nature publishing group Articles Population Study Pregnancy disorders leading to very preterm birth influence neonatal outcomes: results of the population-based ACTION cohort study Luigi Gagliardi1, Franca Rusconi2, Monica Da Frè3, Giorgio Mello4, Virgilio Carnielli5, Domenico Di Lallo6, Francesco Macagno7, Silvana Miniaci8, Carlo Corchia9 and Marina Cuttini10 BACKGROUND: We examined the relationships between pathological entities, remains difficult, and the results of ­pregnancy disorders leading to very preterm birth (spontaneous­ the few epidemiologic studies investigating these aspects in preterm labor, prelabor premature rupture of ­membranes terms of neonatal outcome are conflicting. Mortality, e.g., (PPROM), hypertension/preeclampsia, ­intrauterine growth has been found to be higher (2,3), lower (4,5), or equal (6) in restriction (IUGR), antenatal hemorrhage, and maternal preeclampsia as compared with spontaneous preterm labor. ­infection), both in isolation and grouped together as ­“disorders The same discrepancies occur for bronchopulmonary dys- of placentation” (hypertensive disorders and IUGR) vs. ­“presumed plasia (BPD) (7–10). infection/inflammation” (all the others), and several unfavorable Although it is widely acknowledged that preterm birth neonatal outcomes. is caused by several different pathophysiological processes METHODS: We examined a population-based prospective (11), no consensus exists on their definition and classifi- cohort of 2,085 singleton infants of 23–31 wk gestational age cation. Studies on complications of pregnancies ending in (GA) born in six Italian regions (the Accesso alle Cure e Terapie very preterm birth, and their relationship to outcomes, are Intensive Ostetriche e Neonatali (ACTION) study). complicated by a taxonomy that mixes etiologic and clinical RESULTS: Neonates born following disorders of placentation aspects. A classification that differentiates individual clinical had a higher GA and better overall outcomes than those born presentations, even when sharing a common etiology (e.g., following infection/inflammation. After adjustment for GA, prelabor premature rupture of membranes (PPROM) and however, they showed higher risk of mortality (odds ratio, OR: spontaneous preterm labor), is useful for clinicians to better 1.4; 95% confidence interval, CI: 1.0–2.0), bronchopulmonary tailor treatments to patients but can be detrimental in epi- dysplasia (BPD) (OR: 2.5; CI: 1.8–3.6), and retinopathy of prema- demiologic studies aimed at clarifying associations. Several turity (ROP) (OR: 2.0; CI: 1.1–3.5), especially in growth-restricted years ago, Klebanoff and Shiono (12) proposed that most infants, and a lower risk of intraventricular hemorrhage (IVH) causes of preterm birth can be differentiated into “inside (OR: 0.5; CI: 0.3–0.8) and periventricular leukomalacia (PVL) out” (primary abnormal placentation) and “bottom–up” (OR: 0.6; CI: 0.4–1.1) as compared with infants born following (ascending infections), suggesting that these two categories, ­infection/inflammation disorders. although partially overlapping, reflect different pathophysi- CONCLUSION: Our data confirm the hypothesis that, in ologic pathways. Recently, McElrath et al. (3) combined, very preterm infants, adverse outcomes are both a function in a large cohort of births at <28 wk of gestation, clinical of immaturity (low GA) and of complications leading to pre- information with placental and bacteriological data. They term birth. The profile of risk is different in different pregnancy found higher frequencies of placental histologic inflamma- disorders. tion and presence of microorganisms in pregnancies com- plicated by preterm labor, PPROM, abruption, and cervical nfants born very preterm have a high mortality and mor- insufficiency, whereas preeclampsia and intrauterine growth Ibidity, and the increased risk is likely to reflect a combi- restriction (IUGR) were accompanied by signs of poor pla- nation of immaturity per se, and of the underlying patholo- centation such as infarcts and abundance of syncytial knots. gies causing preterm birth (1). However, disentangling the Therefore, they suggested that very preterm delivery can effect of these two components in clinical and in epide- indeed be categorized into two broad groups: disorders of miologic studies, and estimating the contribution of single ­placentation and intrauterine infection/inflammation (3). 1Pediatrics and Neonatology Division, Woman and Child Health Department, Ospedale Versilia, Lido di Camaiore, Italy; 2Unit of Epidemiology, ‘‘Anna Meyer’’ Children’s University Hospital, Florence, Italy; 3Unit of Epidemiology, Regional Health Agency of Tuscany, Florence, Italy; 4Unit of Prenatal Medicine, Careggi University Hospital, Florence, Italy; ­5Maternal and Child Health Institute, Marche University and Salesi Hospital, Ancona, Italy; 6Unit of Epidemiology, Regional Health Agency of Lazio, Rome, Italy; 7Neonatal ­Intensive Care Unit, S. Maria della Misericordia University Hospital, Udine, Italy; 8Neonatal Intensive Care Unit, Pugliese-Ciaccio Hospital, Catanzaro, Italy; 9International Centre on Birth Defects and ­Prematurity, Rome, Italy; 10Unit of Epidemiology, Bambino Gesù Children’s Hospital, Rome, Italy. Correspondence: Luigi Gagliardi ([email protected]) Received 3 July 2012; accepted 28 November 2012; advance online publication 17 April 2013. doi:10.1038/pr.2013.52 794 Pediatric RESEarch Volume 73 | Number 6 | June 2013 Copyright © 2013 International Pediatric Research Foundation, Inc. Pregnancy disorders and neonatal outcome Articles We used the data of the ACTION (Accesso alle Cure e (253; 12.1%), IUGR (198; 9.5%), and maternal infection as an Terapie Intensive Ostetriche e Neonatali) project, a large pop- indication for delivery (73; 3.5%). “Other” antecedents (e.g., ulation-based cohort study carried out in Italy in very preterm prepregnancy chronic maternal diseases), suspected acute fetal infants, to test the hypothesis that different pregnancy disor- distress, and unknown causes represented only 2% of cases ders that lead to very preterm delivery, considered in isolation each. or grouped together, are associated with different patterns of Table 1 shows the characteristics and outcomes of the important adverse neonatal outcomes. infants by cause of birth. Overall, 77% of the infants received antenatal steroid prophylaxis, and 89% were delivered in level RESULTS III centers. The groups differed for most of the characteristics The cohort analyzed for this study included 2,085 singleton reported. Infants born following spontaneous preterm labor newborn infants. Spontaneous preterm labor was the most had a lower gestational age (GA) than those in other groups. common complication leading to very preterm birth (628 Together with those with antepartum hemorrhage, they were cases; 30.1%), followed by hypertensive disorders of pregnancy less frequently treated with antenatal steroids and delivered in (441; 21.2%), PPROM (355; 17.0%), antepartum hemorrhage level III centers, probably because of the sudden occurrence of Table 1. Characteristics and outcomes of the infants studied according to main antenatal complications leading to preterm birth Spontaneous preterm Hypertensive Maternal Acute fetal Other labor disorders PPROM Hemorrhage IUGR infection distress causes Unknown Total n = 628 n = 441 n = 355 n = 253 n = 198 n = 73 n = 47 n = 47 n = 43 N = 2,085 P value Neonatal characteristics (mean (SD) or (%)) Gestational 27.5 (2.5) 29.1 (1.8) 28.4 (2.2) 28.8 (2.0) 29.3 (1.7) 27.6 (2.4) 29.6 (1.4) 28.9 (2.5) 28.7 (2.3) 28.4 (2.3) <0.001 age Birth 1,149 (386) 1,054 (311) 1,238 (383) 1,276 (365) 929 (317) 1,140 (366) 1,368 (322) 1,371 (481) 1,321 (380) 1,152 (379) <0.001 weight Males 54.5 46.4 56.1 57.3 56.6 52.0 66.0 55.3 58.1 53.9 0.040 Prenatal and neonatal assistance (%) Antenatal 70.4 81.8 87.1 67.2 84.0 84.9 73.8 76.1 63.6 77.3 <0.001 steroids Induced or 30.7 99.3 70.9 96.4 99.5 73.6 100 89.4 85.0 72.1 <0.001 cesarean birth Born in 83.6 93.9 94.4 82.6 98.0 86.3 87.2 97.9 65.1 89.0 <0.001 level III center Mechanical 64.6 60.0 54.1 70.7 60.4 63.9 57.5 67.4 67.5 62.1 0.005 ventilation Neonatal conditions (mean (SD) or (%)) Apgar at 7.1 (2.0) 7.8 (1.5) 7.7 (1.6) 7.3 (1.7) 7.7 (1.5) 7.5 (1.8) 7.6 (1.3) 7.3 (1.8) 7.0 (1.8) 7.5 (1.7) <0.001 5 min Apgar at 32.5 20.0 22.6 29.5 18.5 20.6 26.7 23.4 43.9 25.9 <0.001 5 min <7 Outcomes (%) Total 20.2 7.7 14.2 12.3 14.7 17.8 6.4 10.6 16.3 14.3 <0.001 in-hospital mortality IVH, grade 15.6 2.8 6.8 7.3 4.2 8.7 6.4 8.7 16.7 8.6 <0.001 III–IV Cystic PVL 6.4 3.5 5.4 5.3 2.6 5.7 6.5 8.7 10.0 5.2 0.238 BPD 13.1 14.2 10.5 10.7 15.4 15.0 13.0 9.5 15.6 12.8 0.752 ROP, stage 5.9 4.3 5.2 1.7 2.7 4.5 0.0 2.3 2.4 4.3 0.173 3–4 or plus Main antenatal complication has been identified by clinicians involved in the study according to a priori–defined mutually exclusive categories. BPD, bronchopulmonary dysplasia; IUGR, intrauterine growth restriction; IVH, intraventricular hemorrhage; PPROM, prelabor premature rupture of membranes; PVL, periventricular leukomalacia; ROP, retinopathy of prematurity. Copyright © 2013 International Pediatric Research Foundation, Inc. Volume 73 | Number 6 | June 2013 Pediatric RESEarch 795 Articles Gagliardi et al. 80 This change of OR between GA-unadjusted and GA-adjusted 70 analyses was checked by conducting the analyses in narrow 60 strata of GA (Table 4). In the range of 23–29 wk, effects appear to be homogeneous.