Criteria and non-criteria antiphospholipid autoantibodies screening in patients with late pregnancy morbidity: A cross-sectional study.

INTRODUCTION: Antiphospholipid syndrome (APS) is a cause of pregnancy morbidity. We aim to determine the frequency of criteria and non-criteria anti-phospholipid (aPL) autoantibodies in patients admitted for unexplained fetal death (UFD), pre-eclampsia (PE) and/or fetal growth restriction (FGR). METHODS: All consecutive patients with UFD, PE and/or FGR followed in the department of Obstetrics, Bichat Hospital, University of Paris, Paris, between January 2019 and December 2021 were screened. Patients with available serum stored from the index pregnancy were included. Patients with previously known APS or twin pregnancy were excluded. Testing for aPL autoantibodies included anti-cardiolipin (aCL), anti-ß2GPI (aß2GPI), anti-phosphatidylethanolamine (aPE), anti-phosphatidylserine/prothrombin (aPS/PT) IgG/IgM and anti-annexin V IgG. When available, placenta specimens were analyzed by a pathologist blinded to the aPL status. All clinical characteristics, pregnancy features, and comorbidities were extracted from electronic medical records. RESULTS: Overall 167 (32 (28.8-35.7) years) patients with UFD (n = 28; 16.8 %), PE (n = 60; 35.9 %) and/or FGR (n = 105; 62.9 %) were screened for aPL autoantibodies. Moderate titers of aPL autoantibodies were detected in 33 (n = 33/167, 19.8 %) patients. aPL autoantibodies were non-criteria aPE IgG/IgM in most cases (n = 28/33, 84.8 %). aPS/PT IgG/IgM were found in 11 (n = 11/33, 33.3 %) cases and aCL or aß2GP1 IgG/IgM in 4 (n = 4/33, 12.1 %). Multivariable logistic regression showed that aPL autoantibodies were mostly associated with UFD (OR 4.37 [1.72-11.20], p = 0.002), PE ≤ 34th week of gestation (3.22 [0.86-11.90], p = 0.070) and chronic deciduitis (8.03 [0.89-67.2], p = 0.060) DISCUSSION: The frequency of aPL autoantibodies, mostly aPE, is high in patients with late pregnancy morbidity and may qualify obstetrical APS.

Impact of an e-learning training for interpreting intrapartum fetal heart rate monitoring to avoid perinatal asphyxia: A before-after multicenter observational study.

INTRODUCTION: Perinatal asphyxia, a condition that results from compromised placental or pulmonary gas exchange during the birth process, is rare but can lead to serious neonatal and long-term consequences. The visual analysis of cardiotocography (CTG) is designed to avoid perinatal asphyxia, but its interpretation can be difficult. Our aim was to test the impact of an e-learning training program for interpreting CTG on the rate of avoidable perinatal asphyxia at term. METHOD: We conducted a retrospective multicenter before-after study comparing two periods, before and after the implementation of e-learning training program from July 1, 2016 to December 31, 2016, in CTG interpretation for midwives and obstetricians in five maternity hospitals in the Paris area, France. The training involved theoretical aspects such as fetal physiology and heart rhythm abnormalities, followed by practical exercises using real case studies to enhance skills in interpreting CTG. We included all term births that occurred between the "before" period (July 1 to December 31, 2014) and the "after period (January 1 to June 30, 2017). We excluded multiple pregnancies, antenatal detection of congenital abnormalities, breech births and all scheduled caesarean sections. Perinatal asphyxia cases were analyzed by a pair of experts consisting of midwives and obstetricians, and avoidability of perinatal asphyxia was estimated. The main criterion was the prevalence of avoidable perinatal asphyxia. RESULTS: The e-learning program was performed by 83 % of the obstetrician-gynecologists and 65 % of the midwives working in the delivery rooms of the five centers. The prevalence of perinatal asphyxia was 0.45 % (29/7902 births) before the training and 0.54 % (35/7722) after. The rate of perinatal asphyxia rated as avoidable was 0.30 % of live births before the training and 0.28 % after (p = 0.870). The main causes of perinatal asphyxia deemed avoidable were delay in reactions to severe CTG anomalies and errors in the analysis and interpretation of the CTG. These causes did not differ between the two periods. CONCLUSION: One session of e-learning training to analyze CTG was not associated with a reduction in avoidable perinatal asphyxia. Other types of e-learning, repeated and implemented over a longer period should be evaluated.

Risk Factors for Anal Continence Impairment Following a Second Delivery after a First Traumatic Delivery: A Prospective Cohort Study.

Postpartum anal incontinence is common. After a first delivery (D1) with perineal trauma, follow-up is advised to reduce the risk of anal incontinence. Endoanal sonography (EAS) may be considered to evaluate the sphincter and in case of sphincter lesions to discuss cesarean section for the second delivery (D2). Our objective was to study the risk factors for anal continence impairment following D2. Women with a history of traumatic D1 were followed before and 6 months after D2. Continence was measured using the Vaizey score. An increase ≥2 points after D2 defined a significant deterioration. A total of 312 women were followed and 67 (21%) had worse anal continence after D2. The main risk factors for this deterioration were the presence of urinary incontinence and the combined use of instruments and episiotomy during D2 (OR 5.12, 95% CI 1.22-21.5). After D1, 192 women (61.5%) had a sphincter rupture revealed by EAS, whereas it was diagnosed clinically in only 48 (15.7%). However, neither clinically undiagnosed ruptures nor severe ruptures were associated with an increased risk of continence deterioration after D2, and cesarean section did not protect against it. One woman out of five in this population had anal continence impairment after D2. The main risk factor was instrumental delivery. Caesarean section was not protective. Although EAS enabled the diagnosis of clinically-missed sphincter ruptures, these were not associated with continence impairment. Anal incontinence should be systematically screened in patients presenting urinary incontinence after D2 as they are frequently associated.

Frequency of differential placental transfer to twins of maternal antiretroviral medications.

BACKGROUND: Placental passage of drugs in twins is poorly understood, and is unknown regarding antiretrovirals (ARVs). In the event of large differences in the exposure of 2 twins to the same maternal therapy, this could have a clinical impact in terms of prevention of perinatal HIV transmission or adverse effects. OBJECTIVE: To describe the frequency of differential transplacental passage of antiretrovirals between twins. STUDY DESIGN: The study was performed retrospectively, on data from women included in a multicenter perinatal HIV cohort study. All twin pairs for which the mother received antiretroviral therapy and for which drug concentrations in both of the umbilical cords after cord clamping at delivery were studied. We considered that a difference in concentrations of more than 50 % between twins was a substantial difference (ratios below 0.67 or above 1.50). RESULTS: We analyzed 29 twin pairs, 27 dichorionic and 2 monochorionic diamniotic. Cord blood concentrations differed between the 2 twins by more than 50 % for at least one ARV in 9 twin pairs, 8 dichorionic and 1 monochorionic. Discordant concentrations were observed in one or more cases for several nucleoside reverse transcriptase inhibitors (tenofovir, emtricitabine, lamivudine, zidovudine) and protease inhibitors (atazanavir, lopinavir, saquinavir et ritonavir); within individual twin pairs placental transfer was discordant for one or more ARVs, but identical for others. CONCLUSION: Concentrations differed in nearly one third of twin pairs. This may be due to interindividual genetic variability of placental transporters between dizygotic twins as well as physiological differences between twins.

Congenital Leishmaniasis in a Newborn Infant Whose Mother was Coinfected With Leishmaniasis and HIV.

In utero transmission of Leishmania infantum is the putative mechanism of congenital leishmaniasis. However, this hypothesis is based on limited research. In addition, the consequences for infant newborn development remain to be clarified by additional data. We report here the occurrence, specific management, and monitoring of congenital leishmaniasis in a newborn infant whose mother was coinfected with leishmaniasis and human immunodeficiency virus; transplacental transmission, confirmed by overt clinical disease at birth, was documented, which provides, to our knowledge, the first evidence of hepatic and neurologic impairment in an infant with congenital visceral leishmaniasis.

Pregnancy denial and early infant development: a case-control observational prospective study.

BACKGROUND: The denial of pregnancy is the non-recognition of the state of the current pregnancy by a pregnant woman. It lasts for a few months or for the whole pregnancy, with generally few physical transformations. In this study, we will consider the denial of pregnancy as a late declaration of pregnancy (beyond 20 weeks of gestation) as well as a lack of objective perceptions of this pregnancy. The main objective of this study is to explore the relationship between pregnancy denial and the development of the infant (attachment pattern of the infant, early interactions of mother-infant dyads, and early development of the infant). METHODS: The design is a case-control prospective study, which will compare two groups of mother-infant dyads: a "case" group with maternal denials of pregnancy and a "control" group without denials of pregnancy. A total of 140 dyads (mother + infant) will be included in this study (70 cases and 70 controls) and followed for 18 months. The setting is a national recruitment setting with 10 centers distributed all over France. The follow-up of the "cases" and the "controls" will be identical and will occur over 5 visits. It will include measures of the infant attachment pattern, the quality of early mother-infant interaction and infant development. DISCUSSION: This study aims to examine the pathogenesis of pregnancy denial as well as its consequences on early infant development and early mother-infant interaction. TRIAL REGISTRATION: Clinical Trial Number: NCT02867579 on the date of 16 August 2016 (retrospectively registered).

Does Changing Antiretroviral Therapy in the First Trimester of Pregnancy for Safety Concerns Have an Impact on Viral Suppression?

OBJECTIVE: To determine whether changing antiretroviral therapy (ART) during pregnancy because of concern about fetal risks led to poorer virological outcomes. METHODS: All pregnancies in women with HIV-1 infection enrolled in the national multicenter prospective French Perinatal cohort at 14 week gestation or more were included between January 2005 and December 2015, if the mother was on ART at conception with a plasma viral load <50 copies/mL. The reasons for a change in the ART were analyzed according to treatment guidelines at the time of the pregnancy and defined as for safety concerns in the absence of reported maternal intolerance. Virological and pregnancy outcomes were studied by survival analysis and logistic regression adjusted for a propensity score established for each patient according to baseline characteristics. RESULTS: Of 7079 pregnancies in the overall cohort, 1797 had ART at conception with a viral load <50 copies/mL before 14 week gestation. Of these, 22 changed regimens in the first trimester for intolerance, and 411 of the remaining 1775 (23%) solely for safety concerns. The proportion of change was higher when the initial treatment was not recommended in the national guidelines (OR adjusted: 23.1 [14.0-38.2]), than when it was an alternative option (ORa: 2.2 [1.3-3.7]), as compared to recommended first-line regimens. Treatment changes for safety concerns did not lead to poorer virological control, compared with pregnancies without such changes (19.3% vs. 15.6%, HRa: 1.0 [0.7-1.4]). CONCLUSIONS: Changing ART early in pregnancy to regimens considered safer for pregnancy, and neonatal health did not have a destabilizing effect on viral suppression.

Prevention of shoulder dystocia: A randomized controlled trial to evaluate an obstetric maneuver.

OBJECTIVE: Shoulder dystocia is a major obstetric emergency defined as a failure of delivery of the fetal shoulder(s). This study evaluated whether an obstetric maneuver, the push back maneuver performed gently on the fetal head during delivery, could reduce the risk of shoulder dystocia. STUDY DESIGN: We performed a multicenter, randomized, single-blind trial to compare the push back maneuver with usual care in parturient women at term. The primary outcome, shoulder dystocia, was considered to have occurred if, after delivery of the fetal head, any additional obstetric maneuver, beginning with the McRoberts maneuver, other than gentle downward traction and episiotomy was required. RESULTS: We randomly assigned 522 women to the push back maneuver group (group P) and 523 women to the standard vaginal delivery group (group S). Finally, 473 women assigned to group P and 472 women assigned to group S delivered vaginally. The rate of shoulder dystocia was significantly lower in group P (1·5%) than in group S (3·8%) (odds ratio [OR] 0·38 [0·16-0·92]; P = 0·03). After adjustment for predefined main risk factors, dystocia remained significantly lower in group P than in group S. There were no significant between-group differences in neonatal complications, including brachial plexus injury, clavicle fracture, hematoma and generalized asphyxia. CONCLUSION: In this trial in 945 women who delivered vaginally, the push back maneuver significantly decreased the risk of shoulder dystocia, as compared with standard vaginal delivery.

Pharmacokinetics, safety and efficacy of ritonavir-boosted atazanavir (300/100 mg once daily) in HIV-1-infected pregnant women.

BACKGROUND: Atazanavir/ritonavir (ATV/r) is a boosted protease inhibitor recommended to minimize the risk of mother-to-child HIV-1 transmission (MTCT). We aimed to assess the pharmacokinetics, safety and efficacy of ATV/r in HIV-1-infected pregnant women and their neonates. METHODS: A multicentre, cross-sectional, non-interventional cohort of HIV-1-infected pregnant women receiving ATV/r (300/100 mg once daily) who delivered in three Paris hospitals from 2006 to 2013 was designed. We determined antiretroviral trough plasma concentrations using liquid chromatography-mass spectrometry at each of the three trimesters, delivery and post-partum. ATV concentrations at 24 h (C24h) were interpreted by the 150-850 ng/ml efficacy-tolerance thresholds. Safety data and newborn HIV status were recorded. A mother's virological failure was defined as two successive measurements of plasma HIV-1 RNA>50 copies/ml within the 2 months before delivery. RESULTS: 103 pregnant women were included, mostly from sub-Saharan Africa (88%). ATV C24h at each of the three trimesters and delivery remained similar to post-partum values. No dose adjustment was needed during pregnancy. The median plasma ratio of fetal/maternal ATV level was 0.19 (n=28). Only three patients showed two successive detectable viral loads but <400 copies/ml. Among 82 available newborn data, 16 were born preterm. Three in utero deaths occurred. Tolerance was good with one case of maternal grade 3 hyperbilirubinaemia, no cases in neonates at delivery and no clinically relevant adverse event. No case of MTCT was reported. CONCLUSIONS: In this population, an ATV/r-containing antiretroviral regimen demonstrated good pharmacokinetics, virological efficacy and safety. No significant impact of pregnancy on ATV C24h was found. No dose adjustment was required.

Immunomonitoring of graft-versus-host minor histocompatibility antigen correlates with graft-versus-host disease and absence of relapse after graft.

BACKGROUND: After HLA-identical hematopoietic stem cell transplantation, minor histocompatibility (mH) antigen alloreactivity plays a dominant role in the development of graft-versus-host disease (GVHD) and graft versus leukemia (GVL). STUDY DESIGN AND METHODS: We have analyzed the mH alloreactivity (enzyme-linked immunospot [ELISpot] for interferon-gamma[IFN-gamma] assay) from 24 donor/recipient pairs over a period of 2 years of follow-up and correlated such alloreactivity with the development of GVHD or absence of relapse. Circulating specific T cells anti-mH with multimer HLA-peptides were also studied. RESULTS: We show by ELISpot IFN-gamma assay that alloreactivity during the first 3 months from donor versus recipient or donor versus mismatched identified mH antigens is associated with acute GVHD and GVL effect. In addition, we demonstrate that the donor-versus-recipient reactivity observed after the third month is highly associated with chronic GVHD and GVL (p = 0.0007). Finally, we show by multimer HLA-peptide assay that mH epitope-specific T cells present after 3 months are statistically related to the GVL effect. CONCLUSIONS: Our results provide a robust method to monitor mH antigen graft-versus-host reaction and suggest that current identified mH have predictive value on GVHD and GVL.

Donor KIR3DL1/3DS1 gene and recipient Bw4 KIR ligand as prognostic markers for outcome in unrelated hematopoietic stem cell transplantation.

Given their antileukemic activity, natural killer (NK) cells can alter the outcome of hematopoietic stem cell transplantation (HSCT). The physiologic functions of NK cells are regulated by the interaction of killer immunoglobulin-like receptors (KIR) with specific HLA class I ligands. In the literature, different models based on HLA class I and/or KIR donor (D)/recipient (R) gene disparities are considered as predictors of NK cell alloreactivity. In this retrospective and multicentric French study, we analyzed the clinical impact of the different NK-alloreactivity models in 264 patients who underwent T repleted unrelated HSCT. First, we did not observe that the "KIR ligand-ligand" model had a significant clinical impact on unrelated HSCT outcome, whereas the "missing KIR ligand" model had a significant but limited effect on unrelated HSCT, because only the absence of C1 ligand in patients with myelogenous diseases was associated with a decreased overall survival (OS) (hazard ratio=2.17, P=.005). The "KIR receptor-receptor" and the "KIR receptor-ligand" models seemed the most capable of predicting NK alloreactivity because they had a significant impact on acute graft-versus-host disease (aGVHD) occurrence, OS, and relapse incidence in D/R unrelated pairs. In particular, KIR3DL1 gene mismatches in the GVH direction (D(+)R(-)) and the D KIR3DL1(+)/3DS1(+) and R Bw4(-) combination were respectively correlated with the lowest OS in HLA identical pairs (HR=1.99, P =.02) and the highest incidence of relapse in HLA nonidentical D/R unrelated pairs (HR=4.72, P =.03). Overall, our results suggest a detrimental effect of KIR3DL1(+)/3DS1(+) donor NK cells transplanted into HLA-Bw4(-) patients in the absence of an educational process via KIR3DL1/HLA-Bw4 interactions.

HLA Association with hematopoietic stem cell transplantation outcome: the number of mismatches at HLA-A, -B, -C, -DRB1, or -DQB1 is strongly associated with overall survival.

HLA matching between the donor and recipient improves the success of unrelated hematopoietic stem cell transplantation (HSCT). Because many patients in need of an unrelated transplant have only donors with mismatch, information is needed to evaluate the limits of HLA mismatching. We examined the association of survival, acute graft-versus-host disease (aGVHD) and relapse with HLA-A, -B, -C, -DRB, -DQB1, and -DPB1 mismatching in 334 patients coming from 12 French transplant centers and who received a non-T cell-depleted bone marrow graft from an unrelated donor. All patients were prepared with the use of myeloablative conditioning regimens. Our analyses demonstrate negative effects of HLA mismatching for either HLA-A, -B, -C, -DRB1, or -DQB1 loci on survival. Multivariate Cox analyses showed that a single mismatch was associated with a significant decrement in survival (P=.046, hazard ratio [HR]=1.41, confidence interval [CI] 95% 1.1-1.98). The presence of multiple mismatches was worse for survival (P=.003, HR=1.91, CI 95% 1.26-2.91) and severe aGVHD (grade III-IV) (P=.002, HR=2.51, CI95% 1.41-4.46). The cumulative incidences of aGVHD and relapse in those HLA-A, -B, -C, -DRB1, and -DQB1 identical pairs with 2, 1, or 0 DPB1 incompatibilities were 63%, 50%, and 51%, and 12%, 27%, and 20%, respectively, but these differences were not statistically significant. Similar differences of aGVHD and relapse, but not statistically significant, were observed in those HLA-A, -B, -C, -DRB1, and -DQB1 identical pairs with DPB1 disparities classified into permissive or nonpermissive mismatches according to Zino's classification based on a hierarchy of the immunogenicity of the HLA-DP molecules. "Missing killer cell immunoglobulin-like receptor (KIR) ligand" evaluated on the presence of HLA-C1, -C2, and Bw4 groups in the recipients was not associated with aGVHD, survival, and relapse in this cohort of non-T cell-depleted HSCT.

Differentiation of anti-tumour cytotoxic T lymphocytes from autologous peripheral blood lymphocytes in non-Hodgkin's lymphomas.

We have previously reported that specific anti-tumour cytotoxic T cells (CTL) can be differentiated from tumour-infiltrating lymphocytes (TIL) in non-Hodgkin's lymphoma. We found that the combination of interleukin (IL)-1, IL-2 and IL-12 was very efficient for expansion of CD8+ T-cell receptor (TCR)alphabeta+ T cells and for development of their ability to specifically lyse tumour cells. In this study, we investigated whether anti-tumour T cells could be generated from the peripheral blood of patients using the culture protocol developed for TIL. Autologous T cells and tumour B cells from five patients were included in this study. It was found that polyclonal anti-tumour cytotoxic effector cells were generated when cultured in the presence of IL-1beta, IL-2 and IL-12. Interestingly, tumour cells were lysed by perforin/granzyme-mediated cytolysis and not by CD95-mediated apoptosis. By performing inhibition experiments, it was observed that both CD8+ and CD4+ T cells were responsible for the cytotoxic effect and that they were able to recognize malignant B cells by either a major histocompatibility complex (MHC)-restricted or MHC-non-restricted mechanism. Intriguingly, in addition to interferon-gamma and tumour necrosis factor-alpha, IL-10 was secreted continuously during culture. The source of patient T cells used for the generation of anti-tumour CTL should be based on the results obtained with peripheral blood lymphocytes and TIL.