Risk of severe maternal morbidity associated with in vitro fertilisation: a population-based study.

OBJECTIVE: To investigate the association between in vitro fertilisation IVF and severe maternal morbidity (SMM) and to explore the role of multiple pregnancy as an intermediate factor. DESIGN: Population-based cohort-nested case-control study. SETTING: Six French regions in 2012/13. POPULATION: Cases were 2540 women with SMM according to the EPIMOMS definition; controls were 3651 randomly selected women who gave birth without SMM. METHODS: Analysis of the associations between IVF and SMM with multivariable logistic regression models, differentiating IVF with autologous oocytes (IVF-AO) from IVF with oocyte donation (IVF-OD). The contribution of multiple pregnancy as an intermediate factor was assessed by path analysis. MAIN OUTCOME MEASURES: Severe maternal morbidity overall and SMM according to its main underlying causal condition and by severity (near misses). RESULTS: The risk of SMM was significantly higher in women with IVF (adjusted OR = 2.5, 95% CI 1.8-3.3). The risk of SMM was significantly higher with IVF-AO, for all-cause SMM (aOR = 2.0, 95% CI 1.5-2.7), for near misses (aOR = 1.9, 95% CI 1.3-2.8), and for intra/postpartum haemorrhages (aOR = 2.3, 95% CI 1.6-3.2). The risk of SMM was significantly higher with IVF-OD, for all-cause SMM (aOR = 18.6, 95% CI 4.4-78.5), for near misses (aOR = 18.1, 95% CI 4.0-82.3), for SMM due to hypertensive disorders (aOR = 16.7, 95% CI 3.3-85.4) and due to intra/postpartum haemorrhages (aOR = 18.0, 95% CI 4.2-77.8). Path-analysis estimated that 21.6% (95% CI 10.1-33.0) of the risk associated with IVF-OD was mediated by multiple pregnancy, and 49.6% (95% CI 24.0-75.1) of the SMM risk associated with IVF-AO. CONCLUSION: The risk of SMM is higher in IVF pregnancies after adjustment for confounders. Exploratory results suggest higher risks among women with IVF-OD; however, confidence intervals were wide, so this finding needs to be confirmed. A large part of the association between IVF-AO and SMM appears to be mediated by multiple pregnancy. TWEETABLE ABSTRACT: The risk of severe maternal morbidity is higher in IVF-conceived pregnancies than in pregnancies conceived by other means.

[Maternal mortality among women with Marfan syndrome or vascular Ehlers-Danlos syndrome in France, 2001-2012]. / Mortalité maternelle chez les patientes atteintes de syndromes de Marfan ou d'Ehlers-Danlos vasculaire en France, 2001­2012.

OBJECTIVE: To describe maternal deaths in France associated with Marfan's syndrome or vascular Ehlers-Danlos syndrome. STUDY DESIGN: A retrospective descriptive study based on data from the national confidential enquiry into maternal deaths, in France, during 2001-2012. Characteristics of the patients, their pregnancies and details of their deaths were analysed. The specific maternal mortality ratio by Marfan's syndrome or vascular Ehlers-Danlos syndrome was estimated. RESULTS: Among 973 maternal deaths that occurred during the study period, five (0.4%) had a Marfan's syndrome (n=3) or a vascular Ehlers-Danlos syndrome (n=2), confirmed or suspected. The maternal mortality ratio due to Marfan's syndrome or vascular Ehlers-Danlos syndrome between 2001 and 2012 was 0.04/100,000 live births (IC 95% [0.011-0.2]). Three maternal deaths were caused by aortic dissections and two by other arterial ruptures. The deaths have occurred after 37 weeks of pregnancy for 4 patients, and at fifteen days of post-partum for one patient. The median age of death was 30 years. Three patients were nulliparous. Marfan's syndrome and vascular Ehlers-Danlos syndrome were not identified before the death of these five patients. CONCLUSION: Five patients with, or suspected to have, Marfan's syndrome or vascular Ehlers-Danlos syndrome were identified. Early diagnosis of these syndromes in pregnant women before life threatening events is very important, especially to refer them to appropriate care.

Dry potato extracts improve water holding capacity, shelf life, and sensory characteristics of fresh and precooked beef patties.

The objective was to examine shelf stability, cooked product yield, and sensory characteristics of beef patties that had no binder (Control), incorporated soy flour (Textured Vegetable Protein; TVP) or one of three dry potato extracts: X-TRATOS™ (potato extract), X-TRATOS™ O (potato extract with mustard), or X-TRATOS™ W (potato extract with sodium acid pyrophosphate). In retail display patties, all binders decreased discoloration and lipid oxidation compared to Control, and X-TRATOS™ O was superior (P < 0.05) to all other treatments. Cooking yield was higher (P < 0.05) in patties containing potato extracts compared with patties containing TVP, which had higher yield than Control patties. Beef patties with potato extracts were juicier (P < 0.05) than Control and TVP patties and had higher (P < 0.05) overall acceptability than Control patties. We conclude that potato extracts are effective binders for use in fresh or precooked beef patties because they improve retail shelf life, cooked product yield, and sensory characteristics.

Strategies to improve beef tenderness by activating calpain-2 earlier postmortem.

Our objectives were to determine the effect of post rigor calcium chloride injection or freezing on 1) sarcoplasmic calcium concentration and calpain-2 activity of beef longissimus lumborum (LL) and semimembranosus (SM) steaks aged 1, 4, and 14days post-treatment and on 2) Warner-Bratzler shear force, water holding capacity, and consumer acceptability of LL and SM steaks aged 4 and 14days post-treatment. Free calcium levels in the calcium, frozen, and control steaks averaged 1256, 127, and 121µM for the LL and 1520, 120, and 111µM for the SM, respectively. Measurable LL native calpain-2 activity was lower in calcium and frozen steaks than control steaks (P<0.01), while SM native calpain-2 activity was lowest in calcium steaks and intermediate in frozen steaks (P<0.01). LL calcium steaks were more tender (P=0.04) than control steaks. In conclusion, calcium chloride injection and freezing activate calpain-2 earlier postmortem in both muscles and calcium injection improves LL tenderness.

Long-term neurologic and cardiac correction by intrathecal gene therapy in Pompe disease.

Pompe disease is a lysosomal storage disorder caused by acid-α-glucosidase (GAA) deficiency, leading to glycogen storage. The disease manifests as a fatal cardiomyopathy in infantile form. Enzyme replacement therapy (ERT) has recently prolonged the lifespan of these patients, revealing a new natural history. The neurologic phenotype and the persistence of selective muscular weakness in some patients could be attributed to the central nervous system (CNS) storage uncorrected by ERT. GAA-KO 6neo/6neo mice were treated with a single intrathecal administration of adeno-associated recombinant vector (AAV) mediated gene transfer of human GAA at 1 month and their neurologic, neuromuscular, and cardiac function was assessed for 1 year. We demonstrate a significant functional neurologic correction in treated animals from 4 months onward, a neuromuscular improvement from 9 months onward, and a correction of the hypertrophic cardiomyopathy at 12 months. The regions most affected by the disease i.e. the brainstem, spinal cord, and the left cardiac ventricular wall all show enzymatic, biochemical and histological correction. Muscle glycogen storage is not affected by the treatment, thus suggesting that the restoration of muscle functionality is directly related to the CNS correction. This unprecedented global and long-term CNS and cardiac cure offer new perspectives for the management of patients.

Rapid Discovery of De Novo Deleterious Mutations in Cattle Enhances the Value of Livestock as Model Species.

In humans, the clinical and molecular characterization of sporadic syndromes is often hindered by the small number of patients and the difficulty in developing animal models for severe dominant conditions. Here we show that the availability of large data sets of whole-genome sequences, high-density SNP chip genotypes and extensive recording of phenotype offers an unprecedented opportunity to quickly dissect the genetic architecture of severe dominant conditions in livestock. We report on the identification of seven dominant de novo mutations in CHD7, COL1A1, COL2A1, COPA, and MITF and exploit the structure of cattle populations to describe their clinical consequences and map modifier loci. Moreover, we demonstrate that the emergence of recessive genetic defects can be monitored by detecting de novo deleterious mutations in the genome of bulls used for artificial insemination. These results demonstrate the attractiveness of cattle as a model species in the post genomic era, particularly to confirm the genetic aetiology of isolated clinical case reports in humans.

Effect of extended aging on calpain-1 and -2 activity in beef longissimus lumborum and semimembranosus muscles.

Our objectives were to (Exp. 1) determine the effect of postmortem aging (2, 3, 4, 14, 28, and 42days) on calpain-1 and -2 activity in beef longissimus lumborum (LL) and semimembranosus (SM) steaks and (Exp. 2) determine the effect of postmortem aging for two extended periods (63 and 84days) on calpain-2 activity of beef SM steaks. Calpain-1 was not active in either muscle following 14days of aging. Native calpain-2 activity decreased (P<0.001) with longer aging periods for both the LL and SM in Exp. 1 and for the SM in Exp. 2. Autolyzed calpain-2 activity increased (P<0.001) with longer aging for the LL and SM in Exp. 1 and for the SM in Exp. 2. Our results indicate that both calpain-1 and calpain-2 may contribute to the postmortem improvement of beef tenderness, with calpain-1 being responsible for the tenderness improvement early postmortem and calpain-2 responsible for additional tenderization during extended aging.

Efficient CNS targeting in adult mice by intrathecal infusion of single-stranded AAV9-GFP for gene therapy of neurological disorders.

Adeno-associated virus (AAV) gene therapy constitutes a powerful tool for the treatment of neurodegenerative diseases. While AAVs are generally administered systemically to newborns in preclinical studies of neurological disorders, in adults the maturity of the blood-brain barrier (BBB) must be considered when selecting the route of administration. Delivery of AAVs into the cerebrospinal fluid (CSF) represents an attractive approach to target the central nervous system (CNS) and bypass the BBB. In this study, we investigated the efficacy of intra-CSF delivery of a single-stranded (ss) AAV9-CAG-GFP vector in adult mice via intracisternal (iCist) or intralumbar (it-Lumb) administration. It-Lumb ssAAV9 delivery resulted in greater diffusion throughout the entire spinal cord and green fluorescent protein (GFP) expression mainly in the cerebellum, cortex and olfactory bulb. By contrast, iCist delivery led to strong GFP expression throughout the entire brain. Comparison of the transduction efficiency of ssAAV9-CAG-GFP versus ssAAV9-SYN1-GFP following it-Lumb administration revealed widespread and specific GFP expression in neurons and motoneurons of the spinal cord and brain when the neuron-specific synapsin 1 (SYN1) promoter was used. Our findings demonstrate that it-Lumb ssAAV9 delivery is a safe and highly efficient means of targeting the CNS in adult mice.

Influence of extended aging on beef quality characteristics and sensory perception of steaks from the biceps femoris and semimembranosus.

The objective was to determine the influence of post-fabrication aging (2, 14, 21, 42, and 63days) on beef quality characteristics and consumer sensory perception of biceps femoris (BF) and semimembranosus (SM) steaks. Lipid oxidation and aerobic plate counts increased (P<0.05) with longer aging periods and retail display times. An aging period by day of retail display interaction (P<0.05) was observed for a* and b* values of the BF and SM. Warner-Bratzler shear force values decreased (P<0.05) with longer aging for the SM, while no difference was observed for the BF. Consumer panel results revealed that longer aging periods increased (P<0.05) acceptability of the SM, tenderness of both muscles, and tended to increase (P=0.07) juiciness of the SM. Our results show that extended aging reduces retail color stability yet has positive effects on consumer perception of tenderness of both muscles and overall acceptability of the SM.

Invasive therapies for primary postpartum haemorrhage: a population-based study in France.

OBJECTIVE: To describe the characteristics, management, and outcomes of women undergoing invasive therapies for primary postpartum haemorrhage (PPH). DESIGN: A population-based observational study. SETTING: All 106 maternity units of six French regions. POPULATION: A total of 146 781 women delivering between 2004 and 2006. METHODS: Prospective identification of women with PPH managed with invasive therapies, including uterine suture, pelvic vessel ligation, arterial embolisation, and hysterectomy. MAIN OUTCOME MEASURES: Rate of use and failure rate of invasive therapies, with 95% confidence intervals (95% CIs). RESULTS: An invasive therapy was used in 296 of 6660 women with PPH (4.4%, 95% CI 4.0-5.0), and in 0.2% of deliveries (95% CI 0.18-0.23). A hysterectomy was performed in 72/6660 women with PPH (1.1%, 95% CI 0.8-1.4%), and in 0.05% of deliveries (95% CI 0.04-0.06). A conservative invasive therapy was used in 262 women, including 183 (70%) who underwent arterial embolisation and 79 (30%) who had conservative surgery as the first-line therapy. Embolisation was more frequently used after vaginal than caesarean delivery, and when arterial embolisation was available on site. The failure rate of conservative invasive therapies was 41/262 (15.6%, 95% CI 11.5-20.6) overall, and was higher after surgical than after embolisation procedures, in particular for vaginal deliveries. CONCLUSIONS: Both maternal mortality as a result of obstetric haemorrhage and the rate of invasive therapies used for PPH are high in France. These findings suggest flaws in the initial management of PPH and/or the inadequate use of invasive procedures. TWEETABLE ABSTRACT: Maternal mortality as a result of haemorrhage and the rate of invasive therapies used for PPH are high in France.

Maternal mortality among women with sickle-cell disease in France, 1996-2009.

OBJECTIVE: To describe maternal mortality among women with sickle-cell disease in France. STUDY DESIGN: Data from the national confidential enquiry into maternal deaths and from reference centres for sickle-cell disease were examined to identify women with this disease who died in France during 1996-2009. The maternal mortality ratio among women with sickle-cell disease was estimated and compared with the ratio in the general population. Characteristics of these women and their pregnancies and circumstances of their deaths were examined in detail. RESULTS: Fifteen maternal deaths occurred among an estimated 3300 live births to women with sickle-cell disease, for a maternal mortality ratio of 454 per 100000 live births (95% CI [254; 750]), versus 9.4/100000 in the general population. Ten women were homozygous (SS) for sickle-cell disease, and five were composite heterozygotes. The episode leading to death appeared in the antepartum period for seven women (47%). Two women died of septic shock during pregnancy, one at 6 weeks, the other at 24 weeks. The other 13 women (87%) died postpartum. Thirteen deaths were directly attributable to sickle-cell disease. The other two maternal deaths, both considered direct obstetric causes, were due to amniotic fluid embolism and septic shock after post-amniocentesis chorioamnionitis. The expert committee on maternal mortality judged seven of these 15 deaths (47%) to be avoidable. CONCLUSION: Sickle-cell disease is responsible for a major excess risk of maternal death in France, due mainly to direct complications of the disease.

Influence of extended aging on beef quality characteristics and sensory perception of steaks from the gluteus medius and longissimus lumborum.

The objective was to determine the influence of post-fabrication aging (2, 14, 21, 42, and 63 days) on beef quality characteristics and consumer sensory perception of gluteus medius (GM) and longissimus lumborum (LL) steaks. Lipid oxidation and aerobic plate counts increased (P<0.05) with longer aging periods and retail display times. An aging period by day of retail display interaction (P<0.05) was observed for a* and b* values for both muscles and L* values for the LL. Warner-Bratzler shear force values decreased (P<0.05) with longer aging for the LL, while no difference was observed for the GM. Consumer panel results demonstrated that longer aging periods increased (P<0.05) tenderness of both muscles. Our results indicate that extended aging reduces retail color stability yet has positive effects on consumer perception of tenderness of beef loin muscles.

Effects of dietary potato by-product and rumen-protected histidine on growth, carcass characteristics and quality attributes of beef.

We hypothesized that variable composition in finishing rations, more specifically; the proportion of potato-by-product (PBP) and rumen protected histidine (His) supplementation may influence growth and meat quality attributes. Two different diets were fed (1) finishing ration with corn and barley as grains (CB, n = 20) and (2) substitution of 10% corn, DM basis, with PBP (PBP, n = 20). Additionally, half of each dietary treatment received 50 g/hd/d rumen protected His (HS, n= 20) while the other half received no supplement (NS, n = 20). Inclusion of 10% PBP or HS did not affect growth or carcass traits. Color stability was analyzed using Hunter color values as well as AMSA visual appraisal in both longissimus thoracis (LT) and gluteus medius (GM) muscles. The LT, but not the GM, of CB steers was more color stable over a 9 d simulated retail display compared to those fed a PB diet. Steers receiving HS produced significantly (P < 0.05) more color stable LT and GM steaks.

Efficient central nervous system AAVrh10-mediated intrathecal gene transfer in adult and neonate rats.

Intracerebral administration of recombinant adeno-associated vector (AAV) has been performed in several clinical trials. However, delivery into the brain requires multiple injections and is not efficient to target the spinal cord, thus limiting its applications. To assess widespread and less invasive strategies, we tested intravenous (IV) or intrathecal (that is, in the cerebrospinal fluid (CSF)) delivery of a rAAVrh10-egfp vector in adult and neonate rats and studied the effect of the age at injection on neurotropism. IV delivery is more efficient in neonates and targets predominantly Purkinje cells of the cerebellum and sensory neurons of the spinal cord and dorsal root ganglia. A single intra-CSF administration of AAVrh10, single strand or oversized self-complementary, is efficient for the targeting of neurons in the cerebral hemispheres, cerebellum, brainstem and spinal cord. Green fluorescent protein (GFP) expression is more widespread in neonates when compared with adults. More than 50% of motor neurons express GFP in the three segments of the spinal cord in neonates and in the cervical and thoracic regions in adults. Neurons are almost exclusively transduced in neonates, whereas neurons, astrocytes and rare oligodendrocytes are targeted in adults. These results expand the possible routes of delivery of AAVrh10, a serotype that has shown efficacy and safety in clinical trials concerning neurodegenerative diseases.

Intracisternal delivery of AAV9 results in oligodendrocyte and motor neuron transduction in the whole central nervous system of cats.

Systemic and intracerebrospinal fluid delivery of adeno-associated virus serotype 9 (AAV9) has been shown to achieve widespread gene delivery to the central nervous system (CNS). However, after systemic injection, the neurotropism of the vector has been reported to vary according to age at injection, with greater neuronal transduction in newborns and preferential glial cell tropism in adults. This difference has not yet been reported after cerebrospinal fluid (CSF) delivery. The present study analyzed both neuronal and glial cell transduction in the CNS of cats according to age of AAV9 CSF injection. In both newborns and young cats, administration of AAV9-GFP in the cisterna magna resulted in high levels of motor neurons (MNs) transduction from the cervical (84±5%) to the lumbar (99±1%) spinal cord, demonstrating that the remarkable tropism of AAV9 for MNs is not affected by age at CSF delivery. Surprisingly, numerous oligodendrocytes were also transduced in the brain and in the spinal cord white matter of young cats, but not of neonates, indicating that (i) age of CSF delivery influences the tropism of AAV9 for glial cells and (ii) AAV9 intracisternal delivery could be relevant for both the treatment of MN and demyelinating disorders.

[Frequency, causes and risk factors of postpartum haemorrhage: a population-based study in 106 French maternity units]. / Incidence, étiologies et facteurs de risque de l'hémorragie du post-partum : étude en population dans 106 maternités françaises.

OBJECTIVE: To estimate the incidence, to describe the aetiology and to identify the risk factors of postpartum haemorrhage (PPH). MATERIAL AND METHOD: Prospective study conducted in 106 French maternity units of six perinatal networks between December 2004 and November 2006. PPH was defined by a blood loss superior to 500 mL or necessitating an examination of the uterus, or a peripartum haemoglobin drop superior to 2 g/dL. Severe PPH was defined by at least one of these criteria : peripartum haemoglobin drop superior or equal to 4 g/dL, embolization, conservative surgical procedure, hysterectomy, transfusion, transfer to intensive care or death. RESULTS: The incidence of PPH was 6.4% [CI 95% 6.3-6.5] with variations between maternity units from 1.5% to 22.0%; incidence of severe PPH was 1.7% [CI 95% 1.6-1.8] with variations between units from 0% to 4%. Atony was the main aetiology of PPH, whatever the mode of delivery and severity. The risk factors identified were those classically described in the literature. CONCLUSION: In these six French perinatal networks, in 2005-2006, the PPH profile was characterized by an incidence of severe forms higher than previous population-based estimates from other countries. This suggests a more frequent aggravation of PPH and the implication of inadequate PPH management.

[Maternal mortality in France, 2007-2009]. / Épidémiologie de la mortalité maternelle en France, 2007-2009.

To monitor the maternal mortality which is an indicator of the quality of obstetric and intensive care, France has a specific approach since 1996. Recently linkages have been introduced to improve the inclusion of cases. Here are the results for the 2007 to 2009 period. The identification of the pregnancy associated deaths is lying on different data bases that are medical causes of death, birth register and hospital discharges. To document the cases, confidential enquiries are conducted by two assessors on the field; a committee of medical experts analyses the documents, select the underlying cause and assess the quality of health care. Two hundred and fifty-four obstetric deaths were identified from 2007 to 2009 giving the maternal mortality ratio (MMR) of 10.3 per 100,000 births. The maternal age and nationality, the region of deaths are associated to the MMR. The haemorrhages are the leading cause but their ratio is 1.9 versus 2.5 previously; this decrease results from the postpartum haemorrhage by uterine atony going down. The suboptimal care are still frequent (60%) but slightly less than before. The linkage method should be pursued. Maternal mortality is rather stable in France. We may reach more reduction as deaths due to atony decreased as suboptimal care did.

Retrospective study of Mycoplasma gallisepticum meningoencephalitis in six turkey flocks in western France.

Mycoplasma gallisepticum (MG) meningoencephalitis was diagnosed in six turkey flocks, from 1998 to 2005, in the western part of France. Affected birds were 8-11 weeks old and all displayed neurological signs, especially torticollis, with more than half having concomitant respiratory signs. Microscopical examination of brain samples from birds in all six flocks revealed similar lesions of acute to subacute multifocal parenchymal necrosis, perivascular cuffing, leptomeningitis and vasculitis. Birds from four of the six affected flocks were seropositive for MG and in birds from four flocks MG DNA was detected by polymerase chain reaction performed on tracheal swabs or on samples of formalin-fixed and paraffin wax-embedded brain. To our knowledge, this is the first pathological description of naturally occurring cases of turkey MG meningoencephalitis in Europe.

[French hospital discharge database: data production, validity, and origins of errors in the field of severe maternal morbidity]. / Le programme de médicalisation du système d'information (PMSI) - processus de production des données, validité et sources d'erreurs dans le domaine de la morbidité maternelle sévère.

BACKGROUND: The organization of obstetric care in France brings all women in contact with the hospital system. Thus, hospital discharge data from the Program of Medicalization of the Information System (PMSI) constitute a potentially valuable source of information, particularly regarding rare events such as severe maternal morbidity. These data cover a large population but their quality has not been assessed in that field. Our objectives were to study the processes of production and the validity of PMSI data related to severe maternal morbidity. METHODS: The study was conducted in four French tertiary teaching hospitals (Caen, Cochin [AP-HP, Paris], Grenoble and Lille). First, the organization of each step of the medical information process -production, formatting, verification and processing- was detailed in each center with a standardized form. Second, the validation study was based on the comparison of data related to severe maternal morbid events in the PMSI from these centers for 2006 and 2007, with the content of medical records which constituted the gold standard. Indicators of sensitivities and positive predictive values of PMSI were calculated. RESULTS: The processes of PMSI data production showed major differences between the four centers. In hospital discharge data, diagnoses (eclampsia and pulmonary embolism) had a high proportion of false-positives (68%). Inversely, procedures (four procedures for management of severe haemorrhage) had less than 1% of false-positives, but a low sensitivity with 37% false-negatives which could be corrected in 95%. Regarding intensive care provision, all indicators of hospital data quality were very high. In addition, the validity of hospital data in centers 1 and 2 was higher for all events. CONCLUSION: The heterogeneity of the process of PMSI data production is associated with a variable quality of these data. Intensive care provision can be used in the PMSI, as well as procedures after correction. For diagnoses, the quality of the PMSI data is better in centers having both computerized medical records and steps for verification of medical information.