Bleeding risk in hemophilia A and B carriers: comparison of factor levels determined using chronometric and chromogenic assays.

BACKGROUND: Predicting the bleeding risk in hemophilia A and B carriers (HAC, HBC) is challenging. OBJECTIVE: The objectives of this study were to describe the bleeding phenotype in HAC and HBC using the standardized Tosetto bleeding score (BS); to determine whether the BS correlates better with factor levels measured with a chromogenic assay than with factor levels measured with chronometric and thrombin generation assays; and to compare the results in HAC and HBC. METHODS: This ambispective, noninterventional study included obligate and sporadic HAC and HBC followed at a hemophilia treatment center between 1995 and 2019. RESULTS AND CONCLUSION: The median BS (3, range 0-21 vs. 3.5, range 0-15, P  = ns, respectively) and the abnormal BS rate (35.6% vs. 38.2%, P  = ns) were not significantly different in 104 HAC and 34 HBC (mean age: 38 years, 6-80 years). However, some differences were identified. The risk of factor deficiency was higher in HBC than HAC. Specifically, Factor VIII activity (FVIII):C/Factor IX activity (FIX):C level was low (<40 IU/dl) in 18.3% (chronometric assay) and 17.5% (chromogenic assay) of HAC and in 47% and 72.2% of HBC ( P  < 0.001). Moreover, the FIX:C level thresholds of 39.5 IU/dl (chronometric assay) and of 33.5 IU/dl (chromogenic assay) were associated with very good sensitivity (92% and 100%, respectively) and specificity (80% for both) for bleeding risk prediction in HBC. Conversely, no FVIII:C level threshold could be identified for HAC, probably due to FVIII:C level variations throughout life.

Which risk score best predicts cardiovascular outcome in pregnant women with congenital heart disease?

BACKGROUND: Management of pregnancy and risk stratification in women with congenital heart diseases (CHD) are challenging, especially due to physiological haemodynamic modifications that inevitably occur during pregnancy. AIMS: To compare the accuracy of the existing pregnancy cardiovascular risk scores in prediction of maternal complications during pregnancy in CHD patients. METHOD AND RESULTS: From 2007 to 2018, all pregnant women with a CHD who delivered birth after 20 weeks of gestation were identified. The discriminating power and the accuracy of the five existing pregnancy cardiovascular risk scores [CARPREG, CARPREG II, HARRIS, ZAHARA risk scores, and modified WHO (mWHO)] were evaluated.Out of 104 pregnancies in 65 CHD patients, 29% experienced cardiovascular complications during pregnancy or post-partum. For the five scores, the observed rate of cardiovascular events was higher than the expected risk. The values of area under the ROC curve were 0.75 (0.62-0.88) for mWHO, 0.65 (0.53-0.77) for CARPREG II, 0.60 (0.40-0.80) for HARRIS, 0.59 (0.47-0.72) for ZAHARA, and 0.58 (0.43-0.73) for CARPREG. CONCLUSION: The modified WHO classification appeared to better predict cardiovascular outcome in pregnant women with CHD than the four other existing risk scores.Clinical Trial Registration: Clinicaltrials.gov: NCT04221048.

Use of Remifentanil Associated with Lidocaine for Feticides in Late Terminations of Pregnancy: A Randomized Clinical Trial.

INTRODUCTION: In France, performance of a termination of pregnancy is legally possible without any gestational age limit. After 22 weeks of gestation, a feticide is ethically performed using usually sufentanil and lidocaine. The aim of this study was to compare the use of remifentanil, a fast-acting morphine-derivating product, instead of sufentanil. METHODS: This 2-center randomized, controlled, single-blinded phase-III treatment trial had 2 parallel arms: an experimental group using remifentanil with lidocaine versus a control group receiving sufentanil associated with lidocaine. This trial took place over a 40-month period. The primary outcome was time to fetal asystole after lidocaine injection. The secondary outcome measures were the procedure's success rate, the rate of serious maternal side effects, and the presence of cellular or tissue modifications. RESULTS: The study included 66 women, randomized into 2 groups of similar size and characteristics. Time to fetal asystole did not differ significantly between the groups, with a delay of 4 min (Q1-Q3, 2-11) in the sufentanil group and 4 min (Q1-Q3, 1-10) in the remifentanil group (p = 0.84). Similarly, the success rate of the procedure did not differ significantly. Fetal asystole was procured in <2 min and persisted >1 min for 16 (25.8%) women in our total population: 7 (22.5%) in the sufentanil group and 9 (29.0%) in the remifentanil group, p = 0.77. No severe maternal side effects were observed. Among the 49 fetopathological examinations performed, the few tissue and cell modifications observed did not cause any interpretation difficulties in either group. DISCUSSION/CONCLUSION: Use of remifentanil instead of sufentanil for feticide procedure did not improve time to fetal asystole. No harmful effect was observed for either maternal tolerance or interpretation of the histologic slides.

A prospective cohort study of postpartum glucose metabolic disorders in early versus standard diagnosed gestational diabetes mellitus.

Early gestational diabetes mellitus (eGDM) is diagnosed when fasting plasma glucose before 24 weeks of gestation (WG) is ≥ 5.1 mmol/L, whilst standard GDM is diagnosed between 24 and 28 WG by oral glucose tolerance test (OGTT). eGDM seems to have worse obstetric outcomes than standard GDM. We compared the rates of postpartum glucose metabolism disorders between women with early versus standard GDM in this prospective study on women with GDM from three university hospitals between 2014 and 2016. Patients were included if they were < 24 WG with at least one risk factor for GDM and excluded if they had type 2 diabetes. Patients were assigned to Group 1 (G1) for eGDM according to IADPSG: fasting blood glucose < 24 WG between 5.1 and 7 mmol/L. Group 2 (G2) consisted of patients presenting a standard GDM at 24-28 WG on OGTT results according to IADPSG: T0 ≥ 5.1 mmol/L or T60 ≥ 10.0 mmol g/L or T120 ≥ 8.5 mmol/L. The primary outcome was postpartum OGTT result. Five hundred patients were analysed, with 273 patients undergoing OGTT at 4-18 weeks postpartum: 192 patients in G1 (early) and 81 in G2 (standard). Patients in G1 experienced more insulin therapy during pregnancy than G2 (52.2% versus 32.5%, p < 0.001), but no patients were taking insulin postpartum in either group. G1 patients experienced less preterm labour (2.6% versus 9.1%, p = 0.043), more induced deliveries (38% versus 25%, p = 0.049) and reduced foetal complications (29.2% versus 42.0%, p = 0.048). There was no significant difference in the rate of postpartum glucose metabolism disorders (type 2 diabetes, impaired glucose tolerance, impaired fasting glycaemia) between groups: 48/192 (25%) in G1 and 17/81 (21%) in G2, p = 0.58. Thus the frequency of early postpartum glucose metabolism disorders is high, without difference between eGDM and standard GDM. This supports measurement of fasting plasma glucose before 24 WG and the threshold of 5.1 mmol/L seems appropriate until verification in future studies.Trial registration: NCT01839448, ClinicalTrials.gov on 22/04/2013.

Prenatal ultrasound diagnosis of cleft palate without cleft lip, the new ultrasound semiology.

OBJECTIVES: The aim of this study was to define the prenatal ultrasound semiology of cleft palate without cleft lip using 3D visualization of the fetal palate. METHODS: A prospective longitudinal study was performed in our University Hospital Center from 2011 to 2018. The fetal secondary palate was studied in 3D, starting with 2D axial transverse ultrasound view. We defined a cleft palate as a disruption of the horizontal plate of the palatine bone of the secondary palate. Prenatal findings were correlated to anatomic postnatal examinations performed by a paediatric plastic surgeon. RESULTS: Forty-three cases of cleft palate without cleft lip were prenatally diagnosed, of whom 34 were associated with malformations. We defined four types of disruptive appearances: isolated nonvisualization of the posterior nasal spine; partial-disruption or cleft velum; complete disappearance or V-shaped cleft palate; and complete disappearance or U-shaped cleft palate. The adjusted kappa coefficient, between prenatal and postnatal evaluation, was 0.88 (95% CI: 0.79-0.97), corresponding to an excellent agreement. CONCLUSIONS: Using a strictly axial transverse ultrasound view, visualization of the secondary fetal palate enables to diagnose a cleft palate without cleft lip. This method offers a prenatal anatomic classification of cleft palate with a high level of concordance to postnatal findings.

Fetal growth retardation and hemorheological predictors of oxygen delivery in hypertensive vs normotensive pregnant women.

Physiological modifications of blood rheology during pregnancy and their alterations in pregnant hypertensive women have been extensively studied in the 1980's. Since vascular resistance is higher in hypertensive pregnant women whose newborns are small-for gestational-age (SGA), we investigated in a personal database if growth retardation of newborns is related to the oxygen delivery index (ratio hematocrit/blood viscosity) and to the difference between hematocrit (Hct) and the prediction of its optimal valued based on Quemada's equation. A sample of 38 hypertensive pregnant women (age 29 yr±1) was compared with 64 controls matched for age and gestational age, studied at 35±1 weeks gestation, extracted from a larger series of 162 pregnant women. On the whole the hypertensive group gave birth to smaller children (p = 0.014). Plasma viscosity correlated with blood pressure (BP) only in hypertensive women (r = 0.403 p < 0.05). The bell-shaped curve of predicted optimal Hct of non hypertensive pregnant women was similar to that of non-pregnant women, but in hypertensive women it was shifted toward higher values (p = 0.07), and the predicted optimal Hct (but not the actual one) was correlated with systolic blood pressure (SBP) (r = 0.349 p < 0.001) and diastolic blood pressure (DBP) (r = 0.218 p < 0.05). The predicted optimal Hct/viscosity (h/η) ratio was higher in hypertensive women whose newborns exhibited a low birth weight (p = 0.03), resulting in a higher discrepancy between actual and model-predicted «ideal¼ values of h/η ratio (p = 0.03) and Hct (p = 0.02) compared with the subgroup with no growth retardation. Therefore, in hypertensive women whose newborns exhibited a low birth weight, hemorheological parameters predicting oxygen supply are shifted to lower values than predicted by the model.

Prenatal imaging of genital defects: clinical spectrum and predictive factors for severe forms.

OBJECTIVES: To report the clinical spectrum of genital defects diagnosed before birth, identify predictive factors for severe phenotypes at birth, and determine the rate of associated malformations. PATIENTS AND METHODS: A retrospective study (2008-2017) of 4580 fetuses, identified prenatally with abnormalities evaluated by our Reference Center for Fetal Medicine, included cases with fetal sonographic findings of abnormal genitalia or uncertainty of fetal sex determination. Familial, prenatal and postnatal data were collected via a standardised questionnaire. RESULTS: In all, 61 fetuses were included. The positive predictive value (PPV) of the prenatal diagnosis of genital defects was 90.1%. Most cases were 46,XY-undervirilized boys, 42 cases (68.8%), which included 29 with mid-penile or posterior hypospadias, nine with anterior hypospadias, and epispadias, micropenis, scrotal transposition, and buried penis (one each). In all, 46,XX-virilized girls were identified in seven cases (11.5%), which included four with congenital adrenal hyperplasia, two with isolated clitoromegaly, and one with ovotestis. Other defects included prune belly syndrome and persistent cloaca (six cases). Early detection during the second trimester (58.1% vs 18.8%, P = 0.03), intra-uterine growth restriction (IUGR) (45.2% vs 9.1%, P = 0.06), and curvature of the penis (38.7% vs 0%, P = 0.02), were more frequently related to severe defects in male newborns. Associated malformations (14 cases, 22.9%) and genetic defects (six) were frequent in undervirilized boys. CONCLUSION: Prenatal imaging of genital defects leads to a wide range of phenotypes at birth. Its PPV is high and extra-urinary malformations are frequent. Early diagnosis during the second trimester, associated IUGR, and curvature of the genital tubercle, should raise suspicion of a severe phenotype and may justify delivery near a multidisciplinary disorders/differences of sex development team.

Prognosis of severe congenital heart diseases: Do we overestimate the impact of prenatal diagnosis?

BACKGROUND: Prenatal diagnosis of congenital heart disease (CHD) is controversial because of unclear benefits in terms of morbidity and mortality, and issues with healthcare costs and organization. AIM: To compare, in children with severe CHD, 1-year morbidity and mortality between prenatal and postnatal diagnosis groups. METHODS: All pregnancies and children aged<1 year with a diagnosis of severe CHD were collected over a 5-year period from our database. Severe CHDs were defined as lethal cases, cases leading to medical termination of pregnancy, or children requiring surgery and/or interventional catheterization and/or hospitalization during their first year of life. The primary endpoint was 1-year mortality rate among live births. RESULTS: Overall, 322 cases of severe CHD were identified; 200 had a prenatal diagnosis and there were 97 terminations of pregnancy. Of the 225 live births, 34 died before the age of 1 year. The 1-year mortality rate was not significantly different between prenatal and postnatal groups (16.7% vs. 13.9%; p=0.13). In the prenatal group, prostaglandin use was more important and precocious, duration of hospitalization stay was longer, extracardiac complications were less common and cardiac surgery was performed more frequently and later. An association with chromosomal or syndromic anomalies was a risk factor for 1-year mortality. CONCLUSIONS: Prenatal diagnosis of severe CHD had an impact on the decision regarding termination of pregnancy, but not on the 1-year prognosis among live births. We should now use large multicentre CHD registries to determine the impact of prenatal diagnosis on postnatal management, neurological prognosis and quality of life.

Conservative versus active management in HELLP syndrome: results from a cohort study.

OBJECTIVE: HELLP syndrome exposes to severe maternal and fetal complications. Prompt delivery is thus recommended after 34 weeks of gestation, or earlier in case of nonreassuring maternofetal conditions. However, no consensus has been raised in the treatment of HELLP syndrome occurring before 34 weeks of gestation, when both maternal and fetal conditions are stable: it remains still unclear whether an active attitude should be prioritized over expectant management. Herein, we aimed to compare mother and child outcomes according to the type of obstetrical management, either active or conservative. STUDY DESIGN: Retrospective and multicenter study involving two tertiary care units. In Center A, obstetrical attitude consisted in expectant management: all women received full antenatal betamethasone therapy and pregnancy was prolonged until maternal or fetal follow up indicated delivery. In Center B, management was active: all deliveries were initiated within 48 hours following diagnosis. RESULTS: From 2003 to 2011, 118 patients were included (87 in Center A, 31 in Center B). Both groups of patients were similar regarding maternal and fetal features at baseline. Active management led to increased risks of post-partum hemorrhage (relative risks (RR) = 5.38, 95%CI: 1.2-24.06) and neonatal morbidity including respiratory distress syndrome (RR = 3.1, 95%CI: 1.4-7.1), sepsis (RR = 2.5, 95%CI: 1.1-6.0), necrotizing enterocolitis (RR = 4.8, 95%CI: 1.1-21.2), intracerebral hemorrhage (RR = 5.4, 95%CI: 2.1-13.6), and blood transfusion (RR = 6.1, 95%CI: 1.7-21.7). CONCLUSIONS: Conservative management may be beneficial for both mother and newborn in patients with stable HELLP syndrome. Identification of maternal and fetal specific prognostic factors would allow a better stratification of women with HELLP syndrome according to illness progressive potential, resulting in a more personalized management.

Actual vs optimal fetal hematocrit measured with punctures of cord blood in utero: Relationship with umbilical artery resistance.

Physiological studies on fetal blood in narrow glass tubes have suggested that fetal optimal hematocrit (hct) might be as high as 60%. A theoretical 'ideal' hct can also be predicted with a theoretical curve of hematocrit/viscosity (h/η) ratio vs hct constructed with Quemada's model. We used the database of one of our previous papers on fetal hemorheology to reinterpret its results with this concept. A series of 28 intrauterine cord punctures (between 19 and 33 weeks gestation) with doppler measurements of resistance in umbilical arteries was studied. The theoretical 'optimal hematocrit' was well correlated to actual (r = 0.857, p < 0.01) but systematically lower (Bland-Altman plot +12.1[8.52-15.7]) than the actual one. Umbilical artery resistance index is correlated with actual hematocrit (r = 0.407, p < 0.05), the discrepancy between ideal and actual (r = - 0.542, p < 0.05) but not predicted ideal hematocrit, suggesting that the discrepancy between ideal and actual may reflect an adaptative decrease aiming at reducing vascular resistance. These findings indicate that prediction of ideal hematocrit with Quemada's equation makes sense in fetal blood, and suggest that a 'viscoregulatory mechanism' maintains hematocrit below this theoretical value in order to avoid excess vascular resistance.

Does prenatal MRI enhance fetal diagnosis of intra-abdominal cysts?

OBJECTIVE: The aim of this study was to evaluate the contribution of prenatal magnetic resonance imaging (MRI) to ultrasound (US) in the prenatal diagnosis of intra-abdominal cystic masses, correlated with the postnatal diagnosis. METHODS: In this retrospective, observational study, prenatal MRI and US diagnoses were compared with postnatal diagnoses. MRI was performed in 56 fetuses with intra-abdominal cyst diagnosed by US between 2004 and 2013. Final diagnosis, revealed by postnatal evaluation, was obtained for 49 of them and was taken as the reference. MRI was evaluated as superior, equal, or inferior to US. RESULTS: An accurate diagnosis was provided by US in 25 cases (51%) and by MRI in 36 out of the 49 cases (73.4%). MRI corrected the US diagnosis in 13 cases (26.5%) by providing a more precise localization or additional etiologic information. In two cases (4%), MRI wrongly changed the diagnosis correctly made by US. CONCLUSION: Prenatal MRI better characterized the nature of abdominal cystic lesions previously diagnosed by US in 13 cases. This enhanced postnatal therapeutic planning and so improved parental counseling and pregnancy management.

Survival and morbidity of preterm children born at 22 through 34 weeks' gestation in France in 2011: results of the EPIPAGE-2 cohort study.

IMPORTANCE: Up-to-date estimates of the health outcomes of preterm children are needed for assessing perinatal care, informing parents, making decisions about care, and providing evidence for clinical guidelines. OBJECTIVES: To determine survival and neonatal morbidity of infants born from 22 through 34 completed weeks' gestation in France in 2011 and compare these outcomes with a comparable cohort in 1997. DESIGN, SETTING, AND PARTICIPANTS: The EPIPAGE-2 study is a national, prospective, population-based cohort study conducted in all maternity and neonatal units in France in 2011. A total of 2205 births (stillbirths and live births) and terminations of pregnancy at 22 through 26 weeks' gestation, 3257 at 27 through 31 weeks, and 1234 at 32 through 34 weeks were studied. Cohort data were collected from January 1 through December 31, 1997, and from March 28 through December 31, 2011. Analyses for 1997 were run for the entire year and then separately for April to December; the rates for survival and morbidities did not differ. Data are therefore presented for the whole year in 1997 and the 8-month and 6-month periods in 2011. MAIN OUTCOMES AND MEASURES: Survival to discharge and survival without any of the following adverse outcomes: grade III or IV intraventricular hemorrhage, cystic periventricular leukomalacia, severe bronchopulmonary dysplasia, retinopathy of prematurity (stage 3 or higher), or necrotizing enterocolitis (stages 2-3). RESULTS: A total of 0.7% of infants born before 24 weeks' gestation survived to discharge: 31.2% of those born at 24 weeks, 59.1% at 25 weeks, and 75.3% at 26 weeks. Survival rates were 93.6% at 27 through 31 weeks and 98.9% at 32 through 34 weeks. Infants discharged home without severe neonatal morbidity represented 0% at 23 weeks, 11.6% at 24 weeks, 30.0% at 25 weeks, 47.5% at 26 weeks, 81.3% at 27 through 31 weeks, and 96.8% at 32 through 34 weeks. Compared with 1997, the proportion of infants surviving without severe morbidity in 2011 increased by 14.4% (P < .001) at 25 through 29 weeks and 6% (P < .001) at 30 through 31 weeks but did not change appreciably for those born at less than 25 weeks. The rates of antenatal corticosteroid use, induced preterm deliveries, cesarean deliveries, and surfactant use increased significantly in all gestational-age groups, except at 22 through 23 weeks. CONCLUSIONS AND RELEVANCE: The substantial improvement in survival in France for newborns born at 25 through 31 weeks' gestation was accompanied by an important reduction in severe morbidity, but survival remained rare before 25 weeks. Although improvement in survival at extremely low gestational age may be possible, its effect on long-term outcomes requires further studies. The long-term results of the EPIPAGE-2 study will be informative in this regard.

Thrombosis of torcular herophili: diagnosis, prenatal management, and outcome.

OBJECTIVES: The objective of this article is to describe and assess prenatal imaging findings, fetal and postnatal outcomes of thrombosis of torcular herophili, and to determine diagnostic features, pathophysiology, prognosis, and optimal management. METHODS: Over a decade, we compiled the largest single-center retrospective study of outcomes. Fetal magnetic resonance imaging (MRI) was used to confirm the sonographic suspicion and monitor thrombosis of torcular herophili. We noted prenatal and postnatal imaging specifications, pregnancy outcomes, and clinical and radiological pediatric monitoring. Analysis of findings and review of the literature allowed us to define prognostic factors. RESULTS: In eight cases of prenatal diagnosis of thrombosis of torcular herophili, MRI outcomes were specific. There were five deliveries at full term, two terminations of pregnancy, and one fetal demise in utero. Neonates had a good clinical and radiological outcome. Factors of poor prognosis were deep venous sinus thrombosis, enduring mass effect, brain parenchymal injury, and heart failure related to dural arteriovenous shunt. CONCLUSION: Among dural sinus malformations, thrombosis of torcular herophili with or without extension at the posterior segment of the longitudinal sinus frequently has a good prognosis. It is urgent to wait because the prognosis can only be ascertained over time by means of ultrasound scan and MRI monitoring.

Partial lipodystrophy with severe insulin resistance and adult progeria Werner syndrome.

BACKGROUND: Laminopathies, due to mutations in LMNA, encoding A type-lamins, can lead to premature ageing and/or lipodystrophic syndromes, showing that these diseases could have close physiopathological relationships. We show here that lipodystrophy and extreme insulin resistance can also reveal the adult progeria Werner syndrome linked to mutations in WRN, encoding a RecQ DNA helicase. METHODS: We analysed the clinical and biological features of two women, aged 32 and 36, referred for partial lipodystrophic syndrome which led to the molecular diagnosis of Werner syndrome. Cultured skin fibroblasts from one patient were studied. RESULTS: Two normal-weighted women presented with a partial lipodystrophic syndrome with hypertriglyceridemia and liver steatosis. One of them had also diabetes. Both patients showed a peculiar, striking lipodystrophic phenotype with subcutaneous lipoatrophy of the four limbs contrasting with truncal and abdominal fat accumulation. Their oral glucose tolerance tests showed extremely high levels of insulinemia, revealing major insulin resistance. Low serum levels of sex-hormone binding globulin and adiponectin suggested a post-receptor insulin signalling defect. Other clinical features included bilateral cataracts, greying hair and distal skin atrophy. We observed biallelic WRN null mutations in both women (p.Q748X homozygous, and compound heterozygous p.Q1257X/p.M1329fs). Their fertility was decreased, with preserved menstrual cycles and normal follicle-stimulating hormone levels ruling out premature ovarian failure. However undetectable anti-müllerian hormone and inhibin B indicated diminished follicular ovarian reserve. Insulin-resistance linked ovarian hyperandrogenism could also contribute to decreased fertility, and the two patients became pregnant after initiation of insulin-sensitizers (metformin). Both pregnancies were complicated by severe cervical incompetence, leading to the preterm birth of a healthy newborn in one case, but to a second trimester-abortion in the other. WRN-mutated fibroblasts showed oxidative stress, increased lamin B1 expression, nuclear dysmorphies and premature senescence. CONCLUSIONS: We show here for the first time that partial lipodystrophy with severe insulin resistance can reveal WRN-linked premature aging syndrome. Increased expression of lamin B1 with altered lamina architecture observed in WRN-mutated fibroblasts could contribute to premature cellular senescence. Primary alterations in DNA replication and/or repair should be considered as possible causes of lipodystrophic syndromes.

Fetal serum α-1 microglobulin for renal function assessment: comparison with ß2-microglobulin and cystatin C.

OBJECTIVE: To compare the prognostic value of fetal serum α1-microglobulin with that of ß2-microglobulin and cystatin C for postnatal renal function. METHOD: Retrospective study of α1-microglobulin, ß2-microglobulin, and cystatin C in fetal serum from 126 fetuses with congenital abnormalities of the kidney and urinary tract (73 and 53, respectively). Two groups were defined: group with normal renal function and group with renal failure. For live born infants, renal function was assessed on the basis of serum creatinine (cutoff 50 µmol/L) or glomerular filtration rate (cutoff 75 mL/min/1.73 m2) or both. In case of infant or fetal death, histological kidney lesions were considered. RESULTS: Significant differences (p < 0.001) were observed for the three markers between fetuses with good renal prognosis and those with renal failure (34.4 mg/L vs 67.6 mg/L for α1-microglobulin, respectively; 3.9 mg/L vs 7.35 mg/L, for ß2-microglobulin, respectively; and 1.67 mg/L vs 2.12 mg/L for cystatin C, respectively). Areas under receiver operator curves were used to compare the three markers, 0.96, 0.90, and 0.74 for ß2-microglobulin, α1-microglobulin, and cystatin C, respectively. CONCLUSION: Although α1-microglobulin is significantly different in fetuses with good renal prognosis and those with renal failure, overall, it is a less reliable prognostic marker than fetal serum ß2-microglobulin.

Novel interpretation of molecular diagnosis of congenital toxoplasmosis according to gestational age at the time of maternal infection.

From a prospective cohort of 344 women who seroconverted for toxoplasmosis during pregnancy, 344 amniotic fluid, 264 placenta, and 216 cord blood samples were tested for diagnosis of congenital toxoplasmosis using the same PCR assay. The sensitivity and negative predictive value of the PCR assay using amniotic fluid were 86.3% and 97.2%, respectively, and both specificity and positive predictive value were 100%. Using placenta and cord blood, sensitivities were 79.5% and 21.2%, and specificities were 92% and 100%, respectively. In addition, the calculation of pretest and posttest probabilities and the use of logistic regression allowed us to obtain curves that give a dynamic interpretation of the risk of congenital toxoplasmosis according to gestational age at maternal infection, as represented by the three sample types (amniotic fluid, placenta, and cord blood). Two examples are cited here: for a maternal infection at 25 weeks of amenorrhea, a negative result of prenatal diagnosis allowed estimation of the probability of congenital toxoplasmosis at 5% instead of an a priori (pretest) risk estimate of 33%. For an infection at 10 weeks of amenorrhea associated with a pretest congenital toxoplasmosis risk of 7%, a positive PCR result using placenta at birth yields a risk increase to 43%, while a negative result damps down the risk to 0.02%. Thus, with a molecular diagnosis performing at a high level, and in spite of the persistence of false negatives, posttest risk curves using both negative and positive results prove highly informative, allowing a better assessment of the actual risk of congenital toxoplasmosis and finally an improved decision guide to treatment.

Second- and third-trimester management of medical termination of pregnancy and fetal death in utero after prior caesarean section.

OBJECTIVES: To evaluate the results and risks of a protocol for second- and third-trimester termination of pregnancy after prior caesarean section. STUDY DESIGN: This is a retrospective study, conducted in a level 3 (university hospital) maternity unit between January 2001 and September 2008. 67 women with a history of caesarean section underwent second- and third-trimester termination of pregnancy. The protocol was administration of 600 mg mifepristone the first day and application of laminaria tents the second day. One the third day, 48 h after mifepristone, two 200 µg tablets of misoprostol were given orally every 3 h until delivery. Epidural analgesia was performed routinely. Complications analysed were uterine rupture, labour lasting over 12 h, and bleeding requiring blood transfusion. RESULTS: Delivery was vaginal in 64 cases (95.5%), a median 4 h 20 min (P25: 3 h 5 min, P75: 7 h 7 min) after administration of misoprostol (median number of tablets 2; P25: 2, P75: 4). The median number of tablets of misoprostol was significantly higher for termination of pregnancy than for fetal death in utero (4 vs. 2; p=0.002). The rate of uterine rupture was 4.8% [95% CI: 1.2-14.2]. Bleeding during delivery requiring a transfusion occurred in 2 cases (3.0%; 95% CI: 0.5-11.3). CONCLUSION: A high rate of vaginal delivery was achieved at low doses of misoprostol, with a short median induction-to-delivery interval, and a rate of uterine rupture higher than that observed during attempted vaginal delivery at term in a caesarean scar pregnancy. The rate of severe bleeding during delivery was low.

Prevalence and timing of pregnancy termination for brain malformations.

OBJECTIVE: To determine the prevalence and the timing of pregnancy termination relative to the type of central nervous system (CNS) malformations. Design Retrospective cohort study. SETTING: Multidisciplinary centre for prenatal diagnosis in the Languedoc-Roussillon region, France. POPULATION: A cohort of 481 pregnancy terminations performed between 2005 and 2009. METHODS: Detailed post-termination fetal and neuropathological analyses were carried out to identify the CNS malformations. Then, the prevalence and timing of pregnancy termination were assessed relative to the identified malformations. RESULTS: About one-third of pregnancy terminations (143/481) were performed for severe CNS malformations. Up to 24 weeks of gestation (WG), pregnancy terminations (56.6%) were carried out mainly for defects occurring during the two major first steps of CNS development (neurulation and differentiation of cerebral vesicles). After 24 WG, pregnancy terminations (43.3%) were mainly performed for corpus callosum agenesis (16/17), vermian agenesis (10/12) and gyral anomalies (13/15). For hindbrain malformations and gyral anomalies, there was a significant relationship between the timing of pregnancy termination and the presence of a severe ventriculomegaly at prenatal diagnosis (p=0.002 and p=0.02, respectively). CONCLUSION: By classifying CNS malformations according to the neuropathological analysis, the authors show that the timing and prevalence of pregnancy termination are distributed in a manner that is consistent with what is currently known on the development of brain. They are also influenced by the French prenatal screening policy and the variable expressivity of the brain malformations and associated lesions.

Synechia after uterine compression sutures.

We present a study of 37 women who underwent uterine compression suture for postpartum hemorrhage, with 13 postoperative assessments by hysteroscopy. Synechia occurred in seven patients, of whom three had Asherman syndrome (23% of women who desired pregnancy and had hysteroscopic evaluation) that could not be corrected.

Hypodysfibrinogenaemia due to production of mutant fibrinogen alpha-chains lacking fibrinopeptide A and polymerisation knob 'A'.

Inherited disorders of fibrinogen are rare and affect either the quantity (hypofibrinogenaemia and afibrinogenaemia) or the quality of the circulating fibrinogen (dysfibrinogenaemia) or both (hypodysfibrinogenaemia). Extensive allelic heterogeneity has been found for all these disorders: in congenital afibrinogenaemia for example more than 40 mutations, the majority in FGA , have been identified in homozygosity or in compound heterozygosity. Numerous mutations have also been identified in patients with hypofibrinogenaemia, many of these patients are in fact heterozygous carriers of afibrinogenaemia mutations. Despite the number of genetic analyses performed, the study of additional patients still allows the identification of novel mutations. Here we describe the characterization of a novel FGA intron 2 donor splice-site mutation (Fibrinogen Montpellier II) identified in three siblings with hypodysfibrinogenaemia. Functional analysis of RNA produced by the mutant minigene in COS-7 cells revealed that the mutation led to the in-frame skipping of exon 2. Western blot analysis of COS-7 cells expressing an exon 2 deleted FGA cDNA revealed that an alpha-chain lacking exon 2, which codes in particular for fibrinopeptide A and polymerisation knob 'A', has the potential to be assembled into a hexamer and secreted. Analysis of precipitated fibrinogen from patient plasma showed that the defect leads to the presence in the circulation of alpha-chains lacking knob 'A' which is essential for the early stages of fibrin polymerisation. Fibrin made from purified patient fibrinogen clotted with thrombin displayed thinner fibers with frequent ends and large pores.