Despite major advances in obstetrics and neonatology, many preterm infants (born before 37 weeks gestational age) still experience neonatal mortality or morbidity, require intensive care unit admission at birth, and develop variable combinations of lifelong neurodevelopmental deficits, such as cerebral palsy, impaired cognitive abilities, abnormal perceptual and visual motor function, hearing and vision loss, disorders of attention and executive functions, and behavioral problems.1–3 Poor academic achievement and social functioning result from these deficits. Because the risk of impairment increases with decreasing gestational age at birth, studies of short- and long-term outcomes of preterm infants have focused largely on the most immature children, ie, those born before 33 weeks (or weighing less than 1,500 g at birth),4–5 with some studies concentrating on neonates born before 26 weeks.6 There is a relative paucity of data on larger preterm neonates born at 33 or 34 weeks.
In several studies, neonates born before 30 weeks enjoyed better outcomes when delivered at tertiary-care facilities compared with other facilities.7,8 Beyond 30 weeks, however, there is no well-established policy regarding place of delivery, although the number of births at 30–34 weeks is fivefold that of births before 30 weeks in France.9
Another important issue is the optimal gestational age for delivery in women with pregnancy complications such as gestational hypertension or intrauterine growth restriction (IUGR) or preterm premature rupture of membranes (PROM). Advances in resuscitation at birth and neonatal care for preterm babies have led to greater acceptance of delivery at younger gestational ages, before 34 weeks, in some perinatal centers.10 However, the outcomes of neonates born between 30 and 34 weeks remain unknown.
The aim of this analysis was to evaluate outcomes in a population-based study of infants born between 30 and 34 weeks. Neonatal mortality and morbidity and 5-year neurodevelopmental outcomes were assessed.
PARTICIPANTS AND METHODS
All births that occurred between 30+0 and 32+6 weeks in all maternity units in nine French regions in 1997 were included in the EPIPAGE study,3 as well as all births between 33+0 and 34+6 weeks in April or October of 1997. Due to the high number of births at 33 and 34 weeks, these moderately preterm babies were recruited during only 2 months of 1997. We classified the study participants into five categories based on gestational age: 30, 31, 32, 33, or 34 weeks.
Data on the mother, pregnancy, and neonate were recorded on standardized questionnaires in the maternity unit. Gestational age in completed weeks was determined based on last menstrual period and findings from the early prenatal ultrasonogram. Prenatal corticosteroid therapy was recorded, without regard for course completion. Singletons were further classified into five mutually exclusive groups based on the reason for premature delivery, as previously defined11: maternal hypertension or IUGR, antepartum bleeding, spontaneous preterm labor, preterm PROM, and other complications of pregnancy. The following neonatal data were recorded on standardized forms in the neonatal units: in-hospital death, respiratory distress syndrome, maternofetal and nosocomial infections requiring antibiotic treatment for 1 week or longer, necrotizing enterocolitis, bronchopulmonary dysplasia (defined as oxygen dependency on postnatal day 28), and brain damage documented by cranial ultrasonography. In France, cranial ultrasonography is performed routinely in infants younger than 33 weeks who are admitted to intensive or standard neonatal care units; after 33 weeks, cranial ultrasonography is usually performed as indicated by the occurrence of perinatal asphyxia or presence of clinical abnormalities at birth. Severe white matter injury was defined as cystic periventricular leukomalacia or intraparenchymal hemorrhage, for which variability across centers was likely to be small. We also recorded moderate white matter injury defined as echodensities persisting for more than 14 days without cyst formation or isolated ventricular dilatation without intraventricular hemorrhage. For bleeding in nonparenchymal areas of the brain, we used three indicators: germinal matrix layer hemorrhage, intraventricular hemorrhage without ventricular dilatation, and intraventricular hemorrhage with ventricular dilatation. More than 95% of infants born before 33 weeks underwent cranial ultrasonography, compared with 87% and 64% of infants born at 33 and 34 weeks, respectively. Infants who did not undergo cranial ultrasonography were classified in the group of infants who had normal cranial ultrasonography findings. Finally, we recorded the treatments used in the neonatal unit: endotracheal ventilation, antibiotics for longer than 7 days, caffeine for apnea, phototherapy for jaundice, parenteral nutrition for longer than 10 days, catheter for longer than 10 days, and hospital stay length.
Children discharged alive from the neonatal unit underwent a medical and neuropsychological assessment at 5 years of age. In seven of the nine regions, this assessment was offered to all the infants in the EPIPAGE study; in the two remaining regions (Paris and Haute-Normandie), half the children in the 32- weeks group were selected at random for assessment.
The 5-year assessment was carried out by experienced physicians and neuropsychologists in each region. It included a thorough physical examination and neurological assessment (tone, reflexes, posture, and movements). Physicians recorded their findings on a standardized questionnaire. We used the definition of cerebral palsy developed by the European Cerebral Palsy Network,12 which requires at least two of the following: abnormal posture or movement, increased tone, and hyperreflexia. Three categories of cerebral palsy were distinguished: bilateral spastic cerebral palsy, hemiplegia, and other. When the diagnosis of cerebral palsy was in doubt, a panel of trained pediatricians met to discuss the case. Visual impairment was defined as visual acuity less than 3/10 in one or both eyes and hearing impairment as loss of more than 70 decibels or use of a hearing aid in one or both ears.
The Kaufman Assessment Battery for Children (K-ABC)13 was administered when consistent with the condition of the child and accepted by him or her. The K-ABC for Children yields four global test scores including the Mental Processing Composite (MPC), which is a global measure of cognitive ability. The MPC score was standardized to a mean (±standard deviation) of 100 (±15) based on results in children born in the late 1990s.13 Scores on the MPC less than 70 defined moderate or severe cognitive impairment, and scores between 70 and 85, mild cognitive impairment. Children who performed only part of the tests in the battery were not included in the analysis of cognitive impairment.
The study was approved by the French Data Protection Authority (Commission Nationale de l’Informatique et des Libertés). Informed consent to follow-up was obtained from the parents.
The in-hospital mortality rate was computed as the proportion of liveborn neonates who died before discharge. The neonatal morbidity rate is reported as the number of neonates with morbidities divided by the total number of liveborn infants. The rates of cerebral palsy and cognitive impairment were computed using the number of children evaluated at 5 years of age as the denominator.
For categorical variables, P values were estimated using generalized estimating equation models to take into account the nonindependence of observations due to twins.14 For continuous variables, linear mixed models were used. The links between cerebral palsy and gestational age, pregnancy complications, sex, and antenatal corticosteroid therapy were studied by determining the crude odds ratios and the odds ratios adjusted for prenatal factors. For MPC scores less than 70, an additional variable (socioeconomic status of the family) was included in the analysis. Statistical analysis was performed using STATA 7.0 (StataCorp, College Station, TX) software.
Of the 2,467 infants enrolled in the study, 2,018 were eligible for follow-up, and 1,461 were evaluated at 5 years of age (Table 1).
The distribution of pregnancy complications varied with gestational age. More specifically, in singletons, the proportion of pregnancies with IUGR or hypertension decreased from 26% at 30 weeks to 18% at 34 weeks, whereas the proportion with preterm PROM increased from 19% at 30 weeks to 26% at 34 weeks. The rates of elective preterm delivery were not significantly different across gestational-age groups. The rate of cesarean births decreased as gestational age increased. Antenatal corticosteroid therapy and birth in tertiary-care facilities became less common as gestational age increased. In the 34-week group, 30% of infants were born in level one facilities, and only 63% received antenatal corticosteroid therapy (Table 2).
The rate of adverse neonatal outcomes decreased with increasing gestational age (Table 3). However, respiratory distress syndrome still occurred in 14% of neonates born at 33 weeks and 3% of those born at 34 weeks. Moreover, among survivors, cases of bronchopulmonary dysplasia occurred up to 33 weeks. The rate of maternofetal infection decreased from 7% at 30 weeks to 3% at 34 weeks, and those of nosocomial infection, from 11% at 30 weeks to 2% at 34 weeks. Moderate and severe white matter injury were noted in 11% and 6% of children, respectively, in the 30-week group. Their rates of occurrence decreased significantly with increasing gestational age. Nevertheless, moderate and severe white matter injury still occurred in 8% and 2% of infants at 33 weeks and in 2% and 1% of those at 34 weeks.
Hospital length of stay decreased with increasing gestational age (Table 4). However, 27% of infants born at 34 weeks required admission to the neonatal intensive care unit (NICU); 7% needed endotracheal ventilation; 16% received antibiotics for longer than 7 days, and 5%, parenteral nutrition for longer than 10 days; 9% received caffeine for apneas; and 47% required phototherapy for jaundice.
The cerebral palsy rate was 6% in the 30-week group and 9% in the 31-week group. It fell to less than 1% in the 34-week group (Table 5). Spastic cerebral palsy accounted for about 80% of cerebral palsy cases. The proportion of children with MPC scores below 70 ranged from 10% in the 30- or 31-week group to 5% in the 34-week group. A similar trend was noted for children with Mental Processing Composite scores between 70 and 84. The mean Mental Processing Composite score increased significantly with gestational age, from 94 at 30 weeks to 98 at 34 weeks.
In the multivariate analysis, only gestational age at birth and pregnancy complications were associated with cerebral palsy. Singletons born after idiopathic preterm labor or preterm PROM had a higher risk of cerebral palsy than infants born to hypertensive mothers (Table 6). By contrast, moderate or severe cognitive impairment was significantly associated with gestational age and socioeconomic status but not with pregnancy complications (Table 6). Neither visual nor hearing impairments differed significantly across gestational-age groups.
The EPIPAGE study has important strengths. Our population was composed of all infants born in defined geographic areas, which eliminated the selection bias seen in studies of children from selected perinatal centers. We classified our children based on gestational age, which is a better predictor of neonatal mortality and morbidity than birth weight. Because early ultrasonograms are obtained in virtually all pregnant women in France, we can assume that gestational age estimates were accurate.15 A few studies in tertiary-care centers collected information on morbidities and long-term disabilities of children born at 30–34 completed weeks, but none of them provided separate data for each week of gestational age.8,16–19
Several limitations of our study must be borne in mind. First, information was obtained for 60% to 75% of the eligible survivors. Patient attrition during follow-up can bias the results of longitudinal studies. Tin et al20 reported that children who were difficult to trace were more likely to have severe disabilities than those who were followed up easily. In our study, the proportion of children lost to follow-up increased with gestational age at birth but was not influenced by neonatal brain-damage status, suggesting a limited effect of patient attrition on our estimates of cerebral palsy rates. However, children who were not seen at 5 years of age were born to younger mothers than those of reviewed children.21 Younger maternal age has been associated with lower MPC scores.22 Moreover, in each study group, the K-ABC was not available for children who refused the test or were unable to complete it because of cognitive or attentional difficulties. This may have resulted in underestimation of neurodevelopmental impairments. Second, although the EPIPAGE cohort is large, it is probably not large enough for a reliable investigation of rare adverse events such as necrotizing enterocolitis.
Delivery occurred in level one facilities for about one fourth of infants in the 32-, 33-, and 34- week groups. Although there may be insufficient time for transfer when spontaneous preterm labor or obstetric emergencies occur, some of these early births in level one maternity units were probably avoidable to prevent a mother–infant split due to outborn transfer of the infant to a secondary or tertiary level facility.
In our study, underuse of antenatal corticosteroids may explain the persistent occurrence of respiratory distress syndrome and intracranial bleeding at older gestational ages and the need for endotracheal ventilation in 28% and 7% of 33- and 34- week infants, respectively. Moreover, our results show that many moderately premature infants require other major treatments, such as antibiotics or parenteral nutrition. Prenatal corticosteroid treatment to decrease respiratory distress syndrome should be continued at least until 34 weeks, as recommended.23
Maternofetal and neonatal nosocomial infections decreased with increasing gestational age, probably as a result of immune system maturation.24 In contrast, preterm PROM as a cause for preterm birth and of maternofetal infection increased with gestational age. A possible explanation is the higher rate of preterm PROM due to mechanical factors at 34 weeks than at 30 weeks, contrasting with a higher rate of inflammatory preterm PROM at 30 weeks than at 34 weeks.25–28
Decreases in focal white matter injury or subsequent cerebral palsy were noted when gestational age at birth increased from 30 to 34 weeks, in keeping with previous studies17,29 and with the decreasing vulnerability of white matter to injury as maturation progresses.30 In addition, in our study, in singletons, preterm PROM and idiopathic preterm labor were associated with a higher risk of cerebral palsy than was maternal hypertension. Inflammatory diseases of pregnancy and neonates (such as preterm PROM, chorioamnionitis, or maternal–fetal infection) increase the risk of white matter injury and of subsequent cerebral palsy, by a proinflammatory cytokine cascade.30,31 However, the rates of white matter injury may have been underestimated in our study, because some infants had a single cranial ultrasonography and infants who did not undergo this investigation were classified as having normal cranial ultrasonography findings.
Cognitive impairment was the most common disability at 5 years of age in our cohort, despite the perceived importance of cerebral palsy. Two studies, the Bavarian Longitudinal Study of very low birth-weight infants and an Italian study of infants born between 30 and 34 weeks, showed low mean IQs and presence of neuropsychological abnormalities after 2 years of age,17,32 in keeping with data from studies in moderately low birth weight infants (1,500 to 2,500 g at birth).1 Moreover, whereas cerebral palsy was associated with preterm PROM and idiopathic preterm labor in singletons, moderate and severe cognitive deficits were independent from pregnancy complications.
Immediate and long-term outcomes improved as gestational age increased. Thus, more mature infants had lower mortality rates and were less likely to require NICU admission. Their hospital stays were shorter, and they were more likely to have normal neurodevelopmental findings at 5 years of age. Therefore, specific obstetric interventions aimed at extending pregnancy should be evaluated. The Growth Restriction Intervention Trial is a recent multicenter randomized controlled study comparing immediate delivery to delaying delivery as long as possible (median, 4 days) in the event of fetal compromise between 24 and 36 weeks. Evaluations at 2 years of age showed that the immediate delivery group had a trend toward more disability (including cerebral palsy, little or no vision, hearing aids, or Griffiths developmental quotient less than 70) compared with the delayed delivery group, mostly in infants younger than 31 weeks.33
Although the more mature infants experienced better outcomes, cerebral palsy was noted at 5 years of age in 4% of children born at 33 weeks and 1% of those born at 34 weeks, which is more than 10-fold the rate in the general population.34 Moreover, one fourth of infants born at 33 or 34 weeks had mild to severe cognitive impairment, with MPC scores less than 85 at 5 years of age, which is more than twofold the rate in the general population.13 Children whose MPC scores are in this range require special education programs.1,2 Because there are larger numbers of these children in the 33- and 34-week groups than in the more immature groups, this finding has major implications regarding educational policies and the resources needed to fund them.
In a large population of moderately preterm infants, neonatal mortality, NICU admission with use of intensive therapeutic procedures, and childhood neurodevelopmental disabilities were more common than in term infants. Given the large absolute number of surviving infants in this intermediate gestational-age group, the increased risk of disability has major long-term economic implications and creates a heavy burden for the children and their parents. Additional research on children born after 33 to 36 completed weeks is needed to clarify the causes of preterm births, because a small increase in their rate may translate into huge increases in disease burden and health care costs.
1.Amiel-Tison C, Allen MC, Lebrun F, Rogowski J. Macropremies: underprivileged newborns. Mental Retard Dev Disabil Res Rev 2002;8:281–92.
2.Marlow N. Neurocognitive outcome after very preterm birth. Arch Dis Child Fetal Neonatal Ed. 2004;89:F224–8.
3.Larroque B, Marret S, Ancel PY, Arnaud C, Marpeau L, Supernant K, et al. White matter injury and intraventricular hemorrhage in very preterm infants: the EPIPAGE study. J Pediatr 2003;143:477–83.
4.Lefebvre F, Glorieux J, St-Laurent-Gagnon T. Neonatal survival and disability rate at age 18 months for infants born between 23 to 28 weeks of gestation. Am J Obstet Gynecol 1996;174:833–8.
5.Horbar JD, Badger GJ, Carpenter JH, Fanaroff AA, Kilpatrick S, LaCorte M, et al. Trends in mortality and morbidity for very low birth weight infants, 1991-1999. Pediatrics 2002;110:143–51.
6.Marlow N, Wolke D, Bracewell MA, Samara M, EPIcure Study Group. Neurologic and developmental disability at six years of age after extremely preterm birth. N Engl J Med 2005;325:9–19.
7.Chien LY, Whyte R, Aziz K, Thiessen P, Matthews D, Lee SK, et al. Improved outcome of preterm infants when delivered in tertiary care centers. Obstet Gynecol 2001;98:247–52.
8.Lee SK, McMillan DD, Ohlsson A, Boulton J, Lee DS, Ting S, et al. The benefit of preterm birth at tertiary centers is related to gestational age. Am J Obstet Gynecol 2003;188:617–22.
9.Blondel B, Supernant K, Du Mazaubrun C, Breart G, pour la Coordination nationale des Enquetes Nationales Perinatales. Trends in perinatal health in metropolitan France between 1995 and 2003: results from the National Perinatal Surveys [in French]. J Gynecol Obstet Biol Reprod 2006;35:373–87.
10.Hauth JC. Spontaneous preterm labor and premature rupture of membranes at late preterm gestations: to deliver or not to deliver. Semin Perinatol 2006;30:98–102.
11.Ancel PY, Marret S, Larroque B, Arnaud C, Zupan-Simunek V, Voyer M, et al. Are maternal hypertension and small-for-gestational age risk factors for severe intraventricular hemorrhage and cystic periventricular leukomalacia? Results of the EPIPAGE cohort study. Am J Obstet Gynecol 2005;193:178–84.
12.Surveillance of Cerebral Palsy in Europe. Surveillance of cerebral palsy in Europe: a collaboration of cerebral palsy surveys and registers. Surveillance of Cerebral Palsy in Europe (SCPE). Dev Med Child Neurol 2000;42:816–24.
13.Kaufman A, Kaufman N. Kaufman assessment battery for children (K-ABC). Paris (France): Editions du Centre de Psychologie Appliquée; 1993.
14.Hosmer DW, Lemershow S. Applied logistic regression. 2nd ed. New York (NY): Wiley & Sons; 2000.
15.Blondel B, Norton J, du Mazaubrun C, Breart G. Development of the main indicators of perinatal health in metropolitan France between 1995 and 1998. Results of the national survey [in French]. J Gynecol Obstet Biol Reprod 2001;30:552–64.
16.Wilson A, Gardner MN, Armstrong MA, Folck BF, Escobar GJ. Neonatal assisted ventilation: predictors, frequency, and duration in a mature managed care organization. Pediatrics 2000;105:822–30.
17.Caravale B, Tozzi C, Albino G, Vicari S. Cognitive development in low risk preterm infants at 3-4 years of life. Arch Dis Child Fetal Neonatal Ed 2005;90:F474–9.
18.Himmelmann K, Hagberg G, Beckung E, Hagberg B, Uvebrant P. The changing panorama of cerebral palsy in Sweden. IX. Prevalence and origin in the birth-year period 1995-1998. Acta Paediatr 2005;94:287–94.
19.Escobar GJ, McCormick MC, Zupancic JA, Coleman-Phox K, Armstrong MA, et al. Unstudied infants: outcomes of moderately premature infants in the neonatal intensive care unit. Arch Dis Child Fetal Neonatal Ed 2006;9:F238–44.
20.Tin W, Fritz S, Wariyar U, Hey E. Outcome of very preterm birth: children reviewed with ease at 2 years differ from those followed up with difficulty. Arch Dis Child Fetal Neonatal Ed 1998;79:F83–7.
21.Livinec F, Ancel PY, Marret S, Arnaud C, Fresson J, Pierrat V, et al. Prenatal risk factors for cerebral palsy in very preterm singletons and twins. Obstet Gynecol 2005;105:1341–7.
22.Hack M, Breslau N, Aram D, Weissman B, Klein N, Borawski-Clark E. The effect of very low birth weight and social risk on neurocognitive abilities at school age. J Dev Behav Pediatr 1992;13:412–20.
23.Crowley P. Prophylactic corticosteroids for preterm birth. Cochrane Database Syst Rev 2000;2:CD000065.
24.Mussi-Pinhata MM, Rego MA. Immunological peculiarities of extremely preterm infants: a challenge for the prevention of nosocomial sepsis [in Portuguese]. J Pediatr (Rio J) 2005;81:S59–68.
25.Sebire NJ, Goldin RD, Regan L. Histological chorioamnionitis in relation to clinical presentation at 14-40 weeks of gestation. J Obstet Gynaecol 2001;21:242–5.
26.Ramsey PS, Lieman JM, Brumfield CG, Carlo W. Chorioamnionitis increases neonatal morbidity in pregnancies complicated by preterm premature rupture of membranes. Am J Obstet Gynecol 2005;192:1162–6.
27.Nelson LH, Anderson RL, O’Shea TM, Swain M. Expectant management of preterm premature rupture of the membranes. Am J Obstet Gynecol 1994;171:350–6.
28.Shim SS, Romero R, Hong JS, Park CW, Jun JK, Kim BI, et al. Clinical significance of intra-amniotic inflammation in patients with preterm premature rupture of membranes. Am J Obstet Gynecol 2004;191:1339–45.
29.Drummond PM, Colver AF. Analysis by gestational age of cerebral palsy in singleton births in north-east England 1970-94. Paediatr Perinatal Epidemiol 2002;16:172–80.
30.Kinney HC. The near-term (late preterm) human brain and risk for periventricular leukomalacia: a review. Semin Perinatol 2006;30:81–8.
31.Romero R, Espinoza J, Goncalves LF, Kusanovic JP, Friel LA, Nien JK. Inflammation in preterm and term labour and delivery. Semin Fetal Neonatal Med 2006;11:317–26.
32.Wolke D, Schulz J, Meyer R. Entwicklungslangzeitfolgen bei ehemaligen, sehr unreifen Frühgeborenen. Monatsschr Kinderheilkd 2001;149:53–61.
33.Thornton JG, Hornbuckle J, Vail A, Spiegelhalter DJ, Levene M, GRIT study group. Infant wellbeing at 2 years of age in the Growth Restriction Intervention Trial (GRIT): multicentred randomised controlled trial. Lancet 2004;364:513–20.
34.Cans C, Jouk PS, Racinet C. Frequency of different types of handicaps and their causes [in French]. In: Marret S, Zupan V, editors. Perinatal neurology. Rueil-Malmaison (France): Doin; 2003. p. 46–51.
EPIPAGE Study Group
INSERM U149: B Larroque (national coordinator), PY Ancel, B Blondel, G Bréart, M Dehan, M Garel, M Kaminski, F Maillard, C du Mazaubrun, P Missy, F Sehili, K Supernant.
Alsace: M Durand, 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, JM 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-Loire: G Boog, V Rouger-Bureau, J-C Rozé (Hôpital Mère-Enfant, Nantes)
Paris-Petite-Couronne: PY Ancel, G Bréart, M Kaminski, C du Mazaubrun (INSERM U149, Paris), M Dehan, V Zupan-Simunek (Hôpital Antoine Béclère, Clamart), M Vodovar, M Voyer (Institut de Puériculture, Paris).