C-section and systemic inflammation synergize to disrupt the neonatal gut microbiota and brain development in a model of prematurity.

Infants born very preterm (below 28 weeks of gestation) are at high risk of developing neurodevelopmental disorders, such as intellectual deficiency, autism spectrum disorders, and attention deficit. Preterm birth often occurs in the context of perinatal systemic inflammation due to chorioamnionitis and postnatal sepsis. In addition, C-section is often performed for very preterm neonates to avoid hypoxia during a vaginal delivery. We have developed and characterized a mouse model based on intraperitoneal injections of IL-1ß between postnatal days one and five to reproduce perinatal systemic inflammation. This model replicates several neuropathological, brain imaging, and behavioral deficits observed in preterm infants. We hypothesized that C-sections could synergize with systemic inflammation to induce more severe brain abnormalities. We observed that C-sections significantly exacerbated the deleterious effects of IL-1ß on reduced gut microbial diversity, increased levels of circulating peptidoglycans, abnormal microglia/macrophage reactivity, impaired myelination, and reduced functional connectivity in the brain relative to vaginal delivery plus intraperitoneal saline. These data demonstrate the deleterious synergistic effects of C-section and neonatal systemic inflammation on brain maldevelopment and malfunction, two conditions frequently observed in very preterm infants, who are at high risk of developing neurodevelopmental disorders.

Preterm birth by cesarean section: the gut-brain axis, a key regulator of brain development.

Understanding the long-term functional implications of gut microbial communities during the perinatal period is a bourgeoning area of research. Numerous studies have revealed the existence of a "gut-brain axis" and the impact of an alteration of gut microbiota composition in brain diseases. Recent research has highlighted how gut microbiota could affect brain development and behavior. Many factors in early life such as the mode of delivery or preterm birth could lead to disturbance in the assembly and maturation of gut microbiota. Notably, global rates of cesarean sections (C-sections) have increased in recent decades and remain important when considering premature delivery. Both preterm birth and C-sections are associated with an increased risk of neurodevelopmental disorders such as autism spectrum disorders; with neuroinflammation a major risk factor. In this review, we explore links between preterm birth by C-sections, gut microbiota alteration, and neuroinflammation. We also highlight C-sections as a risk factor for developmental disorders due to alterations in the microbiome.

Prenatal diagnosis of congenital ventricular aneurysm and diverticulum: Prenatal features and perinatal management.

Congenital ventricular diverticulum (VD) and aneurysm are rare cardiac developmental anomalies and their pathophysiology is still unclear. They present as an anomaly of the four chambers view, cardiomegaly, arrhythmia, pericardial effusion, or hydrops. They are usually isolated anomalies. Differential diagnosis between diverticulum and aneurysm is challenging during the prenatal period. Management policy is not uniform either conservative or repeated pericardial puncture. OBJECTIVE: We wanted to describe prenatal features and post-natal outcomes of fetal cardiac out pouching. METHODS: We retrospectively report 6 cases of VD and aneurysm prenatally managed in our fetal medicine unit between 2010 and 2020. All cases were evaluated from the first or second trimester of pregnancy until postnatal follow-up (3 months to 3 years). RESULTS: All six cases underwent a monthly ultrasound follow-up with spontaneous regression of pericardial effusion, and normal hemodynamics at birth No pericardial puncture was done and postnatal outcome was favorable in all cases. CONCLUSION: Based on our experience and on cases previously published, prenatal counseling should be prudent regarding the final diagnosis. Referral and monthly prenatal ultrasound follow-up, birth in a tertiary center after multidisciplinary evaluation and cardiological evaluation at birth still seem mandatory.

The Impact of Mouse Preterm Birth Induction by RU-486 on Microglial Activation and Subsequent Hypomyelination.

Preterm birth (PTB) represents 15 million births every year worldwide and is frequently associated with maternal/fetal infections and inflammation, inducing neuroinflammation. This neuroinflammation is mediated by microglial cells, which are brain-resident macrophages that release cytotoxic molecules that block oligodendrocyte differentiation, leading to hypomyelination. Some preterm survivors can face lifetime motor and/or cognitive disabilities linked to periventricular white matter injuries (PWMIs). There is currently no recommendation concerning the mode of delivery in the case of PTB and its impact on brain development. Many animal models of induced-PTB based on LPS injections exist, but with a low survival rate. There is a lack of information regarding clinically used pharmacological substances to induce PTB and their consequences on brain development. Mifepristone (RU-486) is a drug used clinically to induce preterm labor. This study aims to elaborate and characterize a new model of induced-PTB and PWMIs by the gestational injection of RU-486 and the perinatal injection of pups with IL-1beta. A RU-486 single subcutaneous (s.c.) injection at embryonic day (E)18.5 induced PTB at E19.5 in pregnant OF1 mice. All pups were born alive and were adopted directly after birth. IL-1beta was injected intraperitoneally from postnatal day (P)1 to P5. Animals exposed to both RU-486 and IL-1beta demonstrated microglial reactivity and subsequent PWMIs. In conclusion, the s.c. administration of RU-486 induced labor within 24 h with a high survival rate for pups. In the context of perinatal inflammation, RU-486 labor induction significantly decreases microglial reactivity in vivo but did not prevent subsequent PWMIs.

Perinatal mortality and morbidity, timing and route of delivery in monoamniotic twin pregnancies: a retrospective cohort study.

PURPOSE: Monoamniotic twin pregnancies are at high risk of perinatal complications and fetal loss. The objective of this study is to describe the management and outcomes of monoamniotic twin pregnancies in a French university obstetrics department. METHODS: Retrospective review of all consecutive monoamniotic twin pregnancies managed between 1992 and 2018 in a level-3 university hospital maternity unit. Antenatal variables, gestational age and other neonatal characteristics at delivery, mode of delivery, and its reason were recorded, together with outcomes, including a composite adverse neonatal outcome. RESULTS: Overall, 46 monoamniotic twin pregnancies (92 fetuses) were identified during the study period. Among them, 27 fetal losses and 2 early neonatal deaths were reported. Congenital abnormalities accounted for 33.3% of the 27 fetal losses, and unexpected fetal deaths for 29.6%. Among the 37 women who gave birth to 65 live infants at 23 or more weeks of gestation, 17 had cesarean and 19 vaginal deliveries. Overall and composite adverse neonatal outcomes did not differ significantly for the 33 children born vaginally and the 31 by cesarean deliveries. The prospective risk of intrauterine death in all 92 fetuses reached its nadir of 1.8% at 336/7 weeks. CONCLUSION: This series confirms the still high risk of fetal and neonatal death of these twins and shows that congenital abnormalities but also unexpected fetal deaths account for the majority of pre- and postnatal mortality. Our data suggest that vaginal delivery of monoamniotic twins is safe and that delivery for uncomplicated monoamniotic twins should be considered around 33 weeks of gestation, but not later than 35 weeks.

Use of the Robson classification to understand the increased risk of cesarean section in case of maternal obesity.

BACKGROUND: The aim of this study was to identify characteristics of pregnant women with obesity that contribute to increased cesarean rate. METHODS: Retrospective cohort in a single academic institution between 2012 and 2019. Women who delivered during this period were classified according to the Robson classification. Women with normal body mass index (N = 11,797) and with obesity (N = 2991) were compared. The contribution of each Robson group to the overall caesarean rate were compared. RESULTS: The overall cesarean rate was higher for women with (28.1%) than without (14.2%, p < 0.001) obesity. This result came mainly from Robson group 5a (history of one cesarean). After adjustment for medical factors within this group, the association between maternal obesity and cesarean during labor was significant. CONCLUSIONS: The higher cesarean rate in women with obesity is explained by Robson group 5a in which obesity is an independent risk factor of in labor cesarean delivery.

Double-balloon catheter versus prostaglandin for cervical ripening to induce labor after previous cesarean delivery.

PURPOSE: To compare the effectiveness of cervical ripening by a mechanical method (double-balloon catheter) and a pharmacological method (prostaglandins) in women with one previous cesarean delivery, an unfavorable cervix (Bishop score < 6), and a singleton fetus in cephalic presentation. METHODS: This retrospective study, reviewing the relevant records for the years 2013 through 2017, took place in two French university hospital maternity units. This study included women with one previous cesarean delivery, a liveborn singleton fetus in cephalic presentation, and intact membranes, for whom cervical ripening, with unfavorable cervix (Bishop score < 6) was indicated for medical reasons. It compared two groups: (1) women giving birth in a hospital that uses a protocol for mechanical cervical ripening by a double-balloon catheter (DBC), and (2) women giving birth in a hospital that performed pharmacological cervical ripening by prostaglandins. The principal endpoint was the cesarean delivery rate. The secondary outcome measures were maternal and neonatal outcomes. RESULTS: We compared 127 women with prostaglandin ripening to 117 women with DBC. There was no significant difference between the two groups for the cesarean rate (42.5% in the prostaglandin group and 42.7% in the DBC group; p = 0.973; crude OR 1.01 [0.61-1.68]; adjusted OR 1.55 [0.71-3.37]). The median interval between the start of ripening and delivery did not differ between the groups (28.7 h in the prostaglandin group vs 25.6 h in the DBC group; p = 0.880). Neonatal outcomes did not differ between the groups, either. There was one case of uterine rupture in the prostaglandin group, with no associated maternal or neonatal morbidity. There were no neonatal deaths. The postpartum hemorrhage rate was significantly higher in the DBC group. CONCLUSION: For cervical ripening for women with one previous cesarean, the choice of a pharmacological or mechanical protocol does not appear to modify the mode of delivery or maternal or neonatal morbidity.

Long interpregnancy interval and mode of delivery.

PURPOSE: WHO sets 24 months as the ideal minimum interpregnancy interval (IPI) to minimize maternal and perinatal adverse outcomes. Some studies suggest that an interval longer than 59 months may affect these outcomes, but little is known about its influence on labor. The primary objective of this study was to compare the cesarean delivery rate between primiparous women with a long IPI and, on the one hand, primiparous women with an ideal minimum IPI of 18-24 months and, on the other hand, with nulliparous women. METHODS: This retrospective cohort study of 17 years included nulliparas and primiparas who gave birth to live singleton fetuses in cephalic presentation after 22 weeks of gestation. Women with an IPI < 18 months or from 24 to 59 months were excluded, as were women with planned cesarean. We analyzed three groups: primiparous women with a long IPI defined as > 59 months, primiparous women with an ideal minimum IPI (18-24 months), and nulliparous women. RESULTS: The study included 18,503 women: 1342 women in the "long IPI" group, 1388 in the "ideal minimum IPI" group, and 15,773 in the nulliparous women group. The cesarean delivery rate was significantly higher in the long compared to the ideal minimum IPI group [12.2% vs. 6.3%, respectively; aOR = 2.2 (95% CI 1.6-3.1)], but both groups had similar durations of labor, regardless of mode of delivery. Women in the long IPI group had significantly lower cesarean rates than nulliparous women [12.2% and 14.3%, respectively; aOR = 0.5 (95% CI 0.4-0.7)], and the nulliparous women had a significantly longer mean duration of labor. CONCLUSIONS: Primiparas with a long IPI, compared with ideal minimal IPI have a higher risk of cesarean delivery during labor. Compared with nulliparous women, primiparous women with a long IPI had a lower cesarean rate.

Prenatal diagnosis of megacystis microcolon intestinal hypoperistalsis syndrome by biochemical analysis of fetal urine.

OBJECTIVES: The objective of the study is to determine a model of fetal urine biochemical markers to differentiate megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) from other megacystis. METHOD: This is a retrospective study of biochemical analysis of fetal urine in patients who presented prenatally with megacystis. We studied ß2-microglobulin, sodium, calcium, and phosphorus. Twenty-six patients subsequently diagnosed with MMIHS were compared with 2 control groups: one of end-stage renal failure (64 fetuses) and the second of "good" postnatal renal function (control group, 64 fetuses). RESULTS: Mean fetal urine ß2-microglobulin was significantly higher (P < .001) in end-stage renal failure (15.7 mg/L) than in MMIHS (2.2 mg/L) and the control group (3.2 mg/L). Fetal urine profiles differed significantly (P < .001) between MMIHS and the control group: median sodium 46.5 and 51 mmol/L, median calcium 1.12 and 0.73 mmol/L, and median phosphorus 0.03 and 0.15 mmol/L respectively. Fetal urinary ionic index [ratio: calcium / (phosphorus × sodium)] gave an area under the ROC curve of 0.86, at 54% sensitivity and 97% specificity, with correct classification in 84% of cases. We defined a nomogram to obtain a probability for MMIHS. CONCLUSION: Fetal urinalysis can be helpful in prenatal differentiation of MMIHS from posterior urethral valves with good postnatal renal function.

Anterior Focal Adenomyosis and Bladder Deep Infiltrating Endometriosis: Is There a Link?

STUDY OBJECTIVE: To evaluate the association between bladder deep infiltrating endometriosis (DIE) and anterior focal adenomyosis of the outer myometrium (aFAOM) diagnosed by preoperative magnetic resonance imaging (MRI). DESIGN: An observational, cross-sectional study using prospectively collected data (Canadian Task Force classification II-2). SETTING: Single university tertiary referral center. PATIENTS: All nonpregnant women younger than 42 years who had undergone complete surgical exeresis of endometriotic lesions. For each patient a standardized questionnaire was completed during a face-to-face interview conducted by the surgeon during the month preceding the surgery. Only women with preoperative standardized uterine MRI were retained for this study. INTERVENTIONS: Thirty-nine women with histologically proven bladder DIE and an available preoperative MRI were enrolled in the study. Patients were divided into 2 groups: women with aFAOM (aFAOM (+), n = 19) and women without aFAOM (aFAOM (-), n = 20). Both groups were compared for general characteristics, medical history, MRI findings, and disease severity. MEASUREMENTS AND MAIN RESULTS: Nineteen patients (48.7%) with bladder DIE had aFAOM at preoperative MRI. The rate of associated diffuse adenomyosis was similar in the 2 groups (63.2% [n = 12] vs 73.7% [n = 14]; p = .48). The rate of an associated ovarian endometrioma (OMA) was significantly lower in the aFAOM (+) group (10.5% [n = 2] vs 40.0% [n = 8]; p = .03). There were fewer associated intestinal DIE lesions in the aFAOM (+) group compared with the aFAOM (-) group (26.3% vs 75.0%; p = .02), with lower involvement of the pouch of Douglas (26.3% vs 70%; p < .01). Total American Society for Reproductive Medicine score was significantly lower in the aFAOM (+) group (13.8 ± 12.2 vs 62.2 ± 46.2; p < .01). CONCLUSION: aFAOM is present in only half of women with bladder DIE and appears to be associated with lower associated posterior DIE.

History of Uterine Surgery Is Not Associated With an Increased Severity of Bladder Deep Endometriosis.

STUDY OBJECTIVE: To analyze whether a history of uterine surgery correlates with disease severity in patients with bladder deep infiltrating endometriosis (DIE). DESIGN: This was an observational, cross-sectional study using data collected prospectively (Canadian Task Force classification II-2). SETTING: A single university tertiary referral center. PATIENTS: We included all nonpregnant women younger than age 42 years who had undergone complete surgical exeresis of endometriotic lesions. For each patient, a standardized questionnaire was completed during a face-to-face interview that was conducted by the surgeon in the month preceding the surgery. INTERVENTIONS: One hundred seven women with histologically proven bladder DIE were enrolled in this study. For the purpose of the study, the women were assigned to 2 groups before surgery: a study group that included women with a history of a scarred uterus (SU) (SU+, n = 16) and a control group that included women without SU (SU-, n = 99). Both groups were compared in terms of their general characteristics, medical histories, surgical findings, and the severity of the disease. MEASUREMENTS AND MAIN RESULTS: Patient age and body mass index were higher for the SU+ group as compared to the SU- group (37.9 ± 5.6 vs 32.2 ± 4.7, p < .01, and 24.7 ± 4.9 vs 21.9 ± 2.9, p = .03, respectively). Preoperative painful symptom scores did not differ between the 2 groups. No significant difference was observed in the rates of history for surgery for endometriosis (n = 11 [68.7%] vs n = 49 [53.8], p = .27). Comparison of the anatomic distribution of the lesions did not reveal a significant difference. The total American Society for Reproductive Medicine score did not differ between the groups (32.0 ± 34.4 vs 35.5 ± 34.5, p = .71). The incidence rate of isolated bladder DIE did not differ between the 2 study groups (n = 6 [37.5%] vs n = 40 [43.9%], p = .79). CONCLUSION: SU before surgery for endometriosis was observed in 14.9% of cases of bladder DIE; however, this was not related to an increased severity of the disease. This observational study hence does not appear to support the pathophysiologic hypothesis of a transmyometrial source for bladder DIE.

Trial of labor after cesarean and contribution of pelvimetry in the prognosis of neonatal morbidity.

INTRODUCTION: To estimate the association between an abnormal pelvic dimension at pelvimetry and the occurrence of severe neonatal morbidity after trial of labor after cesarean (TOLAC). MATERIALS AND METHODS: Retrospective observational cases-controls study conducted at a level 3 maternity units between 2006 and 2016. Included women were patient with trial of labor after one previous cesarean section, alive singleton fetus in cephalic presentation ≥ 37WG. Two groups were compared according to pelvic mesures at pelvimetry: pelvic dimension considered as abnormal, defined by Conjugate Diameter <10.5cm and/or Transverse Diameter <12cm and pelvic dimension considered as normal for other women. The primary outcome was a composite criterion of neonatal morbidity and mortality. A logistic multivariate regression model was use to estimate the association between an abnormal pelvic dimension at pelvimetry and the occurrence of severe neonatal morbidity. RESULTS: 2474 women were included. 863 (34.8 %) have a normal pelvic dimension and 1611 (65.2 %) an abnormal. Characteristics of labor were similar in two groups. Success of TOLAC was 84.7 % in normal pelvic group and 64.6 % in abnormal dimension of pelvic group. Neonatal morbidity was similar between two groups (1.7 % in normal pelvic dimension group versus 2.3 % in abnormal pelvic dimension group, p=0.26; crude OR: 1.39 (0.77-2.49) ; adjusted OR : 0.93 (0.51-1.68)). DISCUSSION: There were no association between pelvic dimension at pelvimetry and neonatal morbidity. In case of abnormal pelvic dimension, a combination of more prudence, and stringent user practices, achieve a high rate of vaginal delivery and a neonatal morbidity comparable to the normal pelvic dimension group.

Impact of maternal age on intrapartum caesarean delivery rate in nulliparas with spontaneous labour.

BACKGROUND: The advanced maternal age rate increases in developed countries. Older women have more pre-existing condition than youngest women and develop more frequently obstetrical pathologies responsible for a higher rate of caesarean delivery before labour and labour induction. For aged nulliparous without pathology who experience spontaneous labour, there is few data on the mode of delivery and on physiological labour according to maternal age. OBJECTIVE: To compare the intrapartum caesarean delivery rate according to maternal age, for nulliparous with planned vaginal delivery and spontaneous labour at term. METHODS: Retrospective cohort in a single academic institution between January 2000 and June 2017. All nulliparous women with planned vaginal delivery with live singleton in cephalic presentation at and after 37 weeks of gestation with spontaneous labour were included (n = 10,611). Two groups were compared: nulliparous women aged 20-34 and nulliparous women aged 35 and over. The main outcome was the intrapartum caesarean delivery rate. A subgroup analysis was performed for nulliparous with more advanced maternal age defined as women over 40. RESULTS: Among the 10,611 women included in this analysis, 8,993 (84.8%) were aged 20-34 and 1,618 (15.2%) were aged over 35. From the latter 367 (22.7%) were over 40 years old. The intrapartum caesarean delivery rate was similar between women aged between 20 and 34 and women aged over 35 (10.8% compared to 8.8%; cOR 0.91, 95% CI 0.76-1.08; aOR 0.91, 95% CI 0.76-1.09). The indications of caesarean were similar in both groups. No differences were found between both groups for mean labour duration (430.9 min for the [20-34] years group compared to 428.0 min for the over 35 years group, p = 0.654). The subgroup analysis performed on nulliparous with more advanced maternal age yielded similar results. CONCLUSION: For nulliparous at term in spontaneous labour, an advanced maternal age was not associated with an increased intrapartum caesarean delivery rate.

Lung microRNA deregulation associated with impaired alveolarization in rats after intrauterine growth restriction.

Intrauterine growth restriction (IUGR) was recently described as an independent risk factor of bronchopulmonary dysplasia, the main respiratory sequelae of preterm birth. We previously showed impaired alveolarization in rat pups born with IUGR induced by a low-protein diet (LPD) during gestation. We conducted a genome-wide analysis of gene expression and found the involvement of several pathways such as cell adhesion. Here, we describe our unbiased microRNA (miRNA) profiling by microarray assay and validation by qPCR at postnatal days 10 and 21 (P10 and P21) in lungs of rat pups with LPD-induced lung-alveolarization disorder after IUGR. We identified 13 miRNAs with more than two-fold differential expression between control lungs and LPD-induced IUGR lungs. Validated and predicted target genes of these miRNAs were related to "tissue repair" at P10 and "cellular communication regulation" at P21. We predicted the deregulation of several genes associated with these pathways. Especially, E2F3, a transcription factor involved in cell cycle control, was expressed in developing alveoli, and its mRNA and protein levels were significantly increased at P21 after IUGR. Hence, IUGR affects the expression of selected miRNAs during lung alveolarization. These results provide a basis for deciphering the mechanistic contributions of IUGR to impaired alveolarization.