rate abnormalities, prolonged second at 24 weeks. a major congenital heart abnormality. stage of labor, vacuum assistance, and Minor cardiac findings in 4 patients emergency cesarean delivery, were not Clinical Presentation with a heart murmur included a patent included in the main multivariate analy- Most infants with PAS (58%) pre- ductus arteriosus, a very mild muscu- sis but instead were added to the model sented during the acute neonatal pe- lar hypertrophy, and a small ventral sep- separately to determine whether they riod. Term infants presented fre- tal defect that was thought to be clini- contribute additional risk to PAS be- quently with neonatal seizures (70%), cally insignificant. One infant had a yond that accounted for by the vari- whereas 3 of 4 preterm infants with mild polycythemia (hematocrit level ables in the main model. acute PAS were diagnosed inciden- dropped from 70.5% to 65% during 20

Downloaded from www.jama.com at McGill University Libraries, on January 15, 2007 CHARACTERISTICS ASSOCIATED WITH NEWBORN STROKE hours) that did not require exchange Neuroimaging Findings right (35%), whereas 13% demon- transfusion. Few patients received a co- The diagnosis of PAS was made on strated bilateral arterial distribution in- agulation evaluation, and therefore we either head MRI (70%) or head CT farcts. The majority of strokes in- could not assess the role of prothrom- (30%). Unilateral infarctions were more volved only the middle cerebral artery botic disorders in PAS. common on the left (53%) than on the distribution (74%), with an additional 4 strokes that involved the middle ce- Table 1. Univariate Predictors of Perinatal Arterial Stroke in a Population of Term and rebral artery plus other arteries. Preterm Infants Born at Kaiser Permanente Northern California, 1997-2002 Univariate Risk Factor Analysis No./Total (%)* Odds Ratio Although maternal age, race, body mass Cases Controls (95% Confidence P (n = 37) (n = 111) Interval) Value index, and number of previous miscar- Maternal characteristics riages did not differ between the case Age, y and control groups, case mothers were Ͻ Ͼ 20 2/37 (5) 9/111 (8) 0.7 (0.1-3.9) .99 more likely to be primiparous 20-34 26/37 (70) 87/111 (78) Reference (TABLE 1). Case mothers were also Ն 35 9/37 (24) 15/111 (14) 2.0 (0.8-5.0) .14 more likely to have a history of infer- Race White 14/37 (38) 36/111 (32) Reference tility, although the difference was not Black 4/37 (11) 16/111 (14) 0.6 (0.1-2.5) .56 significant (11% vs 4%, P=.11). Other Hispanic 11/37 (30) 33/111 (30) 0.9 (0.3-2.1) .74 prepartum characteristics more com- Asian 8/37 (22) 25/111 (23) 0.8 (0.3-2.2) .70 monly observed in case mothers in- Other 0/37 1/111 (1) cluded preeclampsia, oligohydram- High body mass index (Ն30) 6/30 (20) 14/89 (16) 1.3 (0.5-3.8) .59 nios, and decreased fetal movement. Primiparity 27/37 (73) 49/111 (44) 3.4 (1.5-7.6) .002 Intrapartum complications associ- Previous miscarriage† 3/21 (14) 14/75 (19) 0.7 (0.1-3.0) .76 ated with PAS included chorioamnion- History of infertility 4/37 (11) 4/111 (4) 3.2 (0.6-18.3) .11 itis, prolonged rupture of membranes, Ovarian stimulation 4/37 (11) 3/111 (3) 4.4 (0.7-30.9) .07 prolonged second stage of labor, fetal Prepartum complications heart rate abnormality, cord abnormal- Intrauterine growth restriction 4/37 (11) 11/109 (10) 1.1 (0.2-4.0) Ͼ.99 ity, vacuum assistance, and emergency Gestational diabetes 4/37 (11) 14/111 (13) 0.8 (0.2-2.9) Ͼ.99 cesarean delivery. A clinical diagnosis of Preeclampsia 7/37 (19) 5/111 (5) 4.9 (1.2-21.0) .01 birth asphyxia or hypoxic ischemic en- Oligohydramnios 5/37 (14) 3/111 (3) 5.6 (1.0-37.6) .02 cephalopathy was given to 6 infants with Decreased fetal movement 12/37 (32) 7/111 (6) 7.1 (2.6-19.4) Ͻ.001 PAS (16%), whereas none of the con- Ͼ Preterm labor‡ 1/31 (3) 3/93 (3) 1.0 (0.02-13.0) .90 trol infants received this diagnosis Intrapartum complications Ͻ Chorioamnionitis 10/37 (27) 12/111 (11) 3.1 (1.1-8.6) .02 (P .001). After delivery, infants with Prolonged rupture of membranes 9/35 (26) 7/107 (7) 4.9 (1.7-14.1) .002 PAS were significantly more likely to be Breech presentation 2/37 (5) 10/111 (9) 0.6 (0.1-2.9) .73 given an Apgar score less than 7 at 5 min- Use of oxytocin 22/36 (61) 51/111 (46) 1.8 (0.9-3.9) .11 utes and to require resuscitation Prolonged second stage of labor 9/36 (25) 4/111 (4) 8.9 (2.2-41.9) Ͻ.001 (Table 1). The umbilical artery pH was Fetal heart rate abnormality 17/37 (46) 16/111 (14) 5.0 (2.2-11.6) Ͻ.001 less than 7.0 in 3 of 11 infants with PAS Meconium (moderate to severe) 8/37 (22) 15/111 (14) 1.8 (0.7-4.5) .24 for whom a cord gas result was available. Cord abnormality 8/37 (22) 7/111 (6) 4.1 (1.4-11.8) .008 Chorioamnionitis was significantly as- Forceps 1/37 (3) 0/111 .25 sociated with PAS only in the absence Vacuum 9/37 (24) 12/111 (11) 2.7 (1.0-6.8) .04 of fetal distress (OR, 5.4; 95% CI, 1.3- Emergency cesarean delivery 13/37 (35) 14/111 (13) 3.8 (1.6-8.9) .002 21.6). No other interactions were found Diagnosis of birth asphyxia 6/37 (16) 0/110 Ͻ.001 in stratified analyses. Furthermore, cho- Infant characteristics rioamnionitis was associated with acute Male sex 15/37 (41) 47/111 (42) 0.9 (0.4-2.0) .85 stroke (OR, 6.1; 95% CI, 1.9-19.2) but Apgar score Ͻ7 at 5 min 15/37 (41) 16/110 (15) 4.0 (1.7-9.2) .01 not with presumed perinatal stroke (OR, Resuscitation at birth 23/37 (62) 29/109 (27) 4.5 (2.1-9.9) Ͻ.001 0.7; 95% CI, 0.1-6.0). The risk factors Postdates (Ն41 wk) 9/37 (24) 16/110 (15) 1.9 (0.8-4.7) .17 for acute and presumed perinatal stroke Gestational weeks, mean (SD) 38.5 (3.7) 37.9 (4.5) .49 were otherwise similar. Birth weight, mean (SD), g 3127 (852) 3203 (923) .66 *Three infants with acute arterial stroke after 2 weeks of age because of meningitis (2) or intraoperative stroke (1) were Multivariate Risk Factor Analysis excluded from this analysis, which excluded 9 frequency-matched controls as well. †Data reflect the percentage of multigravida women who had a history of miscarriage. The following variables were entered ‡Data reflect the percentage of women delivering at term who had preterm labor earlier in the pregnancy. into the main logistic regression model:

Downloaded from www.jama.com at McGill University Libraries, on January 15, 2007 CHARACTERISTICS ASSOCIATED WITH NEWBORN STROKE history of infertility, oligohydram- Placental Pathology we found several significant risk fac- nios, preeclampsia, prolonged rup- Only 3 placental pathologic examina- tors identified during pregnancy. Intra- ture of membranes, cord abnormality, tions were performed in the 40 infants partum complications were also more chorioamnionitis, primiparity, and use with PAS. Findings included a posi- common in infants with PAS, and the of oxytocin (TABLE 2). The risk fac- tive staphylococcus culture on the risk of PAS was dramatically higher in tors that remained independently as- fetal side (1 term infant), funisitis (1 the presence of multiple risk factors. sociated with PAS were infertility (OR, preterm infant), and acute chorioam- The prevalence of PAS has not been 7.5; 95% CI, 1.3-45), preeclampsia (OR, nionitis, together with a placental in- clearly determined. Previous popula- 5.3; 95% CI, 1.3-22.0), chorioamnion- farction (1 preterm infant). Eleven con- tion-15,28,29 and hospital-based14,16,30 es- itis (OR, 3.4; 95% CI, 1.1-10.5), and trol placentas were submitted for timates range from 17 to 93 per 100000 prolonged rupture of membranes (OR, pathologic examination. Findings live births, depending on the study de- 3.8; 95% CI, 1.1-12.8). Seven of the 8 among the 3 control infants born at sign and case definition. We found that infertile women received ovarian- term included a chorangioma (1), pla- PAS was diagnosed in 20 per 100000 live stimulation medications before the con- cental abruption (1), and a normal pla- births. The exclusion of periventricu- ception of the index child. When ovar- centa (1), whereas for the 8 preterm lar and watershed distribution infarc- ian stimulation was entered into the control infants, findings included acute tions, as well as infarctions that appear model in the place of infertility, the ad- chorioamnionitis (3) and a normal pla- to be venous in origin, may explain why justed OR was 13.2 (95% CI, 1.8-98.3). centa (5). our prevalence estimate is within the Although fetal heart rate abnormali- lower range of previous estimates. Our ties, vacuum extraction, and emer- COMMENT findings confirm, however, that the rate gency cesarean delivery were all sig- Perinatal arterial stroke is the most com- of PAS is 17 times higher than the inci- nificantly associated with increased risk mon cause of hemiplegic cerebral palsy, dence of childhood ischemic stroke31 and of PAS in univariate analyses, none of yet the etiology is poorly understood. To as high as the annual incidence of large- these factors remained independently our knowledge, this is the first con- vessel ischemic stroke in adults older associated with PAS after adjustment for trolled study of risk factors for PAS than 18 years (17-23 per 100000).32 the other variables in the multivariate within a population that includes all Although infertility did not repre- model. Prolonged second stage of la- cases diagnosed by neuroimaging, and sent a significant risk factor in univari- bor was a significant univariate predictor of PAS but was also strongly corre- lated with primiparity. As expected, Table 2. Multivariate Odds Ratios for Perinatal Arterial Stroke in a Population of Term and when primiparity was removed from the Preterm Infants Born at Kaiser Permanente Northern California, 1997-2002* model to avoid collinearity, pro- Odds Ratio (95% Confidence Interval) P Value longed second stage of labor was an in- History of infertility 7.5 (1.3-45.0) .03 dependent predictor of PAS (OR, 5.0; Oligohydramnios 5.4 (0.9-31.3) .06 95% CI, 1.2-21.1; P=.03). Preeclampsia 5.3 (1.3-22.0) .02 Prolonged rupture of membranes 3.8 (1.1-12.8) .03 Multiple Risk Factors Cord abnormality 3.6 (1.0-12.7) .05 The following factors were signifi- Chorioamnionitis 3.4 (1.1-10.5) .03 cantly associated with PAS on either Primiparity 2.5 (1.0-6.4) .05 univariate or multivariate analysis and *The variables included in the backward stepwise logistic regression were all those listed above, as well as use of oxy- could be identified before delivery: pri- tocin, which was dropped from the final model (P = .49). miparity, infertility, oligohydramnios, preeclampsia, chorioamnionitis, pro- Table 3. Risk of Perinatal Arterial Stroke (PAS) Stratified by the Number of Risk Factors longed rupture of membranes, de- Present Before Delivery creased fetal movement, prolonged sec- No. (%) ond stage of labor, and fetal heart rate Risk Factors, Cases Controls Odds Ratio Prevalence of PAS abnormalities. As expected, the risk of No.* (n = 37) (n = 111) (95% Confidence Interval) per 1000 PAS increased with the number of these Ն1 30/35 (86) 63/107 (59) 4.2 (1.4-14.8) 0.8 risk factors present (TABLE 3). Only 6% Ն2 24/35 (69) 27/107 (25) 6.5 (2.6-16.5) 1.3 of controls had 3 or more risk factors Ն3 21/35 (60) 6/107 (6) 25.3 (7.9-87.1) 5.1 present compared with 60% of case chil- Ն4† 11/35 (31) 2/107 (2) 24.1 (4.7-230.0) 4.8 dren (OR, 25.3; 95% CI, 7.9-87.1). *Includes risk factors that can be identified before delivery: infertility, preeclampsia, chorioamnionitis, prolonged rupture of membranes, primiparity, oligohydramnios, decreased fetal movement, prolonged second stage of labor, and When 3 or more risk factors are pres- fetal heart rate abnormalities. ent, the probability of delivering a child †The proportion of case children with 5 or more risk factors was 11%. None of the control children had 5 or more risk factors, so an odds ratio could not be calculated. with PAS is as high as 1 in 200.

Downloaded from www.jama.com at McGill University Libraries, on January 15, 2007 CHARACTERISTICS ASSOCIATED WITH NEWBORN STROKE ate analysis, it was an independent pre- riod and not with PAS diagnosed later minimizing potential reporting bias. dictor of PAS after adjustment for in infancy, which suggests that the Strengths of our study include the popu- confounders. This discrepancy is ex- pathogenesis of PAS may differ for in- lation-based setting; blinded evalua- plained by the fact that infertile women fants with earlier presentation com- tion of maternal, prepartum, and intra- were less likely to have other signifi- pared with those with a later presenta- partum factors; and the selection of an cant risk factors such as preeclampsia tion. Alternatively, the presence of appropriate control group. and oligohydramnios, and this nega- chorioamnionitis may increase the like- Perinatal arterial stroke has been at- tive confounding was largely removed lihood of neonatal symptoms, thus tributed to etiologies such as congen- by multivariate analysis. All 4 moth- prompting earlier recognition of PAS. ital heart disease,47 polycythemia,13 in ers with infertility who had a child with We found that intrapartum compli- utero cocaine exposure,48 and neona- PAS in our study were treated with cations were more common in infants tal meningitis.49 Among our cases, only ovarian-stimulation drugs. Ovarian hy- with PAS than in control infants, which 2 infants had neonatal meningitis, 1 had perstimulation syndrome is known to was consistent with previous re- an iatrogenic stroke from brain sur- cause a hypercoagulable state that may ports.20,21,46 However, complications such gery, no infants had major congenital lead to arterial and venous thrombosis as fetal heart rate abnormalities were no heart disease, and 1 infant had a mild in the mother.33,34 To our knowledge, longer independently associated with polycythemia that resolved without this is the first report of infertility treat- PAS after adjustment for maternal vari- intervention. If one makes an assump- ment with ovarian stimulation associ- ables. Furthermore, although fetal dis- tion that the 4 independent risk ated with thrombotic complications in tress and low Apgar scores often lead to factors found in this study do in fact the newborn; whether placental throm- a clinical diagnosis of birth asphyxia, play a causal role, the population- bosis underlies this relationship re- these complications do not always re- attributable fractions (chorioamnion- quires further study. Others have reflect a global hypoxic-ischemic event, as itis, 21%; infertility, 19%; preeclamp- ported an increased risk of cerebral implied by the term birth asphyxia.Inour sia, 16%; and prolonged rupture of palsy after infertility treatment.35,36 study, all 6 infants with PAS who were membranes, 16%) suggest that these Larger studies are needed to confirm the diagnosed with birth asphyxia had a fo- factors may account for a significant association between infertility and PAS cal arterial infarction as opposed to the proportion of PAS cases. and to determine whether the under- more typical neuroimaging findings of A thromboembolic event originat- lying infertility or its treatment might hypoxic-ischemic brain injury, such as ing from an intracranial vessel, extra- be responsible. deep gray-matter or arterial-watershed cranial vessel, the heart, or the pla- Preeclampsia, a strong risk factor for injury, reminding us that the clinical di- centa may lead to an arterial stroke that PAS in our population, is thought to re- agnosis of birth asphyxia is not specific occurs in the perinatal period.1 Al- sult from a vascular defect in the pla- for any single pathogenetic mechanism though placental findings have rarely centa bed, leading to reduced uteropla- of brain injury. been described in PAS, pathologic stud- cental blood flow.37,38 Preeclampsia has Our study was subject to a number of ies have suggested that placental in- been associated with maternal pro- limitations. Despite the large source farction and inflammation may be re- thrombotic disorders, thrombotic le- population, the number of final cases lated to cerebral palsy, a long-term sions in the placenta, and a maternal his- was relatively small, resulting in wide CIs outcome of PAS.50-53 We found similar tory of thromboembolism.39-41 for several effect estimates. There may placental abnormalities in our infants Furthermore, preeclampsia increases the be underascertainment of PAS because with PAS, although only 3 placentas risk of neonatal sinovenous thrombo- 11% of our cohort was lost to fol- were examined. Maternal conditions sis, neonatal encephalopathy, and mo- low-up by 1 year of age, and children that affect placental function, such as tor impairment related to PAS.15,42-44 The with subtle neurologic deficits may not preeclampsia and chorioamnionitis, relationship between prothrombotic dis- have received a neuroimaging study to were found to be independent risk fac- orders, preeclampsia, placental dysfunc- identify a PAS. Insufficient informa- tors for PAS. Together, these data sug- tion, and PAS deserves further study. tion was available on possible risk fac- gest that the placenta may play an im- Chorioamnionitis, a diagnosis that is tors such as smoking, drug use, and so- portant role in the pathogenesis of PAS, usually based on the presence of mater- cioeconomic indicators. Given the although no conclusions can be drawn nal intrapartum fever, has received much retrospective nature of the study, we from this study, given the small num- attention as a predictor for cerebral lacked a uniform neuroimaging proto- ber of placentas examined. palsy.45 However, to our knowledge, this col and relied on medical record docu- Future studies that provide addi- is the first report of clinical chorioam- mentation for determining the pres- tional data on placental pathology, co- nionitis acting as an independent risk ence of risk factors. However, physicians agulation disorders in the mother and factor for PAS. Interestingly, chorioam- typically document maternal complica- fetus, and comprehensive neuroimag- nionitis was associated only with PAS tions in the medical records before ing findings may further elucidate the that was diagnosed in the neonatal pe- knowing the outcome of the child, thus underlying pathogenetic mechanisms

Downloaded from www.jama.com at McGill University Libraries, on January 15, 2007 CHARACTERISTICS ASSOCIATED WITH NEWBORN STROKE of PAS. Only with an improved under- infarction in the term newborn: clinical presentation stroke subtypes: a population-based study of inci- and long-term outcome. J Pediatr. 2000;137:351-355. dence rates among blacks and whites. Stroke. 2004; standing of what causes PAS will we de- 9. Wulfeck BB, Trauner DA, Tallal PA. Neurologic, cog- 35:1552-1556. termine how to prevent this impor- nitive, and linguistic features of infants after early stroke. 33. Yoshii F, Ooki N, Shinohara Y, Uehara K, Mochi- Pediatr Neurol. 1991;7:266-269. maru F. Multiple cerebral infarctions associated with tant cause of neurologic disability in 10. Uvebrant P. Hemiplegic cerebral palsy: aetiol- ovarian hyperstimulation syndrome. Neurology. 1999; children. ogy and outcome. Acta Paediatr Scand Suppl. 1988; 53:225-227. 345:1-100. 34. Rogolino A, Coccia ME, Fedi S, et al. Hyperco- Author Contributions: Dr Wu had full access to all 11. Wu YW, Escobar GJ, Grether JK, Croen LA, Greene agulability, high tissue factor and low tissue factor path- of the data in the study and takes responsibility for JD, Newman TB. Chorioamnionitis and cerebral palsy way inhibitor levels in severe ovarian hyperstimula- the integrity of the data and the accuracy of the data in term and near-term infants. JAMA. 2003;290:2677- tion syndrome: possible association with clinical analysis. 2684. outcome. Blood Coagul Fibrinolysis. 2003;14:277-282. Study concept and design: Croen, Backstrand, Ferriero, 12. Jan MM, Camfield PR. Outcome of neonatal stroke 35. Stromberg B, Dahlquist G, Ericson A, Finnstrom Fullerton, Wu. in full-term infants without significant birth asphyxia. O, Koster M, Stjernqvist K. Neurological sequelae in Acquisition of data: Lee, Croen, Backstrand, Yoshida, Eur J Pediatr. 1998;157:846-848. children born after in-vitro fertilisation: a population- Henning, Lindan, Barkovich, Wu. 13. Amit M, Camfield PR. Neonatal polycythemia caus- based study. Lancet. 2002;359:461-465. Analysis and interpretation of data: Lee, Croen, ing multiple cerebral infarcts. Arch Neurol. 1980;37: 36. Ericson A, Nygren KG, Olausson PO, Kallen B. Hos- Backstrand, Ferriero, Wu. 109-110. pital care utilization of infants born after IVF. Hum Drafting of the manuscript: Lee, Backstrand, Henning, 14. Govaert P, Matthys E, Zecic A, Roelens F, Oos- Reprod. 2002;17:929-932. Wu. tra A, Vanzieleghem B. Perinatal cortical infarction 37. Roberts JM, Cooper DW. Pathogenesis and ge- Critical revision of the manuscript for important in- within middle cerebral artery trunks. Arch Dis Child netics of preeclampsia. Lancet. 2001;357:53-56. tellectual content: Croen, Backstrand, Yoshida, Lindan, Fetal Neonatal Ed. 2000;82:F59-F63. 38. Shah DM. Perinatal implications of maternal Ferriero, Fullerton, Barkovich, Wu. 15. Wu YW, March WM, Croen LA, Grether JK, Es- hypertension. Semin Pediatr Neurol. 2001;8:108-119. Statistical analysis: Lee, Wu. cobar GJ, Newman TB. Perinatal stroke in children with 39. Kupferminc MJ, Eldor A, Steinman N, et al. In- Obtained funding: Ferriero, Wu. motor impairment: a population-based study. creased frequency of genetic thrombophilia in women Administrative, technical, or material support: Lee, Pediatrics. 2004;114:612-619. with complications of pregnancy [published correc- Croen, Yoshida, Henning, Wu. 16. Estan J, Hope P. Unilateral neonatal cerebral in- tion appears in N Engl J Med. 1999;341:384]. N Engl Study supervision: Croen, Barkovich, Wu. farction in full term infants. Arch Dis Child Fetal Neo- J Med. 1999;340:9-13. Financial Disclosures: None reported. natal Ed. 1997;76:F88-F93. 40. Salafia CM, Pezzullo JC, Lopez-Zeno JA, Sim- Funding/Support: This study was funded by the United 17. Hagstrom JN, Walter J, Bluebond-Langner R, Am- mens S, Minior VK, Vintzileos AM. Placental pathologic features of preterm preeclampsia. Am J Obstet Cerebral Palsy Foundation. Dr Wu was supported in atniek JC, Manno CS, High KA. Prevalence of the fac- Gynecol. 1995;173:1097-1105. part by NS35902 from the National Institutes of Health tor V Leiden mutation in children and neonates with thromboembolic disease. J Pediatr. 1998;133:777-781. 41. Pabinger I, Grafenhofer H, Kaider A, et al. Pre- and the National Institute of Neurological Disorders 18. Hogeveen M, Blom HJ, Van Amerongen M, Boog- eclampsia and fetal loss in women with a history of and Stroke, and Ms Lee was supported by the Doris mans B, Van Beynum IM, Van De Bor M. Hyperho- venous thromboembolism. Arterioscler Thromb Vasc Duke Clinical Research Training Program. mocysteinemia as risk factor for ischemic and hem- Biol. 2001;21:874-879. Role of the Sponsor: The United Cerebral Palsy Foun- orrhagic stroke in newborn infants. J Pediatr. 2002;141: 42. Hunt RW, Badawi N, Laing S, Lam A. Preeclamp- dation had no role in the design and conduct of the 429-431. sia: a predisposing factor for neonatal venous sinus study; collection, management, analysis, and inter- 19. Mercuri E, Cowan F, Gupte G, et al. Prothrom- thrombosis? Pediatr Neurol. 2001;25:242-246. pretation of the data; or in the preparation, review, botic disorders and abnormal neurodevelopmental out- 43. Badawi N, Kurinczuk JJ, Keogh JM, et al. Ante- or approval of the manuscript. come in infants with neonatal cerebral infarction. partum risk factors for newborn encephalopathy: the Acknowledgment: We thank Carla Stelling, BS, Roxana Pediatrics. 2001;107:1400-1404. Western Australian case-control study. 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