Glutathione prevents preterm parturition and fetal death by targeting macrophage-induced reactive oxygen species production in the myometrium.

Preterm birth is an inflammatory process resulting from the massive infiltration of innate immune cells and the production of proinflammatory cytokines in the myometrium. However, proinflammatory cytokines, which induce labor in vivo, fail to induce labor-associated features in human myometrial cells (MCs). We thus aimed to investigate if reactive oxygen species (ROS) production could be the missing step between immune cell activation and MC response. Indeed, we found that ROS production is increased in the human preterm laboring myometrium (27% ROS producing cells, respectively, versus 2% in nonlaboring controls), with 90% ROS production in macrophages. Using LPS-stimulated myometrial samples and cell coculture experiments, we demonstrated that ROS production is required for labor onset. Furthermore, we showed that ROS are required first in the NADPH oxidase (NADPHox)-2/NF-κB-dependent macrophage response to inflammatory stimuli but, more importantly, to trigger macrophage-induced MCs transactivation. Remarkably, in a murine model of LPS-induced preterm labor (inducing delivery within 17 hours, with no pup survival), cotreatment with glutathione delayed labor onset up to 94 hours and prevented in utero fetal distress, allowing 46% pups to survive. These results suggest that targeting ROS production with the macrophage-permeable antioxidant glutathione could constitute a promising strategy to prevent preterm birth.

Systemic increase in human maternal circulating CD14+CD16- MCP-1+ monocytes as a marker of labor.

OBJECTIVES: To study the influence of pregnancy and labor on the proportion and level of activation of monocyte subpopulations in human pregnancy. STUDY DESIGN: Peripheral blood samples were obtained from healthy nonpregnant women (n = 6); women in the third-trimester of healthy pregnancies (n = 18) and women with preterm premature rupture of membranes (n = 46), just before delivery for the last 2 groups. Monocyte subpopulations were characterized by flow cytometry using CD14, CD16, and activation level using macrophage chemoattractant protein-1 (MCP-1) and CCR2 antibodies. RESULTS: The relative proportion of each monocyte subset in nonpregnant women was similar to that in women with healthy or complicated pregnancies. However, pregnancy was associated with a significant decrease in MCP-1 expressing monocytes (79.5% ± 19.8% vs 9.3% ± 6.8% and 11.9% ± 8.3% for nonpregnant, healthy pregnancy, and preterm premature rupture of membranes (respectively, P < .05). Spontaneous labor was associated with a return to nonpregnant values for the proportion of MCP-1 expressing monocytes in both normal (74.4% ± 16.9) and preterm premature rupture of membranes pregnancy (68.4% ± 35.6), irrespective of the mode of delivery (vaginal or cesarean section). This was not observed in women who delivered without spontaneous labor onset. CCR-2 (MCP-1 receptor) expression was not modified in monocytes at the time of labor, but was significantly increased in granulocytes (3646 ± 1080 vs 7338 ± 2718 for nonlaboring and laboring preterm premature rupture of membranes, respectively, P < .05) CONCLUSION: In light of previous reports of a role for MCP-1 in labor, our results suggest the downregulation of activation levels of monocytes, via MCP-1 expression might be involved in maternofetal immune tolerance. Monocyte reactivation might be associated with labor.

Clinical presentation and outcome of 20 fetuses with parvovirus B19 infection complicated by severe anemia and/or fetal hydrops.

AIM: The aim of this study was to assess the prognosis of parvovirus B19 infection with severely anemic and/or hydropic fetuses according to initial ultrasound and biological criteria. MATERIAL AND METHODS: Retrospective study of 20 cases of congenital parvovirus B19-proven infection (positive PCR) complicated by fetal anemia and/or hydrops was examined. Anemia was suspected on an elevated peak systolic velocity of the middle cerebral artery and was confirmed by fetal blood sampling. RESULTS: Survival rate was 70% (14/20) overall and 76% (13/17) for fetuses with one or more transfusions. When fetal effusion regressed after the transfusion, all 11 fetuses survived, and neonatal condition was favorable for all. Among the 14 live-born children, there was one neonatal death and one admission to the neonatal care unit with no major complications. CONCLUSION: Despite active management by transfusion in fetuses with parvovirus B19 infection, mortality remained substantial during the acute phase of anemia and fetal hydrops. Regression of effusion appears to be an important variable for prognosis. Non-anemic forms exist with isolated refractory ascites or pleural effusion. Maternal mirror syndrome appears to reflect the intensity and persistence of the fetal anemia.

Practice guidelines for prevention of musculoskeletal disorders in obstetric sonography.

Ergonomics and prevention of musculoskeletal disorders in obstetric sonography is a subject seldom discussed. However, 80% of sonographers describe pain when performing these examinations. The consequences of these disorders can range from impaired quality of life to the complete cessation of professional activity. Some diseases may even require surgical treatments such as carpal tunnel syndrome and shoulder rotator cuff injuries. After joint disorders mainly affecting the upper limbs and neck, deterioration of visual acuity is the second most commonly reported condition. A literature review can identify risk factors, particularly arm abduction greater than 30°, repeated isometric maneuvers without compensatory rest, the level of force applied to the probe, abdominal scanning approaches, examination times longer than 25 minutes, and more than 100 sonographic examinations per month. The ergonomics of the operator's workstation and posture are essential to prevent these disorders. Machine, probe, chair, and examination bed designs are already subject to industrial consensus, but sonographers are responsible for configuring their ideal workstations to preserve their professional and physical potential. Therefore, this article proposes rules of good practice and illustrates recommended positions and those to avoid.

Reference ranges and distribution of placental volume by 3-dimensional virtual organ computer-aided analysis between 11 weeks and 13 weeks 6 days.

OBJECTIVES: The purpose of this study was to determine the feasibility, reproducibility, and distribution of placental volume measurements according to the crown-rump length between 11 weeks and 13 weeks 6 days. METHODS: Images were acquired in 128 pregnancies followed in Burgundy during first-trimester screening sonography using an abdominal 3-dimensional transducer. The placental volume was then calculated by the virtual organ computer-aided analysis method with a rotation angle of 30° by a single operator. RESULTS: Placental volumes ranged from 33.3 to 107.6 cm(3) with a mean ± SD of 62.3 ± 14.8 cm(3); the 5th and 10th percentiles were 38.0 and 44.20 cm(3), respectively, whereas the 90th and 95th percentiles were 80.25 and 86.68 cm(3). An exponential relationship was found between placental volume and crown-rump length: ln placental volume = 0.018 × crown-rump length + 2.93425; ln SD = 0.15; r(2) = 0.58. Finally, the mean placental quotient, defined as the ratio of placental volume to crown-rump length, was 1 ± 0.1 cm(3)/mm; the respective percentile values were 0.74, 0.81, 1.18, and 1.29 cm(3)/mm. No associations were found between parity or smoking and the placental quotient or between obesity and the placental quotient. Intraobserver reproducibility was good, with a mean difference of 0.2 cm(3). CONCLUSIONS: Measurement of placental volume between 11 weeks and 13 weeks 6 days is reliable and reproducible and correlates strongly with crown-rump length.

Ultrasound markers for the detection of women at risk of developing pre-eclampsia.

Pre-eclampsia (PE) is a consequence of an abnormal placental invasion. Uterine artery Doppler (Ut-AD) is directly related to trophoblastic invasion of the spiral arteries, which occurs before 18 weeks' gestation. A correct interpretation of Ut-AD indices and waveform patterns requires a rigorous and standardized methodology, in particular for the definition of notches. To date, aspirin is the only treatment associated with a decreased incidence of PE, and early identification of women at risk is crucial to optimize its use. The diagnostic performance of Ut-AD as a screening test should take into account the characteristics of the population studied. In women at high-risk of PE (i.e., women with a previous history of PE), results vary from a detection rate of 63%, with 25% false-positive results for all forms of PE, to 91% detection with 5% false-positive for early PE if repeated measurements, combined with maternal characteristics, are performed. Multicenter randomized clinical trials failed to demonstrate a benefit from administering aspirin in low-risk women with abnormal Ut-AD. In unselected populations, the use of Ut-AD, alone or integrated into algorithms including maternal characteristics, cannot be recommended for clinical practice at any gestational age. Combination with biological markers is a new field of research that could improve the performance of Ut-AD.

RET and GDNF mutations are rare in fetuses with renal agenesis or other severe kidney development defects.

BACKGROUND: The RET/GDNF signalling pathway plays a crucial role during development of the kidneys and the enteric nervous system. In humans, RET activating mutations cause multiple endocrine neoplasia, whereas inactivating mutations are responsible for Hirschsprung disease. RET mutations have also been reported in fetuses with renal agenesis, based on analysis of a small series of samples. OBJECTIVE AND METHODS: To characterise better the involvement of RET and GDNF in kidney development defects, a series of 105 fetuses with bilateral defects, including renal agenesis, severe hypodysplasia or multicystic dysplastic kidney, was studied. RET and GDNF coding sequences, evolutionary conserved non-coding regions (ECRs) in promoters, 3'UTRs, and RET intron 1 were analysed. Copy number variations at these loci were also investigated. RESULTS: The study identified: (1) a low frequency (<7%) of potential mutations in the RET coding sequence, with inheritance from the healthy father for four of them; (2) no GDNF mutation; (3) similar allele frequencies in patients and controls for most single nucleotide polymorphism variants, except for RET intron 1 variant rs2506012 that was significantly more frequent in affected fetuses than in controls (6% vs 2%, p=0.01); (4) distribution of the few rare RET variants unidentified in controls into the various 5'-ECRs; (5) absence of copy number variations. CONCLUSION: These results suggest that genomic alteration of RET or GDNF is not a major mechanism leading to renal agenesis and other severe kidney development defects. Analysis of a larger series of patients will be necessary to validate the association of the RET intron 1 variant rs2506012 with renal development defects.

Successful pregnancy with the use of nitric oxide donors and heparin after recurrent severe preeclampsia in a woman with scleroderma.

We report the case of a woman with scleroderma who had severe, early-onset preeclampsia on 2 consecutive pregnancies. With a treatment that included aspirin, heparin, and a nitric oxide donor, her third pregnancy ended with a healthy neonate at term. Nitric oxide donors and heparin may play a preventive role on placental dysfunction in scleroderma.

Changes in maternal blood inflammatory markers as a predictor of chorioamnionitis: a prospective multicenter study.

PROBLEM: To evaluate the inflammatory pattern in maternal circulation from women with preterm premature rupture of membranes (PPROM) considering the occurrence of histologically confirmed chorioamnionitis (HCA). METHOD OF STUDY: A prospective study was conducted in 121 women with PPROM between 24 and 34 + 0 weeks of gestation. Association between white blood cells (WBC) count, plasma CRP, IL-6, MCP-1 and IP-10 levels, and HCA was assessed. RESULTS: The rate of HCA was 44.7% (54/121). During the 5 days preceding delivery, median CRP, WBC, and IL-6 levels were significantly higher in the HCA than in no-HCA group (P < 0.001). Variations in IL-6, IP-10 levels, during the 24-72 hr before delivery, were predictors of the occurrence of HCA, but the diagnostic accuracy was low [Receiver Operating Characterictic (ROC) curve, area under the curve (AUC) = 0.56]. CONCLUSION: An increase in IL-6, CRP, IP-10 maternal plasma levels was confirmed in PPROM women with HCA. Longitudinal follow-up of these markers did not add valuable information regarding HCA.

Fetal anemia as a signal of congenital syphilis.

An upsurge in syphilis has been observed almost everywhere over the past decade. The mother's clinical presentation is often uninformative. The diagnosis of maternal syphilis infection is most often based on serologic tests that allow early Extencilline treatment. Syphilis ultrasound findings are non-specific, and delay before treatment can be decisive for prognosis. Fetal anemia is a physiological consequence of severe infection. We confirmed that syphilis can be suggested non-invasively by MCA-PSV measurements in a context of ascitis or atypical hydrops in the absence of usual causes. It is therefore important to perform maternal TPHA/VDRL serology if fetal anemia is suspected. In association with Extencilline treatment, intra uterine transfusion can limit consequences of infection. Reduced fetal movements and non-reactive fetal heart rate may prefigure acute perinatal complications or stillbirth.

Phenotypic spectrum of fetal Smith-Lemli-Opitz syndrome.

The Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive multiple congenital malformation syndrome caused by dehydrocholesterol reductase deficiency. The diagnosis is confirmed by high 7- and secondarily 8-dehydrocholesterol levels in plasma and tissues and/or by detection of biallelic mutations in the DHCR7 gene. The phenotypic spectrum of SLOS is broad, ranging from a mild phenotype combining subtle physical anomalies with behavioral and learning problems, to a perinatally lethal multiple malformations syndrome. The fetal phenotype of SLOS has been poorly described in the literature. We report a series of 10 fetuses with molecularly proven SLOS. Even in young fetuses, the facial dysmorphism appears characteristic. Genital abnormalities are rare in 46,XX subjects. Gonadal differentiation appears histologically normal and in agreement with the chromosomal sex, contrary to what has been previously stated. We observed some previously unreported anomalies: ulnar hypoplasia, vertebral segmentation anomalies, congenital pulmonary adenomatoid malformation, fused lungs, gastroschisis, holomyelia and hypothalamic hamartoma. This latter malformation proves that SLOS phenotypically overlaps with Pallister-Hall syndrome which remains clinically a major differential diagnosis of SLOS.

Management of very early fetal anemia resulting from red-cell alloimmunization before 20 weeks of gestation.

OBJECTIVE: To evaluate the results of management of very early fetal anemia (before 20 weeks of gestation) in cases of red-cell alloimmunization. METHODS: Retrospective study of the outcome of all in utero transfusions performed before 20 weeks of gestation and all pregnancies requiring an in utero transfusion before 20 weeks in our reference center from January 1990 through August 2011 in cases with severe alloimmunization. RESULTS: Twenty-five in utero transfusions were performed in 18 pregnancies in 16 patients during the study period. A vascular access was performed successfully in 22 of the 24 cases in which it was attempted. An intraperitoneal transfusion was necessary in two cases. Two in utero deaths attributable to the intravascular procedure occurred during attempts before 18 weeks of gestation and another, not associated with a transfusion, at 29 weeks. The overall survival rate was 83.3% (compared with 88.0% when the first in utero transfusion took place before 22 weeks). The risk of fetal loss for each transfusion was 8.0% before 20 weeks and 6.3% before 22 weeks. An intraperitoneal transfusion at 17 2/7 weeks allowed one fetus to survive until the first intravascular in utero transfusion could take place at 18 2/7 weeks. CONCLUSION: Fetal anemia before 20 weeks remains at high risk of lethal complications compared with later gestational ages. Technical difficulties in a vascular access are mainly encountered before 18 weeks of gestation. At an earlier gestational age, intraperitoneal transfusion may gain the days necessary to perform an intravascular transfusion more safely. LEVEL OF EVIDENCE: III.