Analysis of MRI brain biometrics in fetuses monitored for intra uterine growth restriction and their prognostic value: Results of a prospective multicenter study.

OBJECTIVE: Show a prognostic value of brain changes in fetuses with intra uterine growth restriction (IUGR) on early neonatal outcome. STUDY DESIGN: We prospectively recruited pregnant women whose fetuses presented fetal weight < 5th centile. A brain MRI was performed between 28 and 32 weeks of gestation (WG). Several brain biometrics were measured (as fronto-occipital diameter (FOD) and transverse cerebellar diameter (TCD)). Neonatal prognosis was evaluated according to a composite criterion. RESULTS: Of the 78 patients included, 62 had a fetal brain MRI. The mean centile value of FOD was lower in the unfavorable outcome group (n = 9) compared to the favorable outcome group (n = 53) (24.5 ± 16.8 vs. 8.6 ± 13.2, p = 0.004). The ROC curve for predicting risk of unfavorable neonatal outcome based on FOD presented an area under the curve of 0.81 (95 % CI, [0.63---0.99]) and a threshold determined at the 3rd centile was associated with sensitivity of 0.78 and a specificity of 0.89. In multivariate analysis, a FOD less than the 3rd centile was significantly associated with an unfavorable neonatal risk. There also was a reduction in TCD (25.5 ± 21.5 vs. 10.4 ± 10.4, p = 0.03) in the unfavorable neonatal outcome group. CONCLUSION: We found an association between a reduction in FOD and TCD in fetal MRIs conducted between 28 and 32 WG in fetuses monitored for IUGR with an unfavorable neonatal outcome. Our results suggest that these biometric changes could constitute markers of poor neonatal prognosis.

Impact of discontinuing oxytocin in active labour on neonatal morbidity: an open-label, multicentre, randomised trial.

BACKGROUND: Oxytocin is effective in reducing labour duration but can be associated with fetal and maternal complications that could potentially be reduced by discontinuing the treatment during labour. We aimed to assess the impact of discontinuing oxytocin during active labour on neonatal morbidity. METHODS: STOPOXY was a multicentre, randomised, open-label, controlled, superiority trial conducted in 21 maternity units in France. Participants who received oxytocin before 4 cm dilation were randomly assigned 1:1 to either discontinuous oxytocin (oxytocin infusion stopped beyond a cervical dilation equal to or greater than 6 cm) or continuous oxytocin (administration of oxytocin continued until delivery). Randomisation was stratified by centre and parity. The primary outcome, neonatal morbidity, was assessed at birth using a composite variable defined by an umbilical arterial pH at birth less than 7·10, a base excess greater than 10 mmol/L, umbilical arterial lactates greater than 7 mmol/L, a 5-min Apgar score less than 7, or admission to the neonatal intensive care unit. Efficacy and safety was assessed in participants who were randomly assigned (excluding those who withdrew consent or were deemed ineligible after randomisation) and had reached a cervical dilation of at least 6 cm. This trial is registered with ClinicalTrials.gov, NCT03991091. FINDINGS: Of 2459 participants randomly assigned between Jan 13, 2020, and Jan 24, 2022, 2170 were eligible to receive the intervention and were included in the final modified intention-to-treat analysis. The primary outcome occurred for 102 (9·6%) of 1067 participants (95% CI 7·9 to 11·5) in the discontinuous oxytocin group and for 101 (9·2%) of 1103 participants (7·6 to 11·0) in the continuous oxytocin group; absolute difference 0·4% (95% CI -2·1 to 2·9); relative risk 1·0 (95% CI 0·8 to 1·4). There were no clinically significant differences in adverse events between the two groups of the safety population. INTERPRETATION: Among participants receiving oxytocin in early labour, discontinuing oxytocin when the active phase is reached does not clinically or statistically significantly reduce neonatal morbidity compared with continuous oxytocin. FUNDING: French Ministry of Health and the Département de la Recherche Clinique et du Développement de l'Assistance Publique-Hôpitaux de Paris.

Long-term neurological and neurodevelopmental outcome of neonatal listeriosis in France: a prospective, matched, observational cohort study.

BACKGROUND: Maternal-neonatal listeriosis is a rare and serious infection. The long-term outcome of surviving infants with early-onset or late-onset listeriosis remains unknown. We aimed to determine the long-term neurological and neurodevelopmental outcome of neonatal listeriosis. METHODS: In this prospective, matched, observational cohort study, we evaluated children born with microbiologically confirmed maternal-neonatal listeriosis in the French MONALISA cohort. At age 5 years, children underwent neurological and neurodevelopmental assessments of sensory deficits, executive function, adaptive behaviour, and cognitive and motor coordination function. The cognitive domain was assessed using the French version of the Wechsler Preschool and Primary Scale of Intelligence, fourth edition, and scored by Full Scale Intelligence Quotient (FSIQ). The motor domain was assessed by physical examination designed to screen for cerebral palsy and developmental coordination disorder. Executive functioning was assessed using the statue and inhibition subtests of Neuropsychological Assessment, second version. The sensory domain was assessed by parental interview, medical report, and clinical assessment. Adaptive behaviour was measured using the Vineland-II behaviour scale from parent-reported assessments of functional communication, socialisation, daily living, and motor skills. Results were compared with gestational age-matched children from two national prospective cohorts: EPIPAGE-2 (preterm infants) and ELFE (term infants from a general population of infants >32 weeks gestation). This study is registered with ClinicalTrials.gov (NCT02580812). FINDINGS: Of 59 children who were alive and eligible to participate in the study, 53 (median age 5 years, IQR 5-6) were enrolled for neurodevelopmental assessments between Oct 26, 2016, and Oct 29, 2019. Of 53 children, 31 (58%) had been born preterm, 22 (42%) had early-onset systemic infection, 18 (34%) had early-onset non-systemic infection, and six (11%) had late-onset systemic infection, all with meningitis. 29 (66%) of 44 children, in whom neurodevelopmental disabilities scores were available, developed at least one disability; eight (18%) children had severe neurodevelopmental disabilities. Of four children with late-onset infection and in whom neurodevelopmental disabilities scores were available, three developed at least one neurodevelopmental disability. Neurological and neurodevelopmental outcomes of children with neonatal listeriosis did not differ from those of gestational age-matched control children without infection (relative risk [RR] of at least one disability 0·99 [95% CI 0·65-1·51; p=0·97]; RR of FSIQ less than -1 SD 0·92 [0·54-1·54; p=0·74]). INTERPRETATION: These results highlight the burden of persistent disability and dominant contribution of prematurity to long-term outcomes in children born with neonatal listeriosis. The findings support the implementation of systematic long-term screening and provision of tailored education and special needs support. FUNDING: Institut Pasteur, Inserm, French Public Health Agency, Contrat de Recherche Clinique, and Assistance Publique-Hôpitaux de Paris.

Cervical Dilators Used Concurrently With Misoprostol to Shorten Labor in Second-Trimester Termination of Pregnancy: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the use of cervical dilators concurrently with misoprostol to shorten labor in second-trimester medical termination of pregnancy. METHODS: This multicenter randomized controlled trial compared the efficacy of cervical dilators inserted concurrently with misoprostol with that of misoprostol, alone, to shorten labor for women undergoing termination of pregnancy between 15 0/7 and 27 6/7 weeks of gestation. The primary outcome was the proportion of women with a duration of labor exceeding 12 hours. Secondary outcomes included median duration of labor, time to amniotomy, side effects, complications, NPRS (Numeric Pain Rating Scale) score, and women's distress as measured by the IES-R (Impact of Event Scale-Revised). These outcomes also were studied separately in the nulliparous subgroup. To demonstrate a reduction of 50% of the proportion of women with a duration of labor exceeding 12 hours in the dilator group, with a power of 80% and a 2-sided 0.05 significance level, a sample of 268 women (134 in each group) was required. RESULTS: Between December 2017 and September 2019, this study enrolled and analyzed 347 women: 174 in the dilator group and 173 in the control group, including 87 and 93 nulliparous patients, respectively. Sociodemographic and obstetric characteristics were similar between groups. The proportion of women with labor exceeding 12 hours was not different between groups (49/174 [28.2%] in the dilator group vs 53/173 [30.6%] in the control group [ P =.61] for the whole population, and 37/87 [42.5%] vs 42/93 [45.2%] [ P =.72], respectively, among nulliparous patients). Median duration of labor was 8.5 hours in the dilator group compared with 9.2 hours in the control group ( P =.65) for the whole population, and 10.5 hours compared with 11.8 hours, respectively, among nulliparous patients ( P =.33). Median time to amniotomy was 3.6 hours in the dilator group compared with 5.0 hours in the control group ( P =.08) for the whole population, and 3.5 hours compared with 6.7 hours, respectively, among nulliparous patients ( P =.003). Side effects, complications, NPRS score, and IES-R score were similar between groups. CONCLUSION: Cervical dilators inserted concurrently with misoprostol did not reduce the proportion of women whose labor exceeded 12 hours compared with misoprostol alone. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT03194230.

Association Between Endometriosis Phenotype and Preterm Birth in France.

Importance: Endometriosis is an inflammatory disease with a heterogeneous presentation that affects women of childbearing age. Given the limitations of previous retrospective studies, it is still unclear whether endometriosis has adverse implications for pregnancy outcomes. Objective: To evaluate the association between the presence of endometriosis and preterm birth and whether the risk varied according to the disease phenotype. Design, Setting, and Participants: This cohort study with exposed and unexposed groups was conducted in 7 maternity units in France from February 4, 2016, to June 28, 2018. Participants included women with singleton pregnancies who were followed up before 22 weeks' gestation along with their newborns delivered at or after 22 weeks' gestation. The final follow-up occurred in July 2019. Data were analyzed from October 7, 2020, to February 7, 2021. Exposures: Women in the endometriosis group had a documented history of endometriosis and were classified according to 3 endometriosis phenotypes: isolated superficial peritoneal endometriosis (SUP), ovarian endometrioma (OMA; potentially associated with SUP), and deep endometriosis (DE; potentially associated with SUP and OMA). Women in the control group did not have a history of clinical symptoms of endometriosis before their current pregnancy. Main Outcomes and Measures: The primary outcome was preterm birth between 22 weeks and 36 weeks 6 days of gestation. Association between endometriosis and the primary outcome was assessed through univariate and multivariate logistic regression analyses and was adjusted for the following risk factors associated with preterm birth: maternal age, body mass index (calculated as weight in kilograms divided by height in meters squared) before pregnancy, country of birth, parity, previous cesarean delivery, history of myomectomy and hysteroscopy, and preterm birth. The same analysis was performed according to the 3 endometriosis phenotypes (SUP, OMA, and DE). Results: Of the 1351 study participants (mean [SD] age, 32.9 [5.0] years) who had a singleton delivery after 22 weeks of gestation, 470 were assigned to the endometriosis group (48 had SUP [10.2%], 83 had OMA [17.7%], and 339 had DE [72.1%]) and 881 were assigned to the control group. No difference was observed in the rate of preterm deliveries before 37 weeks 0 days of gestation between the endometriosis and control groups (34 of 470 [7.2%] vs 53 of 881 [6.0%]; P = .38). After adjusting for confounding factors, endometriosis was not associated with preterm birth before 37 weeks' gestation (adjusted odds ratio, 1.07; 95% CI, 0.64-1.77). The results were comparable for the different disease phenotypes (SUP: 6.2% [3 of 48]; OMA: 7.2% [6 of 83]; and DE: 7.4% [25 of 339]; P = .84). Conclusions and Relevance: This cohort study found no association between endometriosis and preterm birth, and the disease phenotype did not appear to alter the result. Monitoring the pregnancy beyond the normal protocols or changing management strategies for women with endometriosis may not be warranted to prevent preterm birth.

Occurrence and severity of acute respiratory infections during the first year among very preterm infants: an Epipage-2 cohort analysis.

This study aims to describe the incidence of acute respiratory infections (ARI) during the first year in infants born before 32 weeks' gestation, and to analyze and study the risk factors as well as factors associated with oxygen requirement among infants with an ARI, in the palivizumab era. This study included 2571 infants from a nationwide French population-based cohort (Epipage 2). ARI at 1-year corrected age was identified by parental questionnaires. Risk and severity factors included those already known, and detailed information about neonatal morbidities. ARI occurred in 52.2% (n = 1349) of infants. Oxygen therapy was used in 33.2% (n = 391) of infants with an ARI. Risk factors for AII were male sex, bronchopulmonary dysplasia, presence of siblings at home, and childcare in the community together with incomplete treatment palivizumab. Mechanical ventilation in the neonatal period, bronchopulmonary dysplasia, and discharge between October and March were associated with more frequent oxygen requirement. No other factors describing neonatal morbidities were associated with risk of ARI or oxygen requirement.Conclusion: ARIs are still very common during the first year of life of very preterm children, and oxygen therapy is frequently needed. Educational strategies are needed in all families with a very preterm infant. What is Known: • Acute respiratory infections (ARIs) are the first cause of rehospitalizations in preterm children, with bronchopulmonary dysplasia being the main risk factor. • Palivizumab prophylaxis has proven its effect against severe RSV infections, but it is not universal. What is New: • No factor describing neonatal morbidity, except BPD, was associated with ARI occurrence or severity. • BPD and discharge during RSV season were the only factors associated with O2 requirement during ARI.

Full compliance with Respiratory syncytial virus prophylaxis was associated with fewer respiratory-related hospital admissions in preterm children: A cohort study.

AIM: Although well documented in randomised trials, the efficacy of prophylaxis against respiratory syncytial virus (RSV) in real-word conditions is less studied. The objective was to assess the impact of partial versus full RSV prophylaxis for acute respiratory infections (ARIs) and ARI-related hospital admissions in preterm children. METHODS: This study included children born preterm in 2011 in France who were eligible for RSV prophylaxis and received at least one palivizumab dose from October 2011 to March 2012. Full prophylaxis was defined as receiving at least one palivizumab dose for each month of RSV exposure in the community. Children with full and partial prophylaxis were matched, and odds of ARIs and ARI-related hospital admission were compared by logistic regression. RESULTS: Full prophylaxis concerned 861/1083 (80%) children. As compared with full prophylaxis, partial prophylaxis was not associated with ARI occurrence (odds ratio OR 1.3, 95% confidence interval CI 0.9-1.9) but was significantly associated with ARI-related hospital admission during the RSV epidemic (OR 1.9, 95% CI 1.2-2.9). CONCLUSION: During the 2011-2012 RSV epidemic, hospital admission rates were higher for preterm children with partial than full RSV prophylaxis. Improving compliance could help alleviate the burden of RSV on healthcare systems.

SARS-COV-2 IgG antibody response in pregnant women at delivery.

BACKGROUND: The prevalence of COVID-19 infection during pregnancy is not known. COVIPREG is a prospective French multicenter study to assess the seroprevalence at the time of delivery and the maternal and neonatal impact of COVID-19 infection during pregnancy. In order to study factors associated with poor outcomes after COVID-19 Infection during pregnancy and adapt the sample size of the study, a preliminary assessment of the prevalence of SARS-CoV-2 IgG was planned after 500 inclusions in a one perinatal center of Paris area. OBJECTIVES: To assess the prevalence of SARS-CoV-2 IgG antibody response in pregnant women at the time of delivery during the COVID-19 pandemia. STUDY DESIGN: A prospective observational study at Cochin hospital (Level III maternity). Patients admitted for delivery were offered to participate to the study. Each patient participating to the study was tested for anti-SARS-CoV-2-IgG antibodies using a commercially available ELISA. RESULTS: Among the 529 patients included in the COVIPREG study between April 29 and June 26, 529 were assessed for SARS-CoV-2 IgG antibody response and 25 had a positive test, ie 4.7 % with a confidence interval at 95 % [3.0 %-6.9 %]). CONCLUSIONS: Four months after the beginning of the infection in Paris, the seroprevalence of SARS-CoV-2 IgG in pregnant women at the time of delivery is low. Studies evaluating the impact of COVID-19 infection during pregnancy should take this information in account in order to adapt the sample size.

Premedication practices for tracheal intubation in neonates transported by French medical transport teams: a prospective observational study.

OBJECTIVES: Premedication practices for neonatal tracheal intubations have not yet been described for neonatal transport teams. Our objective is to describe the use of sedation/analgesia (SA) for tracheal intubations and to assess its tolerance in neonates transported by medical transport teams in France. SETTING: This prospective observational study was part of the EPIPPAIN 2 project and collected around-the-clock data on SA practices in neonates intubated by all five paediatric medical transport teams of the Paris region during a 2-month period. Intubations were classified as emergent, semiemergent and non-emergent. Sedation level and conditions of intubation were assessed with the Tonus, Reactivity, Awareness and Conditions of intubation to Help in Endotracheal intubation Assessment (TRACHEA score). The scores range from 0 to 10 representing an increasing ladder from adequate to inadequate sedation, and from excellent to very poor conditions of intubation. PARTICIPANTS: 40 neonates intubated in 28 different centres. RESULTS: The mean (SD) age was 34.9 (3.9) weeks, and 62.5% were intubated in the delivery room. 30/40 (75%) of intubations were performed with the use of SA. In 18/30 (60.0%) intubations performed with SA, the drug regimen was the association of sufentanil and midazolam. Atropine was given in 19/40 intubations. From the 16, 21 and 3 intubations classified as emergent, semiemergent and non-emergent, respectively, 8 (50%), 19 (90.5%) and 3 (100%) were performed with SA premedication. 79.3% of intubations performed with SA had TRACHEA scores of 3 or less. 22/40 (55%) infants had at least one of the following adverse events: muscle rigidity, bradycardia below 100/min, desaturation below 80% and nose or pharynx-larynx bleeding. 7/24 (29.2%) of those who had only one attempt presented at least one of these adverse events compared with 15/16 (93.8%) of those who needed two or more attempts (p<0.001). CONCLUSION: SA premedication is largely feasible for tracheal intubations performed in neonates transported by medical transport teams including intubations judged as emergent or semiemergent. TRIAL REGISTRATION NUMBER: NCT01346813; Results.

Educational and health outcomes associated with bronchopulmonary dysplasia in 15-year-olds born preterm.

INTRODUCTION: To evaluate the consequences of bronchopulmonary dysplasia (BPD) on academic outcomes and healthcare use in adolescents born very preterm. METHODS: This cohort study included 15-year-old adolescents born very preterm (< 32 weeks) between 2011 and 2013, with and without BPD, and controls born full term. Data regarding academic performance, current medical follow-up, and family characteristics were collected. Multivariate logistic regression was used to quantify relationships between academic outcomes and BPD. RESULTS: From the 1341 children included in the initial cohort, 985 adolescents were eligible and 351 included (55 preterms with a history of BPD, 249 without, and 47 controls). Among adolescents born very preterm, a history of BPD was associated with a higher risk to attend a school for children with special needs (p < 0.05) and to have repeated a grade (p = 0.01). It was also associated with an increased number of medical and paramedical consultations. A history of BPD was not associated with the parents' employment status, family structure, or the presence of younger siblings. CONCLUSION: This study highlights that a history of BPD is associated with poorer academic outcomes and high healthcare use in adolescence.

Association of Language Skills with Other Developmental Domains in Extremely, Very, and Moderately Preterm Children: EPIPAGE 2 Cohort Study.

OBJECTIVE: To analyze language skills in children born at 24-34 weeks of gestation at 2 years of corrected age and the association between language and other developmental domains. STUDY DESIGN: We included 2424 children (64% of the eligible population) from the French population-based EPIPAGE 2 cohort study. At 2 years' corrected age, children were screened with the French short version of the MacArthur-Bates Communication Developmental Inventories and the Ages and Stages Questionnaire completed by parents. RESULTS: Small lexicon size, <10th percentile of the calibration sample (ie, 28 words in a list of 100) was observed in 135 of 300 children (45%) born at 23-26 weeks, 484 of 1513 (32%) born at 27-31 weeks, and 165 of 611 (27%) born at 32-34 weeks of gestation. Small lexicon size was associated with 2 other language measures: word combination use and the Ages and Stages Questionnaire communication domain score. It was also significantly associated with the Ages and Stages Questionnaire score below the threshold in the other developmental domains (gross motor function, fine motor function, problem solving skills, and personal social skills) for all gestational age groups, after adjustment for potential confounders. Overall, 46% of children with a small lexicon size had ≥1 of these domains below the threshold, as compared with only 22% of children without a small lexicon size. CONCLUSIONS: These results highlight the usefulness of the MacArthur-Bates Communication Developmental Inventories in preterm children, especially those who do not participate in specialized follow-up. A small lexicon size points to developmental difficulties in language and increased risk for other developmental and neurobehavioral functions.

Association between asthma and lung function in adolescents born very preterm: results of the EPIPAGE cohort study.

Prematurity and bronchopulmonary dysplasia (BPD) affect long-term lung function. We studied the respiratory outcome of adolescents born very preterm and controls from the Etude EPIdémiologique sur les Petits Ages Gestationnels cohort and analysed their current lung function in relation to asthma symptoms (categorised in three age groups) from birth. In models including BPD, asthma at each age and confounding factors in the preterm group, BPD and preschool wheeze were the only independent variables associated with FEV1 Preschool wheeze is an independent factor associated with FEV1 impairment in adolescents born very preterm. These results highlight the need for optimal management of early respiratory symptoms in preterm-born infants. TRIAL REGISTRATION NUMBER: Results, NCT01424553.

Ages and Stages Questionnaire at 3 Years for Predicting IQ at 5-6 Years.

OBJECTIVES: To assess the predictive value of the 36-month Ages & Stages Questionnaire (ASQ) score for IQ score at age 5 to 6 years in the general population and to identify factors associated with IQ <85 once the ASQ score is taken into account. METHODS: Data were collected from 939 children enrolled in a population-based prospective cohort study. Developmental outcomes at 36 months were assessed via the ASQ and at 5 to 6 years via the Wechsler Preschool and Primary Scale of Intelligence. The ASQ threshold was identified via the receiver operating characteristic curve. Additional predictive factors to obtain an IQ <85 were investigated, and their interaction with ASQ score was studied. RESULTS: Sixty-nine children (7.3%) had an IQ <85. A 36-month ASQ score threshold of 270 was optimal to identify children with an IQ <85 at 5 to 6 years, with a 0.77 ± 0.11 sensitivity and 0.68 ± 0.03 specificity. Maternal educational level and occupational activity at the time of ASQ completion were associated with the risk of an IQ <85 at a given ASQ level. In the multivariate model, no interaction between the studied factors and ASQ score reached significance. CONCLUSIONS: In the general pediatric population, 36-month ASQ parental reports could be used to identify children at later risk of cognitive delay. Low maternal education level should also be considered as a major risk factor for lower IQ in preschool children regardless of ASQ score.

Assessment of continuous pain in newborns admitted to NICUs in 18 European countries.

AIM: Continuous pain occurs routinely, even after invasive procedures, or inflammation and surgery, but clinical practices associated with assessments of continuous pain remain unknown. METHODS: A prospective cohort study in 243 neonatal intensive care units (NICUs) from 18 European countries recorded the frequency of pain assessments, use of mechanical ventilation, sedation, analgesia or neuromuscular blockade for each neonate for up to 28 days after NICU admission. RESULTS: Only 2113 of 6648 (31.8%) of neonates received assessments of continuous pain, occurring variably among tracheal ventilation (TrV, 46.0%), noninvasive ventilation (NiV, 35.0%) and no ventilation (NoV, 20.1%) groups (p < 0.001). Daily assessments for continuous pain occurred in only 10.4% of all neonates (TrV: 14.0%, NiV: 10.7%, NoV: 7.6%; p < 0.001). More frequent assessments of continuous pain occurred in NICUs with pain guidelines, nursing champions and surgical admissions (all p < 0.01), and for newborns <32 weeks gestational age, those requiring ventilation, or opioids, sedatives-hypnotics, general anaesthetics (O-SH-GA) (all p < 0.001), or surgery (p = 0.028). Use of O-SH-GA drugs increased the odds for pain assessment in the TrV (OR:1.60, p < 0.001) and NiV groups (OR:1.40, p < 0.001). CONCLUSION: Assessments of continuous pain occurred in less than one-third of NICU admissions and daily in only 10% of neonates. NICU clinical practices should consider including routine assessments of continuous pain in newborns.