Studies - PreTerm Delivery / Premature Birth / Prematurity Complications

Cerebral Palsy in PreTerm Infants: a Population-Based Case–Control Study (AP, 2002)

Cerebral Palsy in PreTerm Infants: a Population-Based Case–Control Study of AnteNatal and Intrapartal Risk Factors
Acta Pædiatr 2002; 91: 946–951. Stockholm. ISSN 0803-5253
Jacobsson B, Hagberg G, Hagberg B, Ladfors L, Niklasson A, Hagberg H
Perinatal Center, Departments of Obstetrics and Gynecology , Sahlgrensk a University Hospital and 1Departments of Pediatrics, Queen Silvia Children’s Hospital, Institute for the Health of Women and Children, Go¨ teborg, Sweden

[ED/BR: This 2002 study showed the  60% higher risk of  CP (Cerebral Palsy) for children of mothers with prior IAs (Induced Abortions); yet this information is only found in a table — Table 2 —  and there is ZERO mention of any  CP/IA risk in the main text. — Brent Rooney (MSc), Research Director, Reduce Preterm Risk Coalition,]

Previous studies have indicated that foetomaternal infection increases the risk of spastic cerebral palsy (CP) in term infants, whereas this association appears to be less evident in preterm infants.

The aim of this study was to analyse infection-related risk factors for spastic CP in preterm infants. A population-based series of preterm infants with spastic CP, 91 very preterm (<32 wk) and 57 moderately preterm (32–36 wk), born in 1983–90, were included and matched with a control group (n = 296).

In total, 154 maternal, antenatal and intrapartal variables were retrieved from obstetric records. In the entire group, histological chorioamnionitis/pyelonephritis, long
interval between rupture of membranes and birth, admission–delivery interval <4 h and Apgar scores of <7 at 1 min just significantly increased the risk of CP, and Apgar scores of <7 at 5 and 10 min were strongly associated with an increased risk.

Abruptio placentae, Apgar scores <7 at 1 min and pathological non-stress test (reason for delivery) were significant risk factors of CP only in the moderately preterm and hemiplegic groups, whereas fever before delivery was a significant risk factor in the very preterm and spastic diplegic groups.
Antibiotics during pregnancy was associated with CP only in the spastic diplegic CP group.

Conclusion: Antenatal infections marginally increased the risk of CP. Low Apgar score and abruptio placentae were associated with CP, especially in moderately preterm infants with hemiplegic CP.

Preterm birth is the most important risk factor for cerebral palsy (CP). The risk of CP is inversely proportional to gestational age and the relative risk is 60 times higher at <28 wk of gestation than at term (1, 2). Only 6.1% of infants were born preterm (<37 wk of gestation) during the period 1983–1990 in western Sweden, but they accounted for 41.5% of that region’s CP cases (1, 2).

The number of preterm infants with CP has increased since 1970, mainly related to the parallel decrease in perinatal mortality (1, 2). Although perinatal and neonatal risk factors for CP appear to dominate in the preterm group, further investigation into antenatal and intrapartal risk factors is interesting, as they can act as antecedents to the brain damage resulting in CP. In previous analyses of antenatal risk factors for CP in preterm infants no single risk factor has been consistent across all or even most studies (3–16).

Recent studies suggest that foetoplacental uterine infection/inflammation is important in the initiation of preterm labour and for the development of central nervous system injury and CP (16, 17). The western Swedish population is characterized by a low frequency of perinatal infections (18, 19) and a low rate of preterm birth.

Testing the hypothesis that infection is a risk factor for CP in this population as part of the ongoing CP project (1, 2, 20), applying the uniform and internationally accepted definition of this condition (21), may thus be interesting from a pathophysiological standpoint…..

The term “bad obstetric history” was used when one of following criteria was fulfilled: more than three subsequent spontaneous abortions, one spontaneous abortion after 20 wk of gestation, intrauterine foetal death or an earlier case of perinatal death.

Maternal disease was defined as the presence of any of the following diseases at the onset of the pregnancy: diabetes, hypertension, severe psychiatric disease, asthma, active neoplasia, epilepsy and glomerulonephritis…

The distribution of spastic CP types according to gestational age is shown in Table 1.

Most antenatal/ intrapartal factors were unrelated to CP, and the results
are given for the more frequently reported factors and for variables with significant or borderline significant association to outcome.
Maternal characteristics were comparable in CP and controls (Table 2).

Table 2. Selected maternal factors in cerebral palsy (CP) cases and controls.
                          CP cases        Controls        OR (95% CI) or
                          (n = 148)        (n = 296)        p-value

Maternal age        27 (24–33)     28 (24–33)     p = 0.46
Nulliparous         66 (45)         159 (54)         0.83 (0.67–1.02)
Infertility >1 y     13 (9)         32 (11)         0.78 (0.38–1.50)
Maternal disease     10 (7)         19 (6)         1.05 (0.50–2.21)
Bad obstetric history 17 (11)         19 (6)         1.89 (0.94–3.76)
Previous legal abortion 37 (25)     51 (17)         1.60 (0.99–2.58)

Data are a mean (interquartile range), or n (%).
OR: odds ratio; 95% CI: 95% confidence interval.

The birthweight, standardized for gestational age and gender, did not differ significantly between cases and controls (12% cases and 14% controls were below ¡2 SD). Infectious factors [clinical chorioamnionitis/pyelonephritis, histological chorioamnionitis and long duration of preterm prelabour rupture of membranes (pPROM)] were
associated with an increased risk of CP, whereas treatment with anti-inflammatory corticosteroids was associated with a significantly lower risk (Table 3).

There was a significant association between CP and an admission–delivery interval <4 h (Table 4). Hypertensive disease, cervical insufficiency and iatrogenic reasons for delivery were all associated with a lower occurrence of CP, whereas no difference was found between cases and controls with regard to spontaneous onset of labour [pPROM and p

reterm labour (PTL)] (Table 4).

Decreased viability at birth (low Apgar scores at 1, 5 and 10 min) occurred more frequently in CP cases than in controls (Table 5).
Risk factors for CP were also analysed separately for very and moderately preterm infants, as well as for spastic diplegic and hemiplegic forms of CP (Table 6).
Abruptio placentae and low Apgar scores were associated with a higher risk of CP, especially in the hemiplegic and moderately preterm (32–36 wk) group.
Indicators of infection, such as antibiotics during pregnancy, were associated with diplegic CP.
Fever before onset of delivery was an antecedent of CP in the very preterm (<32 wk) and the diplegic groups (Table 6).

…The strengths of the present study are that virtually all cases of spastic CP in a geographically defined area (birth 1983–1990) were included, the size of the study and the fact that all children with CP were at least 4 y old at diagnosis…

Acknowledgements.—This study was supported by the Swedish Medical Research Council (09455), the Go¨teborg Medical Society, the Folke Bernadotte Foundation for Children with Cerebral Palsy and by Swedish government grants to researchers in public health service (ALF).

1. Hagberg B, Hagberg G, Olow I. The changing panorama of cerebral palsy in Sweden. VI. Prevalence and origin during the birth year period 1983–1986. Acta Paediatr 1993; 82: 387–93
2. Hagberg B, Hagberg G, Olow I, Wendt L van. The changing panorama of cerebral palsy in Sweden. VII. Prevalence and origin in the birth year period 1987–90. Acta Paediatr 1996; 85: 954–60
3. Nelson KB, Ellenberg JH. Predictors of low and very low birth weight and the relation of these to cerebral palsy. JAMA 1985; 254: 1473–9
4. Cooke RW. Cerebral palsy in very low birthweight infants. Arch Dis Child 1990; 65: 201–6
5. Murphy DJ, Sellers S, MacKenzie IZ, Yudkin PL, Johnson AM. Case–control study of antenatal and intrapartum risk factors for cerebral palsy in very preterm singleton babies. Lancet 1995; 346: 1449–54
6. Grether JK, Nelson KB, Emery ES, Cummins SK. Prenatal and perinata l factors and cerebral palsy in very low birth weight
infants. J Pediatr 1996; 128: 407–14
7. Allan WC, Vohr B, Makuch RW, Katz KH, Ment LR. Antecedents of cerebral palsy in a multicenter trial of indomethacin for intraventricula r hemorrhage. Arch Pediatr Adolesc Med 1997; 151: 580–5
8. Spinillo A, Capuzzo E, Orcesi S, Stronati M, Di Mario M, Fazzi E. Antenatal and delivery risk factors simultaneously associated with neonatal death and cerebral palsy in preterm infants. Early Hum Dev 1997; 48: 81–91
9. Gray PH, Hurley TM, Rogers YM, O’Callaghan MJ, Tudehope DI, Burns YR, et al. Survival and neonatal and neurodevelopmental outcome of 24–29 week gestation infants according to primary cause of preterm delivery. Aust N Z J Obstet Gynaecol 1997; 37: 161–8

950 B Jacobsson et al. ACTA PÆDIATR 91 (2002)

10. Yoon BH, Jun JK, Romero R, Park KH, Gomez R, Choi JH, et al. Amniotic  uid in ammatory cytokine s (interleukin-6 , interleukin- 1beta , and tumor necrosis factor-alpha) , neonatal brain white matter lesions, and cerebral palsy. Am J Obstet Gynecol 1997; 177: 19–26
11. O’Shea TM, Klinepeter KL, Dillard RG. Prenatal events and the risk of cerebral palsy in very low birth weight infants. Am J Epidemiol 1998; 147: 362–9
12. Dammann O, Allred EN, Veelken N. Increased risk of spastic diplegia among very low birth weight children after preterm labor or prelabor rupture of membranes. J Pediatr 1998; 132: 531–5
13. O’Shea TM, Klinepeter KL, Meis PJ, Dillard RG. Intrauterine infection and the risk of cerebral palsy in very low-birthweight infants. Paediatr Perinat Epidemiol 1998; 12: 72–83
14. Kim JN, Namgung R, Chang W, Oh CH, Shin JC, Park ES, et al. Prospective evaluation of perinata l risk factors for cerebral palsy and delayed development in high risk infants. Yonsei Med J 1999; 40: 363–70
15. Dunin-Wasowicz D, Rowecka-Trzebick a K, Milewska-Bobul a B, Kassur-Siemiensk a B, Bauer A, Idzik M, et al. Risk factors for cerebral palsy in very low-birthweight infants in the 1980s and 1990s. J Child Neurol 2000; 15: 417–20
16. Yoon BH, Romero R, Park JS, Kim CJ, Kim SH, Choi JH, et al. Fetal exposure to an intra-amniotic in ammation and the development of cerebral palsy at the age of three years. Am J Obstet Gynecol 2000; 182: 675–81
17. Dammann O, Leviton A. Role of the fetus in perinatal infection and neonatal brain damage. Curr Opin Pediatr 2000; 12: 99–104
18. Ladfors L, Tessin I, Mattsson LA, Eriksson M, Seeberg S, Fall O. Risk factors for neonatal sepsis in offspring of women with prelabor rupture of the membranes at 34–42 weeks. J Perinat Med 1998; 26: 94–101
19. Wennerholm UB, Holm B, Mattsby-Baltze r I, Nielsen T, Platz-Christensen J, Sundell G, et al. Fetal Ž bronectin, endotoxin , bacterial vaginosi s and cervical length as predictors of preterm birth and neonatal morbidity in twin pregnancies . Br J Obstet Gynaecol 1997; 104: 1398–404
20. Hagberg B, Hagberg G, Beckung E, Uvebrant P. Changing panorama of cerebral palsy in Sweden. VIII. Prevalence and origin in the birth year period 1991–94. Acta Paediatr 2001; 90: 271–7
21. Mutch L, Alberman E, Hagberg B, Kodama K, Perat MV. Cerebral palsy epidemiology : where are we now and where are we going? Dev Med Child Neurol 1992; 34: 547–51
22. Goldenberg RL, Hauth JC, Andrews WW. Intrauterine infection and preterm delivery. N Engl J Med 2000; 342: 1500–7
23. Mays J, Verma U, Klein S, Tejani N. Acute appendicitis in pregnancy and the occurrence of major intraventricular hemorrhage and periventricular leukomalacia . Obstet Gynecol 1995; 86: 650–2
24. FIGO Subcommittee on Standards in Perinatal Medicine. Guidelines for the use of fetal monitoring. Int J Gynecol Obstet 1987; 159–67
25. Marsal K, Persson PH, Larsen T, Lilja H, Selbing A, Sultan B. Intrauterine growth curves based on ultrasonically estimated foetal weights. Acta Paediatr 1996; 85: 843–8
26. Hagberg G, Hagberg B, Olow I. The changing panorama of cerebral palsy in Sweden 1954–1970. III. The importance of foetal deprivation of supply. Acta Paediatr Scand 1976; 65: 403–8
27. Hagberg B, Hagberg G, Olow I. The changing panorama of cerebral palsy in Sweden 1954–1970. I. Analysis of the general changes. Acta Paediatr Scand 1975; 64: 187–92
28. Verma U, Tejani N, Klein S, Reale MR, Beneck D, Figueroa R, et al. Obstetric antecedent s of intraventricular hemorrhage and periventricular leukomalacia in the low-birth-weight neonate. Am J Obstet Gynecol 1997; 176: 275–81
29. Stanley FJ. Prenatal determinant s of motor disorders. Acta Paediatr 1997; Suppl 422: 92–102
30. Baud O, Foix-L’Helias L, Kaminski M, Audibert F, Jarreau PH, Papiernik E, et al. Antenatal glucocorticoid treatment and cystic periventricular leukomalacia in very premature infants. N Engl J Med 1999; 341: 1190–6
31. Nelson KB, Ellenberg JH. Apgar scores as predictors of chronic neurologic disability. Pediatrics 1981; 68: 36–44

Received Aug. 13, 2001; revisions received Dec. 12, 2001, and Apr. 15, 2002; accepted Apr. 17, 2002
Acta Paediatr 91: 946-951. 2002