Placental Findings and Effect of Alice Héneau, MD,​a Fabien Guimiot, PD, PhD,​b Damir Mohamed, MSc,​c,​d Aline Rideau Batista Novais, MD, PhD,​a CorinneProphylactic Alberti, MD, PhD,​c,​d Olivier Baud, HydrocortisoneMD, PhD,a,​ ​e for the PREMILOC Trial study group in Extremely Preterm Infants OBJECTIVES: abstract

To investigate the relationship between histologic findings of the and response to early postnatal hydrocortisone treatment used to prevent bronchopulmonary METHODS: dysplasia (BPD) in extremely preterm infants. In an exploratory analysis of the Early Low-Dose Hydrocortisone to Improve Survival Without Bronchopulmonary Dysplasia in Extremely Preterm Infants (PREMILOC) trial, detailed placental analyses were performed on the basis of standardized macroscopic and histologic examinations. Placental histology, categorized into 3 groups, was correlated RESULTS: to neonatal outcomes and response to hydrocortisone treatment. Of 523 randomly assigned patients, 457 were analyzed. In total, 125 out of 457 (27%) placentas were classified as normal, 236 out of 457 (52%) placentas were classified as inflammatory, and 96 out of 457 (21%) placentas were classified as vascular. ’ Placental inflammation was associated with a significant, increased rate of BPD-freeP survival at 36 weeks postmenstrual age, independent of gestational age, treatment group, and sex (adjusted odds ratio: 1.72, 95% confidence interval [CI]: 1.05 to 2.82, = .03). Regarding the response to treatment, the strongest benefit of hydrocortisone Pcompared with placebo was found in infants born after placental vascular disease, with significantly more Ppatients extubated at day 10 (risk difference: 0.32, 95% CI: 0.08 to 0.56, = .004) and similar positive direction on survival without BPD (risk difference: 0.23, 95% CI: 0.00 to 0.46, = .06). Adjusted to gestationalP age and treatment groups, placental inflammation was associated with significantly fewer patent ductus arteriosus ligation (adjusted hazard ratio: 0.58, 95% CI: 0.36 to 0.95, = .03). Placental histology was not found to be associated CONCLUSIONS: with other adverse events related to . With these findings, we confirm that early low-dose hydrocortisone confers benefits in extremely preterm infants overall and we suggest there is a higher treatment effect in those born after placental vascular disease.

a b c What’s Known on This Subject: Placenta-mediated NICU, Department of Developmental Biology, and Unit of Clinical Epidemiology, Assistance Publique-Hôpitaux de Paris, Centre Hospitalier Universitaire Robert Debré and University Paris Diderot, Sorbonne Paris-Cité, Paris, complications with fetal consequences are France; dInserm U1123 and Centre d'Investigation Clinique-Épidémiologie Clinique 1426, Paris, France; and associated with bronchopulmonary dysplasia in extremely eDivision of Neonatology and PICU, University Hospitals Geneva, Geneva, Switzerland preterm infants. What This Study Adds: Placental inflammation was associated Dr Héneau conducted the data collection and the analyses and reviewed and revised the with an increased rate of bronchopulmonary dysplasia-free manuscript; Dr Guimiot conducted the placental analyses and reviewed and revised the survival at 36 weeks postmenstrual age. The strongest benefits manuscript; Mr Mohamed designed the analysis plan, conducted the statistical analyses, and ’ of early hydrocortisone on respiratory status were observed in participated in analyses interpretation; Dr Alberti coordinated and supervised the statistical extremely preterm infants born after placental vascular disease. methods and analyses and reviewed and revised the manuscript; Dr Rideau Batista Novais participated in analyses interpretation; Dr Baud conceptualized this study, participated in To cite: Héneau A, Guimiot F, Mohamed D, et al. Placental Findings and Effect of Prophylactic Hydrocortisone in Extremely Preterm Infants. Pediatrics. 2018;141(2):e20171788

Downloaded from www.aappublications.org/news by guest on September 23, 2021 PEDIATRICS Volume 141, number 2, February 2018:e20171788 Article After extremely preterm birth, reduction in the frequency of received placebo or hydrocortisone bronchopulmonary dysplasia surgical ligation for patent ductus hemisuccinate (Hydrocortisone (BPD) is a leading cause of neonatal arteriosus (PDA). Because the UPJOHN 100 mg for injection; SERB mortality and short- and long- antenatal period is crucial for lung Laboratories, Paris, France), 1 mg/kg term respiratory morbidities, and development and its subsequent per day divided into 2 doses per day is a strong risk factor for 1poor vulnerability to postnatal events, we for 7 days, followed by 0.5 mg/kg per neurocognitive outcome. BPD hypothesized that the magnitude of day for 3 days. The cumulative dose is characterized by a disrupted the hydrocortisone treatment effect used in the trial was 8.5 mg/kg. Placental Analysis and Histology alveolar and2, 3​vascular development on BPD could be related to placental in the lungs ‍ that originated, at findings. least partly, in placenta-mediated In this study the 2 main aims were pregnancy complications leading to determine if detailed placental Four hundred and fifty-seven to extremely preterm delivery. histology was associated with placentas that were associated In several retrospective studies, different treatment effects on with infants enrolled in the researchers have pointed out a tight respiratory status and survival PREMILOC trial were prospectively relationship between fetal growth or without BPD in extremely preterm collected and analyzed from 386 placental vascular disease and infants, and whether it could (including 317 single the subsequent development of 4,5​ be associated with any other and 69 multiple). All placentas were chronic lung disease in the infant. complications of extremely preterm analyzed on the basis of placental In a recent cohort study, placental delivery. histolopathology11,12​ as defined by diseases leading to fetal damage were Methods Redline et al. ‍ Data collected were found to be associated with BPD6 reviewed by 2 investigators (A.H. and in extremely preterm infants. The Study Population F.G.) blinded to the treatment group placenta appears to play a key role and the clinical outcomes. Placental in prenatal lung development and, analysis was performed in 2 steps. therefore, in lung vulnerability to The PREMILOC study was a double- The first macroscopic examination several insults, including infections, blind, multicenter trial, in which was conducted and consisted oxidative stress, and chronic 523 extremely preterm infants were of a description of membranes, inflammation. randomly assigned to receive either measurement of the disrupted side, low-dose hydrocortisone or placebo measurement of the placenta, and There has been highly publicized during the first 10 postnatal days. the description of its shape. The controversy regarding postnatal All infants were inborn, delivered length, its insertion steroid use in the most immature before 27 completed weeks, and on the fetal surface, its appearance, infants, which has proved to be an enrolled by 24 hours after birth. and the number of vessels were also ’ unsolved challenge7 for neonatologists The primary outcome was survival analyzed. Fetal and maternal surfaces in preventing BPD. On the basis without BPD at 36 weeks PMA and were depicted. After sectioning of the concept of relative adrenal was analyzed in 521 infants. The trial the umbilical cord, the placenta 8 é insufficiency,​ postnatal steroid use was approved by the National Ethics was weighed and the placenta/ was revisited in a more physiologic Committee (Comit de Protection des weights ratio was calculated. basis as a prophylactic replacement Personnes), the French National Drug Description of placental parenchyma 9 é é é treatment. The Early Low-Dose Safety Agency (Agence Nationale was performed on 1-cm sections. é Hydrocortisone to Improve Survival de S curit du M dicament et des For histology, several samples were Without Bronchopulmonary Produits de Sant , European Clinical collected as follows: 1 fragment Dysplasia in Extremely Preterm Trials Database number 2007- of umbilical cord at both fetal Infants (PREMILOC) study was 002041-20), and the French Data and placental sides, 1 fragment of ’ a multicenter, randomized Protection Authority (Commission membranes and amniotic epithelium, é controlled trial that tested the Nationale de l Informatique et 4 fragments of parenchyma in effect of low-dose hydrocortisone des Libert s). Written informed healthy areas, and all the fragments administered soon after birth to consent was obtained from parents in abnormal areas. All samples ’ µ improve survival without BPD at 36 of all eligible infants before random were then embedded in paraffin weeks postmenstrual age (PMA)10 assignment. The trial was registered and cut at 4 to 5 m thickness on in extremely preterm infants. at clinicaltrials.gov (NCT00623740) Superfrost plus slides. A second Demonstrated in this trial was a before the first patient was enrolled. histologic examination was then significant improvement in survival Study protocol10 has been previously performed13 according to standard without BPD and a significant reported. In brief, infants protocol. The placentas were Downloaded from www.aappublications.org/news by guest on September 23, 2021 2 Héneau et al TABLE 1 Baseline Characteristics of the Population According to Placental Histology Placental and Perinatal Normal Inflammatory Vascular analyzed by the same pathologist Characteristics (F.G.) and compared with other Placenta wt, g N = 118 N = 233 N = 93 placentas at the same gestational age Median (IQR) 219 (180 to 260) 234 (200 to 277) 211 (165 to 264) but without any maternal vascular Minimum; maximum 114; 546 100; 576 84; 580 underperfusion lesions. These Placental trophicity, n (%) N = 124 N = 235 N = 69 placentas came, for example, from Eutrophic 61 (75) 148 (77) 35 (54) pregnancies interrupted for severe Hypertrophic 2 (2) 16 (8) 3 (5) Hypotrophic 17 (21) 26 (14) 27 (42) fetal cardiac malformation or kidney Uncomplete 1 (1) 1 (1) 0 disease. The qualitative analysis PW/FW, % N = 118 N = 233 N = 93 was based on the observation of Median (IQR) 26 (22 to 30) 26 (23 to 31) 26 (22 to 32) at least 10 control placentas for Minimum; maximum 15; 70 14; 78 13; 72 every week of gestational age. The Perinatal and neonatal N = 125 N = 236 N = 96 variables, n (%) different parameters listed in Table Multiple pregnancy 68 (54) 60 (25) 26 (27) 1 were assessed and compared with Tocolysis 89 (72) 171 (72) 46 (48) these control placentas. Slices were Antenatal antibiotics 83 (66) 193 (82) 41 (43) stained with hematoxylin-eosin Antenatal steroids 114 (91) 224 (95) 88 (93) saffron. Vessels of placenta, villi PPROM 23 (18) 103 (44) 14 (15) Hypertension 6 (5) 8 (3) 37 (39) diameter, number of syncytial knots, Vaginal delivery 70 (56) 152 (64) 22 (23) inflammatory cell infiltrates in villous GA at birth, wk and intervillous space, hypoxia, Median (IQR) 26.6 (25.9 to 27.1) 26.4 (25.5 to 27.1) 26.8 (26.0 to 27.4) ischemia, necrosis, and vascular Minimum; maximum 24.7; 27.9 23.9; 27.9 24.3; 27.9 and infection lesions were assessed Birth wt, g Median (IQR) 880 (760 to 970) 880 (750 to 990) 794 (700 to 930) to determine the maturation of Minimum; maximum 580; 1338 570; 1345 550; 1185 placenta and associated lesions. If Birth wt in SDS the assessment was unclear, a second Median (IQR) 0.05 (−0.41 to 0.53) 0.19 (−0.28 to 0.52) −0.59 (−1.29 to 0.22) pathologist (A.H.) analyzed the Minimum; maximum −2.01; 1.67 −1.69; 2.04 −2.52; 1.00 placentas. Female, n (%) 54 (43) 107 (45) 45 (47) GA group, wk, n (%) 24–25 32 (26) 85 (36) 20 (21) The different studied parameters 26–27 93 (74) 151 (64) 76 (79) were classified in 3 groups according Ventilatory support at baseline, to the criteria defined by Redline n (%) 11,12​ Invasive ventilation 101 (81) 195 (83) 77 (80) et al ‍ : •• “ ” Noninvasive ventilation 24 (19) 41 (17) 19 (20) GA, gestational age; PPROM, prolonged (>24 h) premature rupture of membranes; PW/FW, placental weight/fetal weight An inflammatory group of ratio. placentas with with or without funiculitis; •• “ ” •• “ ” A vascular group of placentas A normal group of placentas, a physiologic basis that combined ± with subchorionic thrombosis, in which biometrical parameters oxygen and ventilation support with infarcts, spindly villi, excess of were in the normal range and an assessment15 at 36 weeks 3 days syncytial knots, basal or marginal parenchymal lesions did not of PMA. Severe adverse events hematoma, maternal thrombosis, exceed 5% of placental volume. Primary and Secondary Outcomes (including death, sepsis, PDA and decidual arteriopathy lesions. and Adverse Events ligation, gastrointestinal perforation, In 8 placentas, fetal thrombotic necrotizing enterocolitis, and vasculopathy lesions were found cystic white matter damage) were (Supplemental Table 5). Because noted within 48 hours. PDA was this feature can be found as Data on maternal characteristics diagnosed by clinical signs and a consequence of a maternal and pregnancy events (gestational vascular underperfusion associated diabetes mellitus, placental echocardiographic findings. Severe with severe preeclampsia with or abruption, preeclampsia, mode late-onset sepsis was defined by a without hemolysis, elevated liver of delivery) were extracted from culture positive for pneumonia enzymes, and low platelet count electronic clinical report form. The or a diagnosis of pneumonia 14 ’ syndrome,​ we decided to not primary outcome was survival with significant clinical impact. “ ” ’ ≥ exclude these 8 placentas from the without BPD at 36 weeks PMA. Necrotizing enterocolitis16 was vascular group; and For this trial, BPD was defined on diagnosed as Bell s stage 2. Downloaded from www.aappublications.org/news by guest on September 23, 2021 PEDIATRICS Volume 141, number 2, February 2018 3 Statistical Analysis

Data were described as median and interquartile range (IQR; first quartile to third quartile) for continuous variables and as percent χ for categorical variables. Categorical2 variables were compared by using test. A logistic regression model was used for the entire study population to analyze the impact of placental histology on primary outcome (BPD- free survival) adjusted to gestational age group, hydrocortisone treatment, and sex, 3 variables known to affect the occurrence of BPD. Results are shown as odds ratios (ORs) and their 95% confidence intervals (CIs). FIGURE 1 To analyze the effect of treatment Flowchart. The primary end point was BPD-free survival at 36 weeks’ PMA. on ventilatory support at day 10 in surviving patients and on the P primary outcome according to significance level set at 5%. values In Supplemental Table 5, we show placental histology group, risk were reported by using a Holm details in placental histology findings. difference (RD) and their 95% CIs P adjustment for multiple comparisons. Overall, histologic chorioamnionitis adjusted to gestational age group The analyses were conducted by was observed in 236 out of 457 were computed, and values were using SAS software (version 9.4; SAS (52%) placentas, including 134 corrected by using Bonferroni-Holm placentas with chorioamnionitis and correction for multiple tests. Institute, Inc, Cary, NC). funiculitis (29%). The main features For the study of factors associated Results associated with placental vascular with placental histology, a diseases were spindly villi in 68 polytomous logistic regression was out of 457 (15%) placentas, excess conducted, and ORs and their 95% of syncytial knots in 65 out of 457 CIs were computed. A flowchart of the study is presented (14%), parenchymal infarcts in 48 in Fig 1. Among 523 randomly For the study of predefined postnatal out of 457 (11%), marginal decidual complications associated with assigned patients born from 445 hematoma in 36 out of 457 (8%), prematurity, that is, severe late-onset mothers, 457 placentas from 386 maternal decidual arteriopathy sepsis, PDA ligation, necrotizing mothers (87%) were collected and lesions in 26 out of 457 (6%), enterocolitis, gastrointestinal analyzed. They were classified into subchorionic thrombosis in 14 out of perforation, and cystic white matter 3 groups according to the histologic 457 (3%), basal decidual hematoma damage, we regarded death as a findings defined in the Methods in 8 out of 457 (2%), and fetal competing outcome. We used a Fine section, in the entire population, thrombotic vasculopathy lesions in 8 and Gray model to examine the and according to treatment group. out of 457 (2%) placentas. Placentas effect of placental histologic groups Overall, 125 out of 457 infants (27%) with acute fetal hypoxia (2 out of on subdistributions of competing were delivered without substantial 457) and (1 out of risks. The time period between birth alterations of the placental histology 457) were rare findings. date and the date of the event of (normal group). Histologic evidence interest, death, or discharge from of placental inflammation was In Table 1, we summarize placental the hospital (whichever came first) observed in 236 out of 457 (52%, trophicity and maternal and was calculated up to a maximum inflammatory group) infants. neonatal characteristics by placental of 90 days. The results of these Histologic evidence of placental histology group. Sex ratio was analyses are expressed as hazard vascular disease was detected in 96 similar among the 3 groups. In ratios (HRs) with their 95% CIs. All out of 457 (21%, vascular group) multivariate analysis (Supplemental statistical tests were 2-tailed with the infants. Table 6), compared with the normal Downloaded from www.aappublications.org/news by guest on September 23, 2021 4 Héneau et al TABLE 2 Effect of Early Low-Dose Hydrocortisone on Ventilatory Support at Day 10 in Surviving Patients (N = 424) According to Placental Histology Group group, the inflammatoryP group Variable Hydrocortisone, n (%) Placebo, n (%) RD (95% CI) Pa was significantly associated with Normal N = 53 N = 58 multiple pregnancy ( < .0001), P Noninvasive ventilation 32 (60) 23 (40) 0.20 (−0.01 to 0.41) .05 prolongedP rupture of membranes Invasive ventilation 21 (40) 35 (60) — ( = .0003), and antenatal antibiotics Inflammatory N = 104 N = 118 Noninvasive ventilation 70 (67) 67 (57) 0.10 ( 0.03 to 0.23) .10 ( = .02). The vascularP group was − positively associated with gestational Invasive ventilation 34 (33) 51 (43) — Vascular N = 49 N = 42 hypertension ( = .002) and P Noninvasive ventilation 32 (65) 14 (33) 0.32 (0.08 to 0.56) .004 negatively associatedP with vaginal Invasive ventilation 17 (35) 28 (67) — delivery ( = .001) and multiple —, not applicable. pregnancy ( = .025). a Bonferroni-Holm correction for multiple tests. Next, we performed a logistic regression analysis of the impact TABLE 3 Effect of Early Low-Dose Hydrocortisone on BPD-Free Survival According to Placental of placental histology on BPD-free Histology Group survival (the primary outcome of Variable Hydrocortisone, n (%) Placebo, n (%) RD (95% CI) Pa the PREMILOC trial), adjusted to the Normal N = 59 N = 66 gestational age group, treatment BPD-free survival 32 (54) 37 (56) −0.02 (−0.19 to 0.16) .84 (hydrocortisone and placebo), BPD or death 27 (46) 29 (44) — Inflammatory N = 108 N = 128 and sex. We found that placental BPD-free survival 73 (68) 71 (55) 0.13 (−0.01 to 0.27) .10 inflammation was associated with an ’ BPD or death 35 (32) 57 (45) — increased rate ofP BPD-free survival Vascular N = 51 N = 45 at 36 weeks PMA (OR: 1.72, 95% BPD-free survival 31 (61) 17 (38) 0.23 (−0.00 to 0.46) .06 CI: 1.05 to 2.84, = .03) compared BPD or death 20 (39) 28 (62) — with the normal group. In contrast, a Bonferroni-Holm correction for multiple tests. placental vascular disease was not associated with significant difference Pin the incidence of the primary end point (OR: 0.67, 95% CI: 0.37 to 1.21, group have been found statistically inflammation was associated with = .18) compared with the normal significant regarding the rate of BPD- a significantly lower risk of PDA group. free survival between treatment Pligation and IVH grade 3 to 4, with an groups. However, a positive direction PHR of 0.58 (95% CI: 0.36 to 0.95, The main characteristics of effect in favor of hydrocortisone has = .03) and 0.57 (95% CI: 0.33 to 0.99, ventilatory support at day 10 been observed both in inflammation = .047), respectively, compared (end of the treatment by either and vascular groups with an RD of with the normal group. No significant hydrocortisone or placebo) were 0.10 and 0.23, respectively (Table 3). association was observed between presented in Table 2 for each other neonatal adverse events and placentalP histology group. RDs were Summarized in Table 4 are the rates placental histology. adjusted to gestational age group of severe adverse events related Discussion and values were corrected by to prematurity in each treatment using Bonferroni-Holm correction group, according to placental for multiple tests. We found that histology. We further studied 5 significantly more infants were neonatal complications of interest In this study we assessed the extubated after hydrocortisone in which hydrocortisone might association between perinatal events, treatment compared with placebo. have a positive or negative effect in detailed placental histology, neonatal Not only a positive direction of subgroups of placental histology: outcomes, and the magnitude of the the treatment was observed in severe late-onset sepsis, PDA treatment effect of early postnatal all placental histology groups; ligation, necrotizing enterocolitis, hydrocortisone in infants born a significant effect induced by gastrointestinal perforation, severe extremely preterm. We refined pre prophylactic hydrocortisone on intraventricular hemorrhage (IVH), and pernatal factors associated with ventilatory support at day 10 was cystic white matter damage, and well-defined placental histology reached in infantsP born after placenta death. For each, excluding death, in a large prospective cohort of vascular disease (RD: 0.26, 95% CI: we regarded death as a competing extremely preterm infants. We found 0.02 to 0.50, = .004). Among the 3 event in the analysis using a Fine and that placental inflammation was ’ placental histology groups, none of Gray model. Adjusted to gestational associated with an increased rate the RDs adjusted to gestational age age and treatment groups, placental of BPD-free survival at 36 weeks Downloaded from www.aappublications.org/news by guest on September 23, 2021 PEDIATRICS Volume 141, number 2, February 2018 5 P PMA. The benefits of hydrocortisone treatment on respiratory status were

a found higher in infants born after placental vascular disease. Except for ventilator support on day 10,

HR (95% CI) PDA surgical closure, and IVH grade 3 to 4, placental histology was not found associated with other postnatal complications associated with

Vascular ( N = 96) extreme preterm delivery. 1 (2) 0.45 (0.05 to 4.35) .49 n (%) A strength of this study is the detailed placental histology prospectively Placebo ( n = 45), collected and analyzed in a standardized manner and available in a large majority of pregnancies (and n (%)

HC ( n = 51), matched to 87% of recruited infants). Placental histology items and records P follow international standard and have been analyzed by 2 referent pathologists blinded to treatment

a group and clinical outcomes. Parenchymal lesions have been rigorously analyzed and classified.

HR (95% CI) In particular, vascular lesions 1.06 (0.45 to 2.53) .89 2 (4) 2 (4) 0.62 (0.19 to 2.09) .44 0.83 (0.33 to 2.09) .70 2 (4) 1 (2) 0.58 (0.15 to 2.23) .43 1.45 (0.38 to 5.58) .59 0 are extremely well defined and accurately reported in our records. Although multiple comparisons adjustment for secondary outcomes Inflammatory ( N = 236) 9 (7) 8 (6) 6 (5) n (%) was computed, a limitation of the current study is its exploratory Placebo ( n = 128),

​ design. Another limitation of this ancillary study is the lack of power,

(%) as PREMILOC trial power and sample 7 (6) 4 (4) 2 (2) n size were primarily calculated only

HC ( n = 108), ’ for the outcome of survival without BPD at 36 weeks PMA but not for subgroup analyses.

n (%) One important result of this study

Placebo ( n = 66), that we can substantially add to the literature is that the rate of surviving

Normal ( N = 125) infants without BPD was found higher 2 (3) 2 (3) n (%) 7 (12) 1 (2) 9 (15) 15 (23) 18 (17) 28 (22) 0.81 (0.45 to 1.47) .59 4 (8)in 12 (27) infants 0.93 (0.44 to 1.97) born extremely .85 preterm 15 (25) 18 (27) 32 (30) 28 (22) 0.90 (0.59 to 1.38) .64 16 (31) 12 (27) 1.13 (0.68 to 1.87) .65 13 (22) 16 (24) 15 (14) 21 (16) 0.58 (0.36 to 0.95) .03 8 (16) 16 (36) 1.28 (0.74 to 2.21) .38 14 (24) 11 (17) 16 (15) 21 (16) 0.57 (0.33 to 0.99) .047 2 (4) 9 (20) 0.61 (0.28 to 1.30) .20

HC ( n = 59), after a pregnancy complicated by placental inflammation (mainly due to chorioamnionitis), after adjustment to gestational age, treatment group, and sex. Available literature in which the complex interaction between

b chorioamnionitis and subsequent  Effect of T reatment and Placental Histology on the Occurrence of Severe Adverse Events occurrence17, of18​ BPD is explored remains19 4 E

L conflicting. ‍ Watterberg et al were PDA ligation Placental Histology Event NEC Severe LOS Gastrointestinal perforation 5 (8) 2 (3) IVH grade 3 – 4 Cystic PVL Death Late-onset sepsis was defined by a blood culture positive for pneumonia or a diagnosis of pneumonia with significant clinical impact. Late-onset sepsis was defined by a blood culture positive for pneumonia or diagnosis of HRs were estimated for all severe adverse events except death by a Fine and Gray model that considered death before the event of interest as a competing risk and adjusted for gestational age and treatment groups. The normal placenta group placenta normal groups. The treatment and age gestational for adjusted and risk competing a as interest event of the before considered death that model Gray and Fine a by death except events adverse severe all for estimated were HRs TAB HC, hydrocortisone; LOS, late-onset sepsis; NEC, necrotizing enterocolitis; PVL, periventricular leukomalacia. a b was considered as the reference group. the first to describe an increased rate of BPD after histologic chorioamnionitis, but it was found in infants more Downloaded from www.aappublications.org/news by guest on September 23, 2021 6 Héneau et al mature and neither treated with we found a marked increased risk of In this subpopulation, benefits prenatal steroids nor with exogenous– BPD or death in this vascular group conferred by hydrocortisone were not surfactant. Authors of many other 20 22 compared with both inflammation restricted to respiratory support and studies reported inconsistent data,​ ‍ and normal groups (62% vs 45% and several other positive effects; reduced and authors of recent, large cohort 44%, respectively). PDA ligation, high-grade IVH, and studies finally do not support the death were observed compared with The accumulation of extracellular association between chorioamnionitis placebo. These findings are consistent 23 matrix, increased thickness of and the subsequent risk of BPD. In with the concept of an exacerbated air-blood barrier, atypical elastin particular, researchers of a recent postnatal inflammation associated production, and the dysregulation population-based study strongly with pregnancy complicated by of gene expression involving lung suggested that in homogeneous placental vascular disease. Indeed, inflammation, mostly observed in 38 groups of extremely preterm infants, Leviton et al demonstrated that animal models, may be targeted by histologic chorioamnionitis is not 30,34,​ 35​ small for gestational age neonates 24 hydrocortisone. ‍ ‍ Beneficial associated with BPD. Moreover, were frequently exposed to systemic effects of hydrocortisone treatment preceding exposure to intraamniotic inflammation with elevated serum on ventilator support were also inflammatory insult has been found to concentrations of several cytokines observed in infants exposed to protect the lungs against BPD triggered not at birth, but during the second placental inflammation but with by postnatal systemic inflammation postnatal week. These multiple-hit 25 no significant difference. This in rats. Nevertheless, the association insults (ie, prenatal adverse conditions observation could be because of a between chorioamnionitis and BPD followed by postnatal inflammation low dosage that was able to reverse will probably continue to be debated or hypoxia-ischemia) have been only partly marked perinatal as a complex amalgam of inflammatory documented both in neonates and in inflammation associated with 39,40​ preconditioning, placental preclinical animal models. ‍ More chorioamnionitis. inflammatory and postnatal injury to recently authors of transcriptomic and the developing lung, and many26 factors Vascular placental disease could gene network analyses have revealed that are changing over time. also be related to altered cortisol postnatal deregulation of genes homeostasis in the fetus and controlling neuroinflammation and Another important finding of the in neonates. Indeed, placental the cell cycle in both oligodendrocytes current study is that the highest corticotropin-releasing hormone and microglia in a model41 of fetal beneficial effect of hydrocortisone was found to be stimulated by growth restriction. With these treatment was found in infants whose chronic fetal stress associated36 data, there is growing evidence that placenta had features of vascular with fetal growth retardation. supports placental vascular disease disease. Indeed, the vascular placenta As a result, umbilical cord plasma could sensitize the newborn to various group was found to be associated corticotropin-releasing hormone secondary neonatal insults leading with a significant number of patients and cortisol levels are elevated in to exacerbated neuroinflammation extubated at 10 days and a trend of growth-retarded compared and subsequent respiratory and ’ increased survival without BPD at with normal fetuses. Despite neurologic morbidities. Early use of 36 weeks PMA. These findings could conflicting results regarding hydrocortisone could prevent related – be explained by the strong impact of cortisol cord blood levels at birth complications by reducing postnatal impaired fetal nutrition frequently in intrauterine growth restricted systemic inflammation, that is, PDA, observed when placental vascular infants, in studies of the postnatal BPD, brain damage, and death, not disease occurs, lung development at stress response, researchers only after chorioamnionitis, but above any stage, and lung vulnerability to have revealed blunted cortisol all when birth was associated with 27 – postnatal insults. Authors of many release and lower basal cortisol placental vascular disease. studies have shown that premature, levels in intrauterine growth small for gestational age infants are restricted infants, which suggests Conclusions at higher risk for developing neonatal a long-lasting compromise of the respiratory distress, BPD, and long- pituitary-adrenal 37function and term respiratory morbidities when cortisol response. Altogether, Placental inflammation is associated compared with premature– infants these findings could be used to with an increased rate of survival with a birth weight4,28​ 33appropriate for account for an exacerbated effect without BPD in extremely preterm gestational age. ‍ ‍‍ In the current of hydrocortisone in infants born infants, regardless of gestational study, no statistically significant from placental vascular disease, a age, treatment by hydrocortisone, increased risk of BPD was found in condition associated with a lower and sex. Respiratory status of the vascular group. Nevertheless, median birth in the PREMILOC trial. infants born extremely preterm Downloaded from www.aappublications.org/news by guest on September 23, 2021 PEDIATRICS Volume 141, number 2, February 2018 7 after placental vascular disease Zupan-Simunek and Hasinirina Amel Ouslimani and Elodie Soler; Unit ï é is improved by early postnatal Razafimahefa; CH Pontoise (Pontoise): of Clinical Epidemiology, CHU Robert hydrocortisone. Overall, data confirm Anne Coursol and Sa d Merbouche; CH Debr (Paris): Sandra Argues, Tania that prophylactic hydrocortisone Saint-Denis (Saint-Denis): Pascal Bolot Rilcy, Adyla Yacoubi, and Sabrina confers benefits in extremely preterm and Jean-Marc Kana; CHU Bordeaux Verchere. ç ç infants and, in particular, those born (Bordeaux): Julie Guichoux and Olivier é after placental vascular disease. Brissaud; CHU Besan on (Besan on): G rard Thiriez and Olivier Schulze; Abbreviations PREMILOC Study Group CHU Reims (Reims): Mickael Pomedio é and Patrice Morville; CHU Rouen (Rouen): Thierry Blanc and St phane é é é é BPD: bronchopulmonary Centre Hospitalier Universitaire Marret; CHU Caen (Caen): Bernard é dysplasia (CHU) Robert Debr (Paris): Val rie Guillois and C n ric Alexandre; é ë CI: confidence interval Biran, Ali Bilal, Caroline Farnoux, CHU Angers (Angers): St phane Le HR: hazard ratio Sophie Soud e, and Laure Maury; Bou dec and Bertrand Leboucher; è é IQR: interquartile range Centre Hospitalier (CH) Corbeil- CHU Conception (Marseille): Umberto IVH: intraventricular Essonnes (Corbeil-Essonnes): Mich le Simeoni and Val rie Lacroze; CHU é é hemorrhage Granier and Florence Lebail; Centre Strasbourg (Strasbourg): Pierre Kuhn é ô OR: odds ratio Hospitalier R gional Saint-Denis, La and St phanie Litzler-Renaud; CHU ï PDA: patent ductus arteriosus R union: Duksha Ramful and Sylvain Cochin-Broca-H tel Dieu (Paris): é PMA: postmenstrual age Samperiz; CHU Rennes (Rennes): Elodie Zana-Ta eb and Pierre-Henri PREMILOC: Early Low-Dose Alain Beuch e and Karine Guimard; Jarreau; CHU Armand Trousseau Hydrocortisone to Centre Hospitalier Intercommunal (Paris): Sylvain Renolleau and Virginie Improve Survival de Poissy (Saint-Germain): Fatima El Meau-Petit; CHRU Montpellier ô é é Without Moussawi, Pascal Boileau, and Florence (Montpellier): Gilles Cambonie; Agence é Bronchopulmonary Castela; CHU H pital Nord (Marseille): G n rale des Equipements et des Dysplasia in Claire Nicaise and Renaud Vialet; Produits de Sant (Paris): Annick Tibi; é Extremely Preterm CHU Grenoble (Grenoble): Pierre Direction de la Recherche Clinique é è é ô Infants Andrini and Thierry Debillon; CHU et du D veloppement, Assistance RD: risk difference Antoine B cl re (Paris): V ronique Publique-H pitaux de Paris (Paris): analyses interpretation, and wrote the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. This trial has been registered at www.​eudract.​ema.​europa.​eu (identifier 2007-002041-20) and www.​clinicaltrials.​gov (identifier NCT00623740). DOI: https://​doi.​org/​10.​1542/​peds.​2017-​1788 Accepted for publication Nov 3, 2017 Address correspondence to Olivier Baud, MD, PhD, Division of Neonatology and Pediatric Intensive Care, University Hospitals Geneva, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2018 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: Supported by a research grant from the French Ministry of Health and sponsored by the Département de la Recherche Clinique et de l’Innovation, Assistance Publique-Hôpitaux de Paris (AOM 06 025 and AOM 11 129). The funders had no role in study design, data collection or analysis, decision to publish, or preparation of the manuscript. POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2018 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

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