OBJECTIVES: To investigate the relationship between histologic findings of the placenta and response to early postnatal hydrocortisone treatment used to prevent bronchopulmonary dysplasia (BPD) in extremely preterm infants.
METHODS: 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 to neonatal outcomes and response to hydrocortisone treatment.
RESULTS: Of 523 randomly assigned patients, 457 placentas 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-free 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, P = .03). Regarding the response to treatment, the strongest benefit of hydrocortisone compared with placebo was found in infants born after placental vascular disease, with significantly more patients extubated at day 10 (risk difference: 0.32, 95% CI: 0.08 to 0.56, P = .004) and similar positive direction on survival without BPD (risk difference: 0.23, 95% CI: 0.00 to 0.46, P = .06). Adjusted to gestational 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, P = .03). Placental histology was not found to be associated with other adverse events related to preterm birth.
CONCLUSIONS: 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.
- BPD —
- bronchopulmonary dysplasia
- CI —
- confidence interval
- HR —
- hazard ratio
- IQR —
- interquartile range
- IVH —
- intraventricular hemorrhage
- OR —
- odds ratio
- PDA —
- patent ductus arteriosus
- PMA —
- postmenstrual age
- PREMILOC —
- Early Low-Dose Hydrocortisone to Improve Survival Without Bronchopulmonary Dysplasia in Extremely Preterm Infants
- RD —
- risk difference
What’s Known on This Subject:
Placenta-mediated pregnancy complications with fetal consequences are associated with bronchopulmonary dysplasia in extremely preterm infants.
What This Study Adds:
Placental inflammation was associated with an increased rate of bronchopulmonary dysplasia-free survival at 36 weeks’ postmenstrual age. The strongest benefits of early hydrocortisone on respiratory status were observed in extremely preterm infants born after placental vascular disease.
After extremely preterm birth, bronchopulmonary dysplasia (BPD) is a leading cause of neonatal mortality and short- and long-term respiratory morbidities, and is a strong risk factor for poor neurocognitive outcome.1 BPD is characterized by a disrupted alveolar and vascular development in the lungs2,3 that originated, at least partly, in placenta-mediated pregnancy complications leading to extremely preterm delivery. In several retrospective studies, researchers have pointed out a tight relationship between fetal growth or placental vascular disease and the subsequent development of chronic lung disease in the infant.4,5 In a recent cohort study, placental diseases leading to fetal damage were found to be associated with BPD in extremely preterm infants.6 The placenta appears to play a key role in prenatal lung development and, therefore, in lung vulnerability to several insults, including infections, oxidative stress, and chronic inflammation.
There has been highly publicized controversy regarding postnatal steroid use in the most immature infants, which has proved to be an unsolved challenge for neonatologists in preventing BPD.7 On the basis of the concept of relative adrenal insufficiency,8 postnatal steroid use was revisited in a more physiologic basis as a prophylactic replacement treatment.9 The Early Low-Dose Hydrocortisone to Improve Survival Without Bronchopulmonary Dysplasia in Extremely Preterm Infants (PREMILOC) study was a multicenter, randomized controlled trial that tested the effect of low-dose hydrocortisone administered soon after birth to improve survival without BPD at 36 weeks’ postmenstrual age (PMA) in extremely preterm infants.10 Demonstrated in this trial was a significant improvement in survival without BPD and a significant reduction in the frequency of surgical ligation for patent ductus arteriosus (PDA). Because the antenatal period is crucial for lung development and its subsequent vulnerability to postnatal events, we hypothesized that the magnitude of the hydrocortisone treatment effect on BPD could be related to placental findings.
In this study the 2 main aims were to determine if detailed placental histology was associated with different treatment effects on respiratory status and survival without BPD in extremely preterm infants, and whether it could be associated with any other complications of extremely preterm delivery.
The PREMILOC study was a double-blind, multicenter trial, in which 523 extremely preterm infants were randomly assigned to receive either low-dose hydrocortisone or placebo during the first 10 postnatal days. All infants were inborn, delivered before 27 completed weeks, and enrolled by 24 hours after birth. The primary outcome was survival without BPD at 36 weeks’ PMA and was analyzed in 521 infants. The trial was approved by the National Ethics Committee (Comité de Protection des Personnes), the French National Drug Safety Agency (Agence Nationale de Sécurité du Médicament et des Produits de Santé, European Clinical Trials Database number 2007-002041-20), and the French Data Protection Authority (Commission Nationale de l’Informatique et des Libertés). Written informed consent was obtained from parents of all eligible infants before random assignment. The trial was registered at clinicaltrials.gov (NCT00623740) before the first patient was enrolled. Study protocol has been previously reported.10 In brief, infants received placebo or hydrocortisone hemisuccinate (Hydrocortisone UPJOHN 100 mg for injection; SERB Laboratories, Paris, France), 1 mg/kg per day divided into 2 doses per day for 7 days, followed by 0.5 mg/kg per day for 3 days. The cumulative dose used in the trial was 8.5 mg/kg.
Placental Analysis and Histology
Four hundred and fifty-seven placentas that were associated with infants enrolled in the PREMILOC trial were prospectively collected and analyzed from 386 pregnancies (including 317 single and 69 multiple). All placentas were analyzed on the basis of placental histolopathology as defined by Redline et al.11,12 Data collected were reviewed by 2 investigators (A.H. and F.G.) blinded to the treatment group and the clinical outcomes. Placental analysis was performed in 2 steps. The first macroscopic examination was conducted and consisted of a description of membranes, measurement of the disrupted side, measurement of the placenta, and the description of its shape. The umbilical cord length, its insertion on the fetal surface, its appearance, and the number of vessels were also analyzed. Fetal and maternal surfaces were depicted. After sectioning the umbilical cord, the placenta was weighed and the placenta/fetus weights ratio was calculated. Description of placental parenchyma was performed on 1-cm sections. For histology, several samples were collected as follows: 1 fragment of umbilical cord at both fetal and placental sides, 1 fragment of membranes and amniotic epithelium, 4 fragments of parenchyma in healthy areas, and all the fragments in abnormal areas. All samples were then embedded in paraffin and cut at 4 to 5 µm thickness on Superfrost plus slides. A second histologic examination was then performed according to standard protocol.13 The placentas were analyzed by the same pathologist (F.G.) and compared with other placentas at the same gestational age but without any maternal vascular underperfusion lesions. These placentas came, for example, from pregnancies interrupted for severe fetal cardiac malformation or kidney disease. The qualitative analysis was based on the observation of at least 10 control placentas for every week of gestational age. The different parameters listed in Table 1 were assessed and compared with these control placentas. Slices were stained with hematoxylin-eosin saffron. Vessels of placenta, villi diameter, number of syncytial knots, inflammatory cell infiltrates in villous and intervillous space, hypoxia, ischemia, necrosis, and vascular and infection lesions were assessed to determine the maturation of placenta and associated lesions. If the assessment was unclear, a second pathologist (A.H.) analyzed the placentas.
An “inflammatory” group of placentas with chorioamnionitis with or without funiculitis;
A “vascular” group of placentas with subchorionic thrombosis, infarcts, spindly villi, excess of syncytial knots, basal or marginal hematoma, maternal thrombosis, and decidual arteriopathy lesions. In 8 placentas, fetal thrombotic vasculopathy lesions were found (Supplemental Table 5). Because this feature can be found as a consequence of a maternal vascular underperfusion associated with severe preeclampsia with or without hemolysis, elevated liver enzymes, and low platelet count syndrome,14 we decided to not exclude these 8 placentas from the “vascular” group; and
A “normal” group of placentas, in which biometrical parameters were in the normal range and parenchymal lesions did not exceed 5% of placental volume.
Primary and Secondary Outcomes and Adverse Events
Data on maternal characteristics and pregnancy events (gestational diabetes mellitus, placental abruption, preeclampsia, mode of delivery) were extracted from electronic clinical report form. The primary outcome was survival without BPD at 36 weeks’ PMA. For this trial, BPD was defined on a physiologic basis that combined oxygen and ventilation support with an assessment at 36 weeks ± 3 days of PMA.15 Severe adverse events (including death, sepsis, PDA ligation, gastrointestinal perforation, necrotizing enterocolitis, and cystic white matter damage) were noted within 48 hours. PDA was diagnosed by clinical signs and echocardiographic findings. Severe late-onset sepsis was defined by a blood culture positive for pneumonia or a diagnosis of pneumonia with significant clinical impact. Necrotizing enterocolitis was diagnosed as Bell’s16 stage ≥2.
Data were described as median and interquartile range (IQR; first quartile to third quartile) for continuous variables and as percent for categorical variables. Categorical variables were compared by using χ2 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).
To analyze the effect of treatment on ventilatory support at day 10 in surviving patients and on the primary outcome according to placental histology group, risk difference (RD) and their 95% CIs adjusted to gestational age group were computed, and P values were corrected by using Bonferroni-Holm correction for multiple tests.
For the study of factors associated with placental histology, a polytomous logistic regression was conducted, and ORs and their 95% CIs were computed.
For the study of predefined postnatal complications associated with prematurity, that is, severe late-onset sepsis, PDA ligation, necrotizing enterocolitis, gastrointestinal perforation, and cystic white matter damage, we regarded death as a competing outcome. We used a Fine and Gray model to examine the effect of placental histologic groups on subdistributions of competing risks. The time period between birth date and the date of the event of interest, death, or discharge from the hospital (whichever came first) was calculated up to a maximum of 90 days. The results of these analyses are expressed as hazard ratios (HRs) with their 95% CIs. All statistical tests were 2-tailed with the significance level set at 5%. P values were reported by using a Holm adjustment for multiple comparisons. The analyses were conducted by using SAS software (version 9.4; SAS Institute, Inc, Cary, NC).
A flowchart of the study is presented in Fig 1. Among 523 randomly assigned patients born from 445 mothers, 457 placentas from 386 mothers (87%) were collected and analyzed. They were classified into 3 groups according to the histologic findings defined in the Methods section, in the entire population, and according to treatment group. Overall, 125 out of 457 infants (27%) were delivered without substantial alterations of the placental histology (normal group). Histologic evidence of placental inflammation was observed in 236 out of 457 (52%, inflammatory group) infants. Histologic evidence of placental vascular disease was detected in 96 out of 457 (21%, vascular group) infants.
In Supplemental Table 5, we show details in placental histology findings. Overall, histologic chorioamnionitis was observed in 236 out of 457 (52%) placentas, including 134 placentas with chorioamnionitis and funiculitis (29%). The main features associated with placental vascular diseases were spindly villi in 68 out of 457 (15%) placentas, excess of syncytial knots in 65 out of 457 (14%), parenchymal infarcts in 48 out of 457 (11%), marginal decidual hematoma in 36 out of 457 (8%), maternal decidual arteriopathy lesions in 26 out of 457 (6%), subchorionic thrombosis in 14 out of 457 (3%), basal decidual hematoma in 8 out of 457 (2%), and fetal thrombotic vasculopathy lesions in 8 out of 457 (2%) placentas. Placentas with acute fetal hypoxia (2 out of 457) and placenta praevia (1 out of 457) were rare findings.
In Table 1, we summarize placental trophicity and maternal and neonatal characteristics by placental histology group. Sex ratio was similar among the 3 groups. In multivariate analysis (Supplemental Table 6), compared with the normal group, the inflammatory group was significantly associated with multiple pregnancy (P < .0001), prolonged rupture of membranes (P = .0003), and antenatal antibiotics (P = .02). The vascular group was positively associated with gestational hypertension (P = .002) and negatively associated with vaginal delivery (P = .001) and multiple pregnancy (P = .025).
Next, we performed a logistic regression analysis of the impact of placental histology on BPD-free survival (the primary outcome of the PREMILOC trial), adjusted to the gestational age group, treatment (hydrocortisone and placebo), and sex. We found that placental inflammation was associated with an increased rate of BPD-free survival at 36 weeks’ PMA (OR: 1.72, 95% CI: 1.05 to 2.84, P = .03) compared with the normal group. In contrast, placental vascular disease was not associated with significant difference in the incidence of the primary end point (OR: 0.67, 95% CI: 0.37 to 1.21, P = .18) compared with the normal group.
The main characteristics of ventilatory support at day 10 (end of the treatment by either hydrocortisone or placebo) were presented in Table 2 for each placental histology group. RDs were adjusted to gestational age group and P values were corrected by using Bonferroni-Holm correction for multiple tests. We found that significantly more infants were extubated after hydrocortisone treatment compared with placebo. Not only a positive direction of the treatment was observed in all placental histology groups; a significant effect induced by prophylactic hydrocortisone on ventilatory support at day 10 was reached in infants born after placenta vascular disease (RD: 0.26, 95% CI: 0.02 to 0.50, P = .004). Among the 3 placental histology groups, none of the RDs adjusted to gestational age group have been found statistically significant regarding the rate of BPD-free survival between treatment groups. However, a positive direction effect in favor of hydrocortisone has been observed both in inflammation and vascular groups with an RD of 0.10 and 0.23, respectively (Table 3).
Summarized in Table 4 are the rates of severe adverse events related to prematurity in each treatment group, according to placental histology. We further studied 5 neonatal complications of interest in which hydrocortisone might have a positive or negative effect in subgroups of placental histology: severe late-onset sepsis, PDA ligation, necrotizing enterocolitis, gastrointestinal perforation, severe intraventricular hemorrhage (IVH), cystic white matter damage, and death. For each, excluding death, we regarded death as a competing event in the analysis using a Fine and Gray model. Adjusted to gestational age and treatment groups, placental inflammation was associated with a significantly lower risk of PDA ligation and IVH grade 3 to 4, with an HR of 0.58 (95% CI: 0.36 to 0.95, P = .03) and 0.57 (95% CI: 0.33 to 0.99, P = .047), respectively, compared with the normal group. No significant association was observed between other neonatal adverse events and placental histology.
In this study we assessed the association between perinatal events, detailed placental histology, neonatal outcomes, and the magnitude of the treatment effect of early postnatal hydrocortisone in infants born extremely preterm. We refined pre and pernatal factors associated with well-defined placental histology in a large prospective cohort of extremely preterm infants. We found that placental inflammation was associated with an increased rate of BPD-free survival at 36 weeks’ PMA. The benefits of hydrocortisone treatment on respiratory status were found higher in infants born after placental vascular disease. Except for ventilator support on day 10, PDA surgical closure, and IVH grade 3 to 4, placental histology was not found associated with other postnatal complications associated with extreme preterm delivery.
A strength of this study is the detailed placental histology prospectively collected and analyzed in a standardized manner and available in a large majority of pregnancies (and matched to 87% of recruited infants). Placental histology items and records follow international standard and have been analyzed by 2 referent pathologists blinded to treatment group and clinical outcomes. Parenchymal lesions have been rigorously analyzed and classified. In particular, vascular lesions are extremely well defined and accurately reported in our records.
Although multiple comparisons adjustment for secondary outcomes was computed, a limitation of the current study is its exploratory design. Another limitation of this ancillary study is the lack of power, as PREMILOC trial power and sample size were primarily calculated only for the outcome of survival without BPD at 36 weeks’ PMA but not for subgroup analyses.
One important result of this study that we can substantially add to the literature is that the rate of surviving infants without BPD was found higher in infants born extremely preterm 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 chorioamnionitis and subsequent occurrence of BPD is explored remains conflicting.17,18 Watterberg et al19 were the first to describe an increased rate of BPD after histologic chorioamnionitis, but it was found in infants more mature and neither treated with prenatal steroids nor with exogenous surfactant. Authors of many other studies reported inconsistent data,20–22 and authors of recent, large cohort studies finally do not support the association between chorioamnionitis and the subsequent risk of BPD.23 In particular, researchers of a recent population-based study strongly suggested that in homogeneous groups of extremely preterm infants, histologic chorioamnionitis is not associated with BPD.24 Moreover, preceding exposure to intraamniotic inflammatory insult has been found to protect the lungs against BPD triggered by postnatal systemic inflammation in rats.25 Nevertheless, the association between chorioamnionitis and BPD will probably continue to be debated as a complex amalgam of inflammatory preconditioning, placental inflammatory and postnatal injury to the developing lung, and many factors that are changing over time.26
Another important finding of the current study is that the highest beneficial effect of hydrocortisone treatment was found in infants whose placenta had features of vascular disease. Indeed, the vascular placenta group was found to be associated with a significant number of patients extubated at 10 days and a trend of increased survival without BPD at 36 weeks’ PMA. These findings could be explained by the strong impact of impaired fetal nutrition frequently observed when placental vascular disease occurs, lung development at any stage, and lung vulnerability to postnatal insults.27 Authors of many studies have shown that premature, small for gestational age infants are at higher risk for developing neonatal respiratory distress, BPD, and long-term respiratory morbidities when compared with premature infants with a birth weight appropriate for gestational age.4,28–33 In the current study, no statistically significant increased risk of BPD was found in the vascular group. Nevertheless, we found a marked increased risk of BPD or death in this vascular group compared with both inflammation and normal groups (62% vs 45% and 44%, respectively).
The accumulation of extracellular matrix, increased thickness of air-blood barrier, atypical elastin production, and the dysregulation of gene expression involving lung inflammation, mostly observed in animal models, may be targeted by hydrocortisone.30,34,35 Beneficial effects of hydrocortisone treatment on ventilator support were also observed in infants exposed to placental inflammation but with no significant difference. This observation could be because of a low dosage that was able to reverse only partly marked perinatal inflammation associated with chorioamnionitis.
Vascular placental disease could also be related to altered cortisol homeostasis in the fetus and in neonates. Indeed, placental corticotropin-releasing hormone was found to be stimulated by chronic fetal stress associated with fetal growth retardation.36 As a result, umbilical cord plasma corticotropin-releasing hormone and cortisol levels are elevated in growth-retarded fetuses compared with normal fetuses. Despite conflicting results regarding cortisol cord blood levels at birth in intrauterine growth–restricted infants, in studies of the postnatal stress response, researchers have revealed blunted cortisol release and lower basal cortisol levels in intrauterine growth–restricted infants, which suggests a long-lasting compromise of the pituitary-adrenal function and cortisol response.37 Altogether, these findings could be used to account for an exacerbated effect of hydrocortisone in infants born from placental vascular disease, a condition associated with a lower median birth in the PREMILOC trial.
In this subpopulation, benefits conferred by hydrocortisone were not restricted to respiratory support and several other positive effects; reduced PDA ligation, high-grade IVH, and death were observed compared with placebo. These findings are consistent with the concept of an exacerbated postnatal inflammation associated with pregnancy complicated by placental vascular disease. Indeed, Leviton et al38 demonstrated that small for gestational age neonates were frequently exposed to systemic inflammation with elevated serum concentrations of several cytokines not at birth, but during the second postnatal week. These multiple-hit insults (ie, prenatal adverse conditions followed by postnatal inflammation or hypoxia-ischemia) have been documented both in neonates and in preclinical animal models.39,40 More recently authors of transcriptomic and gene network analyses have revealed postnatal deregulation of genes controlling neuroinflammation and the cell cycle in both oligodendrocytes and microglia in a model of fetal growth restriction.41 With these data, there is growing evidence that supports placental vascular disease could sensitize the newborn to various secondary neonatal insults leading to exacerbated neuroinflammation and subsequent respiratory and neurologic morbidities. Early use of hydrocortisone could prevent related complications by reducing postnatal systemic inflammation, that is, PDA, BPD, brain damage, and death, not only after chorioamnionitis, but above all when birth was associated with placental vascular disease.
Placental inflammation is associated with an increased rate of survival without BPD in extremely preterm infants, regardless of gestational age, treatment by hydrocortisone, and sex. Respiratory status of infants born extremely preterm after placental vascular disease is improved by early postnatal hydrocortisone. Overall, data confirm that prophylactic hydrocortisone confers benefits in extremely preterm infants and, in particular, those born after placental vascular disease.
PREMILOC Study Group
Centre Hospitalier Universitaire (CHU) Robert Debré (Paris): Valérie Biran, Ali Bilal, Caroline Farnoux, Sophie Soudée, and Laure Maury; Centre Hospitalier (CH) Corbeil-Essonnes (Corbeil-Essonnes): Michèle Granier and Florence Lebail; Centre Hospitalier Régional Saint-Denis, La Réunion: Duksha Ramful and Sylvain Samperiz; CHU Rennes (Rennes): Alain Beuchée and Karine Guimard; Centre Hospitalier Intercommunal de Poissy (Saint-Germain): Fatima El Moussawi, Pascal Boileau, and Florence Castela; CHU Hôpital Nord (Marseille): Claire Nicaise and Renaud Vialet; CHU Grenoble (Grenoble): Pierre Andrini and Thierry Debillon; CHU Antoine Béclère (Paris): Véronique Zupan-Simunek and Hasinirina Razafimahefa; CH Pontoise (Pontoise): Anne Coursol and Saïd Merbouche; CH Saint-Denis (Saint-Denis): Pascal Bolot and Jean-Marc Kana; CHU Bordeaux (Bordeaux): Julie Guichoux and Olivier Brissaud; CHU Besançon (Besançon): Gérard Thiriez and Olivier Schulze; CHU Reims (Reims): Mickael Pomedio and Patrice Morville; CHU Rouen (Rouen): Thierry Blanc and Stéphane Marret; CHU Caen (Caen): Bernard Guillois and Cénéric Alexandre; CHU Angers (Angers): Stéphane Le Bouëdec and Bertrand Leboucher; CHU Conception (Marseille): Umberto Simeoni and Valérie Lacroze; CHU Strasbourg (Strasbourg): Pierre Kuhn and Stéphanie Litzler-Renaud; CHU Cochin-Broca-Hôtel Dieu (Paris): Elodie Zana-Taïeb and Pierre-Henri Jarreau; CHU Armand Trousseau (Paris): Sylvain Renolleau and Virginie Meau-Petit; CHRU Montpellier (Montpellier): Gilles Cambonie; Agence Générale des Equipements et des Produits de Santé (Paris): Annick Tibi; Direction de la Recherche Clinique et du Développement, Assistance Publique-Hôpitaux de Paris (Paris): Amel Ouslimani and Elodie Soler; Unit of Clinical Epidemiology, CHU Robert Debré (Paris): Sandra Argues, Tania Rilcy, Adyla Yacoubi, and Sabrina Verchere.
- Accepted November 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:
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.
- Torchin H,
- Ancel PY,
- Goffinet F, et al
- Thébaud B,
- Lacaze-Masmonteil T,
- Watterberg K
- Watterberg KL,
- Gerdes JS,
- Gifford KL,
- Lin HM
- Baud O,
- Maury L,
- Lebail F, et al; PREMILOC Trial Study Group
- Redline RW,
- Boyd T,
- Campbell V, et al; Society for Pediatric Pathology, Perinatal Section, Maternal Vascular Perfusion Nosology Committee
- Watterberg KL,
- Demers LM,
- Scott SM,
- Murphy S
- Lahra MM,
- Beeby PJ,
- Jeffery HE
- Been JV,
- Zimmermann LJ
- Torchin H,
- Lorthe E,
- Goffinet F, et al
- Tyson JE,
- Kennedy K,
- Broyles S,
- Rosenfeld CR
- Pike KC,
- Crozier SR,
- Lucas JS, et al; Southampton Women’s Survey Study Group
- Helderman JB,
- O’Shea TM,
- Kuban KC, et al; ELGAN Study Investigators
- Girard S,
- Kadhim H,
- Beaudet N,
- Sarret P,
- Sébire G
- Copyright © 2018 by the American Academy of Pediatrics