Systematic review and meta-analysis of human milk intake and retinopathy of prematurity: a significant update.

OBJECTIVE: Two recent meta-analyses have studied the association of exclusive or mainly human milk intake (HMI) on retinopathy of prematurity (ROP). One of these meta-analysis found a protective effect of only or mainly HMI on Severe ROP but not on any stage ROP. However, both these meta-analyses did not find protection from any stage ROP or Severe ROP with any amount of HMI. The objective of this study was to study the association between any amount of HMI and the development of All ROP and Severe ROP in very-low birth weight infants (VLBWI) and extremely low birth weight infants (ELBWI) by systematic review using PRISMA-P guidelines and meta-analysis. STUDY DESIGN: Exposure, controls and outcomes studied were any amount of HMI vs no HMI and All ROP/Severe ROP in VLBWI/ELBWI. All ROP was defined as all stages of ROP pooled together, and Severe ROP as ⩾stage 3 ROP and ROP requiring intervention. Results and effect sizes are expressed as odds ratio (OR), relative risk (RR), risk difference (RD) and number needed to treat (NNT) with 95% confidence intervals (95% CI). Data sources used were PubMed, MEDLINE, EMBASE, Cochrane Central Register of Clinical Trials, Scopus and CINAHL until 24 April 2015. Extracted data were pooled using a fixed effects model. Heterogeneity was assessed. Sensitivity analysis was performed. RESULTS: Five hundred nine of 1701 infants who received any amount of HMI developed All ROP vs 310 of 760 infants without HMI developed All ROP with a pooled OR 0.63* (0.51,0.78), RR 0.76* (0.67,0.86) and RD -0.09* (-0.13,-0.05). The NNT with any amount of HMI was 11* (8,20) (*P<0.0001) to prevent one case of All ROP. 204 of 2465 infants who received any amount of HMI developed Severe ROP vs 85 of 764 infants without HMI developed Severe ROP with a pooled OR 0.74* (0.56,0.98), RR 0.77* (0.60,0.98) and RD -0.03* (-0.05,-0.00). The NNT with any amount of HMI was 33* (*P=0.04) to prevent one case of Severe ROP. CONCLUSION: Any amount of HMI is strongly associated with the protection from All ROP and Severe ROP.

Does increasing body mass index affect cerclage efficacy?

OBJECTIVE: To study the relationship between body mass index (BMI) and gestational age (GA) at delivery in patients with cervical insufficiency (CI) undergoing cerclage. STUDY DESIGN: We accessed a database of patients with singleton gestations undergoing cerclage (N=168) for a well-characterized history of CI, shortened cervix <2.5 cm with a history of prior preterm delivery or prolapse of membranes through the external os. Univariate and multivariate logistic regression analysis were performed to compare obstetrical outcomes between obese and normal-weight patients. RESULT: Prior preterm delivery <35 weeks in obese vs normal-weight patients was significantly higher (44% vs 9%), odds ratio=6.9 (95% CI: 2.5, 18.5), with lower mean GA at delivery (32.6±7.0 vs 37.2±3.4 weeks, P<0.001). After controlling for confounders, BMI remained significantly predictive of prematurity (coefficient: -0.12, adjusted R (2)=0.24), such that every additional 1 unit of BMI was associated with a 1-day reduction in GA at delivery (P=0.03). CONCLUSION: An inverse correlation exists between BMI and GA at delivery in patients with CI receiving cerclage. The findings are unexpected given the protective effect of obesity on spontaneous preterm delivery.

Randomised clinical trial: ghrelin agonist TZP-101 relieves gastroparesis associated with severe nausea and vomiting--randomised clinical study subset data.

BACKGROUND: Limited therapeutic options exist for severe gastroparesis, where severe nausea and vomiting can lead to weight loss, dehydration and malnutrition due to inadequate caloric and fluid intake. TZP-101 (ulimorelin) is a ghrelin receptor agonist that accelerates gastric emptying and improves upper gastrointestinal symptoms in diabetic patients with gastroparesis. AIM: To assess effects of TZP-101 in diabetic gastroparesis patients with severe nausea/vomiting and baseline severity scores of ≥3.5 (range: 0-5) on the Gastroparesis Cardinal Symptom Index (GCSI) Nausea/Vomiting subscale. METHODS: Patients were hospitalised and received four single daily 30-min infusions of one of six TZP-101 doses (range 20-600 µg/kg) or placebo. Efficacy was assessed by symptom improvement. RESULTS: At baseline, 23 patients had a mean severity score for GCSI Nausea/Vomiting of 4.45±0.44. Statistically significant improvements over placebo occurred in the 80 µg/kg group for end of treatment changes from baseline in GCSI Nausea/Vomiting subscale (reduction in score of -3.82±0.76, P=0.011) and the GCSI Total score (-3.14±0.78, P=0.016) and were maintained at the 30-day follow-up assessment (-2.02±1.63, P=0.073 and -1.99±1.33, P=0.032 respectively). The proportion of days with vomiting was reduced significantly (P=0.05) in the 80 µg/kg group (mean of 1.2 days of vomiting for four treatment days) compared with placebo (mean of 3.2 days of vomiting across 4 treatment days). CONCLUSIONS: TZP-101 substantially reduced the frequency and severity of nausea and vomiting as well as overall gastroparesis symptoms. The results are consistent with gastrointestinal motility effects of TZP-101, supporting further investigation of TZP-101 in the management of severe gastroparesis.

Safety and efficacy of ghrelin agonist TZP-101 in relieving symptoms in patients with diabetic gastroparesis: a randomized, placebo-controlled study.

BACKGROUND: Gastroparesis, a chronic disorder of abnormal gastric motility, is common in patients with diabetes mellitus. A synthetic, selective ghrelin receptor agonist, TZP-101, is in clinical development for treatment of gastroparesis. This double-blind, randomized, placebo-controlled study evaluated the safety and efficacy of multiple TZP-101 doses in patients with moderate to severe symptomatic diabetic gastroparesis. METHODS: Patients were admitted to the hospital and adaptively randomized to receive a single 30-min intravenous infusion of 20, 40, 80, 160, 320, or 600 µg kg(-1) TZP-101, (n = 57) or placebo, (n = 19) for four consecutive days. Symptoms were evaluated daily with the patient-rated Gastroparesis Cardinal Symptom Index (GCSI) and Gastroparesis Symptom Assessment (GSA). Clinicians rated gastroparesis symptoms on treatment day 4. KEY RESULTS: The 80 µg kg(-1) dose was identified as the most effective dose. On day 4, there was statistically significant improvement compared with placebo in the severity of GCSI Loss of Appetite and Vomiting scores for that dose group (P = 0.034 and P = 0.006). In addition, at the 80 µg kg(-1) dose, the proportion of patients with at least 50% improvement in vomiting score was significantly different (P = 0.019) compared with placebo. Meal-related GSA scores for Postprandial fullness were significantly improved in the 80 µg kg(-1) TZP-101 group compared with placebo (P = 0.012). Clinicians rated the 80 µg kg(-1) group better improved than placebo for overall symptom assessment (P = 0.047). Safety profiles were similar in the placebo and TZP-101 groups and all doses were well-tolerated. CONCLUSIONS & INFERENCES: TZP-101 appears to be safe, well-tolerated, and effective at acutely addressing several gastroparesis symptoms.

Are ultrasonographic myoma characteristics associated with blood loss at delivery?

OBJECTIVES: The presence of myomas in pregnancy is associated with greater blood loss at delivery. The aim of this study was to evaluate whether the sonographic characteristics of myomas can predict blood loss at delivery in women with large myomas. METHODS: Among women who underwent second-trimester ultrasound screening at our department between January 1996 and December 2004, 251 had at least one myoma with a mean diameter > or = 5 cm. Number of myomas (single vs. multiple), maximum diameter of the largest myoma, sum of the maximum diameter of each myoma, change in size of myomas between first and last scan, and location in relation to the placenta and to the presenting part of the fetus (above or below) were analyzed in relation to blood loss at delivery and severe postpartum hemorrhage (> or = 1000 mL). RESULTS: Multivariate analysis showed that the presence of multiple myomas was the only parameter independently associated with amount of blood loss at delivery (P = 0.003). The association between the presence of multiple myomas and severe postpartum hemorrhage was of borderline significance for the statistical power of this study (P = 0.08). CONCLUSIONS: In women with large myomas, the presence of multiple tumors is independently associated with heavier blood loss at delivery but not with postpartum hemorrhage of > or = 1000 mL.

Ghrelin receptor agonist (TZP-101) accelerates gastric emptying in adults with diabetes and symptomatic gastroparesis.

BACKGROUND: TZP-101 is a synthetic, selective ghrelin agonist in development for gastroparesis. AIM: To assess safety and effects of TZP-101 in diabetes patients with symptomatic gastroparesis. METHODS: Adults with type 1 or type 2 diabetes mellitus received placebo and TZP-101 (80, 160, 320 or 600 microg/kg) infusions in a cross-over manner following a radiolabelled meal. Blood glucose levels were stabilized using a hyperinsulinemic-euglycemic clamp. Primary endpoints were gastric half emptying and latency times. Secondary measures included assessment of gastroparesis symptoms and endocrine responses. RESULTS: Ten patients with type 1 (n = 7) or 2 (n = 3) diabetes, moderate-to-severe gastroparesis symptoms and > or =29% retention 4 h after a radiolabelled solid meal were enrolled. TZP-101 produced significant reductions in solid meal half-emptying (20%, P = 0.043) and latency (34%, P = 0.037) times vs. placebo. Reductions in overall postmeal symptom intensity (24%) and postprandial fullness (37%) following TZP-101 infusion were not statistically significant. Most adverse events were mild and self-limiting and there were no identifiable differences in numbers or types of adverse events between TZP-101 and placebo. CONCLUSIONS: This proof-of-concept study demonstrates that the ghrelin agonist TZP-101 is well-tolerated in diabetes patients with moderate-to-severe chronic gastroparesis and shows statistically significant improvements in gastric emptying.

Nomograms of the axial fetal cerebellar hemisphere circumference and area throughout gestation.

OBJECTIVE: The widely applied transcerebellar diameter (TCD) obtained at axial cranial imaging, measures the distance between the lateral aspects of the cerebellum and incorporates the width of the cerebellar vermis. Our objective was to create reference ranges of axial fetal cerebellar hemisphere circumference (CHC) and area (CHA), independent of the cerebellar vermis, throughout gestation. METHODS: This cross-sectional study involved pregnant patients between 14 and 41 weeks of gestation. Inclusion criteria consisted of well-established dates (confirmed by early ultrasound), non-anomalous singleton fetuses and intact amniotic membranes. Sonographic measurements included biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), femur length (FL), humerus length (HL), TCD, and estimated fetal weight (EFW). Values of axial fetal CHC and CHA were each calculated as the mean of three separate measurements. The 5th, 50th and 95th centiles were estimated at each week of gestational age (GA) by least-squares regression for the mean and standard deviation (SD) of the CHC and CHA as functions of GA. r2 and associated P-values for the relationships of CHC and CHA with other sonographic biometric measurements were calculated. RESULTS: The study included 651 consecutive patients. All attempts at obtaining axial fetal CHC and CHA were successful. Mean maternal age was 27.3+/-6.7 years, median gravidity was 1 (range 1-16), and median parity was 1 (range 0-6). Mean CHC (cm) throughout gestation was modeled as -2.091+0.2563xGA (weeks) (SD=-0.075+0.0164xGA), and mean CHA (cm2) was modeled as 0.245-0.0765xGA+0.00506xGA2 (SD=1.167-0.1565xGA+0.006785xGA(2)-0.00008028xGA3). Fetal axial CHC and CHA correlated significantly and strongly with BPD, HC, AC, HL, FL, TCD and EFW (all R2 values were >or=0.95, and all P-values were <0.001). CONCLUSION: Nomograms of axial fetal cerebellar hemisphere circumference and area throughout gestation, independent of the cerebellar vermis, have been provided.

Anticoagulants versus non-steroidal anti-inflammatories or placebo for treatment of venous thromboembolism.

BACKGROUND: Venous thromboembolism (VTE) is the term given to any thromboembolic event (blocking of a blood vessel by a blood clot) occurring in the venous system. The current treatment recommended for VTE is anticoagulation (reduction of the blood's ability to clot). The aim of this review is to summarize results from randomized controlled trials (RCTs) for the effectiveness of anticoagulants (heparins, including low molecular weight heparins and vitamin K antagonists) in the treatment of VTE, compared to non-steroidal anti-inflammatory drugs (NSAIDs) or placebo. OBJECTIVES: To examine the randomized controlled evidence for the effectiveness and safety of anticoagulant treatment compared to NSAIDs or placebo in patients with VTE on the incidence of fatal and non-fatal pulmonary emboli (PE) and the recurrence or extension of deep vein thrombosis (DVT). SEARCH STRATEGY: The Cochrane Peripheral Vascular Diseases (PVD) Group searched their Specialized Trials Register (last searched 26 July 2005) and the Cochrane Central Register of Controlled Trials (CENTRAL) database (last searched Issue 3, 2005). In addition, DKC also searched reference lists and contacted pharmaceutical companies and experts in the field. SELECTION CRITERIA: All randomized trials of anticoagulants versus NSAIDs or placebo in the initial treatment of VTE (DVT or PE or both). DATA COLLECTION AND ANALYSIS: DKC and JM independently assessed trial quality and extracted data. JCP (biostatistician) analyzed the design elements and feasibility of a future randomized controlled trial to determine definitively efficacy and safety of anticoagulants in VTE treatment. MAIN RESULTS: Two RCTs were included. Data were not pooled because of heterogeneity between the studies. The two RCTs were too small to determine any difference in mortality, occurrence of pulmonary emboli, progression or return of DVT between patients treated with anticoagulation and those receiving no anticoagulation. AUTHORS' CONCLUSIONS: The limited evidence from RCTs of anticoagulants versus NSAIDs or placebo is inconclusive regarding the efficacy and safety of anticoagulants in VTE treatment. The use of anticoagulants is widely accepted in clinical practice, so a further RCT comparing anticoagulants to placebo could not ethically be carried out.

Bone marrow fat and bone mineral density on proton MR spectroscopy and dual-energy X-ray absorptiometry: their ratio as a new indicator of bone weakening.

OBJECTIVE: Bone weakening can be affected by agents other than bone mineral density (BMD). Increased bone marrow fat may have a direct link to bone loss. This pilot study analyzes the relationship between bone marrow fat and BMD in subjects with normal and structurally weakened vertebrae. SUBJECTS AND METHODS: Twenty-six subjects underwent both dual-energy X-ray absorptiometry and proton MR spectroscopy of 71 lumbar vertebrae. Fifteen subjects had normal-appearing vertebrae on MRI, and 11 had signs of bone weakening. RESULTS: We found that high bone marrow fat did not consistently equate with low BMD. Bone marrow fat can indicate bone weakening nearly as well as BMD, but neither parameter alone is suitable to be used independently as an indicator. The bone marrow fat/BMD ratio showed significant diagnostic power to detect bone weakening, even in this relatively small subject sample. CONCLUSION: An inverse relationship between bone marrow fat and BMD could not be confirmed. Bone marrow fat can be used to diagnose reduced bone strength nearly as well as BMD. The bone marrow fat/BMD ratio is a significant diagnostic indicator of bone weakening.

Predictive value of transvaginal cervical length in triplet pregnancies for spontaneous preterm delivery at < or = 32 weeks.

OBJECTIVE: To establish whether cervical length is a predictor of spontaneous preterm delivery at < or = 32 weeks in triplet pregnancies. METHODS: This was a case-control study of all triplet pregnancies followed with more than three sonographic assessments of cervical length at 4-week intervals from 1995 to 2000. Cervical length in women delivered spontaneously at < or = 32 weeks (cases) was compared with that of the remaining women (controls). Statistical analysis included Fisher's exact test, chi2 test, one-way analysis of variance, logistic regression and receiver operating characteristic (ROC) curve to determine optimal cervical length thresholds for spontaneous preterm delivery at < or = 32 weeks. RESULTS: Of the 58 women included in the study, 17 (29%) delivered spontaneously at < or = 32 weeks. The preterm delivery group had similar demographic and obstetric variables, but a higher rate of cerclage placement (65% vs 17%, p < 0.001) than controls. Mean +/- standard deviation cervical length was significantly shorter among cases than controls at 16-20.0 weeks (3.0 +/- 1.2 vs. 3.9 +/- 0.8 cm, p = 0.01), but not at 20.1-24.0 weeks (3.5 +/- 1.1 vs. 3.8 +/- 1.0 cm, p = 0.76). Logistic regression analysis determined that cervical length at 16-20 weeks had an odds ratio of 0.43 (95% CI = 0.23, 0.80) for the prediction of spontaneous preterm delivery at < or = 32 weeks. ROC curve analysis identified a cervical length of < or = 2.6 cm as the optimal threshold for the prediction of spontaneous preterm delivery at < or = 32 weeks (sensitivity 41%, specificity 92%). CONCLUSIONS: In a population of triplet gestations with a 29% rate of preterm delivery, cervical length at 16-20.0 weeks, but not at 20.1-24.0 weeks, was inversely correlated with the probability of preterm delivery at < or = 32 weeks.

Optimal thresholds of the lecithin/sphingomyelin ratio and lamellar body count for the prediction of the presence of phosphatidyl glycerol in diabetic women.

OBJECTIVE: To assess the optimal thresholds of the lecithin/sphingomyelin (L/S) ratio and lamellar body count for the prediction of the presence of phosphatidyl glycerol (PG) in diabetic pregnant women. METHODS: We accessed a database of clear amniotic fluid specimens obtained by transabdominal amniocentesis in diabetic women with singleton non-malformed fetuses. PG results were classified as 'absent' or 'present'. Receiver operating characteristic (ROC) curve analysis was constructed of different L/S ratios and lamellar body counts to identify the optimal threshold for prediction of the presence of PG. Sensitivity was defined as the rate of L/S ratio and lamellar body count above specific thresholds among cases with present PG. The false-positive rate was that of L/S ratios or lamellar body counts above specific thresholds among cases with absent PG. Statistical analysis included one-way analysis of variance with post-hoc analysis, with p < 0.05 considered significant. RESULTS: A total of 76 consecutive women were included in the analysis, 74% (n = 56) using insulin and the remainder treated by diet alone. L/S and PG results were both available in 72 women. PG was reported as 'present' in 70% (51/73) of specimens. As expected, there was a significant relationship between L/S ratios and presence of PG (area under the curve = 0.932, p < 0.001). An L/S ratio of > or = 3.0 represented the optimal trade-off between sensitivity (68%) and false-positive rate (6%) in the prediction of present PG. Similarly, there was a significant relationship between lamellar body count values and presence of PG (area under the curve = 0.976, p < 0.001). A lamellar body count of > or = 50 000 represented the optimal trade-off between sensitivity (92%) and false-positive rate (0%) in the prediction of present PG. CONCLUSION: In diabetic pregnant patients, the presence of PG in the amniotic fluid more closely corresponded to an L/S ratio of > or = 3.0 or to a lamellar body count of > or = 50,000.

Pathology findings in preterm placentas of women with autoantibodies: a case-control study.

OBJECTIVE: To evaluate the placental histopathology findings in women with systemic lupus erythematosus or antiphospholipid syndrome delivered preterm. METHODS: We performed a case-control study comparing clinical outcomes and placental histopathology of 18 consecutive singleton pregnancies with systemic lupus erythematosus (n = 9) or antiphospholipid syndrome (n = 9) delivered between 24 and 37 weeks, and 54 controls matched for gestational age and type of preterm delivery (spontaneous or indicated). Placental examinations were performed by a single pathologist, and placental lesions were grouped into four categories: uteroplacental vascular pathology and related villous lesions; coagulation-related damage; chronic inflammation; and acute inflammatory lesions. Statistical analysis included the Mantel-Haenzsel or Fisher's exact test, and logistic regression, with a value of p < 0.05 or an odds ratio (OR) with 95% confidence intervals (Cl) not inclusive of unity considered significant. RESULTS: Lupus anticoagulant was positive in ten out of 18 cases and medium or high positive IgG anticardiolipin antibodies in seven out of 18. Antenatal treatment included corticosteroids (n = 9), low-dose aspirin (n = 15) and heparin (n = 8). Rates of necrotizing enterocolitis (33% vs. 0%, p < 0.001) and of perinatal mortality (33% vs. 9%, p = 0.02) were significantly different between cases and controls, and rates of birth weight < 10th centile approached statistical significance. Uteroplacental vascular lesions (OR 3.7, 95% CI 1.1, 11.7) and coagulation-related damage (OR 16.8, 95% CI 3.9, 72.6) were significantly more common among cases than controls, and rates of chronic inflammatory lesions approached significance. CONCLUSIONS: Cases of systemic lupus erythematosus and antiphospholipid syndrome delivered preterm are associated with a significant increase in placental vascular and coagulation-related lesions, which are reflected clinically by higher rates of perinatal mortality, necrotizing enterocolitis, and small-for-gestational age neonates.

Association of human milk feedings with a reduction in retinopathy of prematurity among very low birthweight infants.

INTRODUCTION: With the increased survival of very low birthweight (VLBW) infants, weighing less than 1500 g at birth, the incidence of retinopathy of prematurity (ROP), a significant cause of blindness among children in the United States, is also increasing. Preterm infants with a positive diagnosis of ROP during the perinatal period are at increased risk for ocular abnormalities and for deficits in visual function during later periods of development. Human milk has many antioxidant constituents including inositol, vitamin E, and beta-carotene that may protect against the development of ROP. OBJECTIVE: The objective of this study was to examine the effect of human milk feedings on the incidence of ROP among VLBW infants. STUDY DESIGN: Observational cohort study. PARTICIPANTS: We identified 283 VLBW infants admitted to the Georgetown University Medical Center Neonatal Intensive Care Unit (NICU) from January 1992 through September 1993. All infants surviving to receive enteral feeding and ophthalmologic examinations for ROP (n=174) were included in the analysis. METHODS: Type of feeding (human milk versus exclusive formula), presence of ROP, and potential confounding variables were abstracted retrospectively from medical records. ROP was present if any stage of ROP was diagnosed at any age during the initial NICU hospitalization; each case was counted once based on the worse severity of ROP in either eye. Multiple logistic regression was used to control for confounders. MAIN OUTCOME MEASURE: ROP. RESULTS: Major predictors of ROP were similar in both feeding groups including gestational age, days on mechanical ventilation, and total number of days on supplemental oxygen. The incidence of ROP differed significantly by type of feeding (human milk -41.0% vs. formula -63.5%, p=0.005). Human milk feeding independently correlated with a reduced odds of ROP (OR: 0.42, 95% CI: 0.19 to 0.93) (p=0.03), controlling for gestational age, duration of supplemental oxygen therapy, 5-minute Apgar score, and race. Human milk feeding independently correlated with a reduced odds of ROP (OR: 0.46, 95% CI: 0.18 to 0.91) (p=0.03), controlling for birthweight, duration of supplemental oxygen therapy, 5-minute Apgar score, and race. CONCLUSION: Human milk feeding among VLBW infants was associated with a lower incidence of ROP compared to exclusively formula-fed VLBW infants after adjusting for confounding variables.

Antenatal corticosteroids and placental histology in preterm birth.

To assess the effects of antenatal corticosteroid use on placental histopathology, we have reviewed a database of 463 consecutive non-anomalous singleton liveborns delivered at less than 32 weeks between April 1988 and December 1994, of which 280 received one or more doses of corticosteroids for promotion of fetal lung maturation. Patients were grouped by the number of corticosteroid doses received (analyzed as none, 1, 2 and 3 or more doses). Clinical and demographic factors were recorded prospectively. Placental histopathology was reviewed blinded to clinical factors except gestational age, and 42 distinct placental lesions were examined and scored for severity. Data were analyzed by contingency tables, one-way analysis of variance, and linear regression analysis. Among clinical variables, univariate analysis showed that the number of corticosteroid doses was significantly related to presence of labour prior to delivery, pre-eclampsia, premature rupture of membranes and clinical suspicion or diagnosis of chorioamnionitis. Using linear regression analysis with these clinical variables as confounders, increased number of doses of antenatal corticosteroids was related to increased severity of villous fibrosis and stromal mineralization, and fewer villous infarcts.

Stereoselective halofantrine disposition and effect: concentration-related QTc prolongation.

AIMS: 1) To characterize the variability of multiple-dose halofantrine pharmacokinetics over time in healthy adults, 2) to correlate the pharmacodynamic measure electrocardiographic (ECG) QT interval with (+)- and (-)-halofantrine plasma concentration and 3) to evaluate the safety and tolerance of halofantrine hydrochloride given over time to healthy adults. METHODS: Twenty-one healthy subjects were enrolled and 13 completed the study (180 days). Subjects received either 500 mg of racemic halofantrine once daily in the fasted state for 42 days, or placebo, and then halofantrine washout was documented for the following 138 days. Pharmacokinetic and pharmacodynamic (ECG QTc) measurements were obtained. RESULTS: Mean accumulation half-times (days) for halofantrine were: 7.0 +/- 4.8 [(+)-halofantrine] and 7.3 +/- 4.8 [(-)-halofantrine]. Mean steady-state concentrations were: 97.6 +/- 52.0 ng ml(-1) [(+)-halofantrine] and 48.5 +/- 20.8 [(-)-halofantrine]. Steady-state oral clearance was: 139 +/- 73 l h(-1) [(+)-halofantrine] and 265 +/- 135 l h(-1) [(-)-halofantrine]. Peak plasma concentrations of both (+)- and (-)-halofantrine were attained at 6 h and maximal ECG QTc prolongation was at 4-8 h following drug administration. Fourteen of 16 subjects who received active drug had ECG QTc prolongation that was positively correlated with both (+)- and (-)-halofantrine concentration. The five subjects who received placebo had no demonstrable change in ECG QTc throughout the study. Conclusions Halofantrine accumulates extensively and shows high intersubject pharmacokinetic variability, is associated with concentration-related ECG QTc prolongation in healthy subjects, and is clinically well tolerated in this subject group.

Drug-induced QT prolongation in women during the menstrual cycle.

CONTEXT: Women have a higher incidence of torsades de pointes than men, but it is not known if the risk of drug-induced torsades de pointes varies during the menstrual cycle. OBJECTIVES: To determine if the degree of QT prolongation in response to ibutilide varies with the menstrual cycle phase and to compare QT prolongation between women and men. DESIGN AND SETTING: Cohort study of men and women who received the same intervention conducted between November 1998 and November 2000 at a general clinical research center of a university hospital. PARTICIPANTS: A volunteer sample of 58 healthy adults (38 men and 20 women) aged 21 to 40 years. INTERVENTION: A low dose of ibutilide (0.003 mg/kg), infused intravenously for 10 minutes. Subjects were monitored for 120 minutes. Women received the intervention on 3 separate occasions to correspond with menstrual cycle phases, which were verified by using hormonal assays. MAIN OUTCOME MEASURE: QT interval, recorded from electrocardiogram at timed intervals during and after ibutilide infusion and standardized for variations in heart rate (QTc). RESULTS: Maximum (mean [SD]) millisecond increase in QTc after ibutilide infusion was greater for women during menses (63 [13]) and the ovulatory phase (59 [17]) compared with women during the luteal phase (53 [14]) and compared with men (46 [16]; P =.002 vs menses and P =.007 vs ovulation). Progesterone (r = -0.40) and progesterone-to-estradiol ratio (r = -0.41), but not estradiol (r = 0.14) or testosterone (r = 0.09), were inversely correlated with ibutilide-induced QT prolongation. CONCLUSIONS: Menstrual cycle and sex differences exist in QTc responses to ibutilide, with the greatest increase in QTc corresponding to the first half of the menstrual cycle.

Premature ovarian failure in women with epilepsy.

PURPOSE: Women with epilepsy (WWE) have an increased risk for several reproductive endocrine disorders that may affect their fertility. The incidence of premature ovarian failure (POF) in women with epilepsy has not been systematically studied. This study examined the incidence of POF in women with epilepsy. METHODS: Fifty consecutively evaluated cognitively normal women with epilepsy, aged 38-64 years, whose seizures began before age 41 years, were interviewed for symptoms of perimenopause and menopause. Endocrine studies, performed in women aged 45 years or younger at the time of evaluation, included serum follicle-stimulating hormone (FSH; done on menstrual cycle day 3 in menstruating women), inhibin A levels when FSH was normal, thyroid-stimulating hormone (TSH), prolactin, and, in menstruating women, menstrual cycle day 20 serum progesterone level. Nonsurgical premature menopause was defined as secondary amenorrhea of >12 months' duration with FSH levels of >14 International Units (IU) in women younger than 42 years. Premature perimenopause was defined by the presence of one or more of the following: somatic perimenopausal symptoms; change in previously regular menstrual cycles without evidence of other reproductive endocrine disturbance; and FSH level of >14 IU or inhibin A level of <7 pg/ml. Similarly aged neurologically normal women seen in the menopause and sleep clinics served as control subjects. Statistical analysis included Fisher's exact test, Kruskal-Wallis test, t test, and multivariate logistic regression analysis with significance set at p < 0.05. RESULTS: Seven (14%) of 50 women with epilepsy had nonsurgical premature perimenopause (six of seven) or menopause (one of seven), compared with three of 82 control (p=0.042). Five of 41 women with localization-related epilepsy (LRE) had POF compared with two of nine women with primary generalized epilepsy (PGE; p=0.595). Mean age of POF was 39.6 years (range, 37-42 years). Seizure duration, age at seizure onset, seizure severity and lateralization, smoking history, age of menarche, body mass index and incidence of depression was not statistically different between women with and without POF. There was no statistically significant association between POF and antiepileptic drugs (AEDs). Women with POF were more likely to have had catamenial exacerbation of their seizures than were women without POF (p=0.02). CONCLUSIONS: Women with epilepsy have an increased risk for developing POF. This finding should be considered in counseling women with epilepsy on family planning.

Use of high-technology care among women with high-risk pregnancies in the United States.

OBJECTIVE: Infant mortality has been reduced dramatically with the development of perinatal regionalized high-technology care. Our objective was to assess use of high technology care among women with high-risk pregnancies in the urban and rural United States. METHODS: The 1988 National Maternal and Infant Health Survey was linked to the 1988 American Hospital Association survey of all obstetrical hospitals. Hospitals were classified into five levels of care based on services and staffing. Women were classified as having high-risk pregnancies using two definitions: (1) gestational age < 34 weeks and birthweight < 1500 g (High Risk I) and (2) the first definition or an antenatal high-risk medical diagnoses (High Risk II). Analyses assessed the proportion of high-risk women delivering in appropriate locations in the rural and urban United States and explored how personal characteristics, insurance status, and use and source of prenatal care influenced where high-risk women delivered. RESULTS: 71.2% of High Risk I and 55.9% of High Risk II women delivered in a high-technology facility (Level IIA or III). Fifty percent of HRI rural women delivered in tertiary high-technology hospitals and 39% of HRII rural women delivered in a high-technology hospital. High-risk urban women were two to three times more likely to deliver in a high-technology facility compared to their rural counterparts. The multivariate analysis showed that Black high-risk women were more likely to deliver in a high-technology setting and that receipt of prenatal care in a private setting lowered the odds of delivering in a high-technology setting when other factors were controlled. CONCLUSIONS: In an era where regionalized perinatal care was not threatened by managed care, a large proportion of high-risk women received care in less than optimal settings. Rural high-risk women delivered in high-technology hospitals less often than their urban counterparts. The multivariate analyses implied that the potential barriers to care may be more important among those considered more socially advantaged, who may be more at the mercy of managed care. The current reimbursement environment, which discourages referral to specialists and high-technology care, could result in less access today.

Risk factors for neonatal intraventricular haemorrhage in spontaneous prematurity at 32 weeks gestation or less.

In this study we aimed to establish which clinical and histopathological factors are associated with early-onset neonatal intraventricular haemorrhage (IVH) in non-iatrogenic preterm delivery before 32 weeks of gestation. We retrospectively reviewed all singleton pregnancies delivered before 32 weeks of gestation after spontaneous onset of preterm labour or preterm membrane rupture during the period January 1993 to June 1997. Clinical and histopathological data in cases with IVH diagnosed at neonatal cranial ultrasound within 72 h of birth (n = 17) were compared with those of neonates not experiencing this complication (non-IVH) (n = 54). Histological lesions analysed were those of acute inflammation and those on a uteroplacental vascular basis. Statistical methods included the Wilcoxon rank sum test, Fisher's exact test, and logistic regression analysis. A P<0.05 was considered significant.IVH and non-IVH groups were not significantly different in birthweight, gestational age at delivery, cord pH at birth, rates of 5-min Apgar score below 7, caesarean delivery, diagnosis of clinical chorioamnionitis or antenatal administration of steroids. Respiratory distress syndrome was more frequently diagnosed in the IVH than non-IVH group (64 per cent versus 33 per cent, P=0.02). Placental acute inflammatory or uteroplacental vascular lesions were present in 100 per cent of IVH neonates versus 22 per cent of non-IVH cases (P<0.001). Logistic regression analysis demonstrated that only respiratory distress syndrome (P = 0.04) and histological evidence of acute placental inflammation (P = 0.02) were significantly and independently associated with IVH. Histopathological evidence of acute inflammatory placental lesions is the best predictor of occurrence of neonatal IVH.