Correlation between neonatal outcomes of twins depends on the outcome: secondary analysis of twelve randomised controlled trials.

OBJECTIVE: To estimate the magnitude of the correlation between neonatal outcomes of twins and demonstrate how this information can be used in the design of randomised controlled trials (RCTs) in women with twin pregnancies. DESIGN: Secondary analysis of data from 12 RCTs. SETTING: Obstetric care in multiple countries, 2004-2012. POPULATION OR SAMPLE: 4504 twin pairs born to women who participated in RCTs to assess treatments given during pregnancy. METHODS: Intraclass correlation coefficients (ICCs) were estimated using log-binomial and linear models. MAIN OUTCOME MEASURES: Perinatal death, respiratory distress syndrome, bronchopulmonary dysplasia, intraventricular haemorrhage, necrotising enterocolitis, sepsis, neonatal intensive care unit admission, birthweight, low birthweight and two composite measures of adverse neonatal outcome. RESULTS: ICCs for the composite measures of adverse neonatal outcome were all above 0.5, indicating moderate to strong correlation between adverse outcomes of twins. For individual neonatal outcomes, median ICCs across trials ranged from 0.13 to 0.79 depending on the outcome. An example illustrates how ICCs can be used in sample size calculations for RCTs in women with twin pregnancies. CONCLUSIONS: The correlation between neonatal outcomes of twins varies considerably between outcomes and may be lower than expected. Our ICC estimates can be used for designing and analysing RCTs that recruit women with twin pregnancies and for performing meta-analyses that include such RCTs. Researchers are encouraged to report ICCs for neonatal outcomes in twins in their own RCTs. TWEETABLE ABSTRACT: Correlation between neonatal outcomes of twins depends on the outcome and may be lower than expected.

Efficacy of antenatal corticosteroids in preterm twins: the EPIPAGE-2 cohort study.

OBJECTIVES: To investigate the efficacy of antenatal corticosteroid (ACS) therapy on short-term neonatal outcomes in preterm twins, and further document the influence of the ACS-to-delivery interval. DESIGN: EPIPAGE-2 is a nationwide observational multicentre prospective cohort study of neonates born between 22 and 34 completed weeks of gestation. SETTING: All French maternity units, except in a single administrative region, between March and December 2011. POPULATION: A total of 750 twin neonates born between 24 and 31 weeks of gestation. METHODS: Exposure to ACSs was examined in four groups: single complete course, with an ACS administration-to-delivery interval of ≤7 days; single complete course, with an ACS-to-delivery interval of >7 days; repeated courses; or no ACS treatment. MAIN OUTCOME MEASURES: Neonatal outcomes analysed were severe bronchopulmonary dysplasia, periventricular leukomalacia or intraventricular haemorrhage grade III/IV, in-hospital mortality, and a composite indicator of severe outcomes. RESULTS: Compared with no ACSs, in multivariable analysis, a single course of ACSs with an administration-to-delivery interval of ≤7 days was significantly associated with a reduced rate of periventricular leukomalacia or intraventricular haemorrhage grade III/IV (aOR 0.2; CI 95% 0.1-0.5), in-hospital mortality (0.3; 0.1-0.6), and the composite indicator (0.1; 0.1-0.3), whereas a single course of ACDs with an administration-to-delivery interval of >7 days did not significantly reduce the frequency of in-hospital mortality (0.7; 0.3-1.8). No significant differences in terms of benefit or risk were found when comparing repeated courses with a single complete course. CONCLUSION: In preterm twins, a single complete course of antenatal corticosteroids was associated with an improvement of severe neurological outcome, whereas reduced in-hospital mortality was seen only when the ACS-to-delivery interval was ≤7 days. TWEETABLE ABSTRACT: A single complete course of antenatal steroids reduced severe neurological morbidity in preterm twins (24-31 weeks).

Overview and expert assessment of off-label use of misoprostol in obstetrics and gynaecology: review and report by the Collège national des gynécologues obstétriciens français.

The literature suggests that misoprostol can be offered to patients for off-label use as it has reasonable efficacy, risk/benefit ratio, tolerance and patient satisfaction, according to the criteria for evidence-based medicine. Both the vaginal and sublingual routes are more effective than the oral route for first-trimester cervical dilatation. Vaginal misoprostol 800µg, repeated if necessary after 24 or 48h, is a possible alternative for management after early pregnancy failure. However, misoprostol has not been demonstrated to be useful for the evacuation of an incomplete miscarriage, except for cervical dilatation before vacuum aspiration. Oral mifepristone 200mg, followed 24-48h later by vaginal, sublingual or buccal misoprostol 800µg (followed 3-4h later, if necessary, by misoprostol 400µg) is a less efficacious but less aggressive alternative to vacuum aspiration for elective or medically-indicated first-trimester terminations; this alternative becomes increasingly less effective as gestational age increases. In the second trimester, vaginal misoprostol 800-2400µg in 24h, 24-48h after at least 200mg of mifepristone, is an alternative to surgery, sulprostone and gemeprost. Data for the third trimester are sparse. For women with an unripe cervix and an unscarred uterus, vaginal misoprostol 25µg every 3-6h is an alternative to prostaglandin E2 for cervical ripening at term for a live fetus. When oxytocin is unavailable, misoprostol can be used after delivery for prevention (sublingual misoprostol 600µg) and treatment (sublingual misoprostol 800µg) of postpartum haemorrhage. The use of misoprostol to promote cervical dilatation before diagnostic hysteroscopy or surgical procedures is beneficial for premenopausal women but not for postmenopausal women. Nonetheless, in view of the side effects of misoprostol, its use as a first-line treatment is not indicated, and it should be reserved for difficult cases. Misoprostol is not useful for placing or removing the types of intra-uterine devices used in Europe, regardless of parity.

Effectiveness of progestogens to improve perinatal outcome in twin pregnancies: an individual participant data meta-analysis.

BACKGROUND: In twin pregnancies, the rates of adverse perinatal outcome and subsequent long-term morbidity are substantial, and mainly result from preterm birth (PTB). OBJECTIVES: To assess the effectiveness of progestogen treatment in the prevention of neonatal morbidity or PTB in twin pregnancies using individual participant data meta-analysis (IPDMA). SEARCH STRATEGY: We searched international scientific databases, trial registration websites, and references of identified articles. SELECTION CRITERIA: Randomised clinical trials (RCTs) of 17-hydroxyprogesterone caproate (17Pc) or vaginally administered natural progesterone, compared with placebo or no treatment. DATA COLLECTION AND ANALYSIS: Investigators of identified RCTs were asked to share their IPD. The primary outcome was a composite of perinatal mortality and severe neonatal morbidity. Prespecified subgroup analyses were performed for chorionicity, cervical length, and prior spontaneous PTB. MAIN RESULTS: Thirteen trials included 3768 women and their 7536 babies. Neither 17Pc nor vaginal progesterone reduced the incidence of adverse perinatal outcome (17Pc relative risk, RR 1.1; 95% confidence interval, 95% CI 0.97-1.4, vaginal progesterone RR 0.97; 95% CI 0.77-1.2). In a subgroup of women with a cervical length of ≤25 mm, vaginal progesterone reduced adverse perinatal outcome when cervical length was measured at randomisation (15/56 versus 22/60; RR 0.57; 95% CI 0.47-0.70) or before 24 weeks of gestation (14/52 versus 21/56; RR 0.56; 95% CI 0.42-0.75). AUTHOR'S CONCLUSIONS: In unselected women with an uncomplicated twin gestation, treatment with progestogens (intramuscular 17Pc or vaginal natural progesterone) does not improve perinatal outcome. Vaginal progesterone may be effective in the reduction of adverse perinatal outcome in women with a cervical length of ≤25 mm; however, further research is warranted to confirm this finding.

[Cervical ripening with misoprostol with a live fetus]. / Maturation cervicale par misoprostol sur fœtus viable.

OBJECTIVES: To evaluate the effectiveness and safety of misoprostol for cervical ripening or induction of labor at term. METHODS: A critical review of studies identified from searches of PubMed and the Cochrane libraries using the following keywords: "misoprostol", "cervical ripening", "epidemiology", "pregnancy outcome", "maternal morbidity", "perinatal death". RESULTS: Vaginal misoprostol in doses of 25 µg three- to six-hourly was similar as dinoprostone in effectiveness (caesarean section rate or vaginal delivery in 24 hours) (LE1) and risks (uterine hyperstimulation, adverse neonatal outcome, uterine rupture, maternal side-effects) (LE1). Published medico-economic studies are not sufficient to evaluate a potential profit to the use of vaginal misoprostol 25 µg (Avis d'Experts). The use of misoprostol in women with prior cesarean delivery or major uterine surgery has been associated with an increase in uterine rupture and therefore should be avoided (LE4). CONCLUSIONS: Review of the current literature favors the use of vaginal misoprostol 25 µg three- to six-hourly equally to dinoprostone accordingly with previous French and international guidelines (World Health Organization and American College of Obstetricians and Gynecologist). The use of misoprostol 25 µg supposes a preparation by the pharmacist to ensure the safety of this precise posology. Medico-economic studies are warranted to attest an economic profit to the use of misoprostol 25 µg in comparison to dinoprostone.

[Unusual fetal teratoma presenting as a posterior mediastinal cyst]. / Présentation atypique d'un tératome fœtal du médiastin postérieur.

Mediastinal cysts are uncommon prenatal findings. As isolated and non-compressing entities, they don't compromise the course of gestation. Massive lesions can compress vital structures, resulting in fetal demise. Thus, close follow-up with sonographic monitoring is recommended until birth. Non-hydroptic fetuses can be managed expectantly. Definitive etiology is known after surgical resection only. We present the first case of posterior mediastinal teratoma associated with severe vertebral abnormalities. After CT scan and fetal MRI, medical termination of pregnancy was decided. Histological examination revealed an immature teratoma. With this unique case report, we discuss the optimal prenatal management of mediastinal cysts.

Evaluation of the measurement of the middle cerebral artery peak systolic velocity before and after placental laser coagulation in twin-to-twin transfusion syndrome.

OBJECTIVE: The aim of this study is to evaluate the incidence of elevated middle cerebral artery peak systolic velocity (MCA-PSV) in twin-to-twin transfusion syndrome (TTTS) before and after laser and its predictive value for intrauterine fetal death (IUFD) occurring within 2 to 7 days following laser. METHOD: This is a 5-year retrospective single-center study on 86 consecutive laser procedures for TTTS. MCA-PSV was measured prior to and 48 h following laser. We correlated perioperative MCA-PSV and fetal survival within 7 days following laser. RESULTS: The incidence of elevated MCA-PSV prior to and following laser (NS) was 8.2% to 9.7% (non significant (NS)). There was no correlation between the incidence of an elevated MCA-PSV prior to laser and fetal survival up to 7 days after laser (NS, χ(2) :3.49). In contrast, the presence of an MCA-PSV above 1.5 MoM 48 h following laser in the former donor puts the former donor at a higher risk for IUFD within a week after surgery [odds ratio (OR):3.42 (interval of confidence (IC) 95%:1.9-30.6), χ(2) :8.68, p < 0.003]. CONCLUSION: The occurrence of an elevated MCA-PSV following laser is related to postoperative donor death within 2 to 7 days after laser.

Evolution of middle cerebral artery peak systolic velocity after a successful laser procedure for iatrogenic twin anemia-polycythemia sequence.

We report a case of twin anemia-polycythemia sequence (TAPS) treated by laser at 24 + 5 weeks' gestation, 7 weeks after a first laser procedure for twin-to-twin transfusion syndrome at 16 + 6 weeks. This management led to the birth of two healthy neonates by Cesarean section at 36 weeks. In this case, weekly measurement of the middle cerebral artery peak systolic velocity allowed us to monitor the twins after both laser treatments and, more specifically, to detect TAPS. Following delivery, placental injection showed a minuscule coagulated arteriovenous anastomosis. Intrauterine transfusion is generally chosen to manage TAPS, but the choice of therapy must consider gestational age, technical difficulties and disease severity. The laser procedure cannot be used as a curative treatment for TAPS in all cases. We propose a decisional algorithm to help clinicians select the appropriate treatment.

Use of emergency contraceptive pill by 15-year-old girls: results from the international Health Behaviour in School-aged Children (HBSC) study.

OBJECTIVE: To describe emergency contraceptive pill (ECP) use and variation across countries/regions; and to explore personal and contextual factors associated with ECP use and differences across countries/regions. DESIGN: Data were obtained from 11 countries/regions in the 2006 Health Behaviour in School-aged Children cross-sectional study. SETTING Data were collected by self-report questionnaire in school classrooms. POPULATION: The analysis is based on 2118 sexually active 15-year-old girls. METHODS: Contraceptive behaviours were compared across countries/regions by chi-square tests. Individual factors related to ECP use were investigated with separate logistic regression models. Multilevel random-intercept models allowed the investigation of individual and contextual effects, by partitioning the variance into student, school and country/region levels. MAIN OUTCOME MEASURES: ECP use at last sexual intercourse. RESULTS: ECP use rate varied significantly across countries/regions. Poor communication with at least one adult (odds ratio [OR] 1.62 [1.12-2.36], P = 0.011) and daily smoking (OR 1.46 [1.00-2.11], P = 0.048) were independently associated with ECP use in comparison with condom and/or birth-control pill use. Sexual initiation at 14 years or later (OR 2.02 [1.04-3.93], P = 0.039), good perceived academic achievement (OR 1.69 [1.04-2.75], P = 0.035) and daily smoking (OR 1.63 [1.01-2.64], P = 0.045) were associated with higher levels of ECP use in comparison with unprotected girls. The country-level variance remained significant in both comparisons. CONCLUSIONS: These data document the large heterogeneity in rates of ECP use between countries/regions. These differences could not be explained by individual or contextual factors, and raise further questions in relation to ECP access for adolescents and their education in its appropriate use.

[Can medical treatment be the first-line treatment for most ectopic pregnancies? A series of 202 patients]. / Peut-on traiter 74 % des grossesses extra-utérines par un traitement médical ? A propos d'une série de 202 patientes.

OBJECTIVES: To assess the efficacy and safety of a liberal policy of medical treatment for ectopic pregnancies (EUP). MATERIAL AND METHODS: Retrospective study of EUP that received active management between January 1999 and December 2003. Patients with rupture or near-rupture and those who refused medical treatment received surgical treatment. Other patients were treated by methotrexate. RESULTS: Two hundred and two EUP were managed; 26 % were treated surgically, 74 % medically. The success rate of medical treatment was 83 %. A ss-hCG threshold of 2526 IU/l was selected. Under this level, the success rate was 90.7 % compared with 68 % when it was higher (p=0.001). Cardiac activity tripled the failure rate. Morbidity with medical treatment consisted of an augmentation in transaminases in 18.8 % and one case of severe dermatosis (0.7 %). Almost half of the patients treated medically required hospitalizations. CONCLUSION: The extension of medical treatment in our population to 74 % of all EUP yielded a high success rate, 83 %.

Successful intrauterine therapy for congenital cystic adenomatoid malformation of the lung. A case report.

Congenital cystic adenomatoid malformation (CCAM) of the lung is a rare abnormality which is amenable to be diagnosed by prenatal ultrasonography. In general, CCAM associated with non-immune hydrops has a poor prognosis unless a fetal intervention is performed. In some series almost 100% of either prenatal or early neonatal deaths are observed without intervention. Recently the cystic adenomatoid malformation volume ratio (CVR) has been proposed as an index to predict the development of hydrops in this condition. If the CVR is >1.6, the risk of hydrops is approximately 75%. We report a case of CCAM (macrocystic type) of the left lung referred to our center at 21 weeks of gestation. Fetal therapy was considered owing to enlargement of the CCAM volume, severe mediastinal shift, right lung compression, polyhydramnios and ascites from 21 to 26 weeks. Thoracoamniotic shunting was performed successfully at 26 weeks with resolution of the cystic mass. At 37 weeks a male infant was born vaginally weighing 3,210 g with Apgar scores of 5 and 10. Resection of the mass was performed uneventfully on day 3. The infant is currently 22 months of age, asymptomatic and in good condition.

Vaginoscopic versus conventional approaches to outpatient diagnostic hysteroscopy: a two-centre randomized prospective study.

BACKGROUND: To compare the tolerability and feasibility of the transvaginal and standard approaches in outpatient diagnostic hysteroscopy. METHODS: This randomized prospective trial was carried out in two centres to compare the transvaginal (n = 200) and conventional (n = 200) approaches during outpatient hysteroscopy. Patients were randomized by a computer-generated list. The main outcome measure was pain during the examination, measured on a visual analogue scale (VAS) graded from 0 to 10 (0 = lowest, 10 = highest). Secondary criteria were ease of instrument passage through the cervix, investigation quality and its duration. For data analysis, we used the chi-squared test or Fischer's exact test for qualitative variables and the Mann-Whitney U-test for quantitative variables. RESULTS: Median VAS was rated at 0.5 for the vaginoscopic and 2 for the standard (P < 0.0001) approaches. The approaches did not differ significantly in investigation quality, procedure duration or ease of cervical passage (although the latter was more often easy transvaginally). CONCLUSIONS: The transvaginal approach is better tolerated than the conventional technique in outpatient diagnostic hysteroscopy.

Mothers' knowledge of screening for trisomy 21 in 1999: a survey in Paris maternity units.

OBJECTIVE: To assess mothers' knowledge of screening tests for trisomy 21. STUDY DESIGN: Interview of all women who had recently delivered a healthy child and were present in 15 Paris maternity units during one of the two non-consecutive days in June 1999 (N = 734). RESULTS: Two-third said that they had access to a nuchal translucency measurement (NTM) and to maternal serum screening (MSS), and 16% to amniocentesis. Thirty-eight percent of the women who had NTMs and 69% of those who had serum screening said that they had been informed of the need for amniocentesis if the results were abnormal. Among the women who had amniocentesis, 20% did not know the risk of miscarriage and 41% had not been informed about the possibility of terminating the pregnancy if trisomy 21 was diagnosed. CONCLUSIONS: Mothers' knowledge about the screening tests for trisomy 21 remains fragmentary. Providing comprehensive information about all these tests should be considered in early pregnancy so that women can make informed choices.

Human immunodeficiency virus screening among pregnant women in France: results from the 1995 National Perinatal Survey.

OBJECTIVE: The aim of the study was to assess how the French legislation requiring physicians to offer human immunodeficiency virus screening routinely at the beginning of prenatal care has been implemented and to explore areas in which improvement is required. STUDY DESIGN: The survey included all births in France during a 7-day period in February 1995. A total of 12,341 women were asked whether they knew whether they had undergone a human immunodeficiency virus antibody test before or during the pregnancy. Factors that could have influenced their knowledge of whether they had been tested were also assessed. RESULTS: Of the women questioned, 87.3% stated that they had been tested before or during pregnancy, 7.6% said that they had not been tested, and 5.1% stated that they did not know whether a test had been performed. Among those who said that they had not been tested before the pregnancy in question, 84. 9% reported that they were tested during the pregnancy. The multivariate analysis revealed that women from North Africa differed significantly from French women in both unawareness of screening status and the proportion who reported not being screened (odds ratio 2.1 with 95% confidence interval 1.6-2.9 and odds ratio 2.4 with 95% confidence interval 1.8-3.1, respectively). There was, however, no significant difference between women from sub-Saharan Africa and French women in these variables. A lower educational level was an important predictor of unawareness of screening status (odds ratio 2.6 with 95% confidence interval 2.0-3.4). Associations were observed between reporting of unscreened status and low levels of use of prenatal care services (<6 prenatal consultations odds ratio 1.3 with 95% confidence interval 1.0-1.6, <3 ultrasonographic examinations odds ratio 1.7 with 95% confidence interval 1.3-2.0, and no prenatal consultation at the maternity hospital odds ratio 1. 5 with 95% confidence interval 1.2-1.8). CONCLUSION: The 1995 National Perinatal Survey, which appears to indicate extensive human immunodeficiency virus screening of pregnant women in France, shows that the nonmandatory nature of the French policy of systematically offering prenatal human immunodeficiency virus screening has not prevented a high proportion of women from learning their screening status. The less comprehensive screening among women in certain subgroups suggests that human immunodeficiency virus information should be better adapted for these women.

Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients.

BACKGROUND: CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy) is commonly overlooked or misdiagnosed owing to its recent identification and its variable mode of presentation. The defective gene in CADASIL is Notch3, which encodes a large transmembrane receptor. To set up a diagnostic test and to delineate the Notch3 domains involved in CADASIL., we undertook mutations analysis in this gene in a group of CADASIL patients. METHODS: 50 unrelated patients with CADASIL and 100 healthy controls were screened for mutations along the entire Notch3 sequence, by means of single-strand conformation polymorphism, heteroduplex, and sequence analysis. FINDINGS: Strongly stereotyped mis-sense mutations, located within the epidermal-growth-factor-like (EGF-like) repeats, in the extracellular domain of Notch3, were detected in 45 patients. Clustering of mutations within the two exons encoding the first five EGF-like repeats was observed (32 patients). All these mutations lead to loss or gain of a cysteine residue and therefore to an unpaired number of cysteine residues within a given EGF domain. None of these mutations was found in the 100 controls. INTERPRETATION: Because of the strong clustering and highly stereotyped nature of the pathogenetic mutations detected in CADASIL patients, and easy and reliable diagnostic test for CADASIL is feasible. The findings suggest that aberrant dimerisation of Notch3, due to abnormal disulphide bridging with another Notch3 molecule or with another protein, may be involved in the pathogenesis of this disorder.

Notch3 mutations in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a mendelian condition causing stroke and vascular dementia.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited condition whose key features include recurrent subcortical ischemic events, migraine attacks and vascular dementia in association with diffuse white-matter abnormalities seen on neuroimaging. Pathologic examination shows multiple small deep cerebral infarcts, a leukoencephalopathy and a nonatherosclerotic nonamyloid angiopathy involving mainly the media of small cerebral arteries. To progress in understanding the pathophysiological mechanisms of this condition, we undertook the identification of the mutated gene. We mapped the CADASIL gene on chromosome 19p13.1. More than 120 families have been referred to our lab. Genetic linkage analysis of 33 of these families allowed us to reduce the size of the genetic interval to less than 1 cM and to demonstrate the genetic homogeneity of this condition. In the absence of any candidate gene, we undertook positional cloning of this gene. We identified, within the CADASIL critical region, the human Notch3 gene, whose sequence analysis revealed deleterious mutations in CADASIL families co-segregating with the affected phenotype. These data establish that this gene causes CADASIL. Identification of the CADASIL gene will provide a valuable diagnostic tool for clinicians and could be used to estimate the prevalence of this underdiagnosed condition. It should help in the understanding of pathophysiological mechanisms of CADASIL and vascular dementia.

Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia.

Stroke is the third leading cause of death, and vascular dementia the second cause of dementia after Alzheimer's disease. CADASIL (for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) causes a type of stroke and dementia whose key features include recurrent subcortical ischaemic events and vascular dementia and which is associated with diffuse white-matter abnormalities on neuroimaging. Pathological examination reveals multiple small, deep cerebral infarcts, a leukoencephalopathy, and a non-atherosclerotic, non-amyloid angiopathy involving mainly the small cerebral arteries. Severe alterations of vascular smooth-muscle cells are evident on ultrastructural analysis. We have previously mapped the mutant gene to chromosome 19. Here we report the characterization of the human Notch3 gene which we mapped to the CADASIL critical region. We have identified mutations in CADASIL patients that cause serious disruption of this gene, indicating that Notch3 could be the defective protein in CADASIL patients.