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

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

Pregnancy outcomes and vaccine effectiveness during the period of omicron as the variant of concern, INTERCOVID-2022: a multinational, observational study.

BACKGROUND: In 2021, we showed an increased risk associated with COVID-19 in pregnancy. Since then, the SARS-CoV-2 virus has undergone genetic mutations. We aimed to examine the effects on maternal and perinatal outcomes of COVID-19 during pregnancy, and evaluate vaccine effectiveness, when omicron (B.1.1.529) was the variant of concern. METHODS: INTERCOVID-2022 is a large, prospective, observational study, involving 41 hospitals across 18 countries. Each woman with real-time PCR or rapid test, laboratory-confirmed COVID-19 in pregnancy was compared with two unmatched women without a COVID-19 diagnosis who were recruited concomitantly and consecutively in pregnancy or at delivery. Mother and neonate dyads were followed until hospital discharge. Primary outcomes were maternal morbidity and mortality index (MMMI), severe neonatal morbidity index (SNMI), and severe perinatal morbidity and mortality index (SPMMI). Vaccine effectiveness was estimated, adjusted by maternal risk profile. FINDINGS: We enrolled 4618 pregnant women from Nov 27, 2021 (the day after WHO declared omicron a variant of concern), to June 30, 2022: 1545 (33%) women had a COVID-19 diagnosis (median gestation 36·7 weeks [IQR 29·0-38·9]) and 3073 (67%) women, with similar demographic characteristics, did not have a COVID-19 diagnosis. Overall, women with a diagnosis had an increased risk for MMMI (relative risk [RR] 1·16 [95% CI 1·03-1·31]) and SPMMI (RR 1·21 [95% CI 1·00-1·46]). Women with a diagnosis, compared with those without a diagnosis, also had increased risks of SNMI (RR 1·23 [95% CI 0·88-1·71]), although the lower bounds of the 95% CI crossed unity. Unvaccinated women with a COVID-19 diagnosis had a greater risk of MMMI (RR 1·36 [95% CI 1·12-1·65]). Severe COVID-19 symptoms in the total sample increased the risk of severe maternal complications (RR 2·51 [95% CI 1·84-3·43]), perinatal complications (RR 1·84 [95% CI 1·02-3·34]), and referral, intensive care unit (ICU) admission, or death (RR 11·83 [95% CI 6·67-20·97]). Severe COVID-19 symptoms in unvaccinated women increased the risk of MMMI (RR 2·88 [95% CI 2·02-4·12]) and referral, ICU admission, or death (RR 20·82 [95% CI 10·44-41·54]). 2886 (63%) of 4618 total participants had at least a single dose of any vaccine, and 2476 (54%) of 4618 had either complete or booster doses. Vaccine effectiveness (all vaccines combined) for severe complications of COVID-19 for all women with a complete regimen was 48% (95% CI 22-65) and 76% (47-89) after a booster dose. For women with a COVID-19 diagnosis, vaccine effectiveness of all vaccines combined for women with a complete regimen was 74% (95% CI 48-87) and 91% (65-98) after a booster dose. INTERPRETATION: COVID-19 in pregnancy, during the first 6 months of omicron as the variant of concern, was associated with increased risk of severe maternal morbidity and mortality, especially among symptomatic and unvaccinated women. Women with complete or boosted vaccine doses had reduced risk for severe symptoms, complications, and death. Vaccination coverage among pregnant women remains a priority. FUNDING: None.

Tranexamic Acid for the Prevention of Blood Loss after Cesarean Delivery.

BACKGROUND: Prophylactic administration of tranexamic acid has been associated with reduced postpartum blood loss after cesarean delivery in several small trials, but evidence of its benefit in this clinical context remains inconclusive. METHODS: In a multicenter, double-blind, randomized, controlled trial, we assigned women undergoing cesarean delivery before or during labor at 34 or more gestational weeks to receive an intravenously administered prophylactic uterotonic agent and either tranexamic acid (1 g) or placebo. The primary outcome was postpartum hemorrhage, defined as a calculated estimated blood loss greater than 1000 ml or receipt of a red-cell transfusion within 2 days after delivery. Secondary outcomes included gravimetrically estimated blood loss, provider-assessed clinically significant postpartum hemorrhage, use of additional uterotonic agents, and postpartum blood transfusion. RESULTS: Of the 4551 women who underwent randomization, 4431 underwent cesarean delivery, 4153 (93.7%) of whom had primary outcome data available. The primary outcome occurred in 556 of 2086 women (26.7%) in the tranexamic acid group and in 653 of 2067 (31.6%) in the placebo group (adjusted risk ratio, 0.84; 95% confidence interval [CI], 0.75 to 0.94; P = 0.003). There were no significant between-group differences in mean gravimetrically estimated blood loss or in the percentage of women with provider-assessed clinically significant postpartum hemorrhage, use of additional uterotonic agents, or postpartum blood transfusion. Thromboembolic events in the 3 months after delivery occurred in 0.4% of women (8 of 2049) who received tranexamic acid and in 0.1% of women (2 of 2056) who received placebo (adjusted risk ratio, 4.01; 95% CI, 0.85 to 18.92; P = 0.08). CONCLUSIONS: Among women who underwent cesarean delivery and received prophylactic uterotonic agents, tranexamic acid treatment resulted in a significantly lower incidence of calculated estimated blood loss greater than 1000 ml or red-cell transfusion by day 2 than placebo, but it did not result in a lower incidence of hemorrhage-related secondary clinical outcomes. (Funded by the French Ministry of Health; TRAAP2 ClinicalTrials.gov number, NCT03431805.).

Hydroxychloroquine levels in pregnancy and materno-fetal outcomes in Systemic Lupus Erythematosus patients.

OBJECTIVES: Data about hydroxychloroquine (HCQ) levels during pregnancy are sparse. We assessed HCQ whole blood levels at first trimester of pregnancy as a potential predictor of maternal and obstetric/fetal outcomes in patients with systemic lupus erythematosus (SLE). METHODS: We included pregnant SLE patients enrolled in the prospective GR2 study receiving HCQ, with at least one available first-trimester whole-blood HCQ assay. We evaluated several cut-offs for HCQ whole blood levels, including ≤200 ng/ml for severe non-adherence. Primary outcomes were maternal flares during the second and third trimesters of pregnancy, and adverse pregnancy outcomes (APOs: fetal/neonatal death, placental insufficiency with preterm delivery, and small-for-gestational-age neonates). RESULTS: We included 174 patients (median age: 32.1 years, IQR 28.8-35.2). Thirty (17.2%) patients had flares, 4 (2.3%) being severe. APOs occurred in 28 patients (16.1%). There were no significant differences in APOs by HCQ level for either those with subtherapeutic HCQ levels (≤500 ng/ml vs >500 ng/ml: 23.5% vs 14.3%, p = 0.19) or those with non-adherent HCQ levels (≤200 ng/ml vs >200 ng/ml: 20.0% vs 15.7%, p = 0.71). Similarly, the overall rate of maternal flares did not differ significantly by HCQ level cut-off, but patients with subtherapeutic (HCQ ≤500 ng/ml: 8.8% vs 0.7%, p = 0.02) and non-adherent HCQ levels (≤200 ng/ml: 13.3% vs 1.3%, p = 0.04) had significantly more severe flares. CONCLUSION: In this large prospective study of pregnant SLE patients, first-trimester subtherapeutic (≤500 ng/ml) and severe non-adherent (≤200 ng/ml) HCQ levels were associated with severe maternal flares, but not with APOs. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02450396.

How I manage pregnancy in women with Glanzmann thrombasthenia.

Glanzmann thrombasthenia (GT) is a rare inherited platelet function disorder caused by a quantitative and/or qualitative defect of the αIIbß3 integrin. Pregnancy and delivery are recognized risk periods for bleeding in women with GT. The newborn may also be affected by fetal and neonatal immune thrombocytopenia induced by the transplacental passage of maternal anti-αIIbß3 antibodies, which can lead to severe hemorrhage and fetal loss. Pregnancy in women with GT thus requires a multidisciplinary approach, including prepregnancy counseling and a treatment plan for delivery for both the mother and child. In this article, we summarize the current knowledge on pregnancy in women with GT and describe how we manage this severe platelet disorder in our clinical practice.

Closed- or open-glottis pushing for vaginal delivery: a planned secondary analysis of the TRAnexamic Acid for Preventing postpartum hemorrhage after vaginal delivery study.

BACKGROUND: The effect on obstetrical outcomes of closed- or open-glottis pushing is uncertain among both nulliparous and parous women. OBJECTIVE: This study aimed to assess the association between open- or closed-glottis pushing and mode of delivery after an attempted singleton vaginal birth at or near term. STUDY DESIGN: This was an ancillary planned cohort study of the TRAAP (TRAnexamic Acid for Preventing postpartum hemorrhage after vaginal delivery) randomized controlled trial, conducted in 15 French maternity units from 2015 to 2016 that enrolled women with an attempted singleton vaginal delivery after 35 weeks' gestation. After randomization, characteristics of labor and delivery were prospectively collected, with special attention to active second-stage pushing and a specific planned questionnaire completed immediately after birth by the attending care provider. The exposure was the mode of pushing, classified into 2 groups: closed- or open-glottis. The main endpoint was operative vaginal delivery. Secondary endpoints were items of maternal morbidity, including severe perineal laceration, episiotomy, postpartum hemorrhage, duration of the second stage of labor, and a composite severe neonatal morbidity outcome. We also assessed immediate maternal satisfaction, experience of delivery, and psychological status 2 months after delivery. The associations between mode of pushing and outcome were analyzed by multivariate logistic regression to control for confounding bias, with multilevel mixed-effects analysis, and a random intercept for center. RESULTS: Among 3041 women included in our main analysis, 2463 (81.0%) used closed-glottis pushing and 578 (19.0%) open-glottis pushing; their respective operative vaginal delivery rates were 19.1% (n=471; 95% confidence interval, 17.6-20.7) and 12.5% (n=72; 95% confidence interval, 9.9-15.4; P<.001). In an analysis stratified according to parity and after controlling for available confounders, the rate of operative vaginal delivery did not differ between the groups among nulliparous women: 28.7% (n=399) for the closed-glottis and 27.5% (n=64) for the open-glottis group (adjusted odds ratio, 0.93; 95% confidence interval, 0.65-1.33; P=.7). The operative vaginal delivery rate was significantly lower for women using open- compared with closed-glottis pushing in the parous population: 2.3% (n=8) for the open- and 6.7% (n=72) for the closed-glottis groups (adjusted odds ratio, 0.43; 95% confidence interval, 0.19-0.90; P=.03). Other maternal and neonatal outcomes did not differ between the 2 modes of pushing among either the nulliparous or parous groups. CONCLUSION: Among nulliparous women with singleton pregnancies at term, the risk of operative vaginal birth did not differ according to mode of pushing. These results will inform shared decision-making about the mode of pushing during the second stage of labor.

Prevalence and risk factors for postpartum depression 2 months after a vaginal delivery: a prospective multicenter study.

BACKGROUND: Very little is known about the prevalence and risk factors of postpartum depression among women with vaginal births without major pregnancy complications. OBJECTIVE: This study aimed to assess the prevalence of postpartum depression and identify its characteristics 2 months after singleton vaginal delivery at or near term. STUDY DESIGN: This was an ancillary cohort study of the TRanexamic Acid for Preventing Postpartum Hemorrhage After Vaginal Delivery randomized controlled trial, which was conducted in 15 French hospitals in 2015-2016 and enrolled women with singleton vaginal deliveries after 35 weeks of gestation. After randomization, the characteristics of labor, delivery, and the immediate postpartum experience, including the experience of childbirth, were prospectively collected. Medical records provided women's other characteristics, particularly any psychiatric history. Of note, 2 months after childbirth, provisional postpartum depression diagnosis was defined as a score of ≥13 on the Edinburgh Postnatal Depression Scale, a validated self-administered questionnaire. The corrected prevalence of postpartum depression was calculated with the inverse probability weighting method to take nonrespondents into account. Associations between potential risk factors and postpartum depression were analyzed by multivariate logistic regression. Moreover, an Edinburgh Postnatal Depression Scale cutoff value of ≥11 was selected to perform a sensitivity analysis. RESULTS: The questionnaire was returned by 2811 of 3891 women (72.2% response rate). The prevalence rates of the provisional diagnosis were 9.9% (95% confidence interval, 8.6%-11.3%) defined by an Edinburgh Postnatal Depression Scale score of ≥13 and 15.5% (95% confidence interval, 14.0%-17.1%) with a cutoff value of ≥11. The characteristics associated with higher risks of postpartum depression in multivariate analysis were mostly related to prepregnancy characteristics, specifically age of <25 years (adjusted odds ratio, 1.8; 95% confidence interval, 1.1-2.9) and advanced age (adjusted odds ratio, 1.8; 95% confidence interval, 1.2-2.6), migration from North Africa (adjusted odds ratio, 2.9; 95% confidence interval, 1.9-4.4), previous abortion (adjusted odds ratio, 1.4; 95% confidence interval, 1.0-2.0), and psychiatric history (adjusted odds ratio, 2.9; 95% confidence interval, 1.8-4.8). Some characteristics of labor and delivery, such as induced labor (adjusted odds ratio, 1.5; 95% confidence interval, 1.1-2.0) and operative vaginal delivery (adjusted odds ratio, 1.4; 95% confidence interval, 1.0-2.0), seemed to be associated with postpartum depression. In addition, bad memories of childbirth in the immediate postpartum were strongly associated with postpartum depression symptoms at 2 months after giving birth (adjusted odds ratio, 2.4; 95% confidence interval, 1.3-4.2). CONCLUSION: Approximately 10% of women with vaginal deliveries have postpartum depression symptoms, assessed by a score of ≥13 on the depression scale that was used at 2 months. Prepregnancy vulnerability factors; obstetrical characteristics, such as induced labor and operative vaginal delivery; and bad memories of childbirth 2 days after delivery were the main factors associated with this provisional diagnosis. A screening approach that targets risk factors may help to identify women at risk of postpartum depression who could benefit from early intervention.

Posttraumatic stress disorder 2 months after cesarean delivery: a multicenter prospective study.

BACKGROUND: The prevalence and risk factors of posttraumatic stress disorder after cesarean delivery, outside high-risk contexts, remain unclear. OBJECTIVE: This study aimed to assess posttraumatic stress disorder prevalence and risk factors at 2 months postpartum among a general population of women with cesarean delivery. STUDY DESIGN: This was a prospective ancillary cohort study of the Tranexamic Acid for Preventing Postpartum Hemorrhage after Cesarean Delivery (TRAAP2) trial, conducted in 27 French hospitals from 2018 to 2020, enrolling women expected to undergo cesarean delivery before or during labor at ≥34 weeks of gestation. After randomization, characteristics of the cesarean delivery and postpartum blood loss were prospectively collected. Two months after childbirth, posttraumatic stress disorder profile (presence of posttraumatic stress disorder symptoms) and provisional diagnosis (positive screening for diagnosis consistent with a posttraumatic stress disorder) were assessed by 2 self-administered questionnaires (Impact of Event Scale - Revised and Traumatic Event Scale). The corrected posttraumatic stress disorder prevalence was estimated with inverse probability weighting to take nonresponse into account. Associations between potential risk factors and posttraumatic stress disorder were analyzed by multivariate logistic or linear regression modeling according to the type of dependent variable. RESULTS: In total, 2785 of 4431 women returned the Impact of Event Scale - Revised questionnaire and 2792 the Traumatic Event Scale (response rates of 62.9% and 63.0%). The prevalence of posttraumatic stress disorder profile was 9.0% (95% confidence interval, 7.8%-10.3%) and of provisional diagnosis 1.7% (95% confidence interval, 1.2%-2.4%). Characteristics associated with a higher risk of posttraumatic stress disorder profile were prepregnancy vulnerability factors (young age, high body mass index, and African-born migrant) and cesarean delivery-related obstetrical factors (cesarean delivery after induced labor [adjusted odds ratio, 1.81; 95% confidence interval, 1.14-2.87], postpartum hemorrhage [adjusted odds ratio, 1.61; 95% confidence interval, 1.04-2.46] and high-intensity pain during the postpartum stay [adjusted odds ratio, 1.90; 95% confidence interval, 1.17-3.11]). Women who had immediate skin-to-skin contact with their newborn were at lower risk of posttraumatic stress disorder (adjusted odds ratio, 0.66; 95% confidence interval, 0.46-0.98), and women with bad memories of delivery on day 2 postpartum were at higher risk (adjusted odds ratio, 3.20; 95% confidence interval, 1.97-5.12). The Impact of Event Scale - Revised and the Traumatic Event Scale yielded consistent results. CONCLUSION: Approximately 1 in 11 women with cesarean deliveries had posttraumatic stress disorder symptoms at 2 months postpartum. Some obstetrical interventions and components of cesarean delivery management may influence this risk.

The ethics of induction of labor at 39 weeks in low-risk nulliparas in research and clinical practice.

The "A Randomized Trial of Induction Versus Expectant Management" trial (ARRIVE trial) published in 2018 suggested that induction of labor can be considered a "reasonable option" for low-risk nulliparous women at ≥39 weeks of gestation. The study results led some professional societies to endorse the option for elective induction of labor at 39 weeks of gestation in low-risk nulliparas, and this has begun to change obstetrical practice. The ARRIVE trial provided valuable information supporting the benefits of induction of labor; however, the trial is insufficient to serve as the primary justification for widespread elective induction of labor at 39 weeks of gestation in low-risk nulliparas because of concerns about external validity. Thus, the French ARRIVE trial was designed to test the hypothesis in a different setting that elective induction of labor at 39 weeks of gestation in low-risk nulliparas leads to a lower cesarean delivery rate than expectant management. This ongoing trial has been criticized as "pseudoscientific" and telling "women where, when, and how to give birth." We reject these allegations and extensively examine the ethical framework that should govern clinical and research interventions, including elective induction of labor at 39 weeks of gestation in low-risk nulliparas. This study aimed to discuss the ethical issues that emerge from randomized trials of elective induction of labor at 39 weeks of gestation in low-risk nulliparas and the ethics of the clinical practice itself. The analysis of existing evidence shows the importance of further research on induction of labor at 39 weeks of gestation in low-risk women. Certain aspects of research ethics in this area, particularly the consent of pregnant women in a context where autonomy remains fragile, call for vigilance. In addition, we emphasize that childbirth is not only a medical object but also a social phenomenon that cannot be regarded only from the perspective of a health risk to be managed by clinical research. Further research on this issue is needed to allow pregnant women to make informed decisions, and the results should be integrated with social issues. The perspective of women is required in constructing, evaluating, and implementing medical interventions in childbirth, such as induction of labor at 39 weeks of gestation.

Survival without severe neonatal morbidity after antenatal betamethasone dose reduction: a post hoc analysis of a randomized non-inferiority trial.

BACKGROUND: Antenatal betamethasone is recommended before preterm delivery to accelerate fetal lung maturation. However, its optimal dose remains unknown. A 50% dose reduction was proposed to decrease the potential dose-related long-term neurodevelopmental side effects, including psychological development, sleep, and emotional disorders. Because noninferiority of the half dose in terms of the need for exogenous surfactant was not shown in the primary analysis, its impact on survival without major neonatal morbidity needs to be investigated. OBJECTIVE: This study aimed to investigate the impact of antenatal betamethasone dose reduction on survival of very preterm infants without severe neonatal morbidity, a factor known to have a strong correlation with long-term outcomes. STUDY DESIGN: We performed a post hoc secondary analysis of a randomized, multicenter, double-blind, placebo-controlled, noninferiority trial, testing half (11.4 mg once; n=1620) vs full (11.4 mg twice, 24 hours apart; n=1624) antenatal betamethasone doses in women at risk of preterm delivery. To measure survival without severe neonatal morbidity at hospital discharge among neonates born before 32 weeks of gestation, we used the definition of the French national prospective study on preterm children, EPIPAGE 2, comprising 1 of the following morbidities: grade 3 to 4 intraventricular hemorrhage, cystic periventricular leukomalacia, necrotizing enterocolitis stage ≥2, retinopathy of prematurity requiring anti-vascular endothelial growth factor therapy or laser, and moderate-to-severe bronchopulmonary dysplasia. RESULTS: After exclusion of women who withdrew consent or had pregnancy termination and of participants lost to follow-up (8 in the half-dose and 10 in the full-dose group), the rate of survival without severe neonatal morbidity among neonates born before 32 weeks of gestation was 300 of 451 (66.5%) and 304 of 462 (65.8%) in the half-dose and full-dose group, respectively (risk difference, +0.7%; 95% confidence interval, -5.6 to +7.1). There were no significant between-group differences in the cumulative number of neonatal morbidities. Results were similar when using 2 other internationally recognized definitions of severe neonatal morbidity and when considering the overall population recruited in the trial. CONCLUSION: In the BETADOSE trial, severe morbidity at discharge of newborns delivered before 32 weeks of gestation was found to be similar among those exposed to 11.4-mg and 22.8-mg antenatal betamethasone. Additional studies are needed to confirm these findings.

Maternal vaccination against COVID-19 and neonatal outcomes during Omicron: INTERCOVID-2022 study.

BACKGROUND: In early 2023, when Omicron was the variant of concern, we showed that vaccinating pregnant women decreased the risk for severe COVID-19-related complications and maternal morbidity and mortality. OBJECTIVE: This study aimed to analyze the impact of COVID-19 during pregnancy on newborns and the effects of maternal COVID-19 vaccination on neonatal outcomes when Omicron was the variant of concern. STUDY DESIGN: INTERCOVID-2022 was a large, prospective, observational study, conducted in 40 hospitals across 18 countries, from November 27, 2021 (the day after the World Health Organization declared Omicron the variant of concern) to June 30, 2022, to assess the effect of COVID-19 in pregnancy on maternal and neonatal outcomes and to assess vaccine effectiveness. Women diagnosed with laboratory-confirmed COVID-19 during pregnancy were compared with 2 nondiagnosed, unmatched women recruited concomitantly and consecutively during pregnancy or at delivery. Mother-newborn dyads were followed until hospital discharge. The primary outcomes were a neonatal positive test for COVID-19, severe neonatal morbidity index, severe perinatal morbidity and mortality index, preterm birth, neonatal death, referral to neonatal intensive care unit, and diseases during the neonatal period. Vaccine effectiveness was estimated with adjustment for maternal risk profile. RESULTS: We enrolled 4707 neonates born to 1577 (33.5%) mothers diagnosed with COVID-19 and 3130 (66.5%) nondiagnosed mothers. Among the diagnosed mothers, 642 (40.7%) were not vaccinated, 147 (9.3%) were partially vaccinated, 551 (34.9%) were completely vaccinated, and 237 (15.0%) also had a booster vaccine. Neonates of booster-vaccinated mothers had less than half (relative risk, 0.46; 95% confidence interval, 0.23-0.91) the risk of being diagnosed with COVID-19 when compared with those of unvaccinated mothers; they also had the lowest rates of preterm birth, medically indicated preterm birth, respiratory distress syndrome, and number of days in the neonatal intensive care unit. Newborns of unvaccinated mothers had double the risk for neonatal death (relative risk, 2.06; 95% confidence interval, 1.06-4.00) when compared with those of nondiagnosed mothers. Vaccination was not associated with any congenital malformations. Although all vaccines provided protection against neonatal test positivity, newborns of booster-vaccinated mothers had the highest vaccine effectiveness (64%; 95% confidence interval, 10%-86%). Vaccine effectiveness was not as high for messenger RNA vaccines only. Vaccine effectiveness against moderate or severe neonatal outcomes was much lower, namely 13% in the booster-vaccinated group (all vaccines) and 25% and 28% in the completely and booster-vaccinated groups, respectively (messenger RNA vaccines only). Vaccines were fairly effective in protecting neonates when given to pregnant women ≤100 days (14 weeks) before birth; thereafter, the risk increased and was much higher after 200 days (29 weeks). Finally, none of the neonatal practices studied, including skin-to-skin contact and direct breastfeeding, increased the risk for infecting newborns. CONCLUSION: When Omicron was the variant of concern, newborns of unvaccinated mothers had an increased risk for neonatal death. Neonates of vaccinated mothers had a decreased risk for preterm birth and adverse neonatal outcomes. Because the protective effect of COVID-19 vaccination decreases with time, to ensure that newborns are maximally protected against COVID-19, mothers should receive a vaccine or booster dose no more than 14 weeks before the expected date of delivery.

Shock index as a predictor of postpartum haemorrhage after vaginal delivery: Secondary analysis of a multicentre randomised controlled trial.

OBJECTIVE: To describe the shock index (SI) distribution during the first 2 hours after delivery and to evaluate its performance when measured 15 and 30 minutes after delivery for predicting postpartum haemorrhage (PPH) occurrence in the general population of parturients after vaginal delivery. DESIGN: Secondary analysis of a multicentre randomised controlled trial testing prophylactic administration of tranexamic acid versus placebo in addition to prophylactic oxytocin to prevent PPH. SETTING: 15 French maternity units in 2015-2016. SAMPLE: 3891 women with a singleton live fetus ≥35 weeks, born vaginally. METHODS: For each PPH-related predicted outcome, we calculated the area under the receiver operating characteristic curve (AUROC) values of the SI at 15 and 30 minutes after delivery and its predictive performance for SI cut-off values of 0.7, 0.9 and 1.1. MAIN OUTCOME MEASURES: Quantitative blood loss ≥1000 ml (QBL ≥1000 ml) measured in a graduated collector bag and provider-assessed clinically significant PPH (cPPH). RESULTS: Prevalence of QBL ≥1000 ml and cPPH was respectively 2.7% (104/3839) and 9.1% (354/3891). The distributions of the SI at 15 and 30 minutes after delivery were similar with a median value of 0.73 and 97th percentile of 1.11 for both. The AUROC values of the 15-minute SI for discriminating QBL ≥1000 ml and cPPH were respectively 0.66 (lower limit of the 95% confidence interval [LCI] 0.60) and 0.56 (LCI 0.52); and for the 30-minute SI 0.68 (LCI 0.61) and 0.49 (LCI 0.43). CONCLUSIONS: The shock index at 15 and 30 minutes after delivery did not satisfactorily predict either QBL ≥1000 ml or clinical PPH.

Maternal occupational exposure to carbonaceous nanoscale particles and neurodevelopmental outcomes in early childhood: Analysis of the French Longitudinal Study of Children - Elfe study.

OBJECTIVE: To investigate the association between occupational exposures to carbonaceous unintentionally emitted nanoscale particles (UNPs) during pregnancy and the child's language development and behaviour at two years old. METHODS: Using data from the French Longitudinal Study of Childhood - ELFE, we selected mothers who worked during pregnancy and their children. Exposure to carbonaceous UNPs was assessed by the MatPUF (job-exposure matrix for ultrafine particles). Children's lexical development was analysed using 'the Mac Arthur - Bates communicative development inventories-words and sentences-short form' (MB-CDI) in a multivariate binary logistic regression. Their risk for autism spectrum disorders was studied using 'the Modified-CHecklist for Autism in Toddler' (M-CHAT) according to the recommended thresholds (low risk = 0-2; intermediate risk = 3-6 and high risk = 7-23) in unordered multinomial logistic regression models. RESULTS: Maternal occupational exposure to carbonaceous UNPs was associated with delayed child language development (ORadj: 1.34; 95 % CI: 1.00, 1.80) but not with behavioural disorders (autism spectrum disorders) at two years old. CONCLUSION: This is the first epidemiological study to show a significant association between maternal occupational exposure to carbonaceous nanoscale particles and child language development at 2 years old.

Opportunities for, and barriers to, uterus-preserving surgical techniques for placenta accreta spectrum.

INTRODUCTION: Placenta accreta spectrum (PAS) can lead to major peripartum morbidity. Appropriate management approaches depend on the clinical severity, each individual's preference, and the treating team's expertise. Peripartum hysterectomy is the most frequently used treatment option. However, it can impact psychological well-being and fertility. We investigated whether conservative treatment with focal resection or leaving the placenta in situ is associated with comparable or lower maternal morbidity than hysterectomy in centers of excellence within the International Society for placenta accreta spectrum (IS-PAS). Furthermore, a survey was conducted to explore potential barriers to conservative management in antenatal counseling and intraoperative decision-making. MATERIAL AND METHODS: Confirmed PAS cases in the prospective IS-PAS database from 22 registered centers between January 2020 and June 2022 were included in the analysis. A separate online survey with 21 questions was answered by the IS-PAS center experts about indications, diagnostic criteria, patient counseling, surgical practice, changes from the preoperative treatment plan, and why conservative management may not be offered. RESULTS: A total of 234 cases were included in the analysis: 186 women received hysterectomy and 38 women were treated by focal resection, and 10 by leaving the placenta in situ. Blood loss was lower in the focal resection group and in the placenta in situ group compared to the hysterectomy group (p = 0.04). 46.4% of the women initially planned for focal resection, and 35.7% of those initially planned for leaving the placenta in situ were ultimately treated by hysterectomy. Our survey showed that the IS-PAS centers preferred hysterectomy according to a woman's wishes (64%) and when they expected less blood loss and morbidity (41%). Eighteen percent of centers did not offer focal resection at all due to a lack of experience with this technique. Reasons for not offering to leave the placenta in situ were avoidance of unexpected reoperation (36%), puerperal infection (32%), or skepticism about the method (23%). CONCLUSIONS: Uterus-preserving treatment strategies such as focal resection appear to be safe alternatives to peripartum hysterectomy. However, less than half of the IS-PAS centers perform them. Acceptance of conservative treatments could be increased by standardized criteria for their implementation and by systematic training for PAS experts.

Neonatal outcomes for women at risk of preterm delivery given half dose versus full dose of antenatal betamethasone: a randomised, multicentre, double-blind, placebo-controlled, non-inferiority trial.

BACKGROUND: Antenatal betamethasone is recommended before preterm delivery to accelerate fetal lung maturation. However, reports of growth and neurodevelopmental dose-related side-effects suggest that the current dose (12 mg plus 12 mg, 24 h apart) might be too high. We therefore investigated whether a half dose would be non-inferior to the current full dose for preventing respiratory distress syndrome. METHODS: We designed a randomised, multicentre, double-blind, placebo-controlled, non-inferiority trial in 37 level 3 referral perinatal centres in France. Eligible participants were pregnant women aged 18 years or older with a singleton fetus at risk of preterm delivery and already treated with the first injection of antenatal betamethasone (11·4 mg) before 32 weeks' gestation. We used a computer-generated code producing permuted blocks of varying sizes to randomly assign (1:1) women to receive either a placebo (half-dose group) or a second 11·4 mg betamethasone injection (full-dose group) 24 h later. Randomisation was stratified by gestational age (before or after 28 weeks). Participants, clinicians, and study staff were masked to the treatment allocation. The primary outcome was the need for exogenous intratracheal surfactant within 48 h after birth. Non-inferiority would be shown if the higher limit of the 95% CI for the between-group difference between the half-dose and full-dose groups in the primary endpoint was less than 4 percentage points (corresponding to a maximum relative risk of 1·20). Four interim analyses monitoring the primary and the secondary safety outcomes were done during the study period, using a sequential data analysis method that provided futility and non-inferiority stopping rules and checked for type I and II errors. Interim analyses were done in the intention-to-treat population. This trial was registered with ClinicalTrials.gov, NCT02897076. FINDINGS: Between Jan 2, 2017, and Oct 9, 2019, 3244 women were randomly assigned to the half-dose (n=1620 [49·9%]) or the full-dose group (n=1624 [50·1%]); 48 women withdrew consent, 30 fetuses were stillborn, 16 neonates were lost to follow-up, and 9 neonates died before evaluation, so that 3141 neonates remained for analysis. In the intention-to-treat analysis, the primary outcome occurred in 313 (20·0%) of 1567 neonates in the half-dose group and 276 (17·5%) of 1574 neonates in the full-dose group (risk difference 2·4%, 95% CI -0·3 to 5·2); thus non-inferiority was not shown. The per-protocol analysis also did not show non-inferiority (risk difference 2·2%, 95% CI -0·6 to 5·1). No between-group differences appeared in the rates of neonatal death, grade 3-4 intraventricular haemorrhage, stage ≥2 necrotising enterocolitis, severe retinopathy of prematurity, or bronchopulmonary dysplasia. INTERPRETATION: Because non-inferiority of the half-dose compared with the full-dose regimen was not shown, our results do not support practice changes towards antenatal betamethasone dose reduction. FUNDING: French Ministry of Health.

Efficacy of early intrauterine balloon tamponade for immediate postpartum hemorrhage after vaginal delivery: a randomized clinical trial.

BACKGROUND: Many questions remain about the appropriate use of intrauterine balloon devices in postpartum hemorrhage after vaginal delivery refractory to first-line uterotonics. Available data suggest that early use of intrauterine balloon tamponade might be beneficial. OBJECTIVE: This study aimed to compare the effect of intrauterine balloon tamponade used in combination with second-line uterotonics vs intrauterine balloon tamponade used after the failure of second-line uterotonic treatment on the rate of severe postpartum hemorrhage in women with postpartum hemorrhage after vaginal delivery refractory to first-line uterotonics. STUDY DESIGN: This multicenter, randomized, controlled, parallel-group, nonblinded trial was conducted at 18 hospitals and enrolled 403 women who had just given birth vaginally at 35 to 42 weeks of gestation. The inclusion criteria were a postpartum hemorrhage refractory to first-line uterotonics (oxytocin) and requiring a second-line uterotonic treatment with sulprostone (E1 prostaglandin). In the study group, the sulprostone infusion was combined with intrauterine tamponade by an ebb balloon performed within 15 minutes of randomization. In the control group, the sulprostone infusion was started alone within 15 minutes of randomization, and if bleeding persisted 30 minutes after the start of sulprostone infusion, intrauterine tamponade using the ebb balloon was performed. In both groups, if the bleeding persisted 30 minutes after the insertion of the balloon, an emergency radiological or surgical invasive procedure was performed. The primary outcome was the proportion of women who either received ≥3 units of packed red blood cells or had a calculated peripartum blood loss of >1000 mL. The prespecified secondary outcomes were the proportions of women who had a calculated blood loss of ≥1500 mL, any transfusion, an invasive procedure and women who were transferred to the intensive care unit. The analysis of the primary outcome with the triangular test was performed sequentially throughout the trial period. RESULTS: At the eighth interim analysis, the independent data monitoring committee concluded that the incidence of the primary outcome did not differ between the 2 groups and stopped inclusions. After 11 women were excluded because they met an exclusion criterion or withdrew their consent, 199 and 193 women remained in the study and control groups, respectively, for the intention-to-treat analysis. The women's baseline characteristics were similar in both groups. Peripartum hematocrit level change, which was needed for the calculation of the primary outcome, was missing for 4 women in the study group and 2 women in the control group. The primary outcome occurred in 131 of 195 women (67.2%) in the study group and 142 of 191 women (74.3%) in the control group (risk ratio, 0.90; 95% confidence interval, 0.79-1.03). The groups did not differ substantially for rates of calculated peripartum blood loss pf ≥1500 mL, any transfusion, invasive procedure, and admission to an intensive care unit. Endometritis occurred in 5 women (2.7%) in the study group and none in the control group (P=.06). CONCLUSION: The early use of intrauterine balloon tamponade did not reduce the incidence of severe postpartum hemorrhage compared with its use after the failure of second-line uterotonic treatment and before recourse to invasive procedures.

Risk factors for unfavorable outcome at discharge of newborns with hypoxic-ischemic encephalopathy in the era of hypothermia.

OBJECTIVE: To re-visit short-term outcomes and associated risk factors of newborns with hypoxic-ischemic encephalopathy (HIE) in an era where hypothermia treatment (HT) is widespread. METHODS: This is a prospective population-based cohort in French neonatal intensive care units (NICU). Neonates born at or after 34 weeks of gestational age with HIE were included; main outcomes were in-hospital death and discharge with abnormal or normal MRI. Associations of early perinatal risk factors, present at birth or at admission to NICU, with these outcomes were studied. RESULTS: A total of 794 newborns were included and HT was administered to 670 (84.4%); 18.3% died and 28.5% and 53.2% survived with abnormal and normal MRI, respectively. Severe neurological status, Apgar score at 5 mn ≤5, lactate at birth ≥11 mMoles/l, and glycemia ≥100 mg/dL at admission were associated with an increased risk of death (relative risk ratios (aRRR) (95% CI) 19.93 (10.00-39.70), 2.89 (1.22-1.62), 3.06 (1.60-5.83), and 2.55 (1.38-4.71), respectively). Neurological status only was associated with survival with abnormal MRI (aRRR (95% CI) 1.76 (1.15-2.68)). CONCLUSION: Despite high use of HT in this cohort, 46.8% died or presented brain lesions. Early neurological and biological examinations were associated with unfavorable outcomes and these criteria could be used to target children who warrant further neuroprotective treatment. TRIAL REGISTRATION: Clinical trial registry, NCT02676063, ClinicalTrials.gov. IMPACT: In this population-based cohort of newborns with HIE where 84% received hypothermia, 46.8% still had an unfavorable evolution (death or survival with abnormal MRI). Risk factors for death were high lactate, low Apgar score, severe early neurological examination, and high glycaemia. While studies have established risk factors for HIE, few have focused on early perinatal factors associated with short-term prognosis. This French population-based cohort updates knowledge about early risk factors for adverse outcomes in the era of widespread cooling. In the future, criteria associated with an unfavorable evolution could be used to target children who would benefit from another neuroprotective strategy with hypothermia.

Incidence and risk factors for severe postpartum haemorrhage in women with anterior low-lying or praevia placenta and prior caesarean: Prospective population-based study.

OBJECTIVE: To assess the incidence and risk factors for severe postpartum haemorrhage (PPH) in women with an anterior low-lying or praevia placenta, prior caesarean and no prenatal suspicion of placenta accreta spectrum (PAS). DESIGN: Population-based study in 176 maternity units in France. POPULATION: All women with anterior low-lying (0-19 mm from the cervical internal os) or praevia placenta, diagnosed prospectively before birth, prior caesarean and no prenatal suspicion of PAS. METHODS: Multivariable logistic regression to identify risk factors for severe PPH in the main population and after exclusion of women with PAS diagnosed only at birth. MAIN OUTCOME MEASURES: Severe PPH defined by a composite criterion either estimated blood loss of ≥1500 ml, transfusion of ≥4 or more units of packed red blood cells, embolisation or surgical treatment. RESULTS: Of the 520 114 women constituting the source population, 230 (0.44/1000 women; 95% confidence interval [CI] 0.38-0.50) met the inclusion criteria. Severe PPH rate was 24.8% (95% CI 19.2-30.4) overall, 27.5% (95% CI 21.8-33.3) in women with placenta praevia and 15.4% (95% CI 10.7-20.0) in women with low-lying placenta. PAS was diagnosed at birth in 22 women (9.9%; 95% CI 5.8-13.4), although previously unsuspected. After their exclusion, severe PPH incidence was 17.3% (95% CI 12.4-22.2). In multivariate analysis, the only factor associated with a higher severe PPH risk was placenta previa (aOR, 3.65; 95%CI, 1.20-15.8). CONCLUSION: Severe PPH is frequent among women with anterior low-lying or praevia placenta and prior caesarean, even after exclusion of women with PAS. The risk of severe PPH for those with praevia is nearly twice that with low-lying placenta.

Tranexamic acid for reduction of blood loss after Caesarean delivery: a cost-effectiveness analysis of the TRAAP2 trial.

BACKGROUND: Prophylactic administration of tranexamic acid is associated with a reduction of blood loss after Caesarean delivery, but cost-effectiveness for this indication has not been assessed. METHODS: We used data from the TRAAP2 trial, a multicentre, double-blinded, RCT aimed at estimating the efficacy of tranexamic acid for preventing postpartum haemorrhage among women undergoing Caesarean delivery. Women recruited at 27 French maternity hospitals from 2018 to 2020 were enrolled before the procedure if they had a Caesarean delivery before or during labour at 34 or more weeks of gestation. The main outcomes were the cost of hospital stay for delivery and the incremental cost per delivery without complication within 90 days after delivery with tranexamic acid compared with placebo. Differences in costs and the incremental net monetary benefit (INMB) were estimated using linear regression models, and the cost-effectiveness probability of tranexamic acid compared with placebo was estimated through the parametric distribution of the INMB. RESULTS: The proportion of women without complications at day 90 was 70.7% in the tranexamic acid group and 66.0% in the placebo group. Mean total costs until occurrence of a complication of interest were €3321 in the tranexamic acid group and €3260 in the placebo group, resulting in a difference between the two groups of 7.2% and €55 after multiple imputation. The adjusted incremental cost-effectiveness ratio was €762 per additional Caesarean delivery without a complication at 90 days after delivery. At a cost-effectiveness threshold of €10,000, the cost-effectiveness probability of tranexamic acid compared with placebo was 99.9%, varying from 5.8% to 100.0% for thresholds from €0 to €10,000 per additional delivery without a complication at day 90. CONCLUSION: Tranexamic acid for the prevention of blood loss is cost-effective in reducing complications after Caesarean delivery at day 90 postpartum. However, the effect size (in cost and effectiveness) is very low. CLINICAL TRIAL REGISTRATION: NCT03431805.

Evaluation of lupus anticoagulant, damage, and remission as predictors of pregnancy complications in systemic lupus erythematosus: the French GR2 study.

OBJECTIVES: The specific roles of remission status, lupus low disease activity state (LLDAS), and damage accrual on the prognosis of pregnancies in women with SLE are unknown. We analysed their impact on maternal flares and adverse pregnancy outcomes (APOs). METHODS: We evaluated all women (≥18 years) with SLE enrolled in the prospective GR2 study with an ongoing singleton pregnancy at 12 weeks (one pregnancy/woman). Several sets of criteria were used to define remission, disease activity and damage. APOs included: foetal/neonatal death, placental insufficiency with preterm delivery and small-for-gestational-age birth weight. First trimester maternal and disease features were tested as predictors of maternal flares and APOs. RESULTS: The study included 238 women (98.3% on hydroxychloroquine (HCQ)) with 230 live births. Thirty-five (14.7%) patients had at least one flare during the second/third trimester. At least one APOs occurred in 34 (14.3%) women. Hypocomplementemia in the first trimester was the only factor associated with maternal flares later in pregnancy (P=0.02), while several factors were associated with APOs. In the logistic regression models, damage by SLICC-Damage Index [odds ratio (OR) 1.8, 95% CI: 1.1, 2.9 for model 1 and OR 1.7, 95% CI: 1.1, 2.8 for model 2] and lupus anticoagulant (LA, OR 4.2, 95% CI: 1.8, 9.7 for model 1; OR 3.7, 95% CI: 1.6, 8.7 for model 2) were significantly associated with APOs. CONCLUSION: LA and damage at conception were predictors of APOs, and hypocomplementemia in the first trimester was associated with maternal flares later in pregnancy in this cohort of pregnant patients mostly with well-controlled SLE treated with HCQ. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT02450396.