In singletons, compared with children born after maternal hypertension, children born after spontaneous preterm labor after PPROM had a higher risk of cerebral palsy. The risk was greatest in case of PPROM with delivery within 24 hours. The results were very similar after adjustment for sex, gestational age, and prenatal corticotherapy (Table 3).
In twins, no significant association was found between pregnancy complications and the risk of cerebral palsy. The prevalence of cerebral palsy was higher in cases of monochorionic placenta than in cases of dichorionic placenta (Table 3), but the association was not significant after adjustment for pregnancy complication, sex, gestational age, and prenatal corticotherapy. The prevalence of cerebral palsy was twice as high in children whose twin had died in utero than in others, but this association was not statistically significant, and the OR was substantially lower after adjustment (Table 3).
These results were obtained from a large and recent population-based cohort of very preterm babies. However, 17% of children were not examined at 2 years. Several studies in other countries have shown that very preterm children that are difficult to follow up are more likely to have severe sensorial, motor, or cognitive impairments at 2 years than children who are easily followed up (Wolke D, Söhne B, Ohrt B, Riegel K. Follow-up of preterm children: important to document dropouts [letter]. Lancet 1995;345:447).28 In our study, nonexamined children had a slightly higher gestational age. The prevalence of cerebral lesions was the same in both groups, indicating that nonexamined children may have a similar risk of developing cerebral palsy as children followed up.
Children with cerebral palsy were identified using the same criteria as the registers in the international literature.18 Given the way in which data were collected at 2 years of age and the number of doctors involved, it is possible that some cases were misdiagnosed. Furthermore, it is recommended that cerebral palsy be diagnosed definitively between the ages of 4 and 5 years,18 because mild forms can be missed at 2 years, and in other cases, a diagnosis made at 2 years may not be confirmed at 5 years. However, there is no evidence that diagnostic errors for cerebral palsy vary according to pregnancy complications or factors specific to twins. Our findings were not modified by the exclusion of the 12 children for whom the diagnosis of cerebral palsy was less sure.
The analytical strategy was chosen according to the hypotheses on the physiopathological mechanisms and the temporal links between factors, to avoid overadjustment.29 Postnatal factors were not controlled for here, because they are not causes of pregnancy complications and because it is unclear whether these factors are intermediate factors or even a consequence of cerebral injuries.8 We did not analyze the role of the mode of delivery. The strong link between pregnancy complications and mode of delivery (more than 90% of cesarean deliveries before labor in the case of hypertension or IUGR, less than 15% in case of PPROM) makes it impossible to separate the respective roles of mode of delivery and pregnancy complications. Because the complications occurred first, we concentrated on the complications rather than the mode of delivery. The relationship between pregnancy and cerebral palsy was not modified by controlling for gestational age and prenatal corticotherapy, suggesting an effect only marginally mediated by these factors.
In singletons, the prevalence of cerebral palsy was higher in children born after preterm labor with intact membranes or PPROM than in those born after other complications. Preterm spontaneous labor and PPROM may be considered as indirect markers of infection, because according to the literature, 15% of patients with spontaneous preterm labor and 35% of patients with PPROM have chorioamnionitis.19,30 An increased risk of cerebral palsy associated with prenatal infection has been reported in preterm children,7 but this has rarely been studied in very preterm children. Of the 4 studies looking at the role of infection in very preterm children, 2 found a significantly increased risk of cerebral palsy;10,31 the other 2 did not find a significant association, although there was a trend toward an increased risk.23,32 One of the mechanisms responsible is the neurotoxicity of cytokines initiating a chain reaction, leading to apoptosis of various brain cell lines, notably oligodendrocytes, which are responsible for myelinization.33
Recent studies and the results of the Epipage study show that the risk of cerebral palsy is lower in children born to a hypertensive mother than in those born after PPROM or preterm labor.6,10,11 However, current data suggest that in utero exposure to infection increases the risk of cerebral lesions rather than that vascular conditions affecting the placenta have a neuroprotective effect.
In previous studies, children with IUGR have often been compared with children without IUGR, in other words to children born in the context of isolated hypertension, hemorrhage, or infection.9,10 The heterogeneous nature of the risk of cerebral palsy for these different situations may explain why published results are not very conclusive. The Epipage study shows that the risk associated with IUGR is of the same order of magnitude as that associated with maternal hypertension.
We found no association between cerebral palsy and hemorrhage, but we encountered the same difficulties as other studies.8 The “hemorrhage” category is heterogeneous in nature: It includes placenta praevia, abruptio placenta, and bleeding during the third trimester and does not take into account the severity or the amount of blood loss. It is possible that children exposed to severe, acute hypoxia during the most severe hemorrhages subsequently develop cerebral lesions. Available information does not make it possible to isolate such a group, and the results concerning hemorrhage must be interpreted with caution.
Unlike singletons, no association was found between cerebral palsy and pregnancy complications for twins. These differences might be explained by differences in the origin of the complications or by a lack of power.
Monochorionic placentation is a factor suspected to be associated with the appearance of cerebral lesions due to multiple vascular anastomoses or anomalies of the placental vascular system. Its role is usually studied indirectly using sex of children, and conflicting results have been reported.13,14,34 In our study, the OR associated with monochorionic placentation was 1.9, compared with 6.0 in the only other published study.15 Although death of the cotwin during pregnancy was associated with an increased risk of cerebral palsy, the association was not significant, probably because of a lack of power for this rare event. However, this result is consistent with the data published in the literature for all gestational ages.13,14
Although the risk of cerebral palsy associated with maternal hypertension and IUGR is lower than that associated with infection in singletons, there is no physiopathological evidence or results from human studies suggestive of a neuroprotective effect. The Epipage study, which is one of a small number of population-based studies to look at very preterm infants, will make it possible to compare the results obtained at 2 and 5 years of age and assess the predictive value of early examination.
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Epipage Study Group
INSERM U149: B. Larroque (national coordinator), P. Y. Ancel, B. Blondel, G. Bréart, M. Dehan, M. Garel, M. Kaminski, F. Maillard, C. du Mazaubrun, P. Missy, F. Sehili, K. Supernant.
Alsace: M. Durant, J. Matis, J. Messer, A. Treisser (Hôpital de Hautepierre, Strasbourg).
Franche-Comté: A. Burguet, L. Abraham-Lerat, A. Menget, P. Roth, J.-P. Schaal, G. Thiriez (CHU St. Jacques, Besançon).
Haute-Normandie: C. Lévêque, S. Marret, L. Marpeau (Hôpital Charles Nicolle, Rouen).
Languedoc-Roussillon: P. Boulot, J.-C. Picaud (Hôpital Arnaud de Villeneuve, Montpellier), A.-M. Donadio, B. Ledésert (ORS Montpellier).
Lorraine: M. André, J.-L. Boutroy, J. Fresson, J. M. Hascoët (Maternité Régionale, Nancy).
Midi-Pyrénées: C. Arnaud, S. Bourdet-Loubère, H. Grandjean (INSERM U558, Toulouse), M. Rolland (Hôpital des enfants, Toulouse).
Nord-Pas-de-Calais: C. Leignel, P. Lequien, V. Pierrat, F. Puech, D. Subtil, P. Truffert (Hôpital Jeanne de Flandre, Lille).
Pays-de-la-Loire: G. Boog, V. Rouger-Bureau, J.-C. Rozé (Hôpital Mère-Enfants, Nantes).
Paris-Petite-Couronne: P.-Y. Ancel, G. Bréart, M. Kaminski, C. du Mazaubrun (INSERM U149, Paris), M. Dehan, V. Zupan (Hôpital Antoine Béclère, Clamart), M. Vodovar, M. Voyer (Institut de Puériculture, Paris).