Behavioral changes in preterm children during nasogastric tube feeding. Comparative study of manual administration by parents versus mechanical administration via electric syringe pump.

INTRODUCTION: Manual feeding by parents using a syringe, a widespread practice in Sweden since the 1980s, favors parents' involvement in childcare tasks. This approach is used in our neonatal unity since 2007. OBJECTIVE: To study the behavioral changes of preterm children during nasogastric tube feeding: manual milk administration by parents (MAP) versus electric syringe administration (ESA) over a 30-minute period. METHOD: This is a randomized, crossover study conducted in the neonatology unit of Toulouse. Preterm children under 33 weeks of age and over 7 days of life were included. A video recording was performed to assess the children's behavioral response, using the Dsilna score. The reviewer was blinded. RESULTS: 15 preterm children with a median gestational age of 30.1 weeks and a median birth weight of 1.210 g were included from March to October 2012. The facility, environment, and state of alertness of children were similar in both groups. Signs of well-being were significantly more prevalent in the MAP group versus the ESA group (36.2 (±8.0) versus 30.7 (±9.5)), (p = 0.04), particularly "hand-to-mouth, mouth gestures, seeking suction and sucking". Although not significant, motor withdrawal signs were more apparent and fluctuating in the ESA group. Qualitative analysis of NIDCAP observations confirms this data. CONCLUSION: There are behavior changes of preterm children during nasogastric tube feeding. This pilot study showed previously undescribed results: MAP is associated with more common well-being signs and could be more widely used in neonatal units.

Unusual fetal ascites and spontaneous bladder rupture in a female fetus: a case report.

BACKGROUND: Fetal bladder rupture causing urinary ascites is uncommon. It is generally related to invasive fetal medicine procedures or obstructive disorders such as in posterior urethral valves in male fetuses. An exceptional case of spontaneous bladder rupture in a female fetus occurred in a pregnant woman treated with high doses of opiates in an intensive care unit. This unusual obstetric situation leads to discussion of the possible causes of fetal bladder rupture, its management, and the pediatric prognosis. CASE PRESENTATION: We report the case of a 30-year-old nulliparous black woman with a history of mesenteric cystic lymphangioma and multiple bowel resections leading to chronic malabsorption. During her pregnancy, our patient presented with an occlusive syndrome and major bilateral renal dilation. Urinary derivation resulted in iatrogenic bilateral ureteral perforation. Our patient thus presented with major uroperitoneum, bilateral pleural effusion and acute renal failure, treated by thoracic drainage and bilateral nephrostomy. Postoperative pain required treatment with level III analgesics. In this context, 5 days after morphine treatment introduction an enlarged fetal bladder was observed, followed 3 days later by voluminous fetal ascites. The diagnosis of spontaneous bladder rupture was suspected. After multidisciplinary discussion, expectant management was decided. At 31 weeks and 4 days gestation, our patient went into spontaneous labor with a subsequent vaginal delivery. The infant required resuscitation and paracentesis of ascites at birth. Her neonatal course was favorable with a simple urethral bladder drainage. Cystography at day 9 was normal. At 2 years of follow-up, the mother and the child have a normal course. CONCLUSIONS: An iatrogenic origin of megacystis in a female fetus must be evoked in the event of maternal administration of high doses of opiates in the second part of her pregnancy. In our case, the megacystis was followed by spontaneous bladder rupture at 30 weeks of gestation, with a favorable maternal fetal issue.

French neonatal society position paper stresses the importance of an early family-centred approach to discharging preterm infants from hospital.

AIM: The families of hospitalised preterm infants risk depression and post-traumatic stress and the preterm infants risk re-hospitalisation. The French neonatal society's aim was to review the literature on how the transition from hospital to home could limit these risks and to produce a position paper. METHODS: A systematic literature review was performed covering 1 January 2000 to 1 January 2018, and multidisciplinary experts examined the scientific evidence. RESULTS: We identified 939 English and French papers and 169 are quoted in the position paper. Most studies stressed the importance of early, personalised and progressive involvement of the family. Healthcare staff and families should assess discharge preparations jointly. This evaluation should assess the capacities of the newborn infant, with regard to its physiological maturity. It should also assess the family's ability to supply the medical, psychological and social assistance required before and after discharge. There should be a structured follow-up process that includes effective communication, various tools, interventions, networks, health and social professionals. CONCLUSION: Discharge preparations may improve the transition from hospital to home and the outcomes for the parents and newborn preterm infant. This early family-centred approach should be structured, coordinated and based on individual needs and circumstances.

Recommendations on the environment for hospitalised newborn infants from the French neonatal society: rationale, methods and first recommendation on neonatal intensive care unit design.

AIM: Hospitalised newborn infants may be stressed due to inappropriate sensory stimuli and early separation from their families, that can negatively impact their neurodevelopment. The French Group of Reflection and Evaluation of the Environment of Newborns (GREEN) issues guidelines based on environmental neonatology and family-centred care. The first recommendation focuses on private family rooms versus large shared rooms. METHODS: These guidelines are based on a systematic evaluation of the literature providing different grades of evidence. Internal and external reviews by multidisciplinary experts examined the scientific evidence of all recommendations. The literature search was performed for the period January 1, 2000 to January 1, 2016 with the keywords 'single room' or 'private room' and 'neonatal intensive care unit'. RESULTS: A total of 25 studies were retained. Most studies reported a positive impact of private rooms on the health of newborn infants and satisfaction of families. Private rooms could lead to sensory deprivation if there is low parental involvement with limited presence and to reduced interaction among caregivers. CONCLUSION: We recommend that neonatal units should mostly have private rooms. With this architectural design, we recommend supporting the staff's needs for changes in the organisation and philosophy of care and to provide improved family support.

Mortality, morbidity and 2-years neurodevelopmental prognosis of twin to twin transfusion syndrome after fetoscopic laser therapy: a prospective, 58 patients cohort study.

OBJECTIVE: To describe the morbidity and mortality and long-term neurodevelopmental outcomes in children born from a Twin-to-Twin Transfusion Syndrome (TTTS) pregnancy treated using laser fetoscopy in Toulouse. POPULATION AND METHOD: All pregnancies with TTTS treated by laser fetoscopy in our centre were included. Antenatal and postnatal morbidity and neonatal morbidity were identified in the medical records retrospectively. The neurodevelopmental outcome was studied using Ages and Stages Questionnaires (ASQ) sent to the parents, an oral interview with the parents and with the child's doctor (last objective neurological examination, rehabilitation needs, learning disabilities). RESULTS: Seventy-one pregnancies, or 144 foetuses, were included from 2008 to 2014, overall survival at 2 years was 72.9% and the survival of at least one child at 2 years was 91.5%, severe neonatal morbidity was 11.2% of the children, severe brain damage accounted for 3.6% of children admitted to the hospital unit. It was possible to study the neurodevelopmental outcome for 58 children (55.3%), with a corrected age from 24 to 95 months. Five children (8.6%) had severe neurological abnormalities and 17 (29.3%) had moderate neurological abnormalities. DISCUSSION: The mortality, neonatal morbidity and long-term neurological morbidity of our cohort are higher than those of premature infants (EPIPAGE-2 French cohort), which confirms the severity of this syndrome, and are comparable to those of the TTTS cohorts described in the literature.

Early diagnosis and care is achieved but should be improved in infants with Prader-Willi syndrome.

BACKGROUND: PWS is a severe neurodevelopmental genetic disorder now usually diagnosed in the neonatal period from hypotonia and feeding difficulties. Our study analyzed the birth incidence and care of infants with early diagnosis. METHODS: Data were collected on 61 infants with a molecular diagnosis of PWS born in 2012 and 2013 in France. RESULTS: Thirty-eight infants with PWS were born in 2013. The median age at diagnosis was 18 days. Birth incidence calculated for 2013 was 1/21,000 births. No case was diagnosed prenatally, despite 9 amniocenteses, including 4 for polyhydramnios. Five infants had delayed diagnosis, after 3 months of life. For 2 of them, the diagnosis was not suspected at birth and for 3, FISH analysis in the neonatal period was normal, with no further molecular studies. Ninety-three percent of the neonates were hospitalized, and 84% needed nasogastric tube feeding for a median of 38 days. Swallowing assessment was performed for 45%, at a median age of 10 days. Physiotherapy was started for 76% during hospitalization. Eighty percent of those diagnosed within the first 3 months were seen by a pediatric endocrinologist within the first week of life. CONCLUSION: Our study is the first to assess the birth incidence of PWS in France, at 1/21,000 births. Some prenatal or neonatal cases remain undiagnosed because of unrecognized clinical signs and the inappropriate choice of the initial molecular test. We also underscore the need to optimize neonatal care of infants with PWS.

High prevalence of cytomegalovirus infection in surgical intestinal specimens from infants with necrotizing enterocolitis and spontaneous intestinal perforation: A retrospective observational study.

BACKGROUND: Necrotizing enterocolitis (NEC) is a severe, often fatal gastrointestinal emergency that predominantly affects preterm infants, and there is evidence that neonatal cytomegalovirus (CMV) infection may in some cases contribute to its pathogenesis. OBJECTIVES: This study aimed to evaluate the prevalence of CMV in infants with NEC. STUDY DESIGN: Seventy intestinal specimens from 61 infants with NEC, spontaneous intestinal perforation (SIP), or related surgical complications were collected at Karolinska University Hospital and Uppsala University Hospital, Sweden. Ten specimens from autopsied infants without bowel disease served as controls. Samples were analyzed for CMV immediate-early antigen (IEA), CMV late antigen (LA), 5-lipoxigenase (5LO) and CMV-DNA by immunohistochemistry (IHC) and in situ hybridization (ISH), respectively. In 10 index samples, CMV DNA was analyzed with Taqman PCR after laser capture microdissection (LCM) of cells positive for CMV IEA by IHC. RESULTS: CMV IEA was detected by IHC in 57 (81%) and CMV LA in 45 (64%) of 70 intestinal specimens from index cases; 2 (20%) of 10 control specimens were positive for both antigens. 5LO was detected in intestinal tissue section obtained from all examined index and controls. CMV DNA was detected in 4 of 10 samples (40%) after LCM. By ISH, all 13 IHC-IEA-positive samples were positive for CMV DNA; however, 3 of 5 IHC-IEA-negative samples (60%) were also positive. CONCLUSIONS: CMV-specific antigens and CMV DNA were highly prevalent in intestinal specimens from infants with NEC, SIP, and related surgical complications. Our findings provide further evidence that neonatal CMV infection contributes to the pathogenesis of these diseases and may affect patient outcome.

Policy of feeding very preterm infants with their mother's own fresh expressed milk was associated with a reduced risk of bronchopulmonary dysplasia.

AIM: Since 2005, the French Food Safety Agency has recommended that very preterm or low-birthweight babies should be fed with pasteurised, expressed breastmilk, and feeding policies on this vary widely in French neonatal units. We investigated the differences between using a mother's expressed milk, in fresh or pasteurised forms, for very preterm infants. METHODS: This observational multicentre study analysed data on 926 very preterm infants: 636 from neonatal units who used the mother's own fresh milk and 290 who used the mother's milk after pasteurisation. We analysed necrotising enterocolitis, bronchopulmonary dysplasia, in-hospital mortality, late-onset sepsis, weight gain, length of hospital stay, the duration of parenteral nutrition and the duration of enteral feeding with a nasogastric tube. Multivariate analyses were conducted to assess the impact of maternal milk policies. RESULTS: After adjustment, there was a reduced risk of bronchopulmonary dysplasia in the fresh milk group with an odds ratio of 0.40 and 95% confidence interval of 0.27-0.67 (p < 0.001). No other statistically significant differences were observed. CONCLUSION: Feeding very preterm infants with their mother's expressed fresh milk was associated with a reduced risk of bronchopulmonary dysplasia, and further investigations are needed to evaluate the clinical impact of this practice.

Recombinant Bile Salt-Stimulated Lipase in Preterm Infant Feeding: A Randomized Phase 3 Study.

INTRODUCTION: Feeding strategies are critical for healthy growth in preterm infants. Bile salt-stimulated lipase (BSSL), present in human milk, is important for fat digestion and absorption but is inactivated during pasteurization and absent in formula. This study evaluated if recombinant human BSSL (rhBSSL) improves growth in preterm infants when added to formula or pasteurized breast milk. PATIENTS AND METHODS: LAIF (Lipase Added to Infant Feeding) was a randomized, double-blind, placebo-controlled phase 3 study in infants born before 32 weeks of gestation. The primary efficacy variable was growth velocity (g/kg/day) during 4 weeks intervention. Follow-up visits were at 3 and 12 months. The study was performed at 54 centers in 10 European countries. RESULTS: In total 415 patients were randomized (rhBSSL n = 207, placebo n = 208), 410 patients were analyzed (rhBSSL n = 206, placebo n = 204) and 365 patients were followed until 12 months. Overall, there was no significantly improved growth velocity during rhBSSL treatment compared to placebo (16.77 vs. 16.56 g/kg/day, estimated difference 0.21 g/kg/day, 95% CI [-0.40; 0.83]), nor were secondary endpoints met. However, in a predefined subgroup, small for gestational age infants, there was a significant effect on growth in favor of rhBSSL during treatment. The incidence of adverse events was higher in the rhBSSL group during treatment. CONCLUSIONS: Although this study did not meet its primary endpoint, except in a subgroup of infants small for gestational age, and there was an imbalance in short-term safety, these data provide insights in nutrition, growth and development in preterm infants. TRIAL REGISTRATION: ClinicalTrials.gov NCT01413581.

PPARγ Is Activated during Congenital Cytomegalovirus Infection and Inhibits Neuronogenesis from Human Neural Stem Cells.

Congenital infection by human cytomegalovirus (HCMV) is a leading cause of permanent sequelae of the central nervous system, including sensorineural deafness, cerebral palsies or devastating neurodevelopmental abnormalities (0.1% of all births). To gain insight on the impact of HCMV on neuronal development, we used both neural stem cells from human embryonic stem cells (NSC) and brain sections from infected fetuses and investigated the outcomes of infection on Peroxisome Proliferator-Activated Receptor gamma (PPARγ), a transcription factor critical in the developing brain. We observed that HCMV infection dramatically impaired the rate of neuronogenesis and strongly increased PPARγ levels and activity. Consistent with these findings, levels of 9-hydroxyoctadecadienoic acid (9-HODE), a known PPARγ agonist, were significantly increased in infected NSCs. Likewise, exposure of uninfected NSCs to 9-HODE recapitulated the effect of infection on PPARγ activity. It also increased the rate of cells expressing the IE antigen in HCMV-infected NSCs. Further, we demonstrated that (1) pharmacological activation of ectopically expressed PPARγ was sufficient to induce impaired neuronogenesis of uninfected NSCs, (2) treatment of uninfected NSCs with 9-HODE impaired NSC differentiation and (3) treatment of HCMV-infected NSCs with the PPARγ inhibitor T0070907 restored a normal rate of differentiation. The role of PPARγ in the disease phenotype was strongly supported by the immunodetection of nuclear PPARγ in brain germinative zones of congenitally infected fetuses (N = 20), but not in control samples. Altogether, our findings reveal a key role for PPARγ in neurogenesis and in the pathophysiology of HCMV congenital infection. They also pave the way to the identification of PPARγ gene targets in the infected brain.

Cytomegalovirus Infection Triggers the Secretion of the PPARγ Agonists 15-Hydroxyeicosatetraenoic Acid (15-HETE) and 13-Hydroxyoctadecadienoic Acid (13-HODE) in Human Cytotrophoblasts and Placental Cultures.

INTRODUCTION: Congenital infection by human cytomegalovirus (HCMV) is a leading cause of congenital abnormalities of the central nervous system. Placenta infection by HCMV allows for viral spread to fetus and may result in intrauterine growth restriction, preeclampsia-like symptoms, or miscarriages. We previously reported that HCMV activates peroxisome proliferator-activated receptor gamma (PPARγ) for its own replication in cytotrophoblasts. Here, we investigated the molecular bases of PPARγ activation in infected cytotrophoblasts. RESULTS: We show that onboarded cPLA2 carried by HCMV particles is required for effective PPARγ activation in infected HIPEC cytotrophoblasts, and for the resulting inhibition of cell migration. Natural PPARγ agonists are generated by PLA2 driven oxidization of linoleic and arachidonic acids. Therefore, using HPLC coupled with mass spectrometry, we disclosed that cellular and secreted levels of 13-hydroxyoctadecadienoic acid (13-HODE) and 15-hydroxyeicosatetraenoic acid (15-HETE) were significantly increased in and from HIPEC cytotrophoblasts at soon as 6 hours post infection. 13-HODE treatment of uninfected HIPEC recapitulated the effect of infection (PPARγ activation, migration impairment). We found that infection of histocultures of normal, first-term, human placental explants resulted in significantly increased levels of secreted 15-HETE and 13-HODE. CONCLUSION: Our findings reveal that 15-HETE and 13-HODE could be new pathogenic effectors of HCMV congenital infection They provide a new insight about the pathogenesis of congenital infection by HCMV.

Cytomegalovirus infection and neonatal outcome in extremely preterm infants after freezing of maternal milk.

BACKGROUND: Cytomegalovirus (CMV) infection acquired from breast milk can cause serious illness in extremely preterm (EPT) infants (<28 weeks). Some neonatal centers freeze maternal milk (MM) to prevent CMV transmission; however, this practice is controversial. In this study, we assessed the CMV transmission rate and neonatal outcome in EPT infants after routine freezing of all MM. METHODS: EPT infants (n = 140) and their mothers were randomized to the intervention group (only freeze-thawed MM) or the control group (combined fresh and freeze-thawed MM). Freeze-thawed MM was frozen at -20°C for ≥3 days before thawing. Mothers had serological tests for CMV, and MM was analyzed for CMV by polymerase chain reaction and CMV culture. Infants underwent CMV screening with urine analysis by CMV-polymerase chain reaction and CMV culture until 12 weeks of age. RESULTS: Congenital CMV infection was detected in 2% of screened infants. The CMV transmission rate in infants fed with CMV-DNA positive milk was 8% (3 of 37) in the intervention group and 6% (2 of 33) in controls. All infants infected by CMV were asymptomatic. The final per-protocol analysis included 56 infants in the intervention group and 65 controls. Neonatal mortality was comparable between the groups (7% vs. 6%). Neonatal morbidity was similar, except for late onset Candida sepsis, which was more frequent in the controls (12% vs. 0%). CONCLUSIONS: Routine freezing of all MM did not affect the rate of CMV transmission but may help to prevent fungal sepsis in EPT infants. This observation merits further investigation.

rhBSSL improves growth and LCPUFA absorption in preterm infants fed formula or pasteurized breast milk.

OBJECTIVES: Preterm infants often experience suboptimal growth, which can affect organ development. The aim of this study was to improve growth by treatment with bile salt-stimulated lipase (BSSL), naturally present in breast milk, but lost after pasteurization, and absent in formula. METHODS: Two clinical trials were performed with a predefined analysis of combined data to investigate the effects of recombinant human BSSL (rhBSSL) treatment on growth velocity and fat absorption in preterm infants. The studies were randomized and double-blinded comparing 7-day treatment with rhBSSL and placebo, administered in pasteurized breast milk or formula, using a crossover design. RESULTS: Sixty-three infants were evaluated for safety. At randomization, the mean (standard deviation) weight was 1467 (193) g and mean postmenstrual age was 32.6 (0.5) weeks. Sixty and 46 infants were evaluated for growth velocity and fat absorption, respectively. rhBSSL treatment significantly improved mean growth velocity by 2.93 g · kg · day (P<0.001) compared with placebo (mean 16.86 vs 13.93 g · kg · day) and significantly decreased the risk of suboptimal growth (<15 g · kg · day) (30% vs 52%, P=0.004). rhBSSL significantly increased absorption of the long-chain polyunsaturated fatty acids, docosahexaenoic acid, and arachidonic acid by 5.76% (P=0.013) and 8.55% (P=0.001), respectively, but had no significant effect on total fat absorption. The adverse-event profile was similar to placebo. CONCLUSIONS: In preterm infants fed pasteurized breast milk or formula, 1 week of treatment with rhBSSL was well tolerated and significantly improved growth and long-chain polyunsaturated fatty acid absorption compared to placebo. This publication presents the first data regarding the use of rhBSSL in preterms and the results have led to further clinical studies.

R5 human immunodeficiency virus type 1 with efficient DC-SIGN use is not selected for early after birth in vertically infected children.

The binding of human immunodeficiency virus (HIV) to C-type lectin receptors may result in either enhanced trans-infection of T-cells or virus degradation. We have investigated the efficacy of HIV-1 utilization of DC-SIGN, a C-type lectin receptor, in the setting of intrauterine or intrapartum mother-to-child transmission (MTCT). Viruses isolated from HIV-1-infected mothers at delivery and from their vertically infected children both shortly after birth and later during the progression of the disease were analysed for their use of DC-SIGN, binding and ability to trans-infect. DC-SIGN use of a child's earlier virus isolate tended to be reduced as compared with that of the corresponding maternal isolate. Furthermore, the children's later isolate displayed enhanced DC-SIGN utilization compared with that of the corresponding earlier virus. These results were also supported in head-to-head competition assays and suggest that HIV-1 variants displaying efficient DC-SIGN use are not selected for during intrauterine or intrapartum MTCT. However, viruses with increased DC-SIGN use may evolve later in paediatric HIV-1 infections.

Urinary aquaporin-2 excretion during ibuprofen or indomethacin treatment in preterm infants with patent ductus arteriosus.

AIM: Water channel AQP2 is the target for vasopressin (AVP) and a major determinant of urinary concentrating capacity. In mature kidneys, prostaglandins counteract the effect of AVP on AQP2 expression at functional sites. We investigated whether disturbances in water homeostasis in infants with patent ductus arteriosus (PDA) treated with prostaglandin inhibitors can be attributed to activation of AQP2. METHODS: In 53 infants with symptomatic PDA (gestational age 24-33 weeks), 30 receiving ibuprofen and 23 indomethacin starting at 2-15 days of life, clinical and biochemical data were collected before treatment and after each dose of the drugs. Urinary AQP2 was determined by dot immunoblotting. RESULTS: Urinary AQP2 level and osmolality were decreased in both groups. Urinary osmolality was overall low and correlated inversely with fluid uptake. In ibuprofen group, there was no correlation of AQP2 level with urinary osmolality. CONCLUSION: There was no AQP2 upregulation in the infants. The low urinary osmolality and dissociation between urinary osmolality and urinary AQP2 level indicate that the fluid retention sometimes observed in PDA infants treated with prostaglandin inhibitors is not caused by increased levels of functional AQP2. Thus, knowledge about the renal physiology of the adult cannot always be transferred to the infant kidney.

Myocardial Infarction in a newborn from a diabetic mother.

We extracted L., the newborn of a diabetic mother, for antenatal diagnostic of myocardial hypertrophy and anomaly of foetal heart rate. Post-natal echocardiography showed severe septal myocardial hypertrophy with latero-basal myocardial akinesia. We did not observe a Doppler gradient through the left ventricular outflow. Selective coronary angiography showed an occlusion of the circumflex artery. Myocardial hypertrophy is a classic complication in newborns of diabetic mothers. The mother's diabetes and neonatal infarction remain an exceptional association. We discuss a different hypothesis to explain coronary occlusion and how myocardial infarction avoided septal obstruction.

Expression of water and ion transporters in tracheal aspirates from neonates with respiratory distress.

AIM: The aim of the study was to determine whether neonatal respiratory distress is related to changes in water and ion transporter expression in lung epithelium. METHODS: The study included 32 neonates on mechanical ventilation: 6 patients with normal lung X-rays (control group), eight with respiratory distress syndrome (RDS), eight with transient tachypnea of the newborn (TTN), 10 with abnormal lung X-rays (mixed group). The protein abundance of water channel AQP5, epithelial sodium channel (ENaC; alpha-, beta- and gamma-ENaC) and Na(+), K(+)-ATPase alpha1 were examined in tracheal aspirates using semiquantitative immunoblotting. RESULTS: beta-ENaC level was significantly lower in RDS group compared with infants with TTN and infants in the control group. AQP5 expression was significantly higher in TTN compared with the infants with RDS and all other infants with abnormal lung X-rays. CONCLUSION: Neonatal respiratory distress is associated with changes in beta-ENaC and AQP5 expression. The lower beta-ENaC expression may be one of the factors that predispose to the development of RDS. The higher AQP5 expression may provide the possibility for reabsorption of postnatal lung liquid, which contributes to quick recovery of infants with TTN.

Behavioral problems and cognitive performance at 5 years of age after very preterm birth: the EPIPAGE Study.

OBJECTIVES: We compared the frequency of behavioral problems in very preterm and term children at 5 years of age. We hypothesized that behavioral problems would be associated with cognitive impairment and environmental factors and that differences between the 2 groups would be reduced but persist after adjusting for cognitive performance and environmental factors. PATIENTS AND METHODS: The Etude Epidémiologique sur les Petits Ages Gestationnels (EPIPAGE) study was a prospective population-based cohort study that included all births occurring between 22 and 32 weeks' gestation and a control group of infants born at 39 to 40 weeks' gestation in 1997 in 9 French regions. Neonatal and obstetrics data were collected at birth. At 5 years of age, sociodemographic status and neurodevelopmental and cognitive development of the children, as well as maternal mental well-being, were assessed. The behavioral problems of 1102 very preterm and 375 term singletons without major impairments were studied by using the parent-completed Strengths and Difficulties Questionnaire. RESULTS: Parents of very preterm children reported significantly more behavioral problems, with a twofold higher prevalence compared with term children for hyperactivity/inattention, emotional symptoms, and peer problems. Behavioral problems were associated with low cognitive performance, developmental delay, hospitalizations of the child, young maternal age, and poor maternal mental well-being. Very preterm children were still at higher risk of behavioral problems compared with term children after adjustment for cognitive performance and all others factors. CONCLUSIONS: Behavioral problems were strongly related to cognitive impairment, but very preterm children were still at higher risk even after adjusting for cognitive performance. Early screening for behavioral problems should be encouraged for all very preterm children, and maternal well-being should also be the focus of special attention.