Intravenous Immunoglobulins for Recurrent Chronic Histiocytic Intervillositis: A Series of Case Studies.

INTRODUCTION: Chronic histiocytic intervillositis (CHI) is a rare inflammatory placental disease characterized by diffuse infiltration of monocytes into the intervillous space and is associated with adverse pregnancy outcomes. No treatment is currently validated and although in some small reports, steroids with hydroxychloroquine have been described. There are no data for other therapies in refractory cases. PATIENTS AND METHODS: We here report four cases of patients with a history of CHI treated with immunoglobulins during a subsequent pregnancy. The four patients with recurrent CHI had failed to previous immunomodulatory therapies with steroids and hydroxychloroquine. All patients had at least four pregnancy losses with histopathological confirmation of CHI for at least one pregnancy loss. The usual pregnancy-loss etiology screening and immunological screening were negative for all the patients. RESULTS: For three patients, intravenous immunoglobulins were initiated at the ßHCG positivity at 1 g/kg every 15 days until delivery. In one case with combined therapy since the beginning of the pregnancy, intravenous immunoglobulins were introduced at 20 WG because of severe growth restriction. Two patients had live births at 36 WG and one patient at 39 WG. One patient, who presented early first-trimester hypertension and severe placental lesions, failed to intravenous immunoglobulins and had a pregnancy loss at 15 WG. CONCLUSION: This is the first report demonstrating the potential benefit of intravenous immunoglobulins in recurrent chronic intervillositis. Larger studies are needed to confirm this potential benefit for patients presenting severe cases of recurrent CHI.

Hydroxychloroquine in recurrent pregnancy loss: data from a French prospective multicenter registry.

STUDY QUESTION: What are the outcomes of pregnancies exposed to hydroxychloroquine (HCQ) in women with a history of recurrent pregnancy loss (RPL), and what factors predict the course of these pregnancies beyond the first trimester? SUMMARY ANSWER: In our cohort of pregnancies in women with a history of RPL exposed to HCQ early in pregnancy, we found that the only factor determining the success of these pregnancies was the number of previous miscarriages. WHAT IS KNOWN ALREADY: Dysregulation of the maternal immune system plays a role in RPL. HCQ, with its dual immunomodulating and vascular protective effects, is a potential treatment for unexplained RPL. STUDY DESIGN, SIZE, DURATION: The FALCO (Facteurs de récidive précoce des fausses couches) registry is an ongoing French multicenter infertility registry established in 2017 that includes women (aged from 18 to 49 years) with a history of spontaneous RPL (at least three early miscarriages (≤12 weeks of gestation (WG)) recruited from several university hospitals. PARTICIPANTS/MATERIALS, SETTING, METHODS: Spontaneous pregnancies enrolled in the FALCO registry with an exposure to HCQ (before conception or at the start of pregnancy) were included. Pregnancies concomitantly exposed to tumor necrosis factor inhibitors, interleukin-1 and -2 inhibitors, intravenous immunoglobulin, and/or intravenous intralipid infusion, were excluded. Concomitant treatment with low-dose aspirin (LDA), low-molecular weight heparin (LMWH), progesterone, and/or prednisone was allowed. All patients underwent the recommended evaluations for investigating RPL. Those who became pregnant received obstetric care in accordance with French recommendations and were followed prospectively. The main endpoint was the occurrence of a pregnancy continuing beyond 12 WG, and the secondary endpoint was the occurrence of a live birth. MAIN RESULTS AND THE ROLE OF CHANCE: One hundred pregnancies with HCQ exposure in 74 women were assessed. The mean age of the women was 34.2 years, and the median number of previous miscarriages was 5. Concomitant exposure was reported in 78 (78%) pregnancies for prednisone, 56 (56%) pregnancies for LDA, and 41 (41%) pregnancies for LMWH. Sixty-two (62%) pregnancies ended within 12 WG, the other 38 (38%) continuing beyond 12 WG. The risk of experiencing an additional early spontaneous miscarriage increased with the number of previous miscarriages, but not with age. The distributions of anomalies identified in RPL investigations and of exposure to other drugs were similar between pregnancies lasting ≤12 WG and those continuing beyond 12WG. The incidence of pregnancies progressing beyond 12 WG was not higher among pregnancies with at least one positive autoantibody (Ab) (i.e. antinuclear Ab titer ≥1:160, ≥1 positive conventional and/or non-conventional antiphospholipid Ab, and/or positive results for ≥1 antithyroid Ab) without diminished ovarian reserve (18/51, 35.3%) than among those without such autoantibody (18/45, 40.0%) (P = 0.63). Multivariate analysis showed that having ≤4 prior miscarriages was the only factor significantly predictive for achieving a pregnancy > 12 WG, after adjustment for age and duration of HCQ use prior to conception (adjusted odds ratio (OR) = 3.13 [1.31-7.83], P = 0.01). LIMITATIONS, REASONS FOR CAUTION: Our study has limitations, including the absence of a control group, incomplete data for the diagnostic procedure for RPL in some patients, and the unavailability of results from endometrial biopsies, as well as information about paternal age and behavioral factors. Consequently, not all potential confounding factors could be considered. WIDER IMPLICATIONS OF THE FINDINGS: Exposure to HCQ in early pregnancy for women with a history of RPL does not seem to prevent further miscarriages, suggesting limited impact on mechanisms related to the maternal immune system. STUDY FUNDING/COMPETING INTEREST(S): The research received no specific funding, and the authors declare no competing interests. TRIAL REGISTRATION NUMBER: clinicaltrial.gov NCT05557201.

Diabetic acidosis with severe fetal hypoxia in pregnancy: Narrative review and case study.

Diabetic ketoacidosis (DKA) in pregnancy could be a disastrous event with increased maternal and perinatal morbidity and mortality. DKA can occur with a normal blood glucose level, known as euglycemic DKA. It particularly affects pregnant women with type I diabetes. Here, we report the case of a 28 year-old primigravid patient, with a diagnosis of type 1 diabetes for 8 years. This patient consulted our department at 29 weeks of gestation with a previous history of headaches, vomiting and diarrhea for 9 h. Blood glucose level was 8.8 mmol/L with a ketone test positive (>15 mg/dL). Blood test showed high anion gap (17.9 mmol/L) with low serum bicarbonate rate (21 mmol/L). Systemic examination and fetal heart rate (FHR) was reassuring. The patient was subsequently discharged. She returned to the clinic 19 h later with further symptoms of nausea, polyuria-polydipsia, asthenia and a weight loss of 4 kg since the day before. Blood sugar was 14.3 mmol/L and a ketone test was strongly positive. Cardiotocography showed fetal tachycardia and repeated late decelerations. A diagnosis of DKA was made and emergency cesarean was performed for fetal distress. At delivery, pH was acidosis (pH: 7.02, lactates: 6.2). The patient was successfully treated with intravenous hydration and insulin. Neonatal evolution was favorable. Pregnant women with type I diabetes can develop euglycemic DKA. Early recognition and prompt treatment could help prevent severe maternal and fetal adverse outcomes. DKA in pregnant women can induce fetal acidosis with abnormal FHR. In this situation, a cesarean can be performed to improve neonatal outcome even inducing a premature delivery. Prolonged pregnancy can lead to irreversible neonatal brain abnormalities.

Massive perivillous fibrin deposition: Diagnosis, obstetrical features, and treatment.

MPVFD (Massive perivillous fibrin deposition) is placental lesion characterized by extensive massive deposits of fibrin in the intervillous space, extending over at least 25 % of the placental volume. Currently, this pathology can only be detected through histopathological examination of the placenta after a pregnancy has ended. The underlying mechanisms are poorly studied, there is no biomarker available for the diagnosis of MPVFD and treatment protocols are experimental and still lacking. The objective of this study is to systematically review the literature on the associated clinicopathologic features, treatment, and prognosis of MPVFD. We ended up with 17 studies, of these 12 studies were considered relevant for this article and included in the final analysis. All studies reporting MPVFD are retrospective. MPVFD is associated with recurrent miscarriage, intra uterine fetal death (IUFD), intra uterine growth restriction (IUGR) and preterm delivery. The prevalence in pregnancies with a delivery after 22 weeks of gestation was at 1.1 % and even higher to 2.7 % in recurrent early miscarriages. The reported risk of fetal death in MPVFD ranges mainly from 15 to 80 %. Preterm delivery is spontaneous in 50 to 70 % of cases and induced by of a severe intrauterine growth restriction (IUGR) in 30 to 50 % of cases depending on the study. Its causes and treatment are still poorly understood, although several avenues have been explored. This review summarizes current understanding of the prevalence, diagnostic features, clinical consequences, immune pathology, and potential prophylaxis against recurrence in this chronic inflammatory placental syndrome.

ART Outcomes After Hysteroscopic Proximal Tubal Occlusion Versus Laparoscopic Salpingectomy for Hydrosalpinx Management in Endometriosis Patients.

The objective of this paper is to compare assisted reproductive technology (ART) cumulative live birth rates after hysteroscopic proximal tubal occlusion and laparoscopic salpingectomy in endometriosis patients, for management of hydrosalpinx. This is an observational cohort study at a university hospital, including all endometriosis patients with hydrosalpinges undergoing ART, between January 2013 and December 2018. The patients underwent either laparoscopic salpingectomy or hysteroscopic proximal tubal occlusion with Essure® when laparoscopy was not an option (extensive pelvic adhesions at exploratory laparoscopy or a history of multiple abdominal surgeries with frozen pelvis). The diagnosis of endometriosis was based on published imaging criteria using transvaginal sonography (TVUS) and magnetic resonance imaging (MRI). Endometriosis patients with hydrosalpinges diagnosed by hysterosalpingography and/or TVUS and/or MRI were included. The primary outcome was the cumulative live birth rate. A total of 104 patients were included in the study; 74 underwent laparoscopic salpingectomy and 30 underwent proximal tubal occlusion with Essure®. The Essure® group had longer infertility durations (58.9 ± 30.0 months vs. 39.5 ± 19.1 months, p = 0.002) and a higher incidence of associated adenomyosis (76.7% vs. 39.1%, p < 0.001) than the salpingectomy group. The cumulative live birth rate was 56.6% after 44 ART cycles in the Essure® group and 40.5% after 99 ART cycles in the salpingectomy group (p = 0.13). In a population of endometriosis patients undergoing ART, women treated by Essure® for management of hydrosalpinx have similar cumulative live birth rates as women treated by laparoscopic salpingectomy.

Chronic Villitis of unknown etiology (VUE): Obstetrical features, outcome and treatment.

Villitis of unknown etiology (VUE) is characterized by lympho-histiocytic infiltrates, which are predominant within the villous stroma. VUE can be of low grade i.e. affecting less than 10 contiguous villi or high grade with either patchy or diffuse subgroups (the later concerning more than 30 % of distal villi). Several other placental lesions could be associated with VUE, in particular in diffuse subgroups, such as diffuse perivillous fibrin deposition and chronic intervillositis. One of the most characteristic features of VUE is the late onset of fetal growth restriction after 32 weeks of gestation, and earlier detection of villitis should first raise an infectious origin. High grade VUE has been associated with fetal growth restriction, prematurity, fetal deaths, recurrent pregnancy loss, central nervous system injury and is characterized by relatively high risk of recurrence (25-50 %). Prospective and well-designed studies are necessary to determine the real prevalence of these adverse pregnancy events associated with VUE. Data about the management of VUE are extremely scarce and thus no recommendation based on the literature review could be actually done.

The Endometrial Immune Profiling May Positively Affect the Management of Recurrent Pregnancy Loss.

Introduction: The endometrial immune profiling is an innovative approach based on the analysis of the local immune reaction occurring in the endometrium at the time of the embryo implantation. By documenting the local immune activation during the period of uterine receptivity, we aim to detect and correct potential imbalances before and at the very beginning of placentation. The main objective of the study was to analyze in women with a history of repeated pregnancy loss (RPL) the association of personalized strategies based on immune dysregulations with live birth rates. The secondary objective was to highlight the main prognostic factors for live births. Methods: This is an observational retrospective analysis of 104 patients with RPL, included between January 2012 and December 2019. Inclusion criteria included a spontaneous fertility with at least three miscarriages, an assessment including a three-dimension ultrasound scan, an endometrial biopsy for uterine immune profiling and a follow-up over at least 6 months with personalized care if indicated after the complete assessment. We defined as a success if the patients had a live birth after the suggested plan, as a failure if the patient either did not get pregnant or experienced a new miscarriage after the targeted therapies. Results: Uterine immune profiling was the only exploration to be significantly associated with a higher live birth rate (LBR) if a dysregulation was identified and treated accordingly (55% vs 45%, p=0.01). On the contrary, an absence of local dysregulation (resulting in an apparently balanced immune environment) was associated with a higher risk of a new miscarriage, suggesting that the cause inducing RPL still needed to be identified. Independently of age and AMH level, dysregulated immune profile is significatively associated with 3 times higher LBR than a non-deregulated profile (OR=3.4 CI 95%1.27-9.84) or five times in case of an overactive profile treated by immunotherapy (OR=5 CI 95% 1.65-16.5). The usage of ART was significantly associated with lower LBR regardless of the presence of a subfertility factor (p=0.012). Personalization of medical care using natural cycle or simple hormonal stimulation is associated with a significantly higher LBR than personalization including ART treatments regardless of maternal age and AMH level (OR= 2.9 CI 95% 1.03-8.88). Conclusion: Our study suggests that some endometrial immune profiles with targeted management of RPL are associated with a higher rate of LBR. ART may be negatively associated with LBR.

How to agree on what is fundamental to optimal teamwork performance in a situation of postpartum hemorrhage? A multidisciplinary Delphi French study to develop the Obstetric Team Performance Assessment Scale (OTPA Scale).

INTRODUCTION: The objective of this study was to develop a new interdisciplinary teamwork scale, the Obstetric Team Performance Assessment (OTPA), for the management of the post-partum hemorrhage, through consensus agreement of obstetric caregivers. The goal is to provide a reliable tool for teaching and evaluating teams in high-fidelity simulation. METHODS: This prospective study is based on an expert consensus, using a Delphi method. The authors developed the "OTPA¼ specifically related to the management of post-partum hemorrhage, using existing recommendations. For the Delphi survey, the scale was distributed to a selected group of experts. After each round of Delphi, authors quantitatively analyzed each element of the scale, based on the percentages of agreement received, and reviewed each comment. This blind examination then led to the modification of the scale. The rounds were continued until 80-100 % agreement with a median overall response score equal to or greater than 8 was obtained for at least 60 % of items. Repeated 3 times, the process led to consensus and to a final version of the OTPA scale. RESULTS: From February to October 2018, 16 of the 33 invited experts participated in four Delphi cycles. Of the 37 items selected in the first round, only 19 (51.3 %) had an agreement of 80-100% with a median overall response score equal to or greater than 8 in the second round, and a third round was conducted. During this third round, 24 of the 37 items were validated (64.9 %) and 82 of the 88 sub-items obtained 80 %-100 % agreement (93.2 %). The fourth round consisted of proposing a weighting of the different items. CONCLUSION: Using a structured Delphi method, we provided a new interdisciplinary teamwork scale (OTPA), for the management of the post-partum hemorrhage. Thus, this scale will be able to be used during high-fidelity scenarii to assess performances of various teams facing a scenari of PPH. Moreover, this scale, focusing some crucial aspects of interdisciplinary teamwork will be useful for teaching purpose.