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Objective: To determine the prevalence, short-term prognosis and pharmacologic management of pulmonary hypertension (PH) among very preterm infants born before 32 weeks gestation (WG)., Study Design: In the EPIPAGE-2 French national prospective population-based cohort of preterm infants born in 2011, those presenting with PH were identified and prevalence was estimated using multiple imputation. The primary outcome was survival without severe morbidity at discharge and was compared between infants with or without PH after adjusting for confounders, using generalized estimating equations models. Subgroup analysis was performed according to gestational age (GA) groups., Results: Among 3383 eligible infants, 3222 were analyzed. The prevalence of PH was 6.0 % (95 % CI, 5.2-6.9), 14.5 % in infants born at 22-27 +6  WG vs 2.7 % in infants born at 28-31 +6  WG (P < .001). The primary outcome (survival without severe morbidity at discharge) occurred in 30.2 % of infants with PH vs 80.2 % of infants without PH (P < .001). Adjusted incidence rate ratios for survival without severe morbidity among infants with PH were 0.42 (0.32-0.57) and 0.52 (0.39-0.69) in infants born at 22-27 +6  weeks gestation and those born at 28-31 +6  weeks, respectively. Among infants with PH, 92.2 % (95 % CI, 87.7-95.2) received sedation and/or analgesia, 63.5 % (95 % CI, 56.6-69.9) received inhaled NO and 57.6 % (95 % CI, 50.9-64.0) received hemodynamic treatments., Conclusion: In this population-based cohort of very preterm infants, the prevalence of PH was 6 %. PH was associated with a significant decrease of survival without severe morbidity in this population., Competing Interests: Declaration of competing interest None of the authors have any conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Extra-uterine growth restriction (EUGR) is common among very preterm (VPT) infants and has been associated with impaired neurodevelopment. Some research suggests that adverse effects of EUGR may be more severe in boys. We investigated EUGR and neurodevelopment at 2 years of corrected age (CA) by sex in a VPT birth cohort., Methods: Data come from a population-based cohort of children born <32 weeks' gestation from 11 European countries and followed up at 2 years CA. Postnatal growth during the neonatal hospitalization was measured with: (1) birthweight and discharge-weight Z-score differences using Fenton charts (2) weight-gain velocity using Patel's model. Published cut-offs were used to define EUGR as none, moderate or severe. Neurodevelopmental impairment was assessed using a parent-report questionnaire, with standardized questions/instruments on motor function, vision, hearing and non-verbal cognition. We estimated relative risks (RR) adjusting for maternal and neonatal characteristics overall and by sex., Results: Among 4197 infants, the prevalence of moderate to severe impairment at 2 years CA was 17.7%. Severe EUGR was associated with neurodevelopmental impairment in the overall sample and the interaction with sex was significant. For boys, adjusted RR were 1.57 (95% Confidence Intervals (CI): 1.18-2.09) for Fenton's delta Z-score and 1.50 (95% CI: 1.12-2.01) for Patel's weight-gain velocity, while for girls they were 0.97 (0.76-1.22) and 1.12 (0.90-1.40) respectively., Conclusion: EUGR was associated with poor neurodevelopment at 2 years among VPT boys but not girls. Understanding why boys are more susceptible to the effects of poor growth is needed to develop appropriate healthcare strategies., Competing Interests: Conflicts of interest The authors have no conflicts of interest to disclose., (Copyright © 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Introduction: After discussion with the parents, periviable infants can receive either active treatment or palliative care. The rate of active treatment in France is lower than in other developed countries, as is the survival rate of infants in this gestational age range. This study's main objective was to assess the effect of a standardized perinatal management protocol (EXPRIM) on the neonatal outcome of children born before 27 weeks of gestation., Methods: A before-and-after study was conducted in the two level-3 hospitals of the Risks and Pregnancy DHU to compare two 16-month periods. The EXPRIM protocol was based on routine administration of prenatal corticosteroid therapy and a scheduled combined obstetric-pediatric group prenatal prognostic evaluation, not based solely on gestational age. The study included all births between 22 weeks and 26 weeks+6 days of gestation, except in utero deaths diagnosed at admission and medical terminations of pregnancy for fetal malformation, both excluded. The principal endpoint was survival without severe neonatal morbidity., Results: The study included 267 women: 116 (128 newborns) in period 1 and 151 (172 newborns) in period 2. The median gestational age at admission to the maternity unit was 2.5 days younger in period 2, and the number of women admitted at 22-23 weeks doubled in period 2 (59 vs 29, respectively). Overall, the rates of live births, NICU transfer, and survival without severe morbidity were similar during the two periods. More infants were liveborn between 22 and 24 weeks in period 2 (66 vs 43). Of all newborns transferred to the NICU, 26 (29%) survived without severe morbidity in period 1 and 46 (39%) in period 2. After multivariate analysis, survival without severe morbidity did not differ significantly., Conclusion: Implementation of the EXPRIM protocol led to active treatment of more mothers and their children at the border of viability, and increased the number of children who survived without severe morbidity even if, overall, there was no statistically significant difference in percentage., (Copyright © 2021. Published by Elsevier Masson SAS.)

Objectives: Angiogenic factors may be involved in lung development. To evaluate the relations between maternal and cord blood angiogenic factors (sFlt-1, placental growth factor [PlGF], soluble endogline [sEng], transforming growth factor β [TGF-beta]) and their association with moderate and severe bronchopulmonary dysplasia (BPD) in very preterm growth-restricted infants., Study Design: Prospective monocentric cohort study. Twenty-four mother-child dyads featuring antepartum preeclampsia, intra-uterine growth restriction (IUGR) and birth before 30 weeks' gestation were included. This ensured a 80% power to test whether sFlt-1 maternal levels would be twice as high in cases of BPD as in the absence of BPD., Main Outcome Measures: Four pro/anti-angiogenic factors from two pathways (sFlt-1, PlGF and sEng, TGF-beta) were measured in maternal serum before delivery (at the time of hospitalization or the day of birth) and in neonates' cord blood. Neonatal outcome was moderate to severe BPD, defined as oxygen requirement for at least 28 days and persistent need for oxygen or ventilatory support at 36 weeks' postmenstrual age., Results: sFlt-1 levels were positively correlated in maternal serum and cord blood (r s  = 0.83, p < .001) but levels of PlGF and TGF-beta and its receptor sEng were not. Among all the factors studied in cord and maternal blood, none was associated with BPD., Conclusions: In IUGR preterm babies born before 30 weeks' gestation from preeclamptic mothers, serum sFlt-1, PlGF and sEng, TGF-β levels were not correlated with BPD. The increased BPD risk in preterm neonates born from preeclamptic mothers cannot be related to high sFlt-1 levels., (Copyright © 2019 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Background: Fetal growth restriction is defined using ultrasound parameters during pregnancy or as a low birthweight for gestational age after birth, but these definitions are not always concordant., Objective: The purpose of this study was to investigate fetal and neonatal outcomes based on antenatal vs postnatal assessments of growth restriction., Study Design: From the EPIPAGE 2 population-based prospective study of very preterm births in France in 2011, we included 2919 singleton nonanomalous infants 24-31 weeks gestational age. We constituted 4 groups based on whether the infant was suspected with fetal growth restriction during pregnancy and/or was small for gestational age with a birthweight <10th percentile of intrauterine norms by sex: 1) suspected with fetal growth restriction/small for gestational age 2) not suspected with fetal growth restriction/small for gestational age 3) suspected with fetal growth restriction/not small for gestational age and 4) not suspected with fetal growth restriction/not small for gestational age. We estimated relative risks of perinatal mortality and morbidity for these groups adjusting for maternal and neonatal characteristics., Results: We found that 22.2% of infants were suspected with fetal growth restriction/small for gestational age, that 11.4% infants were not suspected with fetal growth restriction/small for gestational age, that 3.0% infants were suspected with fetal growth restriction/not small for gestational age, and that 63.4% infants were not suspected with fetal growth restriction/not small for gestational age. Compared with infants who were not suspected with fetal growth restriction/not small-for-gestational-age infants, small-for-gestational-age infants suspected and not suspected with fetal growth restriction had higher risks of stillbirth or termination of pregnancy (adjusted relative risk, 2.0 [95% confidence interval, 1.6-2.5] and adjusted relative risk, 2.8 [95% confidence interval, 2.2-3.4], respectively), in-hospital death (adjusted relative risk, 2.8 [95% confidence interval, 2.0-3.7] and adjusted relative risk, 2.0 [95% confidence interval, 1.5-2.8], respectively), and bronchopulmonary dysplasia (adjusted relative risk, 1.3 [95% confidence interval, 1.2-1.4] and adjusted relative risk, 1.3 [95% confidence interval, 1.1-1.4], respectively), but not severe brain lesions. Risks were not increased for infants suspected with fetal growth restriction but not small-for-gestational-age., Conclusion: Antenatal and postnatal assessments of fetal growth restriction were not concordant for 14% of very preterm infants. In these cases, birthweight appears to be the more relevant parameter for the identification of infants with higher risks of adverse short-term outcomes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Humans share adaptative capacities to stress with other species, as demonstrated on amphibians: the physiological response to experimental water volume and food deprivation results in the activation of the endocrine axes that drive metamorphosis, in particular the neuroendocrine stress system. Unfavorable effects may, however, occur, probably due to inappropriate timing and/or duration of stress: recent experiments are converging to show a profound impairment of hippocampal functioning in the offspring of mothers exposed to prenatal stress. Moreover, fetal changes are likely one of the risk factors for a number of diseases in adulthood.

This review is an attempt to provide an integrative view for the biological changes triggered by fetal stress through a multidisciplinary approach. Acceleration of brain and lung maturation in certain risk pregnancies was first described clinically and confirmed by biochemical, electrophysiological and experimental data. Moreover, new experimental findings suggest that a fetal clock centrally mediated by fetal nutritional status could determine timing of parturition. However, some skepticism persisted about the usefulness of this body of knowledge for obstetrical management in developed countries. The interest concerning this adaptation to intrauterine stress was later renewed from various sources, as developed in Part II.