Continuous infusion versus intermittent bolus doses of indomethacin for patent ductus arteriosus closure in symptomatic preterm infants.

BACKGROUND: Indomethacin is a prostaglandin inhibitor used for the prevention and the treatment of patent ductus arteriosus (PDA). Although a 3-dose schedule has been commonly used, there is no consensus on optimal dosage and duration of indomethacin therapy for PDA closure. There are potential adverse effects of indomethacin use in premature infants such as a reduction in cerebral, mesenteric and renal blood flow and platelet dysfunction. Administering indomethacin continuously over 36-hours has been suggested as a safer and more effective option to prevent such adverse effects. OBJECTIVES: To compare the efficacy and safety of continuous infusion versus bolus administration of indomethacin in closing a symptomatic PDA in preterm infants. SEARCH STRATEGY: The standard search strategy of Cochrane Neonatal Review was used: MEDLINE and EMBASE (1966 - March 2007), Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2007), bibliographies of reviews and trials were examined for references to other trials, previous symposia proceedings published in Pediatric Research (Pediatric Academic Societies Annual Meeting Abstract Book, 1972 - 2006). No language restrictions were applied. SELECTION CRITERIA: Randomized and quasi-randomized controlled trials comparing continuous indomethacin infusion to bolus doses for closure of a symptomatic PDA in preterm infants with a symptomatic PDA diagnosed clinically and/or by echocardiography. DATA COLLECTION AND ANALYSIS: The methodological quality of each study was assessed. Authors were contacted regarding missing data as well as to inquire about the outcomes that were not reported. Meta-analysis was performed to calculate relative risk (RR), risk difference (RD) and 95% confidence intervals (CI). MAIN RESULTS: Only two small trials comparing continuous versus bolus indomethacin were eligible. Analysis of these studies showed that, although the primary outcome of PDA closure on days two and five slightly favored bolus administration, there was no statistical difference between the two groups. The estimates for PDA closure were RR 1.57 (95% CI 0.54, 4.60), RD 0.10 (95% CI -0.13, 0.33) for day 2 and RR 2.77 (95% CI 0.33, 23.14), RD 0.15 (95% CI -0.13, 0.42) for day five. There was no statistical difference between the bolus and continuous groups for the secondary outcomes of reopening of PDA, neonatal mortality, intraventricular hemorrhage (IVH) and necrotizing enterocolitis (NEC). These analyses were based on a very small number of events reported by these trials. None of the trials reported on outcomes such as requirement for retreatment with indomethacin or surgical ligation, mortality, bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), neurodevelopmental outcome and isolated intestinal perforation. The review demonstrated that there was a decrease in cerebral blood flow velocity after bolus injections and that the difference between the bolus and continuous infusion groups remained significant for 12 - 24 hour. In one study (Christmann 2002), the decrease in blood flow was maximum at 10 minutes [MD -46.40 (95% CI -75.41, -17.39)], while the other study (Hammerman 1995) reported a maximum drop at 30 minutes [MD -55.60 (95% CI -62.92, -48.28)]. Similar decrease in blood flow to the renal and mesenteric circulations following bolus administration was reported in one study (Christmann 2002). In both of these circulations, the decrease was maximum 30 minutes after the bolus injection [typical estimates for renal and mesenteric circulations, respectively: MD -42.00 (95% CI -76.59, -7.41) and MD -26.50 (95% CI -45.34, -7.66)] and lasted about two hours. None of the trials detected predefined levels of decreased urine output and increased levels of BUN and creatinine. AUTHORS' CONCLUSIONS: Due to a paucity of events and lack of precision, the available data was found to be insufficient to draw conclusions regarding the efficacy of continuous indomethacin infusion versus bolus injections for the treatment of PDA. Although continuous indomethacin seems to cause less alterations in cerebral, renal and mesenteric circulations, the clinical meaning of this effect is unclear. Definitive recommendations about the preferred method of indomethacin administration i.e. continuous versus bolus infusions for the treatment of PDA in premature infants cannot be made based on the current findings of this review.

Longitudinal associations between asthma and general and abdominal weight status among Norwegian adolescents and young adults: the HUNT Study.

BACKGROUND: In adolescents the temporal directionality to the asthma and adiposity association remains unclear. Asthma may be a consequence of obesity; however, asthma may increase adiposity. OBJECTIVES: This study aimed to assess the associations between (i) baseline weight status and subsequent asthma and (ii) baseline asthma and subsequent weight status after 4 and 11 years of follow-up (N = 1543 and N = 1596, respectively) using data from three, sequentially enrolled population-based surveys of Norwegians aged 12-30 years from 1995 to 2008. METHODS: Weight status was defined as general (body mass index) or abdominal (waist circumference) underweight, normal weight, overweight or obesity. Self-report physician-diagnosed asthma defined asthma status. RESULTS: Over the longitudinal 11-year follow-up, baseline generally overweight or abdominally obese adolescents had increased risk of asthma. Likewise, baseline asthmatics had increased risk of general overweight or abdominal obesity. After sex stratification, these associations were stronger in males. Generally (odds ratio [OR] 1.90; 95% confidence interval [CI] 1.32, 2.73) or abdominally (OR 1.66; 95% CI 1.13, 2.44) overweight males were at increased risk of asthma. Baseline asthmatic males were also at increased risk of general (OR 2.14; 95% CI 1.54, 2.98) and abdominal (OR 1.77; 95% CI 1.27, 2.47) overweight. CONCLUSIONS: Among Norwegian adolescents, a bidirectional association of asthma and adiposity was observed in males. Each baseline condition increased the risk of the other condition over time. No association was observed in females.

Alarums false, alarums real: challenges and threats to the future of epidemiology.

PURPOSE: A review of recent threats and challenges to epidemiology suggests that some represent an opportunity to advance the discipline while others are a major threat to conducting epidemiologic work. METHODS: Two issues are identified which should advance the publication and conduct of epidemiologic research. Three are discussed that exemplify current threats. RESULTS: Epidemiologists have a role in helping journalists improve the communication of risk information in the media. Methodological advances for studies of rare exposure being related to rare disease should reduce the frequency of conflicting results in the epidemiologic literature. Three significant external forces that threaten epidemiologic research are identified. These are: unbridled discovery during litigation as exemplified by Bendectin, breast implants and cellular telephones; over zealous privacy laws; and the negative impact of managed care on epidemiologic research. CONCLUSIONS: The American College of Epidemiology has a major role to play in protecting the profession from some of the real threats that face it, and in helping meet the challenges.

Low-to-moderate gestational alcohol use and intrauterine growth retardation, low birthweight, and preterm delivery.

PURPOSE: Heavy drinking during pregnancy is an established risk factor for fetal alcohol syndrome and other adverse perinatal outcomes. However, there is still debate as to the effects of low-to-moderate drinking during pregnancy. METHODS: This prospective investigation was based on 2714 singleton live births at Yale-New Haven Hospital during 1988-1992. Alcohol drinking during pregnancy was evaluated with respect to intrauterine growth retardation (IUGR), preterm delivery, and low birthweight. RESULTS: Mild drinking, defined as > 0.10-0.25 oz of absolute alcohol per day, during the first month of pregnancy was associated with a protective effect on IUGR (OR, 0.39; 95% confidence interval (CI), 0.20-0.76). Overall, drinking during month 1 of pregnancy suggested a curvilinear effect on growth retardation, with consumption of > 1.00 oz of absolute alcohol per day showing increased risk. Drinking during month 7 was associated with a uniform increase in the odds of preterm delivery; the ORs were 2.88 (95% CI, 1.64-5.05) for light drinking and 2.96 (95% CI, 1.32-6.67) for mild-to-moderate alcohol consumption. CONCLUSIONS: Differences in the risk estimates for IUGR and preterm delivery may indicate etiological differences that warrant further investigation of these outcomes and critical periods of exposure. Low birthweight is not a useful neonatal outcome for this exposure because it is a heterogeneous mix of preterm delivery and IUGR. Despite the observed protective effects of mild drinking on IUGR, the increased risk of preterm delivery with alcohol use supports a policy of abstinence during pregnancy.

Clinically useful measures of effect in binary analyses of randomized trials.

The results of a randomized clinical trial can be reported using relative and/or absolute estimators of treatment effect. These various measures convey different information, and the choice can influence the physician's appreciation of the size of treatment effect and, subsequently, treatment decisions. We compare the estimators with respect to the clinically relevant information conveyed to physicians, and identify which clinical questions can and cannot be answered directly by each. We also identify opportunities for misinterpretation when one estimator is substituted for another, or when an estimator is mislabeled. Clinically important questions are addressed most directly by reporting both relative and absolute effects using relative risk and its complement, relative risk reduction, and risk difference and its reciprocal, number needed to treat. This is true of estimates of treatment effect derived from a single trial and also from meta-analysis of a group of trials. Because the control group's risk affects the numerical value of the odds ratio, the odds ratio cannot substitute for the risk ratio in conveying clinically important information to physicians. This is especially important when large treatment effects are shown in trials carried out in populations at high baseline risk.

Role of oral contraception in congenital malformations of offspring.

In a case control study we examined the relationship between congenital malformations in offspring and maternal exposure to oral contraceptives around the time of conception. There were 1 370 with congenital malformations and 2 968 healthy control infants. Maternal oral contraceptive use was unrelated to malformations considered as a whole whether exposure last occurred in the year before conception [odds ratio = 0.9, p=0.25] or during pregnancy [odds ratio = 1.3, p=0.30]. Exposure during pregnancy doubled the risk for some specific diagnoses, including certain cardiovascular defects, but these increases were not statistically significant. Exposure to specific oestrogens or progestogens was also unrelated to the occurrence of malformations. There was a suggestion that women who both smoked more than 20 cigarettes per day and used oral contraceptives during pregnancy were more likely to deliver a malformed infant than were women who neither used oral contraceptives nor smoked during pregnancy.

Treatment of acute spinal cord injury with methylprednisolone: results of a multicenter, randomized clinical trial.

Although some evidence of neurological improvement with naloxone exists in this trial, the improvement was never significantly better than that seen for placebo. Methylprednisolone (MP) was effective in reducing some of the permanent paralysis after acute spinal cord injury at the doses studied, but only when treatment began within 8 h after injury. There is currently no support for the administration of higher or lower doses of the drug and an apparent contraindication to initiating administration of MP at any dose more than 8 h after injury.

The Second National Acute Spinal Cord Injury Study.

In 1990, the Second National Acute Spinal Cord Injury Study reported that high-dosage methylprednisolone improves neurologic recovery in spinal-injured humans. The study showed that patients who received the drug within 8 hr after injury improved, whereas those who received the drug later did not. The drug significantly increased recovery even in severely injured patients who were admitted with no motor or sensory function below the lesion, contradicting a long-held dogma that such patients would not recover. Some researchers, however, have questioned the stratification of the patient population, the use of summed neurologic change scores, and the absence of functional assessments. The stratification by injury severity and treatment time was planned a priori and based on objective criteria. Detailed analyses revealed no differences between groups attributable to stratification or randomization. While multivariate analyses of the summed neurologic scores were used, the conclusions were corroborated by other analytical approaches that did not rely on summed scores. For example, treatment with methylprednisolone more than doubled the probability that patients would convert from quadriplegia or paraplegia to quadriparesis or paraparesis, analgesia to hypalgesia, and anesthesia to hypesthesia. The treatment also significantly improved neurologic scores in lumbosacral segments, indicating that beneficial effects were not limited to segments close to the lesion site. The treatment did not significantly affect mortality or morbidity. The study strongly suggests that methylprednisolone has significant beneficial effects in human spinal cord injury, that these effects occur only when the drug is given within 8 hr, and that it helps even in patients with severe spinal cord injuries. These conclusions have important implications for spinal cord injury care and research.

Oral contraception and congenital malformations in offspring: a review and meta-analysis of the prospective studies.

The technique of meta-analysis was used to derive typical estimates of the risk of congenital malformations from oral contraceptive (OC) exposure in early pregnancy. Several definitions were used for non-exposure to reduce bias from this source. Congenital heart defects and limb reduction defects were analyzed separately. The typical relative risk from the 12 prospective studies analyzed was 0.99 (95% confidence interval 0.83, 1.19) for all malformations. The definition of non-exposure did not materially change this estimate. The typical risk for congenital heart defects was 1.06 (95% confidence interval 0.72, 1.56) and for limb reduction defects, 1.04 (95% confidence interval 0.30, 3.55). This lack of an association between OCs and birth defects in prospective studies agrees with the results of most of the better-designed case-control studies.

Systematic reviews of medical evidence: the use of meta-analysis in obstetrics and gynecology.

OBJECTIVE: To review the technique of meta-analysis and its uses and limitations in obstetrics and gynecology. DATA SOURCES: We reviewed four major journals in obstetrics and gynecology (American Journal of Obstetrics and Gynecology, Fertility and Sterility, Journal of Reproductive Medicine, and Obstetrics & Gynecology). METHODS OF STUDY SELECTION: Journals were reviewed to determine frequency of meta-analysis as a method of systematic review in obstetrics and gynecology. We also summarized objectives and scientific guidelines for performing a meta-analysis. TABULATION, INTEGRATION, AND RESULTS: Meta-analysis is used with increased frequency in obstetrics and gynecology as a way of systematically reviewing medical evidence. This technique is an attempt to improve on traditional methods of narrative review by an expert and as a framework for evidence-based medicine and developing practice guidelines. By combining data from replicate studies, a meta-analysis can increase statistical power, more precisely estimate the typical effect size of treatment or risk factor, and attempt to resolve controversies in the medical literature. Meta-analysis is a retrospective look at data already collected and is therefore subject to the biases of all retrospective studies. CONCLUSIONS: The technique of meta-analysis requires all the scientific rigor of a randomized clinical trial with careful attention to study design, including a formal protocol for literature search strategies, quality assessment of candidate studies, specific inclusion and exclusion criteria, issues of sampling and publication bias, statistical tests of homogeneity, and sensitivity analysis.

Exposure to prescribed drugs in pregnancy and association with congenital malformations.

In a case-control (N = 1427 and 3001, respectively) study of deliveries in Connecticut the incidence of congenital malformations was 52 per 1000 live births. Of all mothers, 44.5% used at least 1 prescribed drug during pregnancy. Case mothers were more likely than controls to have used a prescription drug (odds ratio [o] = 13, P less than .0001), particularly an antidepressant (o = 7.6), narcotic analgesic (o = 3.6), or tranquilizer (o = 23); P less than .01 for all associations. There was a synergistic relationship with tranquilizer use and smoking in pregnancy, resulting in a o = 3.7 (P less than .01) risk for those exposed to both. The synergistic relationship of tranquilizers-cigarettes with malformations supports existing pharmacologic research and suggests that epidemiologic study of the impact of simultaneous maternofetal exposure to environmental agents may further explain the etiology of some congenital malformations.

Maternal age: an independent risk factor for cesarean delivery.

OBJECTIVE: To evaluate whether there is an increased risk of cesarean delivery in women who delay childbearing into their later reproductive years, using a well-defined cohort and controlling for difference in baseline susceptibility such as complications of pregnancy and labor. METHODS: The current study included all women at least 20 years of age delivering their first child and evaluated between 1988-1991 as part of the prospective Yale Health in Pregnancy Study (N = 735). All women planned to deliver at Yale-New Haven Hospital. The study group was divided into three maternal age groups: 20-29 (N = 422), 30-34 (N = 239), and 35 and over (N = 74). Information collected included demographic characteristics, medical history, pregnancy complications, labor complications, mode of delivery, and pregnancy outcome. RESULTS: The cesarean delivery rates for the three age groups were 16.8% (71 of 422), 26.8% (64 of 239), and 32.4% (24 of 74), respectively. This trend was highly significant when evaluated with chi 2 for linear trend (P = .0002). Within groups of women with and without complications of pregnancy or labor, cesarean rates increased with maternal age. Using stepwise logistic regression to adjust simultaneously for confounding variables, adjusted odds ratios were 1.6 (95% confidence interval [CI] 0.9-2.7) for the women aged 30-34 and 2.3 (95% CI 1.1-4.8) for the 35 and older age group. CONCLUSIONS: Maternal age appears to be an independent risk factor for cesarean delivery. The reasons for this clinically important and statistically significant increased risk are unclear, but may be due to physician and patient concern over pregnancy outcome in older women.

Interpregnancy interval and disparity in term small for gestational age births between black and white women.

OBJECTIVE: To examine the influence of interpregnancy interval on the elevated risk of term small for gestational age (SGA) births to black women. METHODS: This study is a secondary analysis of data from the Delivery Interview Program, a hospital-based cohort study of 12,718 women conducted at the Boston Hospital for Women from 1977 to 1980. The current analysis was limited to black and white parous women who gave birth to term infants during the study and whose last previous pregnancies had also resulted in term, live births. There were 578 black and 3400 white women who met these criteria. The rates of term SGA births for black and white women were calculated according to six interpregnancy intervals (6 or less, 6-12, 12-24, 24-36, 36-60, or longer than 60 months). Multiple logistic regression was used to control for confounding. RESULTS: The overall rate of term SGA births was 6.4% for black women compared with 3.9% for white women (relative risk [RR] 1.7, 95% confidence interval [CI] 1.2, 2.4). Black women were also more likely than white women to have interpregnancy intervals of 6 months or less (9.2% black, 4.8% white; RR 1.9, 95% CI 1.4, 2.6). At every interpregnancy interval, black women had a higher rate of term SGA births than white women. After controlling for interpregnancy interval in a logistic regression analysis, the increased risk of SGA delivery among black women remained unchanged (odds ratio 1.7, 95% CI 1.1, 2.5). CONCLUSION: Although black women were more likely than white women to have SGA births and short interpregnancy intervals, differences in interpregnancy intervals between the races did not explain the disparity in term SGA births.

Occupationally related magnetic field exposure and male subfertility.

OBJECTIVE: To determine whether there is an association between occupationally related magnetic field exposure, as estimated in milligauss (mG), and male subfertility. DESIGN: Nested case-control study using three defined case groups and one standard control group. SETTING: Yale New Haven Hospital Infertility Clinic, New Haven, Connecticut. PATIENTS, INTERVENTIONS: Male partners of couples seeking diagnosis and care at the infertility clinic. Men included in the analysis had complete first semen analysis and interview information. Subjects for this investigation consisted of case groups for motility (n = 177), morphology (n = 135), and concentration (n = 172); controls included men normal on all three parameters (n = 304). MAIN OUTCOME MEASURES: Laboratory confirmation in semen analysis of poor morphology, inadequate motility, and low concentration. Comparisons of occupational magnetic field exposure categories are made between case groups and controls. RESULTS: The odds of high job exposure category to magnetic fields (> 3 mG [> 0.3 muT]) for morphology cases were odds ratio (OR) = 0.6, for motility cases OR = 1.1, and concentration cases OR = 1.0 as compared with controls. No significant association was demonstrated for medium exposure (> 2 to 3 mG) among all case groups. Multivariate adjustment for selected risk factors did not substantially change estimates of risk. CONCLUSIONS: A lack of association between occupationally related categories of magnetic field exposure and male subfertility, as evaluated by morphology, motility, and concentration, has been demonstrated. These findings do not substantiate theories of deleterious effects to male reproductive health from magnetic fields.

Conception delay after oral contraceptive use: the effect of estrogen dose.

A significant delay was observed in conception among 248 former oral contraceptive (OC) users compared with women discontinuing other methods of contraception (n = 1,365). The mean time to conception was 5.88 cycles (95% confidence interval [CI] 5.38, 6.38) for former OC users and 3.64 cycles (95% CI 3.49, 3.79) after other contraceptives. Women discontinuing OCs with higher doses of estrogen (greater than or equal to 50 micrograms) had greater conception delays than those on lower estrogen doses who, in turn, had longer delays than other method users. Oral contraceptive use was associated with significant reductions in conception for each of the first six cycles after discontinuation. This study provides further evidence for a direct effect of oral contraception on delayed conception, suggests that the delay lasts longer than previously thought, and finds that the probability of conception after OC discontinuation depends on the estrogen dose of the OC.

Association of cocaine use with sperm concentration, motility, and morphology.

Use of cocaine within 2 years of their first semen analysis has been found to be twice as common among men with sperm counts less than 20 X 10(6) mL (odds ratio [OR] = 2.1, 95% confidence interval [CI] 1.0, 4.6). Duration of cocaine use for five or more years was more common in men with low sperm motility (OR = 2.0, 95% CI 1.0, 4.1) and in those with low concentrations and a large proportion of abnormal forms. Other major risk factors for these three indicators of male subfertility also have been identified, but the cocaine risk factors remained after adjustment for them. This association, together with the high prevalence of cocaine use in the general male population, suggests cocaine may now be related to male subfertility and that history of use should be ascertained during diagnostic interviews.

The effectiveness of surgery on the treatment of acute spinal cord injury and its relation to pharmacological treatment.

Using data from the Second National Acute Spinal Cord Injury Study (NASCIS II), the authors sought to characterize the role of surgery in the management of traumatic spinal cord injury and to examine the interaction between pharmacological treatment and surgery. Patients who did not undergo surgery had more severe spinal cord injuries initially than those who had surgery. However, no differences in neurological improvement at 1-year follow-up were found between those who underwent surgery and those who did not. The results suggest that either early surgery (< or = 25 hours after injury) or late surgery (> 200 hours) may be associated with increased neurological recovery, particularly motor function, but these results are equivocal. Surgery was not shown to interact with pharmacological treatments, indicating that the effect of drug treatment in NASCIS II, reported elsewhere, is not influenced by surgery. Other independent variables that best predicted improvement in motor score were age of 25 years or younger, incomplete injury, and lower baseline emergency department neurological scores. This study does not provide clinically relevant evidence concerning the efficacy of timing or the value of surgery in treating patients with spinal cord injuries. A randomized study on the timing and efficacy of spinal cord surgery is needed to obtain valid comparisons of the efficacy of surgical treatments.

Effects of timing of methylprednisolone or naloxone administration on recovery of segmental and long-tract neurological function in NASCIS 2.

Previous analyses of the National Acute Spinal Cord Injury Study (NASCIS) have not distinguished recovery of segmental function at the injury level from recovery of the long spinal tracts. Recovery at the injury level could be of considerable clinical significance, but long-tract recovery is the ultimate therapeutic goal. This analysis demonstrates that the greatest proportion of all neurological recovery and of recovery due to treatment with very high doses of methylprednisolone within 8 hours of injury occurs below the lesion. Methylprednisolone treatment administered early following injury has been found to improve recovery below the lesion in patients initially diagnosed as having complete or incomplete injuries; it also leads to greater (but still relatively small) improvement in the injury level. The analysis indicates that delayed treatment with methylprednisolone is associated with decreased neurological recovery. Naloxone administration also improved neurological function below the lesion in patients with incomplete injuries; these results support further experimental work with this drug. This observation of differential neurological response within a narrow treatment window has important implications for both experimental studies and clinical management. Early clinical management with high-dose methylprednisolone is supported by this analysis.

Methylprednisolone and neurological function 1 year after spinal cord injury. Results of the National Acute Spinal Cord Injury Study.

A multi-center double-blind randomized clinical trial was conducted by the National Acute Spinal Cord Injury Study Group to examine the efficacy of high-dose methylprednisolone (1000-mg bolus and 1000 mg daily thereafter for 10 days) compared with that of a standard dose (100-mg bolus and 100 mg daily for 10 days). No significant difference was observed in neurological recovery of motor function, pinprick response, or touch sensation 1 year after injury between the two treatment groups, after adjustment for other potentially confounding factors. Analyses that specifically took into account the patients' total steroid dose and relative weight confirmed the lack of a steroid treatment effect. The case fatality rate was 10.7% during the 1st year after injury, and this was not associated with the steroid treatment protocol or the patient's gender. Deaths did occur significantly more frequently among patients who were completely (15.3%) and partially (8.6%) plegic than among those who were paretic (2.5%, p = 0.0005), and among patients aged 50 years or older (38.6%, p = 0.0001).