Association between Baseline Cortisol Serum Concentrations and the Effect of Prophylactic Hydrocortisone in Extremely Preterm Infants

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Article

Reference

Association between Baseline Cortisol Serum Concentrations and the Effect of Prophylactic Hydrocortisone in Extremely Preterm Infants

RENOLLEAU, Chloe, et al. & PREMILOC Trial Study Group

Abstract

Objective: To define nomograms of serum cortisol values before 24 hours of postnatal life for extremely preterm infants and determine whether baseline cortisol values affect the benefit/risk ratio of prophylactic hydrocortisone to improve survival without bronchopulmonary dysplasia (BPD). Study design: We performed a predefined secondary analysis of the multicenter randomized controlled PREMILOC trial that included inborn infants delivered before 28 weeks of gestation. Nomograms of baseline serum cortisol values measured in 325 enrolled patients were determined for male and female neonates and correlated to perinatal events. BPD-free survival and severe adverse events were analyzed in placebo and hydrocortisone groups according to the cortisol z score in multivariate logistic regression models.

RENOLLEAU, Chloe, et al . & PREMILOC Trial Study Group. Association between Baseline Cortisol Serum Concentrations and the Effect of Prophylactic Hydrocortisone in Extremely Preterm Infants. The Journal of Pediatrics , 2021, vol. 234, p. 65-70.e3

DOI : 10.1016/j.jpeds.2020.12.057 PMID : 33359303

Available at:

http://archive-ouverte.unige.ch/unige:156036

Disclaimer: layout of this document may differ from the published version.

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Association between Baseline Cortisol Serum Concentrations and the Effect of Prophylactic Hydrocortisone in Extremely Preterm Infants

Chloe Renolleau, MD¹, Artemis Toumazi, MSc², Aurelie Bourmaud, PhD², Jean-Franc¸ois Benoist, PhD³,

Didier Chevenne, PhD³, Damir Mohamed, MSc², Corinne Alberti, PhD², Valerie Biran, PhD^1,4, Olivier Baud, PhD^4,5, for the PREMILOC Trial Study Group*

ObjectiveTo define nomograms of serum cortisol values before 24 hours of postnatal life for extremely preterm infants and determine whether baseline cortisol values affect the benefit/risk ratio of prophylactic hydrocortisone to improve survival without bronchopulmonary dysplasia (BPD).

Study designWe performed a predefined secondary analysis of the multicenter randomized controlled PREMI- LOC trial that included inborn infants delivered before 28 weeks of gestation. Nomograms of baseline serum cortisol values measured in 325 enrolled patients were determined for male and female neonates and correlated to perinatal events. BPD-free survival and severe adverse events were analyzed in placebo and hydrocortisone groups according to the cortisol z score in multivariate logistic regression models.

ResultsIncreased cortisol levels measured before 24 hours following birth were associated with a significantly higher chance of BPD-free survival only in placebo-treated infants (aOR [95% CI] 1.57 [1.08-2.27],P= .02) based on sex-specific nomograms for baseline cortisol levels. The cortisol z score for infants treated with prophylactic hydrocortisone predicted a risk of high-grade intraventricular hemorrhage (aOR [95% CI] 1.82 [1.06-3.15], P= .03) and spontaneous intestinal perforation (aOR [95% CI] 4.81 [1.34-17.22],P= .02).

Conclusions We found no predictive value of baseline cortisol levels for BPD-free survival in infants born extremely preterm treated with hydrocortisone. However, high cortisol levels early after birth were associated with a greater risk of severe intraventricular hemorrhage and spontaneous intestinal perforation in infants treated with hydrocortisone and, therefore, a lower benefit/risk ratio for the treatment.(J Pediatr 2021;234:65-70). Trial registrationEudraCT 2007-002041-20,ClinicalTrial.gov: NCT00623740.

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ortisol plays a key role in controlling inflammation, which is recognized to be a major contributor to the pathogenesis of bronchopulmonary dysplasia (BPD).^1-3Fetal cortisol production is limited before 23 weeks of gestation due to the immature hypothalamic-pituitary-adrenal axis and only reaches significant levels after 30 weeks of gestation.^4-6 Neonates born extremely preterm are, therefore, unable to maintain homeostasis

when confronted with the intense stressors associated with intensive care, including oxygen exposure, infection, mechanical ventilation, pain, and inade- quate sensorineural stimuli. In addition, insufficient serum cortisol levels are a well-accepted contributing factor for the development of inflammation- associated BPD.^7,8

BPD is a leading cause of neonatal mortality and short- and long-term respi- ratory morbidity and a strong risk factor for poor neurocognitive outcome.^9,10 Based on the concept of relative adrenal insufficiency,¹¹the use of postnatal steroids has been revisited as a prophylactic replacement treatment.⁸Four randomized clinical trials enrolling nearly 1000 extremely preterm infants showed that prophylaxis of early adrenal insufficiency with low-dose hydrocortisone significantly improved BPD-free survival and patent ductus arteriosus closure.¹² Two adverse events were reported to be associated with this treatment: an

From the¹Neonatal Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, CHU Robert Debre, University Paris Diderot, Sorbone Paris Cite, Paris, France;²Unit of Clinical Epidemiology, Assistance Publique-Hôpitaux de Paris, CHU Robert Debre, University Paris Diderot, Sorbonne Paris-Cite, Inserm U1123 and CIC-EC 1426, Paris, France;³Department of Biochemistry and Hormonology, Assistance Publique- Hôpitaux de Paris, CHU Robert Debre, University Paris Diderot, Sorbone Paris Cite, Paris, France;⁴Inserm U1141, University Paris Diderot, Sorbone Paris Cite, Paris, France; and⁵Division of Neonatology and Pediatric Intensive Care, Children’s University Hospital of Geneva and University of Geneva, Geneva, Switzerland

*List of investigators of the PREMILOC trial is available at www.jpeds.com(Appendix).

Supported by a research grant from the French Ministry of Health and sponsored by the Departement de la Recherche Clinique et du Developpement, Assistance Publique-H^opitaux de Paris (AOM 06 025 and AOM 11 129). The funders had no role in the study design, data collection or analysis, decision to publish, or preparation of the manuscript. The authors declare no conflict of interests.

0022-3476/ª2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://

creativecommons.org/licenses/by-nc-nd/4.0/).

https://doi.org/10.1016/j.jpeds.2020.12.057

BPD Bronchopulmonary dysplasia IVH Intraventricular hemorrhage PMA Postmenstrual age SAE Severe adverse event

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increase in late-onset sepsis reported in the most immature infants, but without an adverse effect on mortality or neuro- developmental outcomes, and an increase in spontaneous intestinal perforation when associated with early indomethacin treatment.

We hypothesized that the benefit/risk ratio of early low- dose hydrocortisone may be improved by considering cortisol values before treatment. Here, we performed a predefined analysis of cortisol measurements in infants enrolled in a trial testing prophylactic hydrocortisone to prevent bronchopulmonary dysplasia in extremely preterm infants (PRE- MILOC trial).¹³

The 2 main objectives of this secondary analysis were to define nomograms of cortisol values in serum within the first day of postnatal life according to sex in this high-risk popu- lation of preterm infants and determine whether baseline cortisol values alter the effect of hydrocortisone treatment on BPD-free survival and severe adverse events (SAEs).

Methods

PREMILOC was a double-blind multicenter trial in which 523 extremely preterm infants were randomly assigned to receive either prophylactic low-dose hydrocortisone or placebo during the first 10 days of postnatal life. 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 of postmenstrual age (PMA) and was analyzed for 521 infants. The trial was approved by the national ethics committee (Comite de Pro- tection des Personnes, Ile-de-France II, Necker), the French National Drug Safety Agency (EudraCT number 2007- 002041-20), and the French data protection authority (Com- mission Nationale de l’Informatique et des Libertes). Written informed consent was obtained from parents of all eligible infants before randomization. The trial was registered at ClinicalTrials.gov (NCT00623740) before the first patient was enrolled. The study protocol has been previously reported. Briefly, infants received placebo or hydrocortisone hemisuccinate (hydrocortisone UPJOHN 100 mg for injec- tion, SERB Laboratories), 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.

Data on maternal characteristics and pregnancy events (gestational diabetes mellitus, placental abruption, pre- eclampsia, mode of delivery) were extracted from the electronic clinical report form of the PREMILOC trial. The primary outcome of the PREMILOC trial was survival without BPD at 36 weeks of PMA. BPD was defined on a physiological basis that combined oxygen and ventilatory support with an assessment at 36 weeks 3 days of PMA.¹⁴SAEs considered in the present ancillary study were those related to hydrocortisone exposure, including SPI, severe late-onset sepsis, defined by a positive blood culture or

diagnosis of pneumonia with a significant clinical impact, and grade 3-4 intraventricular hemorrhage (IVH), according to Papile.¹⁵

For cortisol measurement, samples were collected for 325 infants, mainly from venous umbilical cord blood or, in a few cases, before receiving either placebo or hydrocortisone treatment (within 24 hours of postnatal life). Infants for whom blood samples were available did not differ from the rest of the cohort in terms of gestational age, birth anthro- pometry, or circumstances of preterm delivery. The blood samples obtained from recruiting centers were centrifuged, and serum was separated and stored at 80C until centralized analysis. Serum cortisol was measured using an auto- mated competitive chemiluminescent immunoassay (Advia Centaur CP, Siemens-Healthcare).

The primary outcome of this predefined secondary analysis of the PREMILOC trial was to determine nomograms of baseline serum cortisol values according to sex. Secondary outcomes were the ability of these sex-adjusted baseline cortisol values to predict the beneficial effect of hydrocortisone treatment on BPD-free survival and SAEs in multivariate logistic regression models.

Statistical Analyses

Data are reported as either means (SDs) or medians (IQR) for continuous variables and frequencies (percentages) for categorical variables.

Nomograms of baseline cortisol serum concentrations were defined for males and females separately according to gestational age. Cubic spline curves with Box-Cox transformations were fitted to allow data normalization and determination of the CIs (10th-90th percentile) for cortisol levels in both male and female participants. Histograms of z scores for each sex were also generated showing the normality of the data.

Covariates associated with cortisol levels were identified by performing independent samplettests to compare the major continuous perinatal variables and cortisol z scores, adjusted for sex.

Multivariate logistic regression models were generated for the placebo and hydrocortisone treatment groups to identify the association between baseline cortisol level and BPD-free survival. Selected variables statistically associated with the cortisol z score at a significance level of 20% in the univariate analysis were included in the multivariate models for each treatment group (multiple gestation, antenatal steroids, early onset sepsis, peridural analgesia, and gestational hypertension). The final threshold of significance for exit variables in the multivariate analyses was aPvalue of <.05.

The same process of generating univariate and multivariate logistic regression models was performed to assess the ability of early cortisol levels to predict SAEs associated with hydrocortisone treatment.

All statistical analyses were performed using SAS software v 9.4 (SAS Institute, Inc).

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Results

From among 523 randomized patients (Figure 1; available at www.jpeds.com), 325 serum samples were collected before hydrocortisone treatment within 24 hours after birth (155 in the hydrocortisone group and 170 in the control group).

The baseline characteristics of infants with or without cortisol measurements are summarized in Table I (available at www.jpeds.com). All cortisol values above 2000 nmol/L were recorded as 2000 nmol/L. The mean values (SD) were significantly lower for male than female patients (542 [508] nmol/L vs 691 [565], P = .01). The cortisol serum concentrations (in nmol/L) were nonnormally distributed. Thus, Box-Cox transformation was performed to allow normalization and determination of the mean, SD, and CIs (10th/90th percentiles) for cortisol values according to gestational age for both male and female patients. Cubic regression spline curves were also fitted (Figure 2). Histograms show the normality of

the cortisol z scores for both male and female patients (Figure 3; available atwww.jpeds.com). Cortisol levels did not correlate with gestational age at birth, either when values were in nmol/L (Pearson correlation coefficient:

r = 0.09347,P= .09) or given as z-scores (r = 0.04408, P= .43).

Major perinatal events were correlated with cortisol z scores, adjusted for sex, to better determine covariates associated with cortisol variability early after birth (Table II).

Antenatal steroids and peridural analgesia were significantly associated with lower cortisol levels, whereas multiple gestation, clinical chorioamnionitis, and early onset sepsis were significantly associated with higher cortisol serum concentrations.

We compared baseline serum cortisol concentrations according to BPD-free survival for infants enrolled in the PREMILOC trial between the placebo and hydrocortisone groups (Table III; available at www.jpeds.com). Male and female patients were analyzed separately. There was no

Figure 2. Cortisol serum concentrations inA,male andB,female extremely preterm infants within 24 hours of birth. Dot-plots are according to gestational age at birth.

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statistically significant difference in baseline cortisol levels in terms of the occurrence of BPD-free survival between infants treated with hydrocortisone and those treated with the placebo, based on univariate analysis. Nevertheless, we used a multivariate logistic regression model to assess the association between early cortisol levels and BPD-free survival, adjusted for cortisol-associated noncollinear

perinatal variables (multiple gestation, antenatal steroids, early onset sepsis, peridural analgesia, and gestational hypertension). Such analysis revealed a significant association between the cortisol z score and BPD-free survival for placebo-treated infants (aOR [95% CI] 1.57 [1.08-2.27], P = .02) but not infants treated with hydrocortisone (aOR [95%CI] 1.02 [0.69-1.50], P = .94) (Table IV). Conversely, multiple gestation, early-onset sepsis, and gestational hypertension were found to be associated with a decreased chance of BPD-free survival for infants treated with hydrocortisone.

Finally, we investigated the ability of baseline cortisol levels to predict SAEs associated with hydrocortisone treatment. In univariate analysis, 3 SAEs were found to be associated with the cortisol z score at a significance level of 20%: grade 3-4 IVH and 2 other SAEs reported to be associated with early hydrocortisone treatment in the PREMILOC or other clinical trials: severe late-onset sepsis and SPI. In a logistic regression model adjusted for perinatal variables, the cortisol z score, adjusted for sex, was significantly associated with a risk of grade 3-4 IVH (aOR [95% CI] 1.82 [1.06-3.15],P = .03) for infants treated with hydrocortisone but not those allo- cated to the placebo group (Table V). In addition, we investigated the predictive value of baseline cortisol for the other 2 SAEs. Although we found no association with severe late-onset sepsis (aOR [95% CI] 1.06 [0.72-1.55], P = .78), the cortisol z score was significantly associated with spontaneous intestinal perforation (aOR [95% CI]

4.81 [1.34-17.22], P = .02) for infants exposed to prophylactic hydrocortisone, with a threshold of 889 nmol/L.

Discussion

We performed a refined analysis of the benefit/risk ratio of prophylactic hydrocortisone treatment to improve BPD- free survival in extremely preterm infants. Updated nomograms for baseline cortisol levels were generated from a large cohort of extremely preterm infants enrolled in the PREMI- LOC trial. We re-evaluated primary outcomes and adverse events in a predefined secondary analysis, based on sex- specific cortisol z scores, soon after birth and adjusted to Table II. Association between cortisol serum

concentration (z score adjusted to sex) within the first 24 hours after birth and perinatal characteristics

Variables

Cortisol,

mean z score (SD) Pvalue Multiple gestation

Yes (n = 106) 0.19 (0.90) .02

No (n = 219) 0.09 (1.04)

Tocolysis

Yes (n = 230) 0.05 (1.01) .12

No (n = 93) 0.14 (0.95)

Antenatal antibiotics

Yes (n = 228) 0.07 (0.98) .07

No (n = 97) 0.15 (1.03)

Antenatal steroids

Yes (n = 303) 0.06 (0.99) <.0001

No (n = 22) 0.83 (0.70)

Clinical chorioamnionitis

Yes (n = 157) 0.14 (1.02) .01

No (n = 135) 0.16 (0.94)

Prolonged rupture of membranes (>24 h)

Yes (n = 102) 0.12 (1.03) .16

No (n = 223) 0.05 (0.99)

Gestational diabetes

Yes (n = 16) 0.14 (1.09) .53

No (n = 302) 0.02 (1.00)

Gestational hypertension

Yes (n = 29) 0.31 (0.94) .08

No (n = 296) 0.03 (1.00)

Early onset sepsis (proved or probable)

Yes (n = 39) 0.53 (1.01) .0004

No (n = 286) 0.07 (0.98)

Peridural analgesia

Yes (n = 136) 0.15 (1.02) .008

No (n = 172) 0.15 (0.98)

General anesthesia

Yes (n = 38) 0.14 (1.05) .42

No (n = 272) 0.01 (1.00)

Table IV. Multivariate logistic regression model for the association between cortisol serum concentration in z score adjusted to other perinatal variables, and survival without BPD in infants treated by early hydrocortisone or placebo

Variables

Hydrocortisone

(n = 145) Placebo

(n = 163) aOR [95% CI]* Pvalue aOR [95%CI]* Pvalue Cortisol

(z score, 1 SD)

1.02 [0.69; 1.50] .94 1.57 [1.08; 2.27] .02 Multiple gestation 0.31 [0.14; 0.72] .007 0.52 [0.25; 1.08] .08 Antenatal steroids 3.07 [0.70; 13.38] .14 4.92 [1.08; 22.40] .04 Early-onset sepsis 0.30 [0.10; 0.87] .03 0.76 [0.25; 2.28] .62 Peridural analgesia 1.66 [0.77; 3.57] .20 1.45 [0.75; 2.78] .27 Gestational

hypertension

0.17 [0.05; 0.52] .002 0.33 [0.08; 1.49] .15

*OR adjusted for multiple gestation, antenatal steroids, early onset sepsis, peridural analgesia, and gestational hypertension.

Table V. Multivariate logistic regression model for the association between cortisol serum concentration (z score, 1 SD) and specific adverse neonatal outcomes in infants treated by early hydrocortisone or placebo

SAEs

Hydrocortisone (n = 145)

Placebo (n = 163) aOR [95% CI]* Pvalue aOR [95% CI]* Pvalue Grade 3-4 IVH 1.82 [1.06; 3.15] .03 0.86 [0.47; 1.55] .61 Spontaneous

intestinal perforation

4.81 [1.34; 17.22] .02 1.35 [0.57; 3.21] .50

Severe late-onset sepsis

1.06 [0.72; 1.55] .78 1.07 [0.71; 1.61] .74

*Adjusted for multiple gestation, antenatal steroids, early onset sepsis, peridural analgesia, and gestational hypertension.

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cortisol-associated perinatal variables. Increased cortisol levels measured before 24 hours following birth were associated with a significantly higher chance of BPD-free survival in placebo-treated infants, but this association was not observed for infants treated with hydrocortisone. Regarding SAEs, the cortisol z score was significantly associated with a risk of high-grade IVH and SPI only for infants treated with prophylactic hydrocortisone.

Cortisol is a key hormone in the regulation of several maturational processes in the fetus and during the perinatal and transition phases of neonatal adaptation after birth.

The first days after birth are characterized by relative adrenal insufficiency and the response to cortisol releasing hormone has also been shown to be suboptimal during the first week of life.¹⁶Nevertheless, we report here that high concentrations of cortisol can be released in response to specific perinatal events, including clinical chorioamnionitis and early-onset sepsis. The cortisol values reported here were similar to those already described at birth in very preterm infants.^16-20 Ng et al reported nomograms for cortisol measured in extremely preterm infants using a chemiluminescent immunometric assay, with a mean plasma level of approximately 400 nmol/L, similar to our findings.²⁰Heckmann et al reported a reference range of 73 to 562 nmol/L,²¹also consis- tent with serum cortisol concentrations reported in another cohort of very preterm infants, for whom the values de- pended on perinatal events and postnatal illness.¹⁶ Aucott et al reported median cortisol values ranging from 359 to 441 nmol/L in extremely preterm infants between 12 and 48 hours of life.²² Among infants born before 28 weeks of gestation, we did not find any influence of gestational age at birth. The lower cortisol values associated with gestational age reported in other studies does not appear to be related to cortisol binding globulin secretion²³but rather differences in the incidence of chorioamnionitis as a primary cause of preterm delivery, maturation of the hypothalamic- pituitary-adrenal axis,²⁴or physiological immaturity of enzy- matic systems.²⁵

We found that many factors influence neonatal cortisol levels, including sex, multiple gestation, perinatal infection, epidural analgesia, delivery mode, and antenatal steroid exposure. Such complex crosstalk between cortisol release and the perinatal environment make cortisol a marker of illness during the first postnatal days. Indeed, high cortisol values, in response to perinatal stressors, were found to be associated with systemic inflammation, a risk factor for both the developing brain and lungs. Conversely, low cortisol levels are known to be associated with refractory hypotension, patent ductus arteriosus, and BPD in extremely preterm infants.^26-29 Our data also further support the hypothesis previously proposed by Watterberg et al concerning the role of cortisol levels at birth in the risk of developing BPD.⁷ Indeed, although cortisol levels appeared to be significantly higher for infants surviving without BPD and those not exposed to hydrocortisone, this difference was no longer observed when they received hydrocortisone supplementation.

Conversely, our data provide evidence that excessive cortisol levels may play a role in the occurrence of specific adverse events, including severe IVH and spontaneous intestinal perforation. Moreover, higher cortisol values were significantly associated with these 2 adverse events only in infants exposed to hydrocortisone. Ng et al also reported an association between cortisol levels at birth and IVH in a serial assessment of cortisol levels during the first 3 weeks of life in very preterm infants.¹⁶ Another study showed that high cortisol levels during the first 48 hours of postnatal life are associated with an increased incidence of severe IVH and periventricular leukomala- cia.²² Although this association has not always been observed in very preterm infants,¹⁹ it makes clinical sense because cortisol levels closely correlate with early onset- sepsis and clinical chorioamnionitis, 2 risk factors of IVH. Concerning spontaneous intestinal perforation, our findings are of interest because this adverse event has been reported for infants treated with hydrocortisone, especially when associated with indomethacin.¹² In contrast, high cortisol levels were not predictive of spontaneous intestinal perforation for infants enrolled in the PROPHET trial²²but most cases of spontaneous intestinal perforation were related to an association of hydrocortisone and indomethacin in this study.³⁰ Maternal age, maternal hypertension, fetal growth restriction, twin gestation, neonatal ventilation, use of steroids and indomethacin, infections, and enteric smooth muscle deficiency have been identified as putative risk factors of spontaneous intestinal perforation.^31,32Although these risk factors have not been observed in all studies,³³we provide further evidence to support the potential use of baseline cortisol levels as a predictive marker of spontaneous intestinal perforation. Thus, high cortisol concentrations at baseline, poten- tially predicted through perinatal events, could be used possibly to identify the infants at highest risk for adverse outcomes induced by hydrocortisone. However, we did not find cortisol levels to be predictive of late-onset sepsis soon after birth.

The main strength of this secondary analysis was the large size of the sample, consisting of the highest number of extremely preterm infants ever assessed by centralized cortisol measurement, limiting the analytic bias. However, the study also had several limitations. The main limitation was the relatively large proportion (38%) of infants initially enrolled but not tested for the level of cortisol. However, the baseline characteristics of populations with and without cortisol sampling were found to be similar. The lack of pre- cise timing of antenatal steroid exposure and variability of the timing of blood collection for baseline cortisol measurement may have reduced the precision of the nomograms.

However, most infants (93%) were exposed to a full course of antenatal steroids before delivery and most blood samples were taken at birth. This exploratory study was also under- powered for the detection of true differences in rare clinical outcomes. Finally, all sampling was not performed at birth but always within 24 hours, a limitation that may account

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for the high variability of cortisol values and reduce the ability of the study to reveal associations with outcomes.

In conclusion, we did not find a predictive value of baseline cortisol for BPD-free survival in infants treated with hydrocortisone born extremely preterm. However, we found high cortisol levels early after birth to be associated with a greater risk of severe IVH and spontaneous intestinal perforation in infants treated with hydrocortisone and, therefore, a lower benefit/risk ratio for the treatment. Hydrocortisone treatment failure to improve BPD-free survival may be related to life- threatening adverse events when the baseline cortisol level is high, making supplementation more harmful than beneficial. However, further analysis to identify other baseline factors shortly after birth could improve our ability to identify the preterm infants who are most likely to benefit from hydrocortisone treatment.

n

Submitted for publication Aug 4, 2020; last revision received Nov 18, 2020;

accepted Dec 17, 2020.

Reprint requests: Olivier Baud, PhD, Division of Neonatology, Department of Pediatrics, University Hospitals, Bd de Cluse 30, Geneva, Switzerland. E-mail:

olivier.baud@hcuge.ch

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119-26.

28. Huysman MWA, Hokken-Koelega ACS, De Ridder MAJ, Sauer PJJ. Ad- renal function in sick very preterm infants. Pediatr Res 2000;48:629-33.

29. Watterberg KL, Gerdes JS, Cook KL. Impaired glucocorticoid synthesis in premature infants developing chronic lung disease. Pediatr Res 2001;50:190-5.

30. Watterberg KL, Gerdes JS, Cole CH, Aucott SW, Thilo EH, Mammel MC, et al. Prophylaxis of early adrenal insufficiency to prevent bronchopulmonary dysplasia: a multicenter trial. Pediatrics 2004;114:

1649-57.

31. Holland AJ, Shun A, Martin HC, Cooke-Yarborough C, Holland J. Small bowel perforation in the premature neonate: congenital or acquired? Pe- diatr Surg Int 2003;19:489-94.

32. Attridge JT, Clark R, Walker MW, Gordon PV. New insights into spontaneous intestinal perforation using a national data set: (2) two populations of patients with perforations. J Perinatol 2006;26:185-8.

33. Shah J, Singhal N, da Silva O, Rouvinez-Bouali N, Seshia M, Lee SK, et al.

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Figure 1. Flow chart of the study.

We thank the collaborators of the PREMILOC Study Group: Valerie Biran, Caroline Farnoux, Sophie Soudee, and Laure Maury (CHU Robert Debre, Paris); Michele Granier and Florence Lebail (CH Corbeil-Essonnes); Duksha Ramful and Sylvain Samperiz (CHR Saint-Denis, La Reunion); Alain Beuchee and Karine Guimard (CHU Rennes, France); Fatima El Moussawi, Pascal Boileau, and Florence Castela (CHI Poissy); Claire Nicaise and Renaud Vialet (CHU H^opital Nord, Marseille); Pierre Andrini and Thierry Debillon (CHU Grenoble); Veronique Zupan-Simunek and Hasinir- ina Razafimahefa (CHU Antoine Beclere, Paris); Anne

Appendix

Coursol and Saı¨d Merbouche (CH Pontoise); Pascal Bolot and Jean-Marc Kana (CH Saint-Denis); Julie Guichoux and Olivier Brissaud (CHU Bordeaux); Gerard Thiriez and Oliv- ier Schulze (CHU Besançon); Mickael Pomedio and Patrice Morville (CHU Reims); Thierry Blanc and Stephane Marret (CHU Rouen); Bernard Guillois and Ceneric Alexandre, (CHU Caen); Stephane Le Bou€edec and Bertrand Leboucher (CHU Angers); Umberto Simeoni and Valerie Lacroze (CHU Conception, Marseille); Pierre Kuhn and Stephanie Litzler- Renaud (CHU Strasbourg); Elodie Zana-Taıëb and Pierre- Henri Jarreau (CHU Cochin-Broca-Hôtel Dieu, Paris);

Sylvain Renolleau and Virginie Meau-Petit (CHU Armand Trousseau, Paris); and Gilles Cambonie and Aline Rideau Batista-Novais (CHRU Montpellier).

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Figure 3. Normal distribution of z scores for cortisol measurements for male and female extremely preterm infants. Histograms of Z show normal distribution of the scores and quantile-quantile plots show the distribution of the data against the expected normal distribution.

Table I. Baseline characteristics of infants with and without cortisol measurement

Variables

Cortisol (n = 325)

No cortisol (n = 185)

Male 173 (53%) 104 (56%)

Multiple gestation 106 (33%) 61 (33%)

Tocolysis 230 (71%) 103 (56%)

Antenatal antibiotics 228 (70%) 121 (65%)

Antenatal steroids 303 (93%) 171 (93%)

Chorioamnionitis 157/292 (54%) 75/163 (46%)

Prolonged rupture of membranes (>24 h)

102 (31%) 57 (31%)

Gestational hypertension 29 (9%) 28 (15%)

Epidural analgesia 134/308 (44%) 85/179 (47%)

General anesthesia 38/310 (12%) 30/182 (16%)

Gestational age, median (IQR), wk 26.4 (25.7-27.1) 26.4 (25.7-27.1) Birthweight, median (IQR), g 860 (744-970) 865 (750-970)

Early onset sepsis 39 (12%) 15 (8%)

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Table III. Early serum cortisol concentrations and survival without BPD in infants treated by hydrocortisone or placebo

BPD-free survival

Baseline cortisol

Hydrocortisone (n = 155) Placebo (n = 170)

Male (n = 80) Female (n = 75) Total (n = 155) Male (n = 93) Female (n = 77) Total (n = 170)

Yes n = 45 n = 55 n = 100 n = 46 n = 40 n = 86

Mean (SD), nmol/L 541.0 (433.5) 696.9 (590.7) 626.8 (529.1) 541.9 (546.8) 716.1 (490.4) 622.9 (525.7)

Mean (SD), z-score 0.06 (0.86) 0.01 (1.05) 0.02 (0.96) 0.07 (1.15) 0.15 (0.81) 0.03 (1.01)

No n = 35 n = 20 n = 55 n = 47 n = 37 n = 84

Mean (SD), nmol/L 707.9 (642.3) 767.5 (709.8) 729.6 (661.7) 420.9 (389.4) 614.1 (527.9) 506.0 (462.8)

Mean (SD), z score 0.31 (1.05) 0.01 (1.25) 0.19 (1.12) 0.22 (0.90) 0.14 (1.00) 0.18 (0.94)

Cortisol z score difference

Mean [95% CI] 0.25 [ 0.17 to 0.67] 0.002 [ 0.57 to 0.58] 0.17 [ 0.17 to 0.51] 0.14 [ 0.57 to 0.28] 0.29 [ 0.70 to 0.12] 0.21 [ 0.51 to 0.08]

Pvalue .25 .99 .31 .51 .17 .16

Cortisol nmol/L difference

Mean [95% CI] 166.9 [ 73.02 to 406.8] 70.50 [ 254.2 to 395.2] 102.8 [ 89.37 to 294.9] 121.0 [ 316.2 to 74.24] 102.0 [ 333.2 to 129.2] 116.9 [ 267.0 to 33.18]

Pvalue .17 .67 .29 .22 .38 .13

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