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Aspirin initiated between 11 and 14 weeks of gestation reduces the risk of preterm preeclampsia and other placenta-mediated complications in screen-positive women. Most of these adverse outcomes are associated with maternal vascular malperfusion of the placenta, a disease that begins during the early first trimester. Assuming that aspirin has direct beneficial actions on the developing placenta, tempts clinicians to believe in the maxim that "the earlier the better", however neither the safety nor the effectiveness of aspirin started before 11th week of gestation has been demonstrated. Therefore, outside of research protocols, aspirin should not be started before the 11th week of pregnancy for the prevention of preeclampsia.

The aim of this study was to assess perinatal morbidity associated with spatulas or forceps assisted delivery in preterm birth.This is a retrospective cohort study including all women with assisted deliveries on singleton pregnancy in cephalic presentation, before 37 weeks of gestation, in two tertiary care centers. We compared forceps-assisted deliveries with spatula-assisted deliveries. The main outcome was the rate of neonatal birth trauma. Secondary outcomes included other neonatal parameters, maternal outcomes and obstetric anal sphincter injuries.Out of 37 002 deliveries, 59 (0.2 %) preterm assisted deliveries with forceps and 111 (0.3%) preterm spatulas deliveries were included. The rate of neonatal birth trauma was low for both devices, without significant difference (3.4% in Forceps group vs 0.9% in Spatulas group, p = 0.28). The rate of episiotomy was 79.7% after forceps-assisted delivery and 48.6% for spatulas (p 0.001). The rate of obstetric anal sphincter injuries was 1.7% and 2.7% respectively (p = 0,9).The rate of birth trauma was low in both forceps-assisted deliveries and spatula-assisted deliveries and was not significantly different between the two groups.

OBJECTIVE To evaluate the delivery rate in the occiput posterior position according to the result of manual rotation performed in the case of persistent occiput posterior position. Secondary objectives were perinatal outcomes. METHODS This was a prospective cohort study conducted in two French tertiary care units. All women with a singleton pregnancy after 37 weeks of gestation with a fetus in persistent occiput posterior position and an attempt of manual rotation were included. The main outcome was the occiput position at delivery. The secondary outcomes were duration of labor, mode of delivery, and perineal tears. Two groups were compared according to the result of manual rotation. RESULTS In total, 460 women were included, with a manual rotation success of 62.4%. The success was significantly associated with a decrease in occiput posterior position at vaginal delivery (1.4% vs 57.2%, P

Accelerated placental senescence is associated with preeclampsia (PE) and other pregnancy complications. It is characterized by an accelerated decline in placental function due to the accumulation of senescence patterns such as telomere shortening, mitochondrial dysfunction, oxidative damages, increased expression of phosphorylated (serine-139) histone γ-H2AX, a sensitive marker of double-stranded DNA breaks, accumulation of cross-linked ubiquitinated proteins and sirtuin inhibition. Among the lipid oxidation products generated by the peroxidation of polyunsaturated fatty acids, aldehydes such as acrolein, 4-hydroxy-2-nonenal, 4-oxo-2-nonenal, are present in the blood and placenta from PE-affected women and could contribute to PE pathogenesis and accelerated placental aging. In this review we summarize the current knowledge on premature placental senescence and the role of oxidative stress and lipid oxidation-derived aldehydes in this process, as well as their links with PE pathogenesis. The interest of developing (or not) new therapeutic strategies targeting lipid peroxidation is discussed, the objective being a better understanding of accelerated placental aging in PE pathophysiology, and the prevention of PE bad outcomes.

Premature placental senescence is a hallmark of pregnancy-related disorders such as intrauterine growth restriction (IUGR) and preeclampsia (PE), two major cause of maternal and neonatal morbidity and mortality. Oxidative stress and lipid peroxidation are involved in the pathogenesis of PE and IUGR, and may play a role in placental aging. In this study, we investigated whether 4-hydroxy-2-nonenal (HNE), a lipid peroxidation-derived aldehyde present in preeclamptic placentas, may contribute to premature senescence in placenta-related complications. Placentas from PE-affected women, exhibited several senescence patterns, such as an increased expression of phosphorylated (serine-139) histone γH2AX, a sensitive marker of double-stranded DNA breaks, the presence of lipofuscin granules, and an accumulation of high molecular weight cross-linked and ubiquitinated proteins. PE placentas showed an accumulation of acetylated proteins consistent with the presence of HNE-adducts on sirtuin 1 (SIRT1). Likewise, oxidative stress and senescence markers together with SIRT1 modification by HNE, were observed in murine placentas from mice treated with lipopolysaccharide during gestation and used as models of IUGR. The addition of HNE and ONE (4-oxo-2-nonenal), to cultured HTR-8/SVneo human trophoblasts activated the senescence-associated- β-galactosidase, and generated an accumulation of acetylated proteins, consistent with a modification of SIRT1 by HNE. Altogether, these data emphasize the role of HNE and lipid peroxidation-derived aldehydes in premature placental senescence in PE and IUGR, and more generally in pathological pregnancies.

Objectives To estimate the ability of a combination of first-trimester markers to predict preterm preeclampsia in nulliparous women. Methods We conducted a prospective cohort study of nulliparous women with singleton gestations, recruited between 110 and 136 weeks gestation. Data on the following were collected: maternal age; ethnicity; chronic diseases; use of fertility treatment; body mass index; mean arterial blood pressure (MAP); serum levels of pregnancy-associated plasma protein A (PAPP-A), placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), alpha fetoprotein (AFP), free beta human chorionic gonadotropin (s-hCG); and mean uterine artery pulsatility index (UtA-PI). We constructed a proportional hazard model for the prediction of preterm preeclampsia selected based on the Akaike information criterion. A receiver operating characteristic curve was created with the predicted risk from the final model. Our primary outcome was preterm preeclampsia and our secondary outcome was a composite of preeclampsia, small for gestational age, intrauterine death, and preterm birth. Results Among 4659 nulliparous women with singleton gestations, our final model included 4 variables: MAP MoM, log10PlGF MoM, log10AFP MoM and log10UtA-PI MoM. We obtained an area under the curve of 0.84 (95% CI 0.75–0.93) with a detection rate of preterm preeclampsia of 55% (95% CI 37%–73%) and a false-positive rate of 10%. Using a risk cut-off with a false-positive rate of 10%, the positive predictive value for our composite outcome was 33% (95% CI 29%–37%). Conclusions The combination of MAP, maternal serum PlGF and AFP, and UtA-PI are useful to identify nulliparous women at high risk of preterm preeclampsia but also at high risk of other great obstetrical syndromes.

Objective Preeclampsia is associated with a higher maternal blood levels of soluble fms-like tyrosine kinase-1 (sFlt-1) and lower levels of placental growth factor (PlGF) that appear before clinical onset. We aimed to estimate the normal progression of these biomarkers in normal pregnancies and in those affected by preeclampsia. Methods We conducted a case-cohort study including low-risk nulliparous women recruited at 11–13 weeks gestation (cohort) and women with preeclampsia (cases). Maternal blood was collected at different points during pregnancy including at the time of diagnosis of preeclampsia for cases. Maternal serum PlGF and sFlt-1 concentrations and the sFlt-1/PlGF ratio were measured using B•R•A•H•M•S plus KRYPTOR automated assays and were compared between patients in both groups matched for gestational age. Cases were stratified as early- (≤34 weeks), intermediate- (35–37 weeks) and late-onset (>37 weeks) preeclampsia. Results The cohort consisted of 45 women whose results were compared with those of 31 women who developed preeclampsia, diagnosed at a median gestational age of 32 weeks (range 25–38 weeks). We observed that sFlt-1, PlGF and their ratio fluctuated during pregnancy in both groups, with a significant correlation with gestational age after 28 weeks (P Conclusion PlGF, sFlt-1, and their ratio may be useful in the prediction and diagnosis of early- and intermediate-onset preeclampsia but are not useful for late-onset preeclampsia.

Traditional obstetric units are inadequate for the level of monitoring required in pre-eclamptic patients. It remains to be determined which facility and tools should be implemented. The aim of this work was to identify predictive factors of admission to Intensive Care Unit (ICU) admissions for pregnancy-related hypertensive complications.We conducted an observational, retrospective multicenter study (Toulouse, Nantes). Both have a level III maternity unit and an ICU. The selected patients had one or more of the following diagnoses on admission in the ICU or during hospitalization: pre-eclampsia, eclampsia, HELLP syndrome, Acute Fatty Liver of Pregnancy (AFLP), Hemolytic Uremic Syndrome (HUS). SAPS II, SOFA and APACHE II on admission, and a validated nursing workload assessment score: TISS 28, were collected.211 parturient women were included. According to the multivariate analysis: APACHE II and SAPS 2 severity scores15 were significantly higher in the TISS 28 ≥ 20 group. There were also higher rates of uricemia360 mmol/l.To date, there are no reliable and validated predictive factors of severity to guide the transfer of pre-eclamptic patients to an ICU. The combination of an increased APACHE II score and uricemia, as well as a high care workload score that could help with the transfer of high-risk pre-eclamptic patients to a specific care facility. This hypothesis should be tested prospectively. This work could incite reflection on the value of creating obstetric intensive care units, according to the size of the maternity unit.

Other methods of cigarette consumption include a variety of electronic products, as well as heated tobacco, snus and shisha. The questions in this chapter are: what other methods of consumption are used during pregnancy (either electronic or containing tobacco) and what is their prevalence? What is their benefit/risk balance? Can their use during pregnancy be proposed? Although the fetus is not exposed to the combustible toxins of tobacco, e-cigarette products may contain nicotine, which maintains the exposure of the fetus. Further research is needed on the other components of the electronic cigarette, such as flavorings and propylene glycol and/or glycerol, in order to assess the benefit/risk balance. In addition, some solvents contain ethanol. In the current state of knowledge, the precautionary principle should be respected and not recommend the initiation or continuation of the electronic cigarette during pregnancy (professional agreement). For smoking cessation or electronic cigarette cessation, it is recommended to provide the same advice and to use methods that have already been evaluated (professional agreement). For the JUUL, there are currently no data on obstetrical outcome when used. The use of shisha during pregnancy is associated with decreased fetal growth. It is recommended not to use shisha during pregnancy (GradeC). There are currently no data on the use of heated tobacco and obstetrical outcome.

Objective This study was aimed to estimate the value of transabdominal (TA) ultrasound measurement of cervical length (CL), as an alternative of transvaginal (TV) ultrasound, for universal screening of short cervix in the midtrimester. Study Design We conducted a prospective cohort study of nulliparous women with singleton pregnancy at 20 to 24 weeks of gestation. All participants underwent TA ultrasound followed by TV ultrasound with acquisitions of images and videos of the uterine cervix. A second sonographer, blinded to the participants' data and pregnancy outcomes, measured the CL using TA and TV images and videos. Pearson's correlation test and receiver operating characteristic (ROC) curve analyses were performed. Results A total of 805 participants were recruited, including 780 (97%) where TA CL measurement was feasible. We observed a strong correlation of CL between TA and TV (correlation coefficient: 0.57; p Conclusion Universal short cervix screening in nulliparous women could be performed using TA ultrasound, which could allow the avoidance of TV ultrasound in more than three quarter of women. In low-risk population, TV ultrasound could be reserved to women with TA CL Key Points

HELLP syndrome is a rare and severe pregnancy complication which exposes to severe maternal and fetal morbidity. Management of HELLP syndrome occurring before 34 weeks of gestation (WG) is still controversial but conservative management may be beneficial in patients with stable HELLP syndrome. The aim of the study was thus to identify which maternal and fetal prognostic factors could be predictive of HELLP syndrome evolution.From 2003 to 2016, all patients with HELLP syndrome occurring between 26 and 34 WG were retrospectively enrolled. Study population was stratified according to obstetrical management. Patients in whom delivery was initiated within 48 h following diagnosis constituted the active management group. In the expectant management group, pregnancy was prolonged until maternal or fetal follow up indicated delivery.Ninety-nine patients were included in our study. Among them, 61 were managed expectantly. At baseline, the active management group was more likely to suffer from persistent hyperreflexia (While expectant management in HELLP syndrome might be beneficial through its reduction of prematurity, it cannot be conducted in all patients. Identification of baseline parameters predictive of disease evolution is thus of tremendous importance to define which obstetrical approach should be prioritized.

To evaluate the risk of spontaneous preterm birth on subsequent pregnancies after second stage cesarean section.This is a retrospective cohort study. Women were included if they had their two consecutive births in Toulouse University Hospital in the study period. The first birth was a singleton livebirth at term (≥37 weeks of gestation), divided in three categories according to the mode of delivery: vaginal delivery (group A), cesarean section before the second stage of labor (group B), cesarean section during the second stage of labor (group C). The subsequent pregnancy was the first subsequent pregnancy, conducted after 16 weeks of gestation. The primary outcome was spontaneous preterm birth in the subsequent pregnancy, defined as delivery before 37 weeks of gestation. Secondary endpoints included preterm rupture of membranes in the subsequent pregnancy.Between 2003 and 2018, 7776 women (84.7%) in group A, 1263 (13.8%) in group B and 143 (1.5%) in group C were included. The adjusted odds ratio of spontaneous preterm birth before 37 weeks of gestation after second stage cesarean section was 2.4 (group C vs group A + B, 95% confidence interval: 1.2-4.8), P = 0.01). The rate of preterm rupture of membranes was also significantly higher in group C (6% vs 2% in group A, P = 0.009, 6% vs 3% in group B, P= 0.05) with OR = 3.0 (group C vs group A + B, 95% CI: 1.55-6.16, P 0.001).History of term second stage of labor cesarean section is an independent risk factor for spontaneous preterm birth and for preterm rupture of membrane in the subsequent pregnancy.

This study aimed to estimate the impact of third-trimester ultrasound with measurement of the lower uterine segment thickness (LUST) and estimation of fetal weight (EFW) on maternal and perinatal morbidity among women with a prior cesarean delivery.We performed a secondary analysis of the QUARISMA trial, including women who delivered at term after one prior cesarean delivery in tertiary care centres. Major and minor maternal and perinatal morbidities were compared between centres that had introduced LUST and EFW measurements into routine practice and those that had not, using generalised estimating equations and adjusted odds ratios (aOR). In a secondary analysis, we compared women who underwent a trial of labour with and without LUST and EFW measurements.We observed a significant reduction in major perinatal morbidity (aOR 0.52; 95% CI 0.28-0.96, P = 0.04), minor perinatal morbidity (aOR 0.49; 95% CI 0.25-0.96, P = 0.04), and minor maternal morbidity (aOR 0.56; 95% CI 0.34- 0.94, P = 0.03) but no significant difference in major maternal morbidity (aOR 0.40; 95% CI 0.04-3.69, P = 0.42) in the 2 centres that had introduced third-trimester ultrasound with EFW and LUST measurements (1458 women), compared with the 4 centres (1247 women) that had not. Among women who underwent a trial of labour, we observed a reduction in major perinatal morbidity (aOR 0.25; 95% CI 0.11-0.54, P0.001) and a lower rate of uterine rupture (0% vs. 0.3%, P = 0.045) with LUST and EFW measurements.Third-trimester ultrasound with EFW and LUST measurement is associated with a significant reduction in major perinatal morbidity in women with a prior cesarean delivery.

To estimate the role of first-trimester uterine artery pulsatility index (UtA-PI) for the prediction of small-for-gestational age (SGA).We conducted a prospective cohort study of nulliparous women with singleton pregnancy (Great Obstetrical Syndromes study). UtA-PI was performed at 11 + 0 to 13 + 6 weeks and was reported in multiple of median (MoM). SGA was defined as birth weight below the 10th percentile and stratified as term or preterm SGA. Receiver operating characteristic curves analyses with their area under the curve (AUC) were used to estimate the predictive values of UtA-PI, alone and UtA-PI combined with maternal characteristics. We computed the detection rate and false-positive rate (FPR) of the SOGC SGA screening guidelines in our population.Of 4610 participants, SGA was identified in 486 pregnancies (10.3%), including 15 (0.3%) associated with preterm delivery. Compared with unaffected pregnancies, the mean log UtA-PI was significantly higher in term SGA and preterm SGA. The difference between preterm SGA and unaffected pregnancies remains significant after exclusion of SGA without preeclampsia. First-trimester UtA-PI was more predictive of preterm (AUC: 0.89) than term (AUC: 0.60) SGA (P 0.01). Combined with maternal characteristics, UtA-PI could have predicted 64% of preterm and 20% of term SGA (10% FPR). The SOGC guidelines criteria for early screening of SGA had a detection rate of 21% for a FPR of 21%.First-trimester UtA-PI can be used to predict SGA, but mainly preterm SGA. The current SOGC guidelines criteria for SGA screening are not efficient in nulliparous women.

Objective The study aimed to estimate the predictive value of midtrimester cervical length (CL) and the optimal cut-off of CL that should be applied with asymptomatic nulliparous women for the prediction of spontaneous preterm birth (sPTB). Study Design This is a prospective cohort study of asymptomatic nulliparous women with a singleton gestation. Participants underwent CL measurement by transvaginal ultrasound between 20 and 24 weeks of gestation. The participants and their health care providers remained blinded to the results of CL measurement. The primary outcomes were sPTB before 35 weeks and sPTB before 37 weeks. Receiver operating characteristics (ROC) curve analyses were performed. Analyses were repeated by using multiples of median (MoM) of CL adjusted for gestational age. Results Of 796 participants, the mean midtrimester CL was 40 ± 6 mm with a 1st, 5th, and 10th percentile of 25, 29, and 32 mm, respectively. ROC curve analyses suggest that a cut-off of 30 mm was the optimal CL to predict sPTB before 35 weeks (area under the ROC curve [AUC]: 0.70, 95% confidence interval [CI]: 0.56–0.85) and before 37 weeks (AUC: 0.70, 95% CI: 0.59–0.80). Midtrimester CL Conclusion A midtrimester CL cut-off of 30 mm (instead of 25 mm), or CL less than 0.75 MoM, should be used to identify nulliparous women at high risk of sPTB. Key Points

Objective Daily aspirin, started in the first trimester of pregnancy, is commonly used for the prevention of preeclampsia and fetal growth restriction in multiple gestation. However, the optimal dose remains controversial and the evidence for the use of aspirin in multiple pregnancies is scarce. We aimed to estimate the impact of 80 mg of aspirin in twin pregnancies. Study Design We performed a pilot double-blind randomized trial of women with twin pregnancies recruited between 8 and 14 weeks of gestation. Fifty participants (25 in each group) were randomized to 80 mg of aspirin daily at bedtime or a placebo from randomization until 36 weeks of gestation. Primary and secondary outcomes included the birth weight of live infants, preeclampsia, and aspirin responsiveness evaluated by a platelet aggregation test (platelet function assay [PFA]-100). Results All participants were followed until birth, including 48 and 47 live newborns in the aspirin and the placebo groups, respectively. The mean birth weight difference between the aspirin (2,385 ± 529 g) and placebo (2,224 ± 706 g) groups was of 179 g (95% confidence interval [CI]: −172–531 g, p = 0.32). We observed two (8%) cases of preeclampsia in the aspirin group and no case with placebo (p = 0.49). Most importantly,16 of 24 participants who received aspirin (67%; 95% CI: 45–84%) had a normal PFA-100 test at 22 to 23 weeks, including the two cases of preeclampsia, suggesting that the majority of the participants were nonresponsive to 80 mg of aspirin. Conclusion Our results suggest that the majority of women with twin pregnancies showed a lack of response to a daily dose of 80 mg of aspirin according to the PFA-100 test, compared with the expected 29% of nonresponsiveness in singleton pregnancies. A daily dose of 80 mg of aspirin is likely to be insufficient for the prevention of preeclampsia and other placenta-mediated complications in twin pregnancies. Key Points

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., Graphical abstract Image 1, Highlights • 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.

INTRODUCTION: Preeclampsia (PE), but mainly preterm PE, is associated with deep placentation disorders. We aimed to compare placental pathologies in pregnancies affected by term and preterm PE comp...

International audience; Objectives: To provide up-to-date evidence-based guidelines for the management of smoking cessation during pregnancy and the post-partum period.Study design: A systematic review of the international literature was undertaken between January 2003 and April 2019. MEDLINE, EMBASE databases and the Cochrane library were searched for a range of predefined key words. All relevant reports in English and French were classified according to their level of evidence ranging from 1(highest) to 4(lowest). The strength of each recommendation was classified according to the Haute Autorité de Santé (French National Authority for Health) ranging from A (highest) to C (lowest).Results: \"Counselling\", including all types of non-pharmacological interventions, has a moderate benefit on smoking cessation, birth weight and prematurity. The systematic use of measuring expired air CO concentration does not influence smoking abstinence, however, it may be useful in assessing smoked tobacco exposure prior to and after quitting. The use of self-help therapies and health education are recommended in helping pregnant smokers quit and should be advised by healthcare professionals. Nicotine replacement therapies (NRT) may be prescribed to pregnant women who have failed to stop smoking after trying non-pharmacological interventions. Different modes of delivery and dosages can be used in optimizing their efficacy. Smoking in the postpartum period is essential to consider. The same treatment options as during pregnancy can be used.Conclusion: Smoking during pregnancy concerns more than a hundred thousand women each year in France resulting in a major public health burden. Healthcare professionals should be mobilised to employ a range of methods to reduce or even eradicate it.

Objectives To determine whether the surgical learning curve impact the spontaneous pregnancy rate in infertile patients undergoing removal of deep infiltrating endometriosis Material and Methods Single center retrospective study including the first 50 consecutive infertile women suffering from deep infiltrating endometriosis and referred to a single surgeon. All patients underwent laparoscopic removal of deep endometriosis lesions. The study population was stratified in two subgroups, namely the early group (including the first 25 cases) and the late group (comprising the 25 subsequent cases). Pregnancy and live birth rates, surgical morbidity and clinical recurrence rate were compared between study groups. Results Overall, spontaneous pregnancy rate (40 % in the early group versus 56 % in the late group, p = 0.25), live birth rate (40 % versus 44 %, p = 0.77) and clinical recurrence rate (16 % versus 4%, p = 0.16) did not significantly differ between the study groups. Logistic regression analysis revealed that ASRM stage, EFI score, and body mass index were the only significant prognostic factors of postoperative spontaneous fertility. Conclusion Surgical resection of deep infiltrating endometriosis in infertile women is associated with high spontaneous pregnancy and live birth rates. The surgeon’s learning curve does not impact postoperative fertility outcomes.

Objective Increased expression of soluble fms-like tyrosine kinase 1 (sFlt-1), associated with a decrease in placental growth factor (PlGF), plays a key role in the pathogenesis of preeclampsia (PE). We evaluated the prognostic value of the sFlt-1/PlGF ratio for the onset of adverse maternofetal outcomes (AMFO) in case of early-onset PE with attempted expectant management. Study Design From October 2016 through November 2018, all singleton pregnancies complicated by early-onset PE (before 34 weeks of gestation) were included in a cohort study. The plasma levels of sFlt-1 and PlGF were blindly measured on admission. For the statistical analysis, we performed a bivariate analysis, a comparison of the receiving operating characteristic curves and a survival analysis estimated by the Kaplan–Meier method. Results Among 109 early PE, AMFO occurred in 87 pregnancies (79.8%), mainly hemolysis, elevated liver enzymes, and low platelet count syndrome and severe fetal heart rate abnormalities requiring urgent delivery. The area under the curve (AUC) of sFlt-1/PlGF ratio was 0.82 (95% confidence interval [CI]: 0.73–0.88) for the risk of AMFO and the difference between the AUCs was significant for each separate standard parameter (p = 0.018 for initial diastolic blood pressure, p = 0.013 for alanine aminotransferase, p Conclusion The sFlt-1/PlGF ratio is an additional tool in the prediction of AMFO in proven early-onset PE, which is likely to improve care by anticipating severe complications. Key Points

Objective To compare the effects of 80 mg and 160 mg of aspirin, initiated in the first trimester of pregnancy, on mid-trimester uterine artery pulsatility index (UtA-PI) in women with a history of preeclampsia. Methods We performed a pilot double-blind randomized controlled trial. Pregnant women with a history of preeclampsia were recruited between 100/7 and 136/7 weeks gestation and randomly assigned to take either 80 or 160 mg of aspirin daily at bedtime from randomization to 356/7 weeks gestation. The primary outcome was mean UtA-PI at 22–24 weeks. Secondary outcomes included the rate of fetal growth restriction and preeclampsia, stratified as term (≥37 weeks), preterm ( Results A total of 107 participants were randomized, including 41 (38%) with a history of preterm preeclampsia and 16 (15%) with a history of early-onset preeclampsia. We observed no significant difference in mean UtA-PI at 22–24 weeks between the 2 groups (0.97; 95% CI 0.88–1.05 vs. 0.97; 95% CI 0.88–1.07, P = 0.9). The rates of fetal growth restriction (8% vs. 2%; P = 0.20); preeclampsia (12% vs. 15%; P = 0.78), preterm preeclampsia (4% vs. 2%; P = 0.56), and early-onset preeclampsia (0% vs. 2%; P = 0.52) were similar in both groups. No serious adverse events associated with the study treatment were reported. Conclusion We observed no significant difference in UtA-PI between the two doses of aspirin, but we observed low rates of fetal growth restriction and preterm and early-onset preeclampsia (all less than 5%). The benefits of aspirin for the prevention of preterm preeclampsia is probably not related to the improvement of deep placentation alone.

To evaluate the rate of mid-trimester microbial invasion of the amniotic cavity (MIAC) in asymptomatic women and its association with preterm birth. This is a prospective cohort study of asymptomatic women undergoing mid-trimester amniocentesis for genetic testing between 14 and 24 weeks of gestation. For each participant, a sample of amniotic fluid was incubated in an aerobic and anaerobic facultative culture media and another sample was tested for the presence of specific Mycoplasma species (Ureaplasma urealyticum, Ureaplasma parvum, and Mycoplasma hominis) using quantitative-PCR. Results were not revealed to the participants or their health care providers. All participants were followed until delivery. MIAC was defined by a positive culture or a positive PCR for Mycoplasma species. The primary outcome was a spontaneous preterm birth or preterm premature rupture of membranes before 35 weeks of gestation. We included 812 women at a median gestational age of 16 5/7 (interquartile: 15 6/7–17 4/7) weeks. Twenty-six (3.2%) had a spontaneous delivery before 35 weeks. We observed no case of positive PCR for Mycoplasma species and 4 (0.5%) cases of positive culture that were all considered to be skin contaminants. None of those four cases was associated with preterm birth. Nulliparity, low family income and history of preterm birth were associated with spontaneous delivery before 35 weeks. We found no case of mid-trimester MIAC using a combination of culture and Mycoplasma-specific PCR techniques in a large cohort of low-risk asymptomatic pregnant women. We estimate that mid-trimester MIAC is rare in low-risk population but more sensitive and broad-range microbiologic techniques, such as 16S DNA detection by PCR, could be further evaluated.

To estimate the optimal midtrimester cervical length (CL) threshold for the prediction of spontaneous preterm birth (sPTB) in asymptomatic pregnant women.This is a prospective observational cohort study including asymptomatic women with singleton pregnancies who underwent CL measurement by transabdominal and/or transvaginal ultrasound between 19°Out of 3,449 participants, 28 (0.8%) had a sPTB before 35 weeks and 99 (2.9%) had a sPTB before 37 weeks. Receiver operating characteristics (ROC) curves suggest that a cut-off of 30 mm was the optimal CL to predict sPTB before 35 weeks (sensitivity: 43%; specificity: 97%) and sPTB before 37 weeks (sensitivity: 21%; specificity: 97%). While a CL25 mm was an important risk factor for sPTB before 35 weeks (relative risk: 31; 95% confidence interval: 13-73), women with a CL between 25 and 30 mm were also at greater risk (relative risk: 12; 95% confidence interval: 4 - 35) compared to women with CL ≥30 mm.A midtrimester CL30 mm should be considered to identify women at high-risk of sPTB.

Placental Growth Factor (PlGF) is used for the prediction of preeclampsia (PE), a syndrome associated with maternal vascular malperfusion (MVM). Our goal is to determine the correlation between PlGF and MVM.We performed a secondary analysis of the PEARL study that included nulliparous women with PE (cases), and low-risk nulliparous women recruited in early pregnancy (controls). All participants provided blood samples at diagnosis of PE (cases), or between 26 and 34 weeks (controls) for measurement of PlGF (B·R·A·H·M·S plus KRYPTOR automated assays), that was transformed into multiple of median (MoM). Placental examination was performed for the diagnosis of MVM based on the Amsterdam Placental Workshop Group Consensus Statement. Nonparametric tests and receiver operating characteristic (ROC) curves were used to compare PlGF in pregnancies with, and without PE, stratified by the presence of MVM.Third trimester PlGF was lower in PE cases with MVM (N = 20; median: 0.04 MoM; interquartile: 0.03-0.09; p0.0001), and in controls with MVM (N = 4; 0.30MoM; 0.07-0.52; p = 0.002) compared to controls without MVM (N = 29; 0.99 MoM; 0.67-1.52). PlGF in PE cases without MVM (N = 5; 0.18 MoM; 0.17-1.64) was not significantly different than in controls without MVM but the sample size was small. ROC curve demonstrated a greater predictability of PlGF for PE with MVM than PE without MVM (AUC: 0.99 vs. 0.38; p0.0001).Third trimester PlGF is a better predictor of PE associated with MVM than a predictor of PE without MVM. We hypothesize that PlGF is a stronger marker of MVM than PE.

Background: To explore the use of maternal urine proteome for the identification of preeclampsia biomarkers. Methods: Maternal urine samples from women with and without preeclampsia were used for protein discovery followed by a validation study. The targeted proteins of interest were then measured in urine samples collected at 20–24 and 30–34 weeks among nine women who developed preeclampsia, one woman with fetal growth restriction, and 20 women with uncomplicated pregnancies from a longitudinal study. Protein identification and quantification was obtained using liquid chromatography–tandem mass spectrometry (LC–MS/MS). Results: Among the 1108 urine proteins quantified in the discovery study, 21 were upregulated in preeclampsia and selected for validation. Nineteen (90%) proteins were confirmed as upregulated in preeclampsia cases. Among them, two proteins, ceruloplasmin and serpin A7, were upregulated at 20–24 weeks and 30–34 weeks of gestation (p &lt, 0.05) in cases of preeclampsia, and could have served to identify 60% of women who subsequently developed preeclampsia and/or fetal growth restriction at 20–24 weeks of gestation, and 78% at 30–34 weeks, for a false-positive rate of 10%. Conclusions: Proteomic profiling of maternal urine can differentiate women with and without preeclampsia. Several proteins including ceruloplasmin and serpin A7 are upregulated in maternal urine before the diagnosis of preeclampsia and potentially fetal growth restriction.

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.

International audience; OBJECTIVE:HELLP syndrome exposes to severe maternal and fetal complications. Prompt delivery is thus recommended after 34 weeks of gestation, or earlier in case of nonreassuring maternofetal conditions. However, no consensus has been raised in the treatment of HELLP syndrome occurring before 34 weeks of gestation, when both maternal and fetal conditions are stable: it remains still unclear whether an active attitude should be prioritized over expectant management. Herein, we aimed to compare mother and child outcomes according to the type of obstetrical management, either active or conservative.STUDY DESIGN:Retrospective and multicenter study involving two tertiary care units. In Center A, obstetrical attitude consisted in expectant management: all women received full antenatal betamethasone therapy and pregnancy was prolonged until maternal or fetal follow up indicated delivery. In Center B, management was active: all deliveries were initiated within 48 hours following diagnosis.RESULTS:From 2003 to 2011, 118 patients were included (87 in Center A, 31 in Center B). Both groups of patients were similar regarding maternal and fetal features at baseline. Active management led to increased risks of post-partum hemorrhage (relative risks (RR) = 5.38, 95%CI: 1.2-24.06) and neonatal morbidity including respiratory distress syndrome (RR = 3.1, 95%CI: 1.4-7.1), sepsis (RR = 2.5, 95%CI: 1.1-6.0), necrotizing enterocolitis (RR = 4.8, 95%CI: 1.1-21.2), intracerebral hemorrhage (RR = 5.4, 95%CI: 2.1-13.6), and blood transfusion (RR = 6.1, 95%CI: 1.7-21.7).CONCLUSIONS:Conservative management may be beneficial for both mother and newborn in patients with stable HELLP syndrome. Identification of maternal and fetal specific prognostic factors would allow a better stratification of women with HELLP syndrome according to illness progressive potential, resulting in a more personalized management.

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 (O2•–). 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 pO2 (O2 1%) or to pO2 changes (O2 1–20%), in order to generate oxidative stress. Trophoblasts exposed to low pO2, 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 pO2 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 pO2 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., Graphical abstract fx1, Highlights • eNOS is S-glutathionylated in preeclamptic placentas. • Oxidative stress evoked by pO2 changes, triggers eNOS S-glutathionylation in HTR8. • pO2 changes alter the invasive potential of HTR8 in the wound closure model. • The NO donor NOC-18 restores the invasive potential of HTR8.

To evaluate spatulas for entrapment of the after-coming head (EAH) during vaginal breech delivery, in the setting of failed usual manoeuvres (Bracht or Mauriceau). We led a retrospective cohort study in two tertiary referral hospital in France. From 2003 to 2018, we included all deliveries of live children requiring the use of spatulas (Thierry’s and Teissier’s) for EAH during vaginal breech delivery. Over the period, 59 breech deliveries with spatulas for EAH were enrolled (prevalence 2.3%). No vaginal delivery failures were found. The average term was 36 weeks of gestation. Mean maternal age was 29.4 years and median parity was 1. 50.8% of the foetuses presented as complete breech, 40.7% as frank breech, and 8.5% as footling breech. Maternal morbidity was low: no obstetrical lesions of the anal sphincter, 28% episiotomy (performed before application of instruments in most cases). There was no evidence of foetal over-morbidity. The average weight of the foetuses was 2635g. There was no serious trauma associated with the use of spatulas: only one case of skin lesion and a case of non-severe cephalhematoma could be attributed to the instrument. Mean arterial pH was 7.19, the median 5-min Apgar score was 10. In compliance with obstetrical mechanics, spatulas should be considered as an effective instrument during EAH with maternal and foetal safety. This is the first cohort describing the use of an instrument to manage EAH during vaginal breech delivery, while knowledge and mastery of this technique are essential to manage this situation.

The Fetal Medicine Foundation proposed a competing risks model for early identification of women at a high risk of preterm preeclampsia, typically associated with deep placentation disorders. The Great Obstetrical Syndromes include a spectrum of pregnancy complications (preeclampsia, intrauterine growth restriction, preterm birth, late spontaneous abortion, and abruptio placentae) that are also associated with deep placentation disorders.This study aimed to estimate the rate of placenta-mediated pregnancy complications in nulliparous women with a positive first-trimester Fetal Medicine Foundation preterm preeclampsia screening test.We conducted a prospective cohort study of nulliparous women recruited at 11 to 14 weeks of gestation. Maternal characteristics, mean arterial blood pressure, levels of maternal serum biomarkers (pregnancy-associated plasma protein-A, placental growth factor, and soluble fms-like tyrosine kinase-1), and mean uterine artery pulsatility index were obtained to calculate the risk of preterm preeclampsia according to the Fetal Medicine Foundation algorithm. The predicted risks were dichotomized as a positive or negative test according to 2 risk cutoffs (1 in 70 and 1 in 100). The detection rate, false-positive rate, and positive and negative predictive values were calculated for placenta-mediated complications, including preeclampsia, small for gestational age (birthweight10th percentile), fetal death, preterm birth, and a composite outcome, including any of the foregoing. The same analyses were computed for a composite of severe outcomes, including preterm preeclampsia, severe small for gestational age (less than third percentile), and fetal death.We included 4575 participants with complete observations, of whom 494 (10.8%) had an estimated risk of preterm preeclampsia of ≥1 in 70 and 728 (15.9%) had a risk of ≥1 in 100. The test based on a risk cutoff of 1 in 70 could have correctly predicted up to 27% of preeclampsia, 55% of preterm preeclampsia, 18% of small for gestational age, 24% of severe small for gestational age, and 37% of fetal deaths at a 10% false-positive rate. The test based on a cutoff of 1 in 100 could have predicted correctly up to 35% of preeclampsia, 69% of preterm preeclampsia, 25% of small for gestational age, 30% of severe small for gestational age, and 53% of fetal deaths at a 15% false-positive rate. The positive predictive value of a screening test for preterm preeclampsia of ≥1 in 70 was 3% for preterm preeclampsia, 32% for the composite outcome, and 9% for the severe composite outcome.Nulliparous women with a first-trimester positive preterm preeclampsia Fetal Medicine Foundation screening test are at a higher risk of both preterm preeclampsia and other severe placenta-mediated pregnancy complications. Approximately 1 woman of 10 identified as high risk by the Fetal Medicine Foundation algorithm developed at least 1 severe placenta-mediated pregnancy complication.

Background We performed a systematic review and meta-analysis to assess the efficacy and safety of heparin for preventing adverse obstetrical outcomes in pregnant women with antiphospholipid syndrome (APS). Methods We reviewed randomized controlled trials from CENTRAL, EMBASE, MEDLINE, and Web of science (inception to November 5th 2019), and relevant article reference lists. Two reviewers independently screened and extracted data from trials investigating heparin, including Low Molecular Weight Heparin (LMWH) and unfractionated heparin (UFH) at any dose, associated or not with aspirin, compared to any comparator group in pregnant women with APS. Internal validity was assessed in duplicate using the Cochrane Risk of Bias tool. The strength of evidence was assessed in duplicate using the Grading of Recommendations Assessment, Development and Evaluation framework. Our primary outcome was live birth rate. Secondary outcomes included preeclampsia, preterm birth, intra-uterine growth restriction (IUGR) and thromboembolism. Safety outcomes included maternal or neonatal bleedings, heparin-induced thrombocytopenia and allergy. Subgroup analyses were conducted to explore heterogeneity. Results From 2395 identified citations, 13 trials (1916 patients) met inclusion criteria. Heparin, associated or not with aspirin, significantly increased the rate of live birth compared to any comparator (RR 1.20; 95 % CI 1.09−1.33, I2 = 67 %, 1916 patients, low-certainty evidence). In subgroup analyses, LMWH and UFH were independently associated with greater rates of live birth: RR 1.15 (95 % CI 1.04–1.28, I2 = 71 %, 1684 patients, 9 trials) and RR 1.45 (95 % CI 1.16–1.81, I2 = 19 %, 149 patients, 4 trials) respectively. Heparin associated or not to aspirin, significantly decreased the rate of preeclampsia compared to any comparator (RR 0.32; 95 % CI 0.12−0.87, I2 = 0%, 465 patients, 8 trials) but was not associated with differential rates of preterm birth nor IUGR. Heparin was associated with minor bleeding (bruises, epistaxis): RR 2.58 (95 % CI 1.03−6.43, I2 = 16 %, 653 patients, 9 trials). No serious maternal or neonatal adverse events were reported in the included studies. Conclusions In pregnant women with APS, heparin, associated or not to aspirin, significantly improved the live birth rate compared to any comparator and decreased the risk of preeclampsia, without increasing maternal and neonatal severe morbidity.

To compare the short- and long-term perineal consequences (at 6 months postpartum) and short-term neonatal consequences of instrumental rotation (IR) to those induced by assisted delivery (AD) in the occiput posterior (OP) position, in case of manual rotation failure. A prospective observational cohort study; tertiary referral hospital including all women presenting with persistent OP position who delivered vaginally after manual rotation failure with attempted IR or AD in OP position from September 2015 to October 2016. Maternal and neonatal outcomes of all attempted IR deliveries were compared with OP operative vaginal deliveries. Main outcomes measured were pelvic floor function at 6 months postpartum including Wexner score for anal incontinence and ICIQ-FLUTS for urinary symptoms. Perineal morbidity comprised severe perineal tears, corresponding to third and fourth degree lacerations. Fetal morbidity parameters comprised low neonatal Apgar scores, acidaemia, major and minor fetal injuries and neonatal intensive care unit admissions. Among 5265 women, 495 presented with persistent OP positions (9.4%) and 111 delivered after manual rotation failure followed by AD delivery: 58 in the IR group and 53 in the AD in OP group. The incidence of anal sphincter injuries was significantly reduced after IR attempt (1.7% vs. 24.5%; p

To compare the maternal and neonatal outcomes associated with Instrumental Rotation (IR) to operative vaginal delivery in occiput posterior (OP) position with Thierry's spatulas (TS), in the setting of failed manual rotation (MR).We led a prospective observational cohort study in a tertiary referral hospital in Toulouse, France. All women presenting in labor with persistent OP position at full cervical dilatation and who delivered vaginally after failed MR and with IR or OP assisted delivery were included from January 2014 to December 2015. The main outcomes measured were maternal morbidity parameters including episiotomy rate, incidence and severity of perineal lacerations, perineal hematomas and postpartum hemorrhage. Severe perineal tears corresponded to third and fourth degree lacerations. Fetal morbidity outcomes comprised neonatal Apgar scores, acidemia, fetal injuries, birth trauma and neonatal intensive care unit admissions.Among 9762 women, 910 (9.3%) presented with persistent OP position at full cervical dilatation and 222 deliveries were enrolled. Of 111 attempted IR, 97 were successful (87.4%). The incidence of anal sphincter injuries was significantly reduced after IR attempt (1.8% vs. 12.6%; p 0.002). Both groups were similar regarding most fetal outcomes and no birth trauma occurred in our study population. In a multivariable logistic regression analysis, OP operative delivery was a significant risk factor of severe perineal lacerations (OR = 9.5; 95% CI: 2.05-44.05).Our results support the use of IR in order to reduce perineal morbidity associated with OP assisted delivery, in the setting of a failed manual rotation.

Preeclampsia is a leading cause of pregnancy complications and affects 3-7% of pregnant women. Pathophysiology of preeclampsia is still unclear. According to the two-stage model of preeclampsia, the abnormal and hypoperfused placenta (stage 1) releases factors to the bloodstream, which are responsible for the maternal symptoms (stage 2), characterised by a systemic inflammation and endothelial dysfunction. Oxidative stress plays an important role in the pathophysiology of the preeclampsia and could be the common denominator between the two. This review summarizes the current knowledge of a new potential etiology of the disease, with a special focus on oxidative stress. We also review the different factors that have been proposed to cause endothelial cell dysfunction in preeclampsia, and trials investigating the role of antioxidant supplementation in preeclampsia.