Low arterial blood pressure, often referred to as hypotension, is a common condition during the first postnatal days of very premature infants and has been associated with an increased risk of death or other adverse outcomes such as bronchopulmonary dysplasia or intraventricular hemorrhage (1).

Although hypotension management remains controversial (2–5), there is a consensus to promote multimodal hemodynamic assessment in premature infants, especially with the use of neonatologist-performed echocardiography (NPE) (6). By providing a more comprehensive assessment of the pathophysiological mechanisms leading to low systemic perfusion than blood pressure measurement alone, NPE could theoretically help clinicians decide whether or not to start treatment, and if yes, to choose the most appropriate treatment strategy (7). NPE has been adopted in many NICUs in recent decades (8) and has been shown to influence therapeutic decisions in studies with historical control groups (9, 10), but its impact on clinical outcomes has been assessed only once, when it was used to systematically screen for patent ductus arteriosus (PDA) among preterm infants born before 30 weeks of gestation (11).

The French population-based EPIPAGE-2 (EPIdémiologie des Petits Ages GEstationnels) prospective cohort study recruited premature births in 2011 (12) and collected the use of NPE to assess hemodynamics in the first 72 h after birth. These real-life data offer a unique opportunity to evaluate the association of NPE use with therapeutic management and outcomes in hypotensive preterm infants in a situation where randomization of this imaging practice at the level of a unit seems difficult.

We thus aimed to compare survival, survival without significant morbidity at discharge, and early hemodynamic therapeutic management in preterm infants born before 30 weeks of gestational age who had an episode of hypotension and did or did not have at least one NPE during their first 72 postnatal hours, after adjustment for confounding by indication. We hypothesized that babies in whom NPE was used would receive a specific hemodynamic management and would thus have better outcomes at discharge.

Among the 2,136 premature infants born before 30 weeks of gestation in the EPIPAGE-2 cohort and admitted to the NICU, 966 were eligible and 809 were included in the study (Figure 1). Baseline characteristics of the unmatched and matched cohorts are summarized in Table 1. Of the 320 infants in the NPE group and 489 in the no-NPE group, 229 from each group could be matched for gestational age and propensity score (Figure 1). In the unmatched cohort, infants in the NPE group had more frequent markers of severity but matched pairs had standardized differences below 10% for all variables included in the propensity score (Figure 2). The overlap of propensity scores in the NPE and no-NPE groups was limited for extreme values meaning that most infants with a high probability of having NPE actually did and that most infants with a low probability of having it did not (online Supplementary Figure 1).

In the unmatched cohort, 213 (66.9%) of 320 infants from the NPE group received antihypotensive therapies vs. 169 (34.1%) of 489 in the no-NPE group (p < 0.001, Table 2). Survival at discharge did not differ significantly between the NPE and no-NPE groups [244/320 (77.5%) vs. 396/489 (82.4%), respectively; p = 0.08; Table 3] but survival without severe morbidity was lower in the NPE than in the no-NPE group [156/320 (50.7%) vs. 281/489 (59.8%), respectively; p = 0.012; Table 3].

In the matched cohort, 144 (62.9%) of 229 infants from the NPE group received antihypotensive therapies vs. 99 (43.0%) of 229 infants in the no-NPE group (p < 0.001, Table 2). Among infants treated with antihypotensive therapies, the most frequent treatment was volume expansion, administered to 118 (82.1%) of 144 treated infants in the NPE group and to 79 (80.5%) of 99 treated infants in the no-NPE group (p = 0.67, Table 2). The median amount of administered volume was significantly higher in the NPE group than in in the no-NPE group [20 (13–30) vs. 20 (16–40) ml/kg, p = 0,013; Table 2].

Among infants treated with antihypotensive therapies, the use of inotropic drugs was more frequent in the NPE than the no-NPE group [77/144 (53.7%) vs. 37/99 (37.8%), respectively; p = 0.023; Table 2]. The comparison of antihypotensive treatment combinations did not reach a statistically significant difference between the two groups (p = 0.07, Table 2).

Reasons for administering antihypotensive treatments differed significantly between the groups (p < 0.001), but the most frequently reported reason was isolated hypotension in both the NPE (49/144, 41.6%) and no-NPE (48/99, 56.1%) groups. More infants in the NPE than the no-NPE group received a treatment to close the PDA in their first 3 days after birth [78/229 (33.9%) vs. 43/229 (18.7%), respectively; p = 0.001; Table 2].

In the matched cohort, no significant difference between the NPE and no-NPE groups was found for survival (OR 1.01, 95% CI 0.64 to 1.60; p = 0.95; Table 3) or survival without severe morbidity at discharge (OR 0.92, 95% CI 0.63 to 1.34; p = 0.66; Table 3).

Sensitivity analyses using IPTW and logistic regression provided results similar to those of the main analysis (Supplementary Figure 2).

Subgroup analyses stratified for the severity of hypotension yielded no significant differences between the NPE and no-NPE groups among those with minMAP ≤ or > GA-5 (Supplementary Table 1) or among treated or untreated infants (Supplementary Table 2).

In this real-life nationwide prospective study, NPE was used to assess hemodynamic status in around 40% of preterm infants born before 30 weeks of gestation with hypotension occurring in the first three postnatal days. After adjusting for confounding by indication, we found no association between NPE use and in-hospital survival or survival without severe morbidities. NPE was associated with more frequent use of antihypotensive therapies, but the nature of these therapies was very similar whether NPE was used or not, except for the amount of volume expansion, which was larger in the NPE group. This study included a large sample of premature infants and used robust statistical methods, which contribute to the external validity of the findings.

The use of NPE is variable in NICUs worldwide, ranging from 9% in the United States (18) to 94% in Italy (19). We did not confirm our initial hypothesis that NPE use would be associated with improved outcomes. Actually, many issues must be resolved before evidence-based guidelines predicated on echocardiographic findings can be adopted: effective training must be implemented, relevant and reproducible echocardiographic markers must be identified and widely adopted, and therapeutic interventions based on these markers must be assessed. To date, none of these things has happened: the existing literature on NPE use for guiding hemodynamic management in preterm neonates is currently insufficient (20) and no randomized controlled trial assessing therapeutic options for increasing blood pressure in preterm infants has succeeded in improving important clinical outcomes (21–26). In line with recommendations from adult intensivists (27), standardizing the use of neonatal echocardiography in hemodynamic clinical research should be strongly encouraged.

Contrary to our initial hypothesis, we found little differences between therapeutic interventions among treated infants according to NPE use. Most of the treated hypotensive infants received volume expansion, and the most frequently used inotropic drug was dopamine, as observed in an international survey contemporaneous with the EPIPAGE-2 study (28). Although volume expansion can increase blood pressure, its wide use is not supported by either long-term clinical benefits (22) or pathophysiological mechanisms (5). Similarly, dopamine is effective for increasing blood pressure but does not improve blood flow or clinical outcomes (21). The recently published multicenter, double-blind, placebo-controlled hypotension in preterm infants (HIP) trial failed to establish any definitive conclusion on the effect of dopamine on survival without brain injury due to insufficient recruitment, leaving the relevance of its use in this context unknown (25).

Interestingly, infants in the NPE groups received PDA treatment more frequently in the first three postnatal days than did the no-NPE group, and the latter showed no catch-up PDA treatments afterwards. We speculate that for these infants, NPE might have helped to identify PDA as the cause of hypotension and led to the administration of treatment (29).

Our study has several limitations. First, we had no information on the timing of NPE in relation to the treatment decision. Therefore, we could not distinguish infants who were treated or untreated based on echocardiographic findings from those who underwent NPE once the treatment started. We also had no information on the number of scans and the timeline of any treatment modifications that followed them. Second, the reasons for performing NPE were also missing, so we could speculate that patients in the NPE-group had clinical conditions leading clinicians to perform NPE. This could explain a more frequent use of anti-hypotensive therapies in the NPE group. Third, we had no information on the existence of a local protocol to guide the assessment and management of hypotension in each NICU, which might have influenced the effects of NPE use. Fourth, the study reflects practices from 2011, which might have changed a decade later. Moreover, the questionnaire did not collect the use of epinephrine or milrinone, which were rarely used in France at that time. Fifth, as in any observational study, residual confounding might persist. However, the use of NPE seems impossible to randomize at the level of a single department or hospital, and the feasibility of a cluster-randomized trial is questionable for that would require that some centers already using NPE to agree to stop using it while the other centers would need to follow a proper training program to implement NPE use. Thus, it is likely that the use of NPE can essentially be assessed only through observational studies (30).

In French NICUs in 2011, NPE was used for the hemodynamic assessment of fewer than half of the very preterm infants with hypotension. NPE use was associated with more frequent use of antihypotensive therapies but had little impact on their type and did not appear to influence survival or survival without severe morbidity at discharge. These results do not argue against the use of NPE in this context but rather underline the gap in our knowledge of how to interpret NPE findings, the need for training and echocardiographic-based clinical research on neonatal hemodynamic management, and the necessity for evidence about the benefits of antihypotensive therapies in this vulnerable population.

The data analyzed in this study is subject to the following licenses/restrictions: The procedures carried out with the French data privacy authority (CNIL, Commission nationale de l'informatique et des libertés) do not provide for the transmission of the database. Consultation by the editorial board or interested researchers may nevertheless be considered, subject to prior determination of the terms and conditions of such consultation and in respect for compliance with the applicable regulations. Requests to access these datasets should be directed to xavier.durrmeyer@chicreteil.fr.

The studies involving human participants were reviewed and approved by Commission Nationale de l'Informatique et des Libertés (CNIL) n°911009 the consultative committee on the treatment of information on personal health data for research purposes (approval granted November 18, 2010, reference 10.626) the committee for the protection of people participating in Biomedical Research (approval granted March 18, 2011, reference Comité de Protection des Personnes (CPP) SC-2873. Written informed consent from the participants' legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.

Members of the Hemodynamic EPIPAGE2 Study Group: Gilles Cambonie, MD, PhD (Department of Neonatal Medicine, Montpellier University Hospital, Montpellier, France); Jean-Christophe Rozé, MD, PhD (Department of Neonatal Medicine, Nantes University Hospital, Nantes, France); Pierre-Yves Ancel, MD, PhD (INSERM, U1153,Obstetrical, Perinatal and Pediatric Epidemiology Team, Epidemiology and Biostatistics Sorbonne, Paris, France); Laetitia Marchand-Martin, MS (INSERM, U1153,Obstetrical, Perinatal and Pediatric Epidemiology Team, Epidemiology and Biostatistics Sorbonne, Paris, France); Mélanie Durox, MSc (INSERM, U1153, Obstetrical, Perinatal and Pediatric Epidemiology Team, Epidemiology and Biostatistics Sorbonne, Paris, France); Veronique Gournay, MD, PhD (Pediatric Cardiology Unit, Nantes University Hospital, Nantes, France); Xavier Durrmeyer, MD, PhD (Department of Neonatal Medicine, Intercommunal hospital, Creteil, France); Laurent Storme, MD, PhD (Department of Neonatal Medicine, Lille University Hospital, Lille, France); Raphael Porcher, PhD (INSERM, U1153, METHODS Team, Epidemiology and Statistics Sorbonne Paris Cité Research Center, Paris, France); Patrice Morville, MD (Department of Neonatal Medicine, Reims University Hospital, Reims, France);Olivier Brissaud, MD (Department of Neonatal Medicine, Bordeaux University Hospital, Bordeaux, France); Patrick Truffert, MD, PhD (Department of Neonatal Medicine, Lille University Hospital, Lille, France); Antoine Bouissou, MD (Department of Neonatal Medicine, Tours University Hospital, Tours, France); Isabelle Ligi, MD, PhD (Department of Neonatal Medicine, Marseille University Hospital, Marseille, France); Marie-Odile Marcoux, MD (Department of Neonatal Medicine, Toulouse University Hospital, Toulouse, France); Fabrice Cneude, MD (Department of Neonatal Medicine, Grenoble University Hospital, Grenoble, France); Geraldine Gascoin, MD, PhD (Department of Neonatal Medicine, Angers University Hospital); Gerard Thiriez, MD, PhD (Department of Neonatal Medicine, Besançon University Hospital, Besançon, France); Hugues Patural, MD, PhD (Department of Neonatal Medicine, St Etienne University Hospital, St Etienne, France); Doriane Madeleneau, MD (Department of Neonatal Medicine, Cochin University Hospital, Paris, France); Antoine Burguet, MD, PhD (Department of Neonatal Medicine, Dijon University Hospital, Dijon, France); Patrick Pladys, MD, PhD (Department of Neonatal Medicine, Rennes University Hospital, Rennes, France).

GG, GC, J-CR, OB, LS, P-YA, and XD participated in the data collection. LM-M performed all data analysis, and XD validated them. RR, XD, and HT wrote the first draft. All authors initiated and designed the protocol, participated in data interpretation, reviewing of the manuscript, and approved the final manuscript.

This study was supported by the French Institute of Public Health Research/Institute of Public Health and its partners the French Health Ministry, the National Institute of Health and Medical Research, the National Institute of Cancer, and the National Solidarity Fund for Autonomy; grant ANR-11-EQPX-0038 from the National Research Agency through the French Equipex Program of Investments in the Future; and the PremUp Foundation. The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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