Cerebral palsy (CP) was defined before the specific

Perinatal Factors Associated With Cerebral Palsy in Children Born in Sweden Kristina Thorngren-Jerneck, MD, PhD, and Andreas Herbst, MD, PhD OBJECTIVE: To identify perinatal factors associated with cerebral palsy (CP). METHODS: This was a case control study based on the Swedish Medical Birth Registry and the Swedish Hospital Discharge Registry, including 2,303 infants born in Sweden 1984 1998 with a diagnosis of CP and 1.6 million infants without this diagnosis. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. RESULTS: Infants born preterm had a highly increased risk for CP, and constituted 35% of all cases; OR 34 (95% CI 29 39) in weeks23 27, OR 37 (95% CI 32 42) in weeks 28 29, OR 26 (95% CI 23 30) in weeks 30 31, and OR 3.9 (95% CI 3.4 4.4) in weeks 32 36. Boys had a higher risk (sex ratio 1.36:1), particularly before term (sex ratio 1.55:1). Other factors associated with CP were being small or large for gestational age at birth, abruptio placentae (OR 8.6, 95% CI 5.6 13.3), maternal insulin-dependent diabetes mellitus type 1 (OR 2.1, 95% CI 1.4 3.1), preeclampsia (OR 1.5, 95% CI 1.3 2.4), being a twin (OR 1.4, 95% CI 1.1 1.6), maternal age older than 40 years (OR 1.4, 95% CI 1.1 1.8) or 35 39 years (OR 1.2, 95% CI 1.1 1.4), primiparity (OR 1.2, 95% CI 1.1 1.3), and smoking (OR 1.2, 95% CI 1.1 1.3). In term infants, low Apgar scores were associated with a high risk for CP; OR 62 (95% CI 52 74) at score 6 at 5 minutes, OR 498 (95% CI 458 542) at score 3. Other factors associated with CP in term infants were breech presentation at vaginal birth (OR 3.0, 95% CI 2.4 3.7), instrumental delivery (OR 1.9, 95% CI 1.6 2.3), and emergency cesarean delivery (OR 1.8, 95% CI 1.6 2.0). From the Departments of Pediatrics and Obstetrics & Gynecology, Clinical Sciences, Lund University Hospital, Lund, Sweden. Supported by grants from the Vårdal Institute, Lund University, the Royal Physiographic Society, and the Linnéa and Josef Carlsson Foundation. The authors thank Petra Otterblad-Olausson, the National Board of Health and Welfare Sweden, for providing data from registers. The authors also thank Professor Bengt Källén, Tornblad Institute, Lund University for his essential contribution with the data analysis, and Dr. Lena Westbom for valuable comments on the study. Corresponding author: Kristina Thorngren-Jerneck, MD, PhD, Department of Pediatrics, University Hospital, Lund University, SE-221 85 Lund, Sweden; e-mail: kristina.thorngren-jerneck@med.lu.se. 2006 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/06 CONCLUSION: Preterm birth entails a high risk for CP, but 65% of these children are born at term. Several obstetric factors and low Apgar scores are associated with CP. (Obstet Gynecol 2006;108:1499 1505) LEVEL OF EVIDENCE: II-2 Cerebral palsy (CP) was defined before the specific cause was known, and the diagnosis is based on a clinical description, giving no information on cause. 1 Perinatal factors were suggested as causally important already by Little in 1862 (quoted by Osler 1889). 2 Today, many investigators claim that most cases of CP are due to prenatal events, and the relative importance of intrapartum events is under debate. Hagberg et al 3,4 have emphasized birth asphyxia as a relatively frequent cause of CP in infants born at term. -based registers in West Sweden, Western Australia, Britain, and East Denmark have provided valuable information about the associations between CP and perinatal events. 3 7 At present, there is no national registry for CP in Sweden. However, the Swedish Hospital Discharge Registry contains information about children with a diagnosis of CP who have been treated as in-patients in Swedish hospitals. The Swedish Medical Birth Registry provides data on 98 99% of all infants born in Sweden and is one of the most complete birth registries in the world. We recently investigated perinatal risks and outcome for newborn term infants with low Apgar scores registered in the Swedish Medical Birth Registry, and found associations between low Apgar scores and several obstetric factors, as well as with cerebral palsy. 8 The aim of this study was to describe perinatal characteristics in children with CP and to identify associated perinatal factors. MATERIALS AND METHODS The study was based on data from the Swedish Hospital Discharge Registry, which includes the diag- VOL. 108, NO. 6, DECEMBER 2006 OBSTETRICS & GYNECOLOGY 1499

noses of all in-patients treated in Swedish hospitals. We identified all children (n 2,629) born in Sweden 1984 1998, who were at least once discharged from the hospital with a diagnosis of CP during these years, with or without other diagnoses. We searched the database, using codes from the International Classification of Diseases, 8th, 9th, and 10th revision (ICD-8, ICD-9, and ICD-10). 9 The children were at least 4 years old at the time of the study. The records of the identified children were linked with the Swedish Medical Birth Registry, which is compiled from copies of medical records from antenatal care, delivery, and pediatric examinations of the newborns. The Registry covers the whole country of Sweden and contains data on 98 99% of all deliveries. A quality analysis of the Swedish Medical Birth Registry has been published. 10 During the study period, 1984 1998, 1,592,034 children born in Sweden were registered in the Registry. Among the 2,629 children with CP, 2,303 were born in Sweden and could be linked with the Registry, and these children constituted the case group. The control group included the 1,589,731 children registered in the Swedish Medical Birth Registry without a diagnosis of CP in the Swedish Hospital Discharge Registry. We also linked the records of the children with CP with the Registry for Malformations in Sweden 11 to identify diagnoses of malformations. Among the 2,303 children with CP, 559 (24%) had any type of malformation; 174 infants (7.5%) had central nervous system (CNS) malformations, and 367 had other malformations. Of the 174 children with CNS malformations, we classified 48 as having a true prenatal malformation (myelomeningocele, hydrocephalus with head circumference more than 37 cm at birth, or more than 3 standard deviations (SD) if born preterm; microcephalus with a head circumference less than 32 cm at term, or less than 3 SDif born preterm). Chromosomal disorders were found in 17 children with CP. In the analyses of perinatal factors, we excluded the true prenatal CNS malformations (n 48), all non-cns malformations except persistent ductus arteriosus and retentio testis (which could be consequences of prematurity), and chromosomal disorders (n 17). Perinatal factors were studied in the remaining 1,927 children and compared with all children born during the study period who were alive at the age of 1 year (1.6 million infants). In the Swedish Medical Birth Registry, gestational duration is estimated from the expected date of delivery according to second trimester ultrasonography if performed, otherwise according to last menstrual period. During the study period, the expected date of delivery was in 98% estimated by ultrasonographic biometry. Birth weight deviation from the expected weight was calculated using growth curves obtained from the Swedish Medical Birth Registry and standardized for gestational age, parity, and gender. 12 Weight calculations were performed only for singletons, due to lack of normal weight curves for multiple births. In the study, the following variables were considered: maternal age (5-year classes), parity (number of previous deliveries plus 1), smoking habits in early pregnancy (0, less than 10, or 10 or more cigarettes per day), diabetes mellitus, gestational diabetes, singleton or multiple birth, infant gender, birth weight, gestational age (completed weeks) at birth, fetal presentation, and mode of delivery. In term infants, we also evaluated the associations between CP and Apgar score at 1, 5, and 10 minutes. We could not with certainty discriminate a registered Apgar score of 0 from missing data, and the number of Apgar scores 1 at 5 and 10 minutes were higher than expected and probably included some erroneously registered Apgar scores of 10. Therefore, the analysis of association between Apgar scores and CP was restricted to scores 1 8 at 1 minute, and 2 8 at 5 and 10 minutes, using scores 9 10 as reference. Infant mortality was investigated using the Statistics Sweden Death Registry, which is linked to the Swedish Medical Birth Registry. To estimate the prevalence of CP in the population, the rate of a CP diagnosis was assessed for children born during 1984 1990 (the first half of the study period), being 11 years or older at the time of the study. Statistical analyses were made by Mantel-Haenszel 13 procedure with stratifications as stated, and risks were expressed as odds ratios. We used a test-based method for the estimation of the 95% confidence intervals (CIs). 14 We used 2 analyses, including Breslow and Day tests, 15 for calculating differences in percentages. RESULTS Among 741,349 children born during 1984 1990 registered in the Swedish Medical Birth Registry, 1,478 had a diagnosis of CP in the Swedish Hospital Discharge Registry, a rate of 2.0 per 1,000. The mortality in the total cohort of 2,303 children with CP born 1984 1998 (including malformations and chromosomal disorders) was 0.65% before 1 year, 1.3% before 2 years, 2.6% before 4 years, and 5% before 10 years of age. Maternal factors were evaluated in all 2,289 1500 Thorngren-Jerneck and Herbst Perinatal Factors and Cerebral Palsy OBSTETRICS & GYNECOLOGY

mothers of children with a diagnosis of CP. Maternal demographic characteristics are shown in Table 1. Maternal age younger than 20 years and older than 34 years were associated with CP, after stratifying for year of birth and smoking (Table 2). Cerebral palsy was more frequent in the first child compared with higher parities (OR 1.18, 95% CI 1.08 1.29). This difference was not found in women aged younger than 25 years (OR 0.95, 95% CI 0.80 1.13), but was significant in women aged 25 34 years, (OR 1.25, 95% CI 1.12 1.40) and older than 34 years (OR 1.48, 95% CI 1.14 1.91). Smoking in early pregnancy was an associated factor (OR 1.20, 95% CI 1.10 1.32) after stratification for year of birth, maternal age, and parity. Maternal insulin-dependent diabetes mellitus doubled the risk for CP (OR 2.09, 95% CI 1.41 3.09), whereas gestational diabetes showed no significant association (OR 1.13, 95% CI 0.62 2.05). Among the 2,303 children with CP, 1,325 were boys and 976 girls (sex ratio 1.36:1). Boys were significantly more frequent among children with CP born preterm (sex ratio 1.55:1). Among term infants the sex ratio was 1.27:1. The increased sex-ratio among preterm infants with CP was more marked than for term infants (Breslow and Day test: P.006). Table 1. Maternal Demographic Characteristics for Mothers of Infants With a Diagnosis of Cerebral Palsy and for the Total Study Cerebral Palsy (n 2,289) (N 1,574,734) Age (y) 19 or younger 88 (3.9) 41,482 (2.6) 20 24 520 (22.7) 334,564 (21.2) 25 29 757 (33.1) 582,693 (37.0) 30 34 597 (26.1) 421,260 (26.8) 35 39 269 (11.8) 164,208 (10.4) 40 or older 58 (2.5) 30,527 (1.9) Parity 1 988 (43.2) 647,046 (41.1) 2 725 (31.7) 559,637 (35.5) 3 371 (16.2) 253,640 (16.1) 4 or more 205 (9.0) 114,411 (7.3) Smoking Nonsmokers 1,446 (63.2) 1,138,709 (72.3) 1 10 cigarettes per day 392 (17.1) 211,623 (13.4) More than 10 cigarettes per day 242 (10.6) 127,365 (8.0) Unknown 209 (9.0) 97,037 (6.2) Number of infants in birth Singleton pregnancies 2,108 (92.1) 1,537,140 (97.6) Twin pregnancies 174 (7.6) 37,399 (2.4) Higher-order pregnancies 7 (0.3) 1,251 (0.08) Data are n (%). Table 2. Association Between Maternal Age, Parity, and Cerebral Palsy Odds Ratio 95% Confidence Interval Maternal age (y) 19 or less 1.29 1.03 1.62 20 24 0.97 0.87 1.08 25 29 0.84 0.76 0.92 30 34 1.07 0.97 1.18 35 39 1.23 1.07 1.40 40 or more 1.39 1.07 1.81 Parity 1 1.18 1.08 1.29 2 0.89 0.82 0.98 3 0.91 0.81 1.02 4 or more 1.02 0.88 1.19 Odds ratio with 95% confidence interval is stratified for year of birth and smoking. The analysis of maternal age is also stratified for parity, and the analysis of parity is stratified for maternal age. In the population the gender ratio boys:girls is 1.06:1, for preterm infants 1.18:1, and for term infants 1.05:1. Twins had an increased risk for developing CP (OR 1.37, 95% CI 1.14 1.65) after stratification for year of birth, maternal age, parity, and smoking habits. Among the 2,303 children with CP, there were 174 twin pairs, with one (n 164) or both twins (n 10), having CP. In five pairs, the sex of the cotwin was unknown. Among the remaining 169 twin pairs, 131 had identical sex and 38 unlike sex. There were eight triplets with CP, belonging to six sets and one quadruplet with CP. Among all 2,288 children with CP and known gestational age, 65% (n 1,477) were born at term, 35% (n 811) were born preterm (less than 37 weeks), 20 (n 461) before 32 weeks, 9% (n 289) before 30 weeks, and6%(n 135) before 28 weeks. The risk of CP was highly increased in children born very preterm (Table 3). Of singleton infants born before 32 gestational weeks without malformations, 2.7% had a diagnosis of CP. No significant association between postterm birth (42 completed gestational weeks or more) and CP was found (OR 1.2, CI 0.99 1.5). Low birth weight (less than 2,500 g) was associated with CP, but the majority of these children were born preterm. The distribution of gestational age in relation to birth weight in infants with CP is shown in Figure 1. In singleton infants, a birth weight below 2 SD at term birth was associated with CP (Table 4). A birth weight above 3 SD was associated with CP at term as well as at preterm birth. In the analyses of perinatal factors, only case infants without significant malformations (n 1,927) VOL. 108, NO. 6, DECEMBER 2006 Thorngren-Jerneck and Herbst Perinatal Factors and Cerebral Palsy 1501

Table 3. Odds Ratios for Cerebral Palsy According to Gestational Age at Birth, Stratified for Year of Birth, Maternal Age, Parity, and Smoking Habits* Gestational Age (wk) Cerebral Palsy (n 1,746) (N 1,548,122) Adjusted Odds Ratio 95% Confidence Interval 23 27 90 (2.9) 3,105 33.5 29.0 38.6 28 29 100 (3.1) 3,180 36.7 32.1 42.0 30 31 120 (2.4) 5,064 26.2 23.0 29.9 32 36 254 (0.4) 71,376 3.9 3.4 4.4 37 41 1,065 (0.08) 1,356,486 1.0 Reference 42 or more 117 (0.1) 108,911 1.2 0.99 1.5 Data are n (%). * Multiple pregnancies and infants with malformations or unknown gestational age at birth are excluded. or emergency cesarean delivery (OR 1.80, 95% CI 1.62 1.99). Elective cesarean delivery was not associated with CP (OR 1.01, 95% CI 0.75 1.37). Compared with infants in cephalic presentation, breech presentation was associated with an increased risk of CP in vaginally delivered infants (OR 2.98, 95% CI 2.42 3.67), but with a reduced risk of CP in infants delivered by elective cesarean (OR 0.36, 95% CI 0.14 0.88). The ORs for CP with different Apgar scores (as compared with score 9 or 10) at 1, 5, and 10 minutes at term birth are presented in Table 5. The risk of CP increased with decreasing scores, with the highest OR for CP with a 1-minute score of 1 and a 5-minute Apgar score of 3. Fig. 1. The distribution of gestational age in relation to birth weight in 2,303 children with cerebral palsy. Thorngren-Jerneck. Perinatal Factors and Cerebral Palsy. Obstet Gynecol 2006. were included. Abruptio placentae was highly associated with CP (OR 8.58, 95% CI 5.63 13.3), and preeclampsia carried a significant risk (OR 1.46, 95% CI 1.30 2.35). Premature rupture of membranes (OR 0.97, 95% CI 0.36 2.60) or a diagnosis of maternal bleeding (OR 0.90, 95% CI 0.70 1.06) was not associated with CP. There were no major differences in term as compared with preterm deliveries concerning these findings. In term infants, the risk for CP was increased after instrumental delivery (OR 1.93, 95% CI 1.62 2.30), DISCUSSION This study has three major points. The risk of CP was high in children born preterm, especially before 32 weeks. Even so, the majority of infants with CP were born at term and only 20% before 32 weeks, and CP is therefore quantitatively mainly an issue of term infants. The rate of preterm births in Sweden is low and declined from 6.3% in 1984 to 5.6% in 2001, 16 and in other settings, the relative importance of preterm birth may be higher. Finally, even if it is recognized that most cases of CP in term infants are due to antenatal events, this study revealed associations between various perinatal factors and cerebral palsy. Case ascertainment was obtained from a national register and might not be as good as in studies based on children treated in habilitation centers. Among children with CP, those with tetraplegia, severe disability, or complicating seizures, are more often referred to hospitals than children with less severe forms of CP and are therefore more likely to be registered in the Swedish Hospital Discharge Registry. Children with hemiplegia or diplegia are more often referred to hospitals for orthopedic surgery. It 1502 Thorngren-Jerneck and Herbst Perinatal Factors and Cerebral Palsy OBSTETRICS & GYNECOLOGY

Table 4. Odds Ratios and 95% Confidence Intervals for Cerebral Palsy According to Deviation From Expected Birth Weight at the Actual Gestational Age (Expressed as Standard Deviations)* Cerebral Palsy (n 1,705) (N 1,542,422) Adjusted Odds Ratio 95% Confidence Interval All More than 3 SD 48 5,991 6.2 4.8 8.0 3 SD or more and less than 2 SD 97 30,048 2.6 2.1 3.2 2 SD or more and 2 SD or less 1,463 1,428,280 1.0 Reference More than 2 SD and 3 SD or less 59 63,844 1.0 0.8 1.3 More than 3 SD 38 14,259 2.9 2.1 3.9 Term birth 1,155 1,461,005 More than 3 SD 17 3,130 5.8 3.8 8.9 3 SD or more and less than 2 SD 56 24,679 2.5 1.9 3.2 2 SD or more and 2 SD or less 1,034 1,359,878 1.0 Reference More than 2 SD and 3 SD or less 34 60,646 0.8 0.6 1.1 More than 3 SD 14 12,672 1.7 0.98 2.8 Preterm birth 550 81,687 More than 3 SD 30 2,886 1.4 0.9 2.0 3 SD or more and less than 2 SD 39 5,287 1.0 0.7 1.4 2 SD or more and 2 SD or less 429 68,317 1.0 Reference More than 2 SD and 3 SD or less 28 3,299 1.3 0.9 2.0 More than 3 SD 24 1,898 2.1 1.4 3.1 SD, standard deviation. Data numbers of subjects. * Only singleton pregnancies are included, and infants with malformations, unknown gestational weight at birth, or unknown birth weight are excluded. Figures are presented for the total cohort, term births (at least 37 completed gestational weeks), and preterm births (less than 37 completed weeks). Table 5. Odds Ratios and 95% Confidence Intervals for Cerebral Palsy With Different Apgar Scores at Term Birth* Apgar Score CP (n) 1 Minute 5 Minutes 10 Minutes (n) OR 95% CI CP (n) (n) OR 95% CI CP (n) (n) OR 95% CI 0 17 Unknown 17 Unknown 4 Unknown 1 80 2,950 52 46 59 19 Unknown 6 Unknown 2 60 3,967 27 22 32 22 487 302 261 349 8 195 117 87 158 3 46 5,178 15 12 19 55 797 498 458 542 19 192 354 305 412 4 32 6,847 8.1 6.1 11 47 1,208 256 229 285 50 391 375 340 413 5 30 10,011 5.5 4.1 7.5 40 1,928 138 119 159 32 453 253 224 285 6 46 20,211 4.5 3.5 5.8 40 4,395 62 52 74 37 954 122 105 142 7 51 42,193 2.3 1.8 3.0 35 9,244 25 20 32 41 2,566 53 45 63 8 109 120,858 2.1 1.8 2.4 62 28,081 17 14 20 50 9,056 18 15 22 9 10 678 1,175,828 1.0 Reference 868 1,342,991 1.0 Reference 652 1,374,052 1.0 Reference CP, cerebral palsy; OR, odds ratio; CI, confidence interval. * Only singleton births are included, and infants with malformations are excluded. Stratification was made for gestational age. should be emphasized that in this study, the identification of a child with CP in Swedish Hospital Discharge Registry was made even if the hospitalization was due to a non-cp disorder. Children with CP not registered in the Swedish Hospital Discharge Registry might have resulted in a bias of all risk estimates toward 1.0, as might some erroneous CP diagnoses. In the birth cohorts of 1984 1990 (children at least 11 years old at the case ascertainment), we found that 2.0 per 1,000 children born in Sweden had been given a CP diagnosis during hospital treatment. Provided a reasonable diagnostic accuracy, the studied group of children includes the major part of the total CP population, as compared with the previously reported prevalence of 2.1 2.4 1.9 per 1,000 liveborn from western Sweden during 1987 1998 3,4,17 and 2.2 per 1,000 liveborn children from southern Sweden during 1990 93. 18 Also in the Swedish Medical Birth Registry, diagnostic quality varies and underascertainment of both maternal and infant diagnoses VOL. 108, NO. 6, DECEMBER 2006 Thorngren-Jerneck and Herbst Perinatal Factors and Cerebral Palsy 1503

will occur. This phenomenon will also bias risk estimates toward 1.0. We had to restrict the studied factors to those available in the Swedish Medical Birth Registry, and could therefore not assess all factors of interest, eg, acid base status at birth and maternal fever during labor. The study was also restricted to children born in Sweden. When linking the registry containing children with CP (Swedish Hospital Discharge Registry) with the birth registry (Swedish Medical Birth Registry), 12% of the children with CP were missing in the Swedish Medical Birth Registry. The majority of these were probably born abroad. A study from Southern Sweden showed an overrepresentation of CP among immigrant and adopted children. 18 In the present study we did not divide CP into subgroups. It is well known that the dyskinetic-athetoid type of CP and spastic tetraplegia are the most common types of CP in children born at term who have suffered from perinatal asphyxia and hypoxic ischemic encephalopathy. 3,19 This is important to note when comparing the results of this study to others, because some epidemiologic studies only refer to spastic CP. 20 Many claim that only a small proportion of CP is the consequence of intrapartum events, 21 estimated to 8, 16 or 9 21%. 22 However, a recent Swedish report attributed 58% of CP in term infants to birth asphyxia. 4 In the present study, we found high odds ratios for some perinatal events. Vaginal breech delivery, a well-known risk-factor for adverse perinatal outcome, 23 was significantly associated with CP (OR 3.0), and so was abruptio placentae (OR 8.4), a potential cause of fetal hypoxia. Instrumental delivery and emergency cesarean delivery were both associated with CP. The similar OR for CP with these interventions supports the interpretation that these associations reflect the indications to intervene, and not the interventions as such. Postterm delivery has been associated with low Apgar scores 8 and neonatal encephalopathy. 21 In the present study the risk for developing CP was not significantly increased in infants born postterm (OR 1.2, 0.99 1.5). Low Apgar scores were highly associated with CP, and although low scores may reflect compromise of different origin, 24,25 5-minute Apgar scores below 4 at term in nonmalformed neonates are often associated with acidemia at birth, indicating intrapartum hypoxia, and with neonatal encephalopathy. 25 Although high, the risk of CP was lower for infants with Apgar score 2 at 5 or 10 minutes than for those with Apgar scores 3 or 4. This might be explained by a higher mortality in the most severely depressed neonates (although only those alive at 1 year were included), and by the fact that the proportion of erroneously registered scores (in the population) is likely to be higher for scores occurring at a low frequency. For this reason, and since scores of 0 were difficult to distinguish from missing scores, we did not include Apgar scores of 0, or scores 1 at 5 and 10 minutes in the analysis. Similar to others, 26,27 we found an association between small birth weight and CP, but this was restricted to children born at term. Interestingly, infants born very large for gestational age also had an increased risk, more pronounced for preterm than for term infants. One explanation to the increased risk in large for gestational age preterm infants might be hydrops of some very ill infants. That CP is overrepresented in twins is well known. 28 We found an OR for CP in twins of 1.4 compared with OR 3.6 found by Grether et al. 28 At least part of the association between twinning and CP may be explained by the higher rate of preterm birth in twin pregnancy. The number of twins in our material was not large enough to adjust for gestational age. In conclusion, the risk of CP is high in children born preterm, but the majority of infants with CP are born at term. Even if most cases of CP in term infants are due to antenatal events, this study revealed associations between various perinatal factors and cerebral palsy. REFERENCES 1. Stanley FJ, Blair E, Alberman E. Cerebral palsies: epidemiology and causal pathways. New York (NY): Cambridge University Press; 2000. 2. Osler W, Mitchell RG. The cerebral palsies of children. London (UK): Mac Keith Press; 1987. 3. Hagberg B, Hagberg G, Beckung E, Uvebrant P. Changing panorama of cerebral palsy in Sweden. VIII. 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