[The ethics of fetal myelomeningocele surgery]. / Réflexions éthiques concernant la chirurgie fœtale de réparation des myéloméningocèles.

Fetal myelomeningocele surgery was introduced in France in 2014. Developments in prenatal diagnosis of neural tube defects have accompanied the development of prenatal diagnosis. This fetal surgery represents one of the three possible care paths for pregnant women faced with this prenatal diagnosis. The ethical issues of this fetal surgery are discussed and in particular regarding prenatal counselling and patient autonomy of choice.

New insights in cerebral findings associated with fetal myelomeningocele: a retrospective cohort study in a single tertiary centre.

OBJECTIVE: To investigate cerebral anomalies other than Chiari type 2 malformation in fetuses with myelomeningocele (MMC). DESIGN: A retrospective cohort study in a single tertiary centre. SETTING: A review of associated cerebral anomalies in cases with prenatal diagnosis of myelomeningocele. POPULATION: Seventy cases of fetal myelomeningocele. METHODS: Ultrasound and MRI images were blindly reviewed. Postnatal imaging and results of the postmortem results were also reviewed. The association between cerebral anomalies and the following ultrasound findings was measured: level of the defect, ventriculomegaly, microcephaly and fetal talipes. MAIN OUTCOME MEASURES: A microcephaly was observed in 32/70 cases (46%) and a ventriculomegaly was observed in 39/70 cases (56%). Other cerebral anomalies were diagnosed in 47/70 (67%). RESULTS: Other cerebral anomalies were represented by 42/70 cases with abnormal CC (60%), 8/70 cases with perinodular heterotopia (PNH; 11%), 2/70 cases with abnormal gyration (3%). MRI performed only in fetal surgery cases confirmed the ulltrasound findings in all cases and provided additional findings in two cases (PNH). Risk ratios of fetal cerebral anomalies associated with MMC did not reach significance for microcephaly, ventriculomegaly, talipes or the level of the defect There was an overall good correlation between pre- and postnatal findings with a Kappa value of 0.79 [95% CI 0.57-1] and 82% agreement. CONCLUSION: Fetal brain anomalies other than Chiari type 2 malformation are frequently observed in fetuses with myelomeningocele, predominantly represented by CC anomalies. Whether these associated cerebral anomalies have an impact on selecting cases eligible for fetal surgery needs further evaluation. TWEETABLE ABSTRACT: Fetal cerebral anomalies other than Chiari type 2 malformation, microcephaly, and ventriculomegaly may be associated with MMC in up to 67% of the cases.

Prevalence of COL4A1 and COL4A2 mutations in severe fetal multifocal hemorrhagic and/or ischemic cerebral lesions.

OBJECTIVE: To establish the prevalence of COL4A1 and COL4A2 gene mutations in fetuses presenting with a phenotype suggestive of cerebral injury. METHODS: This was a single-center retrospective analysis of all cases of fetal cerebral anomalies suggestive of COL4A1 or COL4A2 gene mutation over the period 2009-2018. Inclusion criteria were: (1) severe and/or multifocal hemorrhagic cerebral lesions; (2) multifocal ischemic-hemorrhagic cerebral lesions. These anomalies could be of different ages and associated with schizencephaly or porencephaly. Between fetuses with and those without a mutation, we compared gestational age at the time of diagnosis, parity and fetal gender. RESULTS: Among the 956 cases of cerebral anomaly diagnosed in our center during the 10-year study period, 18 fetuses were identified for inclusion. A pathogenic COL4A1 gene mutation was found in five of these cases, among which four were de-novo mutations. A variant of unknown significance was found in four fetuses: in the COL4A1 gene in one case and in the COL4A2 gene in three cases. No COL4A1 or COL4A2 mutation was found in the remaining nine fetuses. The median (interquartile range) gestational age at diagnosis was significantly lower in cases with a mutation (24 (22-26) weeks) than in cases without a mutation (32 (29.5-34.5) weeks) (P = 0.03). CONCLUSIONS: A phenotype suggestive of cerebral injury was found in 18 of the 956 (1.9%) cases in our population, in 28% of which there was an associated COL4A1 or COL4A2 mutation. COL4A1 and COL4A2 gene mutations should be sought systematically in cases of severe and/or multifocal hemorrhagic or ischemic-hemorrhagic cerebral lesions, with or without schizencephaly or porencephaly. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

[Feticide procedures in second and third trimesters terminations of pregnancy]. / Geste d'arrêt de vie fœtale : techniques pour les interruptions médicales de grossesse des deuxième et troisième trimestres.

Performing a feticide as part of termination of late pregnancy is recommended in many countries. Feticide avoids a live birth of a severely affected premature newborn and prevents fetal pain. There are limited data on feticide procedures since only a few countries in the world authorize late termination of pregnancy. The objective of this review was to assess the most appropriate feticide procedure based on published data during the last thirty years. Administration of an initial fetal analgesia followed by a lethal lidocaine injection through the umbilical cord, under ultrasound guidance, appears to be the most effective, safe and ethical way to perform feticide. According to the current knowledge regarding the risk of fetal pain and survival of extremely preterm infants, a feticide should be discussed as early as 20-22 weeks of gestation.

Interaction of Cutibacterium acnes with human bone marrow derived mesenchymal stem cells: a step toward understanding bone implant- associated infection development.

Crosstalk between mesenchymal stem cells (MSCs) and bacteria plays an important role in regulating the regenerative capacities of MSCs, fighting infections, modulating immune responses and maintaining tissue homeostasis. Commensal Cutibacterium acnes (C. acnes) bacterium becomes an opportunistic pathogen causing implant-associated infections. Herein, we examined MSCs/C. acnes interaction and analysed the subsequent bacteria and MSCs behaviours following infection. Human bone marrow derived MSCs were infected by two clinical and one laboratory C. acnes strains. Following 3h of interaction, all bacterial strains were able to invade MSCs. Viable intracellular bacteria acquired virulence factors by increasing biofilm formation and/or by affecting macrophage phagocytosis. Although the direct and indirect (through neutrophil stimulation) antibacterial effects of the MSCs secretome were not enhanced following C. acnes infection, ELISA analysis revealed that C. acnes clinical strains are able to license MSCs to become immunosuppressive cell-like by increasing the secretion of IL-6, IL-8, PGE-2, VEGF, TGF-ß and HGF. Overall, these results showed a direct impact of C. acnes on bone marrow derived MSCs, providing new insights into the development of C. acnes during implant-associated infections. STATEMENT OF SIGNIFICANCE: The originality of this work relies on the study of relationship between human bone marrow derived mesenchymal stem cells (MSCs) phenotype and C. acnes clinical strains virulence following cell infection. Our major results showed that C. acnes are able to invade MSCs, inducing a transition of commensal to an opportunistic pathogen behaviour. Although the direct and indirect antibacterial effects were not enhanced following C. acnes infection, secretome analysis revealed that C. acnes clinical strains were able to license MSCs to become immunosuppressive and anti-fibrotic cell-like. These results showed a direct impact of C. acnes on bone marrow derived MSCs, providing new insights into the development of C. acnes during associated implant infections.

[Prenatal diagnosis and postnatal outcome of isolated intra-abdominal calcifications: A 10-year experience from a referral fetal medicine center]. / Diagnostic prénatal et issue néonatale des calcifications intra-abdominales isolées : étude rétrospective sur 10 ans.

INTRODUCTION: Intra-abdominal calcifications (iAC) detected during fetal ultrasound examinations are characterized by their isolated or associated nature, as well as their location. Our objective was to describe all cases of isolated iAC along with their etiological investigations and neonatal outcome, during a 10-year practice in a referral center. METHODS: We conducted a retrospective descriptive monocentric study on neonates diagnosed with isolated iAC after antenatal expert ultrasound scan and referred to the Multidisciplinary Center for Prenatal Diagnosis at Trousseau Hospital and born between January 1st, 2008 and June 30th, 2018. The exclusion criteria were: retroperitoneal calcifications, iAC associated with other digestive abnormalities or with congenital malformations. RESULTS: The 32 isolated iAC cases accounted for 46% of all iAC. Nine cases were excluded for missing neonatal data. Among the 23 remaining isolated iAC cases, we observed 15 intra-hepatic calcifications, 5 peri-hepatic and two peritoneal calcifications. One fetus had both intra- and peri-hepatic calcifications. The majority of iAC remained stable throughout pregnancy. No cases of aneuploidy, fetal infection, or cystic fibrosis were detected. The neonatal outcome was favorable in all cases. CONCLUSIONS: In case of isolated and stable iAC after expert ultrasound scan, after having ruled out infectious diseases of the fetus and looked for the most frequent mutations of cystic fibrosis in the parents, the prognosis is favorable. Fetal karyotyping is recommended when additional structural anomalies are present.

Impact of clinical and/or histological chorioamnionitis on neurodevelopmental outcomes in preterm infants: A literature review.

OBJECTIVE: To determine the impact of clinical and/or histological chorioamnionitis on neurodevelopmental outcomes in premature infants. METHODS: A review of the literature appeared in PubMed between 1997 and 2016 was conducted to examine the association between clinical and/or histological chorioamnionitis and neurologic impairment in the neonates (intraventricular hemorrhage, periventricular leukomalacia and white matter damage) and in infants (cerebral palsy and neurodevelopmental delay). RESULTS: The first meta-analysis published in 2000 observed that clinical chorioamnionitis was associated with cystic periventricular leukomalacia and cerebral palsy and that histologic chorioamnionitis was associated with periventricular leukomalacia only. A second meta-analysis in 2010 found that cerebral palsy was associated with both clinical and histological chorioamnionitis. But most recent studies over the last decade based on large cohorts found no effect of chorioamnionitis on neurological outcomes, even if they had several methodological limitations. CONCLUSION: According to the findings of the most recent studies, clinical or histological chorioamnionitis does not seem to be associated with neonatal white matter injuries, or with cerebral palsy. Further studies are needed to assess the impact of chorioamnionitis on long-term neurological development.

[Intrauterine blood transfusion: Status report of 4years of practice in France (2011-2014)]. / Transfusions fœtales érythrocytaires : état des lieux sur 4 ans en France (2011­2014).

OBJECTIVES: The aim of our study was to evaluate in utero blood transfusion's (IUT) performed in France, among the French prenatal diagnosis centers in order to study the etiology of severe anemia requiring IUT. METHODS: We conducted a national retrospective descriptive study between 2011 and 2014. The data were collected using a survey sent by email to all French prenatal diagnosis centers. RESULTS: Among the 49 centers, 18 (38 %) had performed at least one IUT during the study period. The geographical repartition of these centers was appropriate for the "Aquitaine Pyrénées" region. Five centers performed 68 % of the national activity and one center performed 40 % the national activity. Each year, a mean of 204 IUTs were performed in 113 pregnancies. The principal etiology of severe fetal anemia requiring IUT was hemolytic disease of the fetus (69 % of the etiologies) with anti-RhD being the most prevalent antibody. The second etiology was represented by parvovirus B19 infection (17 % of IUTs). CONCLUSION: The French IUT activity was stable in numbers and indications during the study period. A national register could be set up in order to better evaluate prospectively the number of pregnancies concerned by IUT and to study the prevalence of hemolytic disease of the fetus due to anti-RhD antibodies.

[Prevention of spontaneous preterm birth (excluding preterm premature rupture of membranes): Guidelines for clinical practice - Text of the Guidelines (short text)]. / Recommandations pour la pratique clinique : prévention de la prématurité spontanée et de ses conséquences (hors rupture des membranes) ­ Texte des recommandations (texte court).

OBJECTIVES: To determine the measures to prevent spontaneous preterm birth (excluding preterm premature rupture of membranes)and its consequences. MATERIALS AND METHODS: The PubMed database, the Cochrane Library and the recommendations from the French and foreign obstetrical societies or colleges have been consulted. RESULTS: In France, premature birth concerns 60,000 neonates every year (7.4 %), half of them are delivered after spontaneous onset of labor. Among preventable risk factors of spontaneous prematurity, only cessation of smoking is associated to a decrease of prematurity (level of evidence [LE] 1). This is therefore recommended (grade A). Routine screening and treatment of vaginal bacteriosis in general population is not recommended (grade A). Asymptomatic women with single pregnancy without history of preterm delivery and a short cervix between 16 and 24 weeks is the only population in which vaginal progesterone is recommended (grade B). A history-indicated cerclage is not recommended in case of only past history of conisation (grade C), uterine malformation (Professional consensus), isolated history of pretem delivery (grade B) or twin pregnancies in primary (grade B) or secondary (grade C) prevention of preterm birth. A history-indicated cerclage is recommended for single pregnancy with a history of at least 3 late miscarriages or preterm deliveries (grade A).). In case of past history of a single pregnancy delivery before 34 weeks gestation (WG), ultrasound cervical length screening is recommended between 16 and 22 WG in order to propose a cerclage in case of length<25mm before 24 WG (grade C). Cervical pessary is not recommended for the prevention of preterm birth in a general population of asymptomatic women with a twin pregnancy (grade A) and in populations of asymptomatic women with a short cervix (Professional consensus). Although the implementation of a universal transvaginal cervical length screening at 18-24 weeks of gestation in women with a singleton gestation and no history of preterm birth can be considered by individual practitioners, this screening cannot be universally recommended. In case of preterm labor, (i) it is not possible to recommend one of the methods over another (ultrasound of the cervical length, vaginal examination, fetal fibronectin) to predict preterm birth (grade B); (ii) routine antibiotic therapy is not recommended (grade A); (iii) prolonged hospitalization (grade B) and bed rest (grade C) is not recommended. Compared with placebo, tocolytics are not associated with a reduction in neonatal mortality or morbidity (LE2) and maternal severe adverse effects may occur with all tocolytics (LE4). Atosiban and nifedipine (grade B), contrary to betamimetics (grade C), can be used for tocolysis in spontaneous preterm labour without preterm premature rupture of membranes. Maintenance tocolysis is not recomended (grade B). Antenatal corticosteroid administration is recommended to every woman at risk of preterm delivery before 34 weeks of gestation (grade A). After 34 weeks, evidences are not consistent enough to recommend systematic antenatal corticosteroid treatment (grade B), however, a course might be indicated in the clinical situations associated with the higher risk of severe respiratory distress syndrome, mainly in case of planned cesarean delivery (grade C). Repeated courses of antenatal corticosteroids are not recommended (grade A). Rescue courses are not recommended (Professional consensus). Magnesium sulfate administration is recommended to women at high risk of imminent preterm birth before 32WG (grade A). Cesarean is not recommended in case of vertex presentation (Professional consensus). Both planned vaginal or elective cesarean delivery is possible in case of breech presentation (Professional consensus). A delayed cord clamping may be considered if the neonatal or maternal state so permits (Professional consensus). CONCLUSION: Except for antenatal corticosteroid and magnesium sulfate administration, diagnostic tools or prenatal pharmacological treatments implemented since 30 years to prevent preterm birth and its consequences have not matched expectations of caregivers and families.

[Lifestyle recommendations for prevention of spontaneous preterm birth in asymptomatic pregnant women]. / Mode de vie et règles hygiénodiététiques pour la prévention de la prématurité spontanée chez la femme enceinte asymptomatique.

OBJECTIVES: To establish recommendations for lifestyle of pregnant women and its impact on spontaneous preterm births. MATERIAL AND METHODS: We searched Pubmed and Cochrane databases and checked reference lists of retrieved studies. This review of the literature concerns only women who have no symptoms for the ongoing pregnancy. RESULTS: Concerning maternal occupation during pregnancy, there is a mild increase of the risk of preterm birth only for women who work more than 40hours a week or who have hard working conditions according to a fatigue score (LE2). With a weekly working time of 35hours, it is not recommended to prescribe routinely a sick leave to pregnant women in order to prevent preterm birth (grade B). Practicing exercise during pregnancy does not increase the risk of preterm birth before 37 weeks (LE2) and is recommended for women with normal pregnancy (grade A). Sexual intercourses during pregnancy do not increase the risk of prematurity (LE2), even for women with a history of preterm birth (LE3). A dietary pattern including vegetables, fruits and whole grain cereals during pregnancy might be associated with a lower risk of spontaneous preterm birth (LE3), while vitamin D and omega-3 supplementation has no effect on the gestational age of delivery (LE1). A dietary pattern including fruits, vegetables and whole grain cereals is thus recommended (grade C). Smoking is associated with spontaneous preterm birth (NP2). Smoking cessation interventions can result in 6 % smoking withdrawal in late pregnancy and 14 % reduction of preterm birth, while nicotine replacement therapies taken alone, such as nicotine-based patches, has no effect on both outcomes. Smoking cessation is also recommended in pregnant women, whatever the gestational age (grade A). Psychological disorders such as depression, anxiety and maternal stress are significantly associated with preterm birth (LE1). Among asymptomatic patients with a short cervix, bed rest is not associated with a reduction of preterm birth (LE3), and is also not systematically recommended (grade C). For multiple pregnancies without any symptoms, systematic hospitalization with bed rest is not recommended (grade A), especially since bed rest is associated with more thromboembolic events (LE3). CONCLUSION: Among preventable risk factors of spontaneous prematurity, cessation of smoking has been demonstrated to be effective on the decrease of preterm birth. A dietary pattern including vegetables, fruits and whole grain cereals might be also associated with a reduction of spontaneous prematurity.

[Maintenance tocolysis with calcium channel blockers]. / Tocolyse d'entretien par les inhibiteurs calciques.

AIM OF THE STUDY: The objective of initial tocolysis is to prolong pregnancy for 48 hours, in order to allow fetal lung maturation with corticosteroids. Maintenance tocolysis is defined by the prolongation of tocolytic therapy beyond 48 h. Although the 2002 guidelines of the French College did not recommend to prolong tocolysis beyond 48 h, about 60% of obstetricians prescribe maintenance tocolysis. METHOD: Nifedipine is the most frequently used treatment for maintenance tocolysis. Five randomised studies and two metaanalyses have compared maintenance tocolysis with nifedipine, with placebo or no treatment. RESULTS-CONCLUSION: Maintenance tocolysis with calcium channel blockers does not reduce the risk of preterm birth and does not improve perinatal outcome. Tocolytic treatment after 48 hours of initial tocolysis has no beneficial effect (level of evidence 1).

Determination of optimal timing of serial in-utero transfusions in red-cell alloimmunization.

OBJECTIVES: To assess the performance of middle cerebral artery peak systolic velocity (MCA-PSV) and of the expected daily decrease in fetal hemoglobin in determining the timing of serial in-utero transfusions (IUT) in red-cell alloimmunization. METHODS: This was a retrospective study of a continuous series of suspected anemic fetuses undergoing IUT between June 2003 and December 2012. Doppler measurement of MCA-PSV and pre- and post-transfusion hemoglobin levels were recorded at the time of the first, second and third IUT. Receiver-operating characteristics (ROC) curves and negative and positive predictive values of MCA-PSV in the prediction of severe fetal anemia were calculated. The daily decrease of fetal hemoglobin (Hb) between IUTs was calculated. Regression analysis was used to assess the correlation between pretransfusion fetal hemoglobin and MCA-PSV, and between observed and expected (by projection of daily decreases) pretransfusion fetal hemoglobin levels. RESULTS: One hundred and eleven fetuses required an IUT, of which 96 and 67 received a second and third IUT, respectively. The area under the ROC curve for MCA-PSV in the prediction of severe fetal anemia was not different for each rank of transfusion. The positive predictive value of MCA-PSV decreased from 75.3% at the first IUT, to 46.7% and 48.8% at the second and third IUTs, respectively, while the negative predictive value for a 1.5-MoM threshold remained high (88.9% at the second and 91.7% at the third IUT). The mean daily decrease in hemoglobin following each transfusion was 0.45, 0.35 and 0.32 g/dL, respectively. There was a persistent linear correlation between fetal hemoglobin and MCA-PSV and between observed and expected fetal hemoglobin levels. CONCLUSIONS: Both MCA-PSV and projection of daily decrease in hemoglobin are reliable means of diagnosing fetal anemia following previous IUTs. The high negative predictive value of MCA-PSV could allow subsequent IUTs to be postponed in selected cases.

[Severe neonatal acidosis: comparison and analysis of obstetrical practices in two French perinatal centers]. / Comparaison des taux d'acidose néonatale sévère et analyse des pratiques obstétricales dans deux maternités françaises.

OBJECTIVES: To identify and compare risk factors for severe neonatal acidosis, defined by an umbilical artery pH inferior to 7.00, and clinical practices in two different perinatal centers. PATIENTS AND METHODS: In a retrospective study, from 2003 to 2008, in two university perinatal centers (Poitiers and Saint-Antoine in Paris) on all term pregnancies complicated by severe neonatal acidosis (umbilical artery pH<7.00), we elected to compare the following risk factors: maternal characteristics, medical and obstetrical histories, progress of pregnancy, labour and delivery as well as the neonatal status. RESULTS: Among 23,508 births, 177 term newborns had severe neonatal acidosis. The rate was similar for both perinatal centers of Poitiers and Saint-Antoine (0.92% and 0.77% respectively). Factors associated with severe neonatal acidosis were similar in both centers: maternal age, thick meconium, prior cesarean section. There were differences in obstetrical practices between the two centers: there were more caesarean sections and assisted vaginal deliveries in Paris and more inductions of labour in Poitiers. CONCLUSION: Severe neonatal acidosis is associated with the geographical origin, the progress of labour and the mode of delivery. It seems that severe neonatal acidosis is unrelated to cesarean delivery.