Obstetrics & Gynecology:
Prenatal Risk Factors for Cerebral Palsy in Very Preterm Singletons and Twins
Livinec, Florence MD*; Ancel, Pierre-Yves MD, PhD*; Marret, Stéphane MD, PhD†; Arnaud, Catherine MD, PhD‡; Fresson, Jeanne MD§; Pierrat, Véronique MD, PhD¶; Rozé, Jean-Christophe MD, PhD∥; Escande, Benoít MD**; Thiriez, Gérard MD**; Larroque, Béatrice MD, PhD*; Kaminski, Monique MSc*; for the Epipage Group
From the *Research Unit on Perinatal Health and Women's Health, INSERM U149, Villejuif, France; †Charles Nicolle Hospital, Rouen, France; ‡Research Unit on Epidemiology and Public Health, INSERM U558, Toulouse, France; §Department of Neonatology, University Hospital, Nancy, France; ¶Jeanne de Flandre Hospital, Lille, France; ∥Mère-Enfant Hospital, Nantes, France; **Hautepierre Hospital, Strasbourg, France; and ℅Saint-Jacques Hospital, Besançon, France.
*For a list of members of the Epipage Study Group, see the Appendix.
Funded by a contract with INSERM (National Institute of Health and Medical Research) by Merck-Sharp et Dohme-Chibret, the Fondation de la Recherche Médicale, the Direction Générale de la Santé of the Ministère des Affaires Sociales, and the Programme Hospitalier de Recherche Clinique.
Address reprint requests to: Dr. F. Livinec, INSERM U149, 16 Avenue Paul Vaillant-Couturier, Villejuif Cedex 94807, France; e-mail: firstname.lastname@example.org.
Received October 27, 2004. Received in revised form January 28, 2005. Accepted February 16, 2005.
OBJECTIVE: To identify the main prenatal risk factors for cerebral palsy in very preterm singletons and twins.
METHODS: The data were from the Epipage study, which included all very preterm children (< 33 weeks) born in 1997 in 9 regions of France. The analysis included 1,954 children for whom a medical questionnaire was completed at the age of 2 years (83% of the surviving children). The risk factors studied were pregnancy complications and specific factors in twins (type of placenta and death of cotwin). Logistic regression analysis was carried out for singletons and generalized estimating equation models used for twins.
RESULTS: The proportion of cerebral palsy was 8% in singletons and 9% in twins. For singletons, spontaneous preterm labor (adjusted odds ratio [OR] 3.4, 95% confidence interval [CI] 1.7–6.7), preterm premature rupture of membranes (PPROM) with short latency (adjusted OR 4.9, 95% CI 2.0–11.8), and prolonged PPROM (adjusted OR 2.7, 95% CI 1.4–5.3) were associated with a higher risk of cerebral palsy than was hypertension. No such link was found between these pregnancy complications and cerebral palsy in twins. For twins, a monochorionic placenta (OR 1.9, 95% CI 1.0–3.6) increased the risk of cerebral palsy, but the OR became nonsignificant after adjustment (OR 1.7, 95% CI 0.8–3.4).
CONCLUSION: In very preterm singletons, spontaneous preterm labor and PPROM increased the risk of cerebral palsy compared with hypertension.
LEVEL OF EVIDENCE: II-2
In the last 20 years, the mortality of preterm and very preterm infants has been reduced between 25% and 55%.1–4 This improvement in survival includes children with brain lesions or children at risk of developing such lesions because of their extreme immaturity.5,6 This raises questions about the neurological outcome for these children and the risk factors associated with the development of cerebral palsy.
The role of prenatal risk factors is currently open to numerous questions. In a recent meta-analysis of 26 studies, Wu and Colford7 showed that clinical or histological chorioamnionitis was associated with a higher risk of cerebral palsy, but this work did not specifically concern very preterm children. In a review of studies on very low birth weight children,11 the risk of cerebral palsy was lower for children born to mothers with preeclampsia than for other children. Topp et al9 found the risk of cerebral palsy to be lower for children with intrauterine growth restriction (IUGR) born between 28 and 30 weeks of gestation than for children without IUGR, but not for children born at 31–32 weeks. However, other studies have shown that the neurological prognosis associated with IUGR did not differ from that of other children.10,11 Maternal hemorrhage has also been suggested to be a risk factor for cerebral palsy, but according to the literature, this association has not always been observed.8
For twins, the rate of cerebral palsy has been found to be higher when one of the twins died, but gestational age was not taken into account.12–14 In very preterm children, Burguet et al15 reported an odds ratio (OR) of 6 associated with a monochorionic placenta, and Adegbite et al16 found that the risk of neurological defects was multiplied by 3 or 4. However, few studies have looked at very preterm twins.
Our aims were to study the contributions of vascular, hemorrhagic, and infectious conditions to the risk of cerebral palsy in very preterm babies and to identify factors specific to twins (type of placenta and death of cotwin) in a large population-based study.
MATERIALS AND METHODS
The Epipage study is a population-based cohort study of very preterm infants who were followed from birth until the age of 5 years. The population included all children born between 22 and 32 weeks in 1 of the 9 study regions between January 1 and December 31, 1997.17 Infants were recruited in maternity units, and the initial data were collected in maternity and neonatal units. All children born between 22 and 31 weeks who survived long enough to be discharged from hospital were included in the follow-up. In 2 regions (Paris area and Haute-Normandie), only 1 in 2 of the children born at 32 weeks was randomly selected for the follow-up. In the other regions, all children born at 32 weeks were included. In total, 2,382 children were selected for follow-up after discharge from hospital. Eighteen children died between being discharged and their second birthday. The parents of 106 (4%) of the survivors refused to participate. At 2 years of age (uncorrected for prematurity), 1,960 detailed questionnaires were completed by the doctor treating each child.
We used the definition of cerebral palsy proposed by the European Cerebral Palsy Network.18 Children with cerebral palsy were identified by clinical examination. The neurological status of 4 children still requiring artificial respiration at 2 years of age was not available, and therefore these children were excluded. Two children with cerebral palsy probably caused by physical violence were also excluded. When there was doubt about whether a child had cerebral palsy, a team of clinicians met to discuss the case. Finally, 12 children who had several signs suggestive of cerebral palsy, but for whom the doctor had some doubts about the diagnosis or clinical examination, were considered as borderline cerebral palsy. In total, 165 of 1,954 children were considered to have cerebral palsy, including the 12 borderline cases. Children with cerebral palsy are described elsewhere (paper in preparation).
Singletons and twins were analyzed separately because of differences in the risk of cerebral palsy and because of specific risk factors in the case of twin pregnancies. The 83 surviving triplets, including 4 with cerebral palsy, and the 3 surviving quadruplets, without cerebral palsy, were excluded from the analysis. The analysis included 1,339 singletons and 529 twins.
Information on pregnancy and delivery were collected from medical records. The gestational age is reported in completed weeks of amenorrhea and was the best obstetric estimate, mostly based on an early prenatal ultrasound examination. Pregnancy complications were always present in births before 33 weeks. In the absence of a group without any pregnancy-related complications, the consequence of any given condition on the risk of cerebral palsy can only be determined in comparison with all other conditions. Thus, a composite variable was built for pregnancy complications. We determined a hierarchy, such that one main condition was attributed to each birth, although in some cases, there would be several conditions coexisting. This resulted in 7 mutually exclusive classes. Class 1 included maternal hypertension without IUGR, hypertension being defined by systolic blood pressure of 140 mm Hg or greater or diastolic blood pressure of 90 mm Hg or greater. Class 2 included all cases with IUGR, defined as birth weight below the 10th percentile for gestational age in Epipage, including those with hypertension or hemorrhage. Class 3, antepartum hemorrhage, included abruptio placenta, placenta praevia, and other hemorrhagic syndromes, without hypertension or IUGR. Class 4 included cases of spontaneous preterm labor before rupture of the membranes and without hypertension, IUGR, hemorrhage, or preterm premature rupture of membranes (PPROM). We distinguished between PPROM in which delivery took place less than 24 hours after the rupture (class 5) and PPROM in which delivery occurred after more than 24 hours since the rupture (class 6) because the rate of microbial invasion of the amniotic cavity is higher in women for whom the delay between rupture and delivery is short.19 Finally, class 7 contained all other cases of preterm delivery. Hypertension and IUGR were classified in priority because they usually appear before hemorrhage, spontaneous labor, or PPROM during the pregnancy. Maternal hypertension was the reference class because it is often associated with a lower risk of cerebral palsy in preterm birth.20 In twins, the type of placenta (monochorionic or dichorionic) and intrauterine death of the cotwin were studied. Prenatal corticotherapy consisted of treatment with betamethasone or dexamethasone, regardless of whether the cure was complete or not.
All proportions and the χ2 tests were weighted to take into account the differences in the follow-up inclusion rate by gestational age and region using the correction of Rao and Scott21: A weight of 2 was applied to children born at 32 weeks in 2 regions (Paris area and Haute-Normandie), and a weight of 1 was applied to all other children. In singletons, weighted logistic regression models were used to study the relationships between pregnancy complications and cerebral palsy after adjustment for confounding factors. In twins, generalized estimating equation models were used to take into account the nonindependence of observations.22 The links between cerebral palsy and pregnancy complications were studied alone (crude odds ratios) and then after adjustment for sex, because this is a risk factor for cerebral palsy.6,23 We also adjusted for gestational age and prenatal corticotherapy as prognostic factors for cerebral palsy8,24 and because the distribution of pregnancy complications varies with gestational age.25,26 However, gestational age and prenatal corticotherapy may be intermediate factors in the causal pathway between pregnancy complications and cerebral palsy.27 Adjusting for their effect helped us to interpret the associations not mediated by gestational age between pregnancy complications and cerebral palsy. Statistical analysis was performed with SAS 8 (SAS Institute Inc, Cary, NC) and STATA 7.0 (Stata Corporation, College Station, TX) software. The study was approved by the French Data Protection Authority (Commission Nationale de l'Informatique et des Libertés).
Of the children assessed, 113 singletons (8%) and 48 twins (9%) had cerebral palsy (Table 1). The prevalence of cerebral palsy decreased with increasing gestational age and appeared to be higher in boys than girls, but the difference was not significant. Singletons born after PPROM with delivery within 24 hours or after spontaneous preterm labor with intact membranes were less likely to have received corticotherapy in the prenatal period than the others (Table 2). Cesarean section before labor was very common in cases of hypertension, IUGR, and antepartum hemorrhage, but rare in other conditions (Table 2). As for twin-specific factors, monochorionic placenta was more frequently associated with hypertension and IUGR than with other conditions (Table 2). The death of the cotwin occurred in 7% of cases. This event only occurred in cases of antepartum hemorrhage, spontaneous labor, or PPROM (Table 2). Although death of the cotwin was more common in case of monochorionic placenta, the relation was not statistically significant.
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). Cited Here...
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