Preeclampsia (PE) is a multifactorial pregnancy disease, characterized by new-onset gestational hypertension with (or without) proteinuria or end-organ failure, exclusively observed in humans. It is ...a leading cause of maternal morbidity affecting 3–7% of pregnant women worldwide. PE pathophysiology could result from abnormal placentation due to a defective trophoblastic invasion and an impaired remodeling of uterine spiral arteries, leading to a poor adaptation of utero-placental circulation. This would be associated with hypoxia/reoxygenation phenomena, oxygen gradient fluctuations, altered antioxidant capacity, oxidative stress, and reduced nitric oxide (NO) bioavailability. This results in part from the reaction of NO with the radical anion superoxide (O2•−), which produces peroxynitrite ONOO-, a powerful pro-oxidant and inflammatory agent. Another mechanism is the progressive inhibition of the placental endothelial nitric oxide synthase (eNOS) by oxidative stress, which results in eNOS uncoupling via several events such as a depletion of the eNOS substrate L-arginine due to increased arginase activity, an oxidation of the eNOS cofactor tetrahydrobiopterin (BH4), or eNOS post-translational modifications (for instance by S-glutathionylation). The uncoupling of eNOS triggers a switch of its activity from a NO-producing enzyme to a NADPH oxidase-like system generating O2•−, thereby potentiating ROS production and oxidative stress. Moreover, in PE placentas, eNOS could be post-translationally modified by lipid peroxidation-derived aldehydes such as 4-oxononenal (ONE) a highly bioreactive agent, able to inhibit eNOS activity and NO production. This review summarizes the dysfunction of placental eNOS evoked by oxidative stress and lipid peroxidation products, and the potential consequences on PE pathogenesis.
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•Physiological ROS production is enhanced during pregnancy.•eNOS is one of the main target of oxidative stress in PE placenta.•eNOS is S-glutathionylated in PE placentas.•eNOS is modified by lipid oxidation products in PE placentas.
Objective
To evaluate the use of new bipolar vessel sealing system like LigaSure™ compared to the standard surgical technique (suture) during emergency peripartum hysterectomy (EPH).
Methods
A ...retrospective observational bicentric study was conducted from February 2005 to August 2018 in the maternity wards of the University Hospital of Toulouse and Angers. All EPHs performed up to 24 h after delivery were included. The main outcome was the total blood loss. Secondary outcomes were operating time, number of blood transfusions, per and postoperative complications. A subgroup analysis was performed between hysterectomies performed in emergency and scheduled hysterectomies.
Results
Among 111,266 deliveries, 86 women (0.07%) underwent EPH, 29 were operated upon with LigaSure™, 57 with the traditional technique. In the LigaSure™ arm, there were statistically lower blood loss (3198 mL vs 4223 mL,
p
= 0.02), fewer blood transfusions (62.1% vs 94.7%,
p
= 0.0003, confirmed in subgroup analysis), and fewer perioperative complications (8.3% vs 45.5%,
p
= 0.04) for scheduled hysterectomies.
Conclusion
Bipolar vessel sealing systems such as LigaSure™ are a surgical instrument, easy to use for the surgeon, with an interest in the management of EPH, particularly for total blood loss, transfusions, and intraoperative complications.
Preeclampsia (PE) is a leading cause of pregnancy complications, affecting 3–7% of pregnant women worldwide. The pathophysiology of preeclampsia involves a redox imbalance, oxidative stress and a ...reduced nitric oxide (NO) bioavailability. The molecular and cellular mechanisms leading to the dysfunction of the placental endothelial NO synthase (eNOS) are not clarified. This study was designed to investigate whether aldehydes generated by lipid peroxidation products (LPP), may contribute to placental eNOS dysfunction in PE. The analysis of placentas from PE-affected patients and normal pregnancies, showed a significant increase in protein carbonyl content, indicative of oxidative stress-induced protein modification, as shown by the accumulation of acrolein, 4-hydroxynonenal (HNE), and 4-oxo-2(E)-nonenal (ONE) adducts in PE placentas. In contrast, the levels of these LPP-adducts were low in placentas from normal pregnancies. Immunofluorescence and confocal experiments pointed out a colocalization of eNOS with ONE-Lys adducts, whereas eNOS was not modified in normal placentas. LC-MS/MS analysis of recombinant eNOS preincubated with ONE, allowed to identify several ONE-modified Lys-containing peptides, confirming that eNOS may undergo post-translational modification by LPP. The preincubation of HTR-8/SVneo human trophoblasts (HTR8) with ONE, resulted in ONE-Lys modification of eNOS and a reduced generation of NO. ONE inhibited the migration of HTR8 trophoblasts in the wound closure model, and this was partly restored by the NO donor, NOC-18, which confirmed the important role of NO in the invasive potential of trophoblasts. In conclusion, placental eNOS is modified by ONE in PE placentas, which emphasizes the sensitivity of this protein to oxidative stress in the disturbed redox environment of preeclamptic pregnancies.
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•Lipid peroxidation products accumulate in placentas from preeclampsia.•ONE-Lys adducts accumulate on eNOS in preeclamptic placentas.•Recombinant eNOS is modified by ONE on Lys residues.•ONE modifieseNOS and alters NO production in HTR8 trophoblasts.•The migration of HTR8 inhibited by ONE is restored by the NO donor NOC-18.
Prolonged pregnancies are a frequent indication for induction of labour. When the cervix is unfavourable, cervical ripening before oxytocin administration is recommended to increase the likelihood of ...vaginal delivery, but no particular method is currently recommended for cervical ripening of prolonged pregnancies. This trial evaluates whether the use of mechanical cervical ripening with a silicone double balloon catheter for induction of labour in prolonged pregnancies reduces the cesarean section rate for nonreassuring fetal status compared with pharmacological cervical ripening by a vaginal pessary for the slow release of dinoprostone (prostaglandin E2).
This is a multicentre, superiority, open-label, parallel-group, randomised controlled trial conducted in 15 French maternity units. Women with singleton pregnancies, a vertex presentation, ≥41+0 and ≤42+0 weeks' gestation, a Bishop score <6, intact membranes, and no history of cesarean delivery for whom induction of labour was decided were randomised to either mechanical cervical ripening with a Cook Cervical Ripening Balloon or pharmacological cervical ripening by a Propess vaginal pessary serving as a prostaglandin E2 slow-release system. The primary outcome was the rate of cesarean for nonreassuring fetal status, with an independent endpoint adjudication committee determining whether the fetal heart rate was nonreassuring. Secondary outcomes included delivery (time from cervical ripening to delivery, number of patients requiring analgesics), maternal and neonatal outcomes. Between January 2017 and December 2018, 1,220 women were randomised in a 1:1 ratio, 610 allocated to a silicone double balloon catheter, and 610 to the Propess vaginal pessary for the slow release of dinoprostone. The mean age of women was 31 years old, and 80% of them were of white ethnicity. The cesarean rates for nonreassuring fetal status were 5.8% (35/607) in the mechanical ripening group and 5.3% (32/609) in the pharmacological ripening group (proportion difference: 0.5%; 95% confidence interval (CI) -2.1% to 3.1%, p = 0.70). Time from cervical ripening to delivery was shorter in the pharmacological ripening group (23 hours versus 32 hours, median difference 6.5 95% CI 5.0 to 7.9, p < 0.001), and fewer women required analgesics in the mechanical ripening group (27.5% versus 35.4%, difference in proportion -7.9%, 95% CI -13.2% to -2.7%, p = 0.003). There were no statistically significant differences between the 2 groups for other delivery, maternal, and neonatal outcomes. A limitation was a low observed rate of cesarean section.
In this study, we observed no difference in the rates of cesarean deliveries for nonreassuring fetal status between mechanical ripening with a silicone double balloon catheter and pharmacological cervical ripening with a pessary for the slow release of dinoprostone.
ClinicalTrials.gov NCT02907060.
Decreased nitric oxide (NO) bioavailability plays a critical role in the pathophysiology of preeclampsia (PE). Recent evidence indicates that S-glutathionylation may occur on the endothelial nitric ...oxide synthase (eNOS), leading to eNOS uncoupling, characterized by a decreased NO production and an increased generation of superoxide anion (O
). We hypothesized that eNOS glutathionylation may occur in PE placentas and participate in eNOS dysfunction. The glutathionylation of eNOS was investigated in thirteen PE-affected patients and in nine normal pregnancies. Immunofluorescence, confocal microscopy and western-blot experiments carried out on eNOS immunoprecipitates, revealed a high level of eNOS glutathionylation in PE placentas, mostly reversed by dithiotreitol (DTT), thus indicative of S-glutathionylation. In order to investigate whether eNOS glutathionylation may alter trophoblast migration, an important event occurring during early placentation, cultured HTR-8/SVneo human trophoblasts (HTR8) were exposed either to low pO
(O
1%) or to pO
changes (O
1-20%), in order to generate oxidative stress. Trophoblasts exposed to low pO
, did not undergo oxidative stress nor eNOS S-glutathionylation, and were able to generate NO and migrate in a wound closure model. In contrast, trophoblasts submitted to low/high pO
changes, exhibited oxidative stress and a (DTT reversible) S-glutathionylation of eNOS, associated with reduced NO production and migration. The autonomous production of NO seemed necessary for the migratory potential of HTR8, as suggested by the inhibitory effect of eNOS silencing by small interfering RNAs, and the eNOS inhibitor L-NAME, in low pO
conditions. Finally, the addition of the NO donor, NOC-18 (5 µM), restored in part the migration of HTR8, thereby emphasizing the role of NO in trophoblast homeostasis. In conclusion, the high level of eNOS S-glutathionylation in PE placentas provides new insights in the mechanism of eNOS dysfunction in this disease.
Prenatal discovery of fetal bilateral hyperechogenic kidneys is very stressful for pregnant women and their family, and accurate diagnosis of the cause of the moderate forms of this pathology is very ...difficult. Hepatocyte nuclear factor-1beta that is encoded by the TCF2 gene is involved in the embryonic development of the kidneys. Sixty-two pregnancies with fetal bilateral hyperechogenic kidneys including 25 fetuses with inaccurate diagnosis were studied. TCF2 gene anomalies were detected in 18 (29%) of these 62 patients, and 15 of these 18 patients presented a complete heterozygous deletion of the TCF2 gene. Family screening revealed de novo TCF2 anomalies in more than half of the patients. TCF2 anomalies were associated with normal amniotic fluid volume and normal-sized kidneys between -2 and +2 SD in all patients except for two sisters. Antenatal cysts were detected in 11 of 18 patients, unilaterally in eight of 11. After birth, cysts appeared during the first year (17 of 18), and in patients with antenatal cysts, the number increased and developed bilaterally with decreased renal growth. In these 18 patients, the GFR decreased with longer follow-up and was lower in patients with solitary functioning dysplastic kidney. Heterozygous deletion of the TCF2 gene is an important cause of fetal hyperechogenic kidneys in this study and showed to be linked with early disease expression. The renal phenotype and the postnatal evolution were extremely variable and need a prospective long-term follow-up. Extrarenal manifestations are frequent in TCF2-linked pathologies. Therefore, prenatal counseling and follow-up should be multidisciplinary.
To evaluate immediate perineal and neonatal morbidity associated with instrumental rotations performed with Thierry's spatulas for the management of persistent posterior occiput (OP) positions.
...Retrospective study including all persistent occiput posterior positions with vaginal OP delivery, from August 2006 to September 2007. Occiput anterior deliveries following successful instrumental rotation were included as well. We compared maternal and neonatal immediate outcomes between spontaneous deliveries, rotational and non rotational assisted deliveries, using χ(2) and Anova tests.
157 patients were enrolled, comprising 46 OP spontaneous deliveries, 58 assisted OP deliveries and 53 deliveries after rotational procedure. Instrumental rotation failed in 9 cases. Mean age and parity were significantly higher in the spontaneous delivery group, while labor duration was shorter. There were no significant differences in the rate of severe perineal tears and neonatal adverse outcomes between the 3 groups.
Instrumental rotation using Thierry's spatulas was not associated with a reduced risk of maternal and neonatal morbidity for persistent OP deliveries. Further studies are required to define the true interest of such procedure in modern obstetrics.
In early human pregnancy, uterine decidual NK cells (dNK) are abundant and considered as cytokine producers but poorly cytotoxic despite their cytolytic granule content, suggesting a negative control ...of this latter effector function. To investigate the basis of this control, we examined the relative contribution to the cytotoxic function of different activating receptors expressed by dNK. Using a multicolor flow cytometry analysis, we found that freshly isolated dNK exhibit a unique repertoire of activating and inhibitory receptors, identical among all the donors tested. We then demonstrated that in fresh dNK, mAb-specific engagement of NKp46-, and to a lesser extent NKG2C-, but not NKp30-activating receptors induced intracellular calcium mobilization, perforin polarization, granule exocytosis and efficient target cell lysis. NKp46-mediated cytotoxicity is coactivated by CD2 but dramatically blocked by NKG2A coengagement, indicating that the dNK cytotoxic potential could be tightly controlled in vivo. We finally found that in dNK, mAb-specific engagement of NKp30, but not NKp46, triggered the production of IFN-gamma, TNF-alpha, MIP-1alpha, MIP-1beta, and GM-CSF proinflammatory molecules. These data demonstrate a differential, controlled role of NKp46- and NKp30-activating receptors expressed by dNK that could be critical for the outcome of pregnancy and the killing of uterine cells infected by pathogens.
We aimed at developing a core outcome and variables of interest set to investigate the effects of mediolateral episiotomy on Obstetric Anal Sphincter Injury (OASI) during and after operative delivery ...in nulliparous women in a large-scale one-year observational French study including 15,000 women (INSTRUMODA).
A list of outcomes and variables of interest was suggested to obstetricians participating in the INSTRUMODA study using online questionnaires divided into 7 categories: the woman's history and course of pregnancy, course of labor, modalities of operative delivery, episiotomy characteristics, immediate maternal morbidity, one-year maternal morbidity, immediate neonatal morbidity. We used a three-round DELPHI method to reach a consensus. In the first round, outcomes and variables considered as essential by 70% or more of obstetricians were included in the corpus whereas they were excluded when 70% rated them as "not important". In the second round, non-consensual outcomes and variables were reassessed and excluded or definitively included if considered as "not important" or essential by 50% or more of the obstetricians. During the first round, obstetricians were invited to suggest new outcomes and/or variables that were then assessed in the second and third round. We used the same method to develop a core outcome and variables of interest set in a population of women in the community recruited via an association of patients. At the end of the procedure the core outcome and variables of interest sets were merged to provide the final core outcome set for the INSTRUMODA study.
Fifty-three obstetricians and 16 women filled out questionnaires. After the 3 rounds of Delphi procedure in each population, 74 outcomes and variables were consensually reported by obstetricians and 92 by women in the community. By mixing these two consensual corpora we reported a final consensual list of 114 variables of interest and outcomes for both obstetricians and women.
We established a core outcome and variables of interest set among obstetricians and women in the community to investigate the association between mediolateral episiotomy and OASI during operative delivery.
The INSTRUMODA study was registered on https://clinicaltrials.gov on June 25, 2020 ( NCT04446780 ).
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