The Phytochemistry and Pharmacology of Tulbaghia, Allium, Crinum and Cyrtanthus: 'Talented' Taxa from the Amaryllidaceae.

Amaryllidaceae is a significant source of bioactive phytochemicals with a strong propensity to develop new drugs. The genera Allium, Tulbaghia, Cyrtanthus and Crinum biosynthesize novel alkaloids and other phytochemicals with traditional and pharmacological uses. Amaryllidaceae biomolecules exhibit multiple pharmacological activities such as antioxidant, antimicrobial, and immunomodulatory effects. Traditionally, natural products from Amaryllidaceae are utilized to treat non-communicable and infectious human diseases. Galanthamine, a drug from this family, is clinically relevant in treating the neurocognitive disorder, Alzheimer's disease, which underscores the importance of the Amaryllidaceae alkaloids. Although Amaryllidaceae provide a plethora of biologically active compounds, there is tardiness in their development into clinically pliable medicines. Other genera, including Cyrtanthus and Tulbaghia, have received little attention as potential sources of promising drug candidates. Given the reciprocal relationship of the increasing burden of human diseases and limited availability of medicinal therapies, more rapid drug discovery and development are desirable. To expedite clinically relevant drug development, we present here evidence on bioactive compounds from the genera Allium, Tulgbaghia, Cyrtanthus and Crinum and describe their traditional and pharmacological applications.

Antimicrobial Compounds from Microorganisms.

Antimicrobial resistance is an exigent public health concern owing to the emergence of novel strains of human resistant pathogens and the concurrent rise in multi-drug resistance. An influx of new antimicrobials is urgently required to improve the treatment outcomes of infectious diseases and save lives. Plant metabolites and bioactive compounds from chemical synthesis have found their efficacy to be dwindling, despite some of them being developed as drugs and used to treat human infections for several decades. Microorganisms are considered untapped reservoirs for promising biomolecules with varying structural and functional antimicrobial activity. The advent of cost-effective and convenient model organisms, state-of-the-art molecular biology, omics technology, and machine learning has enhanced the bioprospecting of novel antimicrobial drugs and the identification of new drug targets. This review summarizes antimicrobial compounds isolated from microorganisms and reports on the modern tools and strategies for exploiting promising antimicrobial drug candidates. The investigation identified a plethora of novel compounds from microbial sources with excellent antimicrobial activity against disease-causing human pathogens. Researchers could maximize the use of novel model systems and advanced biomolecular and computational tools in exploiting lead antimicrobials, consequently ameliorating antimicrobial resistance.

Association between gestational age at birth, antenatal corticosteroids, and outcomes at 5 years: multiple courses of antenatal corticosteroids for preterm birth study at 5 years of age (MACS-5).

BACKGROUND: The Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study (MACS) showed no benefit in the reduction of major neonatal mortality/morbidity or neurodevelopment at 2 and 5 years of age. Using the data from the randomized controlled trial and its follow-up, the aim of this study was to evaluate the association between gestational ages at birth in children exposed to single versus multiple courses of antenatal corticosteroid (ACS) therapy in utero and outcomes at 5 years of age. METHOD: A total of 1719 children, with the breakdown into groupings of <30, 30-36, and ≥ 37 weeks gestation at birth, contributed to the primary outcome: death or survival with a disability in one of the following domains: neuromotor, neurosensory, and neurobehavioral/emotional disability and were included in this analysis. RESULTS: Gestational age at birth was strongly associated with the primary outcome, p < 0.001. Overall, the interaction between ACS groups and gestational age at birth was not significant, p = 0.064. Specifically, in the 2 preterm categories, there was no difference in the primary outcome between single vs. multiple ACS therapy. However, for infants born ≥37 weeks gestation, there was a statistically significant increase in the risk of the primary outcome in multiple ACS therapy, 48/213 (22.5%) compared to 38/249 (15.3%) in the single ACS therapy; OR = 1.69 [95% CI: 1.04, 2.77]; p = 0.037. CONCLUSION: Preterm birth (<37 weeks gestation) remained the primary factor contributing to an adverse outcome regardless of the number of courses of ACS therapy. Children born ≥ 37 weeks and exposed to multiple ACS therapy may have an increased risk of neurodevelopmental/neurosensory impairment by 5 years of age. To optimize outcomes for infants/children, efforts in reducing the incidence of preterm birth should remain the primary focus in perinatal research. TRIAL REGISTRATION: This study has been registered at (identifier NCT00187382).

Multiple courses of antenatal corticosteroids for preterm birth study: outcomes in children at 5 years of age (MACS-5).

IMPORTANCE: A single course of antenatal corticosteroid therapy is recommended for pregnant women at risk of preterm birth between 24 and 33 weeks' gestational age. However, 50% of women remain pregnant 7 to 14 days later, leading to the question of whether additional courses should be given to women remaining at risk for preterm birth. The Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study (MACS) was an international randomized clinical trial that compared multiple courses of antenatal corticosteroids with a single course in women at risk of preterm birth. OBJECTIVE: To determine the effects of single vs multiple courses of antenatal corticosteroid therapy on death or neurodevelopmental disability (neuromotor, neurosensory, or neurocognitive/neurobehavioral function) at 5 years of age in children whose mothers participated in MACS. Our secondary aims were to determine the effect on height, weight, head circumference, blood pressure, intelligence, and specific cognitive (visual, spatial, and language) skills. DESIGN, SETTING, AND PARTICIPANTS: Cohort follow-up study of children seen between June 2006 and May 2012 at 55 centers. In total, 1724 women (2141 children) were eligible for the study, of whom 1728 children (80.7% of the 2141 eligible children) participated and 1719 children contributed to the primary outcome. INTERVENTION: Single and multiple courses of antenatal corticosteroid therapy. MAIN OUTCOMES AND MEASURES: The primary outcome was death or survival with a neurodevelopmental disability in 1 of the following domains: neuromotor (nonambulatory cerebral palsy), neurosensory (blindness, deafness, or need for visual/hearing aids), or neurocognitive/neurobehavioral function (abnormal attention, memory, or behavior). RESULTS: There was no significant difference between the groups in the risk of death or neurodevelopmental disability: 217 of 871 children (24.9%) in the multiple-courses group vs 210 of 848 children (24.8%) in the single-course group (odds ratio, 1.02 [95% CI, 0.81 to 1.29]; P = .84). CONCLUSIONS AND RELEVANCE: Multiple courses, compared with a single course, of antenatal corticosteroid therapy did not increase or decrease the risk of death or disability at 5 years of age. Because of a lack of strong conclusive evidence of short-term or long-term benefits, it remains our opinion that multiple courses not be recommended in women with ongoing risk of preterm birth. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00187382.

Effect of antenatal corticosteroids on fetal growth and gestational age at birth.

OBJECTIVE: To estimate the effect of multiple courses of antenatal corticosteroids on neonatal size, controlling for gestational age at birth and other confounders, and to determine whether there was a dose-response relationship between number of courses of antenatal corticosteroids and neonatal size. METHODS: This is a secondary analysis of the Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study, a double-blind randomized controlled trial of single compared with multiple courses of antenatal corticosteroids in women at risk for preterm birth and in which fetuses administered multiple courses of antenatal corticosteroids weighed less, were shorter, and had smaller head circumferences at birth. All women (n=1,858) and children (n=2,304) enrolled in the Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study were included in the current analysis. Multiple linear regression analyses were undertaken. RESULTS: Compared with placebo, neonates in the antenatal corticosteroids group were born earlier (estimated difference and confidence interval [CI]: -0.428 weeks, CI -0.10264 to -0.75336; P=.01). Controlling for gestational age at birth and confounding factors, multiple courses of antenatal corticosteroids were associated with a decrease in birth weight (-33.50 g, CI -66.27120 to -0.72880; P=.045), length (-0.339 cm, CI -0.6212 to -0.05676]; P=.019), and head circumference (-0.296 cm, -0.45672 to -0.13528; P<.001). For each additional course of antenatal corticosteroids, there was a trend toward an incremental decrease in birth weight, length, and head circumference. CONCLUSION: Fetuses exposed to multiple courses of antenatal corticosteroids were smaller at birth. The reduction in size was partially attributed to being born at an earlier gestational age but also was attributed to decreased fetal growth. Finally, a dose-response relationship exists between the number of corticosteroid courses and a decrease in fetal growth. The long-term effect of these findings is unknown. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00187382. LEVEL OF EVIDENCE: II.

Maternal side-effects after multiple courses of antenatal corticosteroids (MACS): the three-month follow-up of women in the randomized controlled trial of MACS for preterm birth study.

OBJECTIVE: A single course of antenatal corticosteroids (ACS) is associated with a reduction in respiratory distress syndrome and neonatal death. Multiple Courses of Antenatal Corticosteroids Study (MACS), a study involving 1858 women, was a multicentre randomized placebo-controlled trial of multiple courses of ACS, given every 14 days until 33+6 weeks or birth, whichever came first. The primary outcome of the study, a composite of neonatal mortality and morbidity, was similar for the multiple ACS and placebo groups (12.9% vs. 12.5%), but infants exposed to multiple courses of ACS weighed less, were shorter, and had smaller head circumferences. Thus for women who remain at increased risk of preterm birth, multiple courses of ACS (every 14 days) are not recommended. Chronic use of corticosteroids is associated with numerous side effects including weight gain and depression. The aim of this postpartum assessment was to ascertain if multiple courses of ACS were associated with maternal side effects. METHODS: Three months postpartum, women who participated in MACS were asked to complete a structured questionnaire that asked about maternal side effects of corticosteroid use during MACS and included the Edinburgh Postnatal Depression Scale. Women were also asked to evaluate their study participation. RESULTS: Of the 1858 women randomized, 1712 (92.1%) completed the postpartum questionnaire. There were no significant differences in the risk of maternal side effects between the two groups. Large numbers of women met the criteria for postpartum depression (14.1% in the ACS vs. 16.0% in the placebo group). Most women (94.1%) responded that they would participate in the trial again. CONCLUSION: In pregnancy, corticosteroids are given to women for fetal lung maturation and for the treatment of various maternal diseases. In this international multicentre randomized controlled trial, multiple courses of ACS (every 14 days) were not associated with maternal side effects, and the majority of women responded that they would participate in such a study again.

Multiple courses of antenatal corticosteroids for preterm birth study: 2-year outcomes.

OBJECTIVE: The aim of this study was to determine the effects of repeated courses of prenatal corticosteroid therapy versus placebo on death or neurologic impairment among the children enrolled in the Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study, at 18 to 24 months of age. METHODS: A total of 2305 infants were eligible for follow-up evaluation; 2104 infants (1069 in the prenatal corticosteroid therapy group and 1035 in the placebo group) were monitored. The primary outcome was death or neurologic impairment, defined as either cerebral palsy or cognitive delay, at 18 to 24 months of age. The secondary outcomes were measurements of growth (height, weight, and head circumference). RESULTS: Children exposed to multiple courses of prenatal corticosteroid therapy had similar rates of death or neurologic impairment, compared with children exposed to placebo (148 children [13.8%] vs 142 children [13.7%]; odds ratio: 1.001[95% confidence interval: 0.75-1.30]; P = .95). They had a mean weight of 11.94 kg, compared with 12.14 kg in the placebo group (P = .04), a mean height of 85.51 cm, compared with 85.46 cm (P = .87), and a mean head circumference of 48.18 cm, compared with 48.25 cm (P = .45). CONCLUSIONS: Multiple courses of prenatal corticosteroid therapy, given every 14 days, did not increase or decrease the risk of death or neurologic impairment at 18 to 24 months of age, compared with a single course of prenatal corticosteroid therapy. Continued follow-up monitoring of these children is necessary to assess neurobehavioral function, school performance, and possible susceptibility to disease.

Gabapentin use in hyperemesis gravidarum: a pilot study.

Among 7 subjects with hyperemesis gravidarum (HG), we found gabapentin therapy to be associated with mean reductions in nausea and emesis from Baseline to Days 12-14 of 80% and 94%, respectively. There have been 2 congenital defects among 7 exposed infants. Gabapentin may be effective in the treatment of HG.

Multiple courses of antenatal corticosteroids for preterm birth (MACS): a randomised controlled trial.

BACKGROUND: One course of antenatal corticosteroids reduces the risk of respiratory distress syndrome and neonatal death. Weekly doses given to women who remain undelivered after a single course may have benefits (less respiratory morbidity) or cause harm (reduced growth in utero). We aimed to find out whether multiple courses of antenatal corticosteroids would reduce neonatal morbidity and mortality without adversely affecting fetal growth. METHODS: 1858 women at 25-32 weeks' gestation who remained undelivered 14-21 days after an initial course of antenatal corticosteroids and continued to be at high risk of preterm birth were randomly assigned to multiple courses of antenatal corticosteroids (n=937) or placebo (n=921), every 14 days until week 33 or delivery, whichever came first. The primary outcome was a composite of perinatal or neonatal mortality, severe respiratory distress syndrome, intraventricular haemorrhage (grade III or IV), periventricular leucomalacia, bronchopulmonary dysplasia, or necrotising enterocolitis. Analysis was by intention to treat. All patients and caregivers were unaware of the treatment given. This trial is registered as number ISRCTN2654148. FINDINGS: Infants exposed to multiple courses of antenatal corticosteroids had similar morbidity and mortality to those exposed to placebo (150 [12.9%] vs 143 [12.5%]). Those receiving multiple doses of corticosteroids also weighed less at birth than those exposed to placebo (2216 g vs 2330 g, p=0.0026), were shorter (44.5 cm vs 45.4 cm, p<0.001), and had a smaller head circumference (31.1 cm vs 31.7 cm, p<0.001). INTERPRETATION: Multiple courses of antenatal corticosteroids, every 14 days, do not improve preterm-birth outcomes, and are associated with a decreased weight, length, and head circumference at birth. Therefore, this treatment schedule is not recommended. FUNDING: Canadian Institutes of Health Research.

The costs of planned cesarean versus planned vaginal birth in the Term Breech Trial.

BACKGROUND: The Term Breech Trial compared the safety of planned cesarean and planned vaginal birth for breech presentations at term. The combined outcome of perinatal or neonatal death and serious neonatal morbidity was found to be significantly lower among babies delivered by planned cesarean section. In this study we conducted a cost analysis of the 2 approaches to breech presentations at delivery. METHODS: We used a third-party-payer (i.e., Ministry of Health) perspective. We included all costs for physician services and all hospital-related costs incurred by both the mother and the infant. We collected health care utilization and outcomes for all study participants during the trial. We used only the utilization data from countries with low national rates of perinatal death (< or = 20/1000). Seven hospitals across Canada (4 teaching and 3 community centres) were selected for unit cost calculations. RESULTS: The estimated mean cost of a planned cesarean was significantly lower than that of a planned vaginal birth (7165 dollars v. 8042 dollars per mother and infant; mean difference -877 dollars, 95% credible interval -1286 dollars to -473 dollars). The estimated mean cost of a planned cesarean was lower than that of a planned vaginal birth for both women having a first birth (7255 dollars v. 8440 dollars) and women having had at least one prior birth (7071 dollars v. 7559 dollars). Although the treatment effect was largest in the subgroup of women having their first child, there was no statistically significant interaction between treatment and parity since the 95% credible intervals for difference in treatment effects between parity equalling zero and parity of one or greater all include zero. INTERPRETATION: Planned cesarean section was found to be less costly than planned vaginal birth for the singleton fetus in a breech presentation at term in the Term Breech Trial.

Correlations of placental perfusion and PlGF protein expression in early human pregnancy.

OBJECTIVE: The purpose of this study was to investigate temporal correlations between maternal serum placenta growth factor levels and placental perfusion in early human pregnancies. STUDY DESIGN: Systolic umbilical artery Doppler blood flow velocity indices at fetal and placental insertion sites were measured between 7 and 22 weeks of gestation from normal singleton pregnancies. Maternal serum placenta growth factor levels were determined by enzyme-linked immunosorbent assay. RESULTS: Maternal serum placenta growth factor levels showed an exponential increase at approximately 14 weeks of gestation. Placenta perfusion, as estimated by systolic Doppler blood flow indices, significantly increased with gestational age (P < .0001). There was a close association between placenta growth factor expression levels and evidence of increased placenta perfusion (P < .033). CONCLUSION: The significant increase in serum placenta growth factor coincides with the increased perfusion of the maternal/fetal interface at approximately 12 to 14 weeks of gestation. Correlation of placenta growth factor expression and placental perfusion suggests that placenta growth factor may contribute to assuring adequate vascular development/function of the placenta early in gestation.

A model-based study of passive joint properties on muscle effort during static stance.

This study examined the impact of lower extremity joint stiffnesses and simulated joint contractures on the muscle effort required to maintain static standing postures after a spinal cord injury (SCI). Static inverse computer simulations were performed with a three-dimensional 15 degree of freedom musculoskeletal model placed in 1600 different standing postures. The required lower extremity muscle forces were calculated through an optimization routine that minimized the sum of the muscle stresses squared, which was used as an index of the muscle effort required for each standing posture. Joint stiffnesses were increased and decreased by 100 percent of their nominal values, and contractures were simulated to determine their effects on the muscle effort for each posture. Nominal muscle and passive properties for an individual with a SCI determined the baseline muscle effort for comparisons. Stiffness changes for the ankle plantar flexion/dorsiflexion, hip flexion/extension, and hip abduction/adduction directions had the largest effect on reducing muscle effort by more than 5 percent, while changes in ankle inversion/eversion and knee flexion/extension had the least effect. For erect standing, muscle effort was reduced by more than 5 percent when stiffness was decreased at the ankle plantar flexion/dorsiflexion joint or hip flexion/extension joint. With simulated joint contractures, the postural workspace area decreased and muscle effort was not reduced by more than 5 percent for any posture. Using this knowledge, methods can be developed through the use of orthoses, physical therapy, surgery or other means to appropriately augment or diminish these passive moments during standing with a neuroprosthesis.

Mothers' views of their childbirth experiences 2 years after planned Caesarean versus planned vaginal birth for breech presentation at term, in the international randomized Term Breech Trial.

OBJECTIVE: To compare mothers' views at 2 years postpartum after participation in a randomized trial of planned Caesarean and planned vaginal birth for a singleton fetus in breech presentation at term. STUDY DESIGN: In selected centres in the Term Breech Trial, mothers completed a structured questionnaire at approximately 2 years postpartum to assess their likes and dislikes about their childbirth experiences and their views about their intrapartum care and care providers. RESULTS: Of 1159 mothers from 85 centres, 917 (79.1%) completed a follow-up questionnaire at 2 years postpartum. Baseline information was similar for both the planned Caesarean and planned vaginal birth groups. Planned Caesarean was associated with less worry about the baby's health (P < 0.001). While other differences were noted in likes and dislikes about their childbirth experiences, women's evaluations of the quality of intrapartum care, the helpfulness of staff, and their involvement in decision-making did not differ in the planned Caesarean delivery and planned vaginal birth groups. CONCLUSION: Planned mode of delivery influences aspects of women's evaluations of their childbirth experiences but does not affect evaluations of the quality of intrapartum care, support from care providers, or amount of involvement in decision-making.

Outcomes of children at 2 years after planned cesarean birth versus planned vaginal birth for breech presentation at term: the International Randomized Term Breech Trial.

OBJECTIVE: The purpose of this study was to determine whether planned cesarean delivery for the singleton fetus in breech presentation at term reduces the risk of death or neurodevelopmental delay at 2 years of age. STUDY DESIGN: In selected centers in the Term Breech Trial, children were screened for abnormalities at > or =2 years of age with the Ages and Stages Questionnaire, followed by a neurodevelopmental assessment if the Ages and Stages Questionnaire score was abnormal. RESULTS: A total of 923 of 1159 children (79.6%) from 85 centers were followed to 2 years of age. The risk of death or neurodevelopmental delay was no different for the planned cesarean than for the planned vaginal birth groups (14 children [3.1%] vs 13 children [2.8%]; relative risk, 1.09; 95% CI, 0.52- 2.30; P = .85; risk difference, +0.3%; 95% CI, -1.9%, +2.4%). CONCLUSION: Planned cesarean delivery is not associated with a reduction in risk of death or neurodevelopmental delay in children at 2 years of age.

Maternal outcomes at 2 years after planned cesarean section versus planned vaginal birth for breech presentation at term: the international randomized Term Breech Trial.

OBJECTIVE: This study was undertaken to compare maternal outcomes at 2 years postpartum after planned cesarean section and planned vaginal birth for the singleton fetus in breech presentation at term. STUDY DESIGN: In selected centers in the Term Breech Trial, mothers completed a structured questionnaire at 2 or more years postpartum to determine their health in the previous 3 to 6 months. RESULTS: A total of 917 of 1159 (79.1%) mothers from 85 centers completed a follow-up questionnaire at 2 years postpartum. There were no differences between groups in breast feeding, relationship with child or partner, pain, subsequent pregnancy, incontinence, depression, urinary, menstrual or sexual problems, fatigue, or distressing memories of the birth experience. Planned cesarean section was associated with a higher risk of constipation (P = .02). CONCLUSION: Maternal outcomes at 2 years postpartum are similar after planned cesarean section and planned vaginal birth for the singleton breech fetus at term.

Effects of spinal cord injury on lower-limb passive joint moments revealed through a nonlinear viscoelastic model.

We developed a mathematical model to describe the lower-limb passive joint moments to investigate and compare these moments in a small sample of able-bodied volunteers and individuals with long-standing motor complete paraplegia. Isokinetic tests, which were performed on a sample of four subjects with spinal cord injuries (SCIs) and five uninjured individuals, measured the passive moments at the ankle, knee, and hip joints throughout their ranges of motion in the sagittal and coronal planes. We fitted an 11-parameter nonlinear viscoelastic model to the acquired passive moment data (mean square error ranging from 0.020 to 5.1 Nm2) to compare subject populations and to determine the influences of joint velocity and passive coupling between adjacent joints. Although the passive moment curves of the SCI and able-bodied groups exhibited many similarities in shape, a repeated measures analysis of variance (ANOVA) that compared the passive moment curves of the two groups indicated a statistically significant (p < 0.01) difference for every joint except the knee. This new model for passive joint moments should prove to be useful in examining how changes in passive properties affect bipedal function and movement.

External cephalic version beginning at 34 weeks' gestation versus 37 weeks' gestation: a randomized multicenter trial.

OBJECTIVE: In about 3% to 4% of all pregnancies at term, the fetal presentation will be noncephalic. External cephalic version (ECV) at term has been shown to decrease the rate of noncephalic presentation at birth and to decrease the rate of cesarean section associated with breech presentation. However, success rates for ECV are low. We did a randomized trial to compare a policy of beginning ECV early, at between 34 and 36 weeks' gestation, and beginning ECV at 37 to 38 weeks' gestation. STUDY DESIGN: At 25 centers in seven countries, 233 women with a singleton breech fetus were randomly assigned to having an ECV procedure done early (at between 34 weeks 0 days and 36 weeks 0 days), or delayed (at between 37 weeks 0 days and 38 weeks 0 days). An experienced practitioner undertook the ECV procedure, and repeat ECV procedures were allowed. Tocolytics and use of epidural analgesia were included as part of the protocol. The primary outcome was the rate of noncephalic presentation at birth. An intention-to-treat analysis was used. RESULTS: Data were received for 232 women, with 116 women in each of the early and delayed ECV groups. Of these, 86.2% in the early ECV group and 67.2% in the delayed ECV group had at least one ECV performed. The rate of noncephalic presentation at birth in the early ECV group was 66 of 116 (56.9%) and 77 of 116 (66.4%) in the delayed ECV group (relative risk [RR] [95% CI] 0.86 [0.70-1.05], P =.09). The rate of serious fetal complications and the rate of preterm birth at <37 weeks were not significantly increased in the early ECV group compared with the delayed ECV group (6.9% vs 7.8%, RR [95% CI] 0.89 [0.36-2.22], P =.69 and 8.6% vs 6.1%, RR [95% CI] 1.42 [0.56-3.59], P =.31, respectively). The rate of cesarean section in the early ECV group was 75 of 116 (64.7%) and 83 of 116 (71.6%) in the delayed ECV group (RR [95% CI] 0.90 [0.76-1.08], P =.32). Neonatal outcomes were comparable in the two groups. The rate of reversion to noncephalic was low in both groups. The majority of women in both groups indicated that they would consider having an ECV in another pregnancy. CONCLUSION: Early ECV performed at 34 to 36 weeks compared with 37 to 38 weeks may reduce the risk of noncephalic presentation at delivery. A large pragmatic trial of early ECV is now required to assess this approach further in terms of cesarean section rates and neonatal outcomes before changes in clinical practice.

The relationship of von Willebrand factor binding to activated platelets from healthy neonates and adults.

von Willebrand Factor (VWF) is important in platelet adhesion and shear-dependent platelet activation. We performed flow cytometric analyses of VWF binding to and activation of platelets from healthy neonates, children, and adults. Platelets from cord blood (n = 38; gestational age: 36-42 wk; birth weight: 2.4-5.1 kg), neonatal venous blood (n = 19; d 2-3 of life), children (n = 15; age: 1.5-16.3 y), and adults (n = 22; age: 18-55 y) were studied. Binding of VWF was assessed using an antihuman VWF polyclonal antibody and a FITC-conjugated secondary antibody. Platelet activation was determined by the expression of CD62P, CD63, CD41, CD42b, activated GPIIb/IIIa (PAC-1), procoagulant surface (as reflected by annexin V binding), and microparticle formation. Although the mean percentage of VWF-positive platelets was not significantly higher in unstimulated platelets from 2- to 3-d-old neonates, their platelets were more activated than those from adults, and there was a positive correlation of VWF binding with platelet activation (CD62P: r = 0.74, p < 0.001; annexin V: r = 0.46, p < 0.05). In adults, after in vitro activation of platelets with thrombin and ADP, VWF binding to platelets increased and correlated significantly with CD62P expression (r = 0.71, p < 0.001). VWF binding to unstimulated neonatal platelets was, however, higher than that to in vitro-stimulated platelets from adults at the same level of expression of platelet activation markers. Further studies are required to assess the mechanism and significance of VWF binding to activated platelets in the neonatal period.

Abdominal versus vaginal cerclage after a failed transvaginal cerclage: a systematic review.

OBJECTIVE: The purpose of this study was to compare the outcomes of pregnancy after transabdominal cerclage versus after transvaginal cerclage in patients with a failed transvaginal cerclage during a previous pregnancy. STUDY DESIGN: MEDLINE and EMBASE were searched in English. We included studies that reported perinatal and/or maternal outcomes in women who had a transabdominal cerclage or a transvaginal cerclage placed at or before 20 weeks of gestation, after having had a failed nonemergent transvaginal cerclage in a previous pregnancy. Data were included for individual patients if they met the inclusion criteria, and their outcomes were reported separately. We excluded patients with cervical amputation because transvaginal cerclage is not an option for these women because of technical difficulty. RESULTS: Fourteen studies met the inclusion criteria. Thirteen of the studies were case series (12 retrospective and 1 prospective), and one study was a retrospective cohort study. In total, 157 women in the studies had a failed vaginal cerclage in a previous pregnancy; 117 women had a subsequent transabdominal cerclage; 40 women had a subsequent transvaginal cerclage. The likelihood of perinatal death or delivery at <24 weeks was 6.0% (95% CI, 3.8%-8.2%) after transabdominal cerclage and 12.5% (95% CI, 2.7%-22.7%) after transvaginal cerclage. The likelihood of serious operative complications after transabdominal cerclage was 3.4% (95% CI, 0.01%, 6.8%). There were no serious operative complications after transvaginal cerclage. CONCLUSION: Transabdominal cerclage may be associated with a lower risk of perinatal death or delivery at <24 weeks of gestation, but it may be associated with a higher risk of serious operative complications. A multicenter randomized controlled trial should be conducted to address this question.

Multiple versus single courses of antenatal corticosteroids for preterm birth: a pilot study.

OBJECTIVES: (1) To determine the feasibility of a multicentre, randomized, double-masked, placebo-controlled trial to investigate the effects of multiple courses of antenatal corticosteroids (ACS), more than 7 days following the initial course of ACS therapy, on perinatal or neonatal mortality or neonatal morbidity. (2) To determine the risk of complications that would require discontinuation of ACS therapy. (3) To determine if multiple courses of ACS have an effect on the concentrations of plasma cortisol and adrenocorticotropin hormone (ACTH) in cord blood and in maternal blood immediately following delivery, compared to a single course of ACS. METHODS: Women at 24 to 30 weeks' gestation, at continued increased risk of preterm birth 7 or more days following a single course of ACS, were randomized to receive weekly courses of betamethasone or placebo until 33 weeks' gestation or delivery. RESULTS: Women were recruited at two hospitals in Toronto from 01 September 1999 to 31 August 2000. Of the 78 women who were approached and were eligible for the study, 12 (15%) were recruited and 66 (85%) refused to participate. Of the 66 refusals, 38 (58%) did not feel their physicians were supportive of the study, 10 (15%) did not want to be randomized, and 4 (6%) had other personal reasons for refusing to enter the trial. Fourteen women (21%) had physicians who did not allow them to join the study. The lack of physician support was due to concerns related to the potential adverse effects of multiple courses of ACS. There were no complications requiring discontinuation of ACS. Plasma cortisol and ACTH concentrations in cord and maternal blood taken after delivery were not significantly different between ACS and placebo groups. CONCLUSION: A multicentre randomized controlled trial is required to determine the benefits and risks of multiple versus a single course of ACS. If the study protocols are supported by physicians and their patients, a multicentre randomized controlled trial is feasible.