Kenneth F. Schulz

Research: increasing value, reducing waste 2

Correctable weaknesses in the design, conduct, and analysis of biomedical and public health research studies can produce misleading results and waste valuable resources. Small effects can be difficult to distinguish from bias introduced by study design and analyses. An absence of detailed written protocols and poor documentation of research is common. Information obtained might not be useful or important, and statistical precision or power is often too low or used in a misleading way. Insufficient consideration might be given to both previous and continuing studies. Arbitrary choice of analyses and an overemphasis on random extremes might affect the reported findings. Several problems relate to the research workforce, including failure to involve experienced statisticians and methodologists, failure to train clinical researchers and laboratory scientists in research methods and design, and the involvement of stakeholders with conflicts of interest. Inadequate emphasis is placed on recording of research decisions and on reproducibility of research. Finally, reward systems incentivise quantity more than quality, and novelty more than reliability. We propose potential solutions for these problems, including improvements in protocols and documentation, consideration of evidence from studies in progress, standardisation of research efforts, optimisation and training of an experienced and non-conflicted scientific workforce, and reconsideration of scientific reward systems.

Blinding and exclusions after allocation in randomised controlled trials: survey of published parallel group trials in obstetrics and gynaecology.

Abstract Objective: To assess the methodological quality of approaches to blinding and to handling of exclusions as reported in randomised trials from one medical specialty. Design: Survey of published, parallel group randomised controlled trials. Data sources: A random sample of 110 reports in which allocation was described as randomised from the 1990 and 1991 volumes of four journals of obstetrics and gynaecology. Main outcome measures: The adequacy of the descriptions of double blinding and exclusions after randomisation. Results: Though 31 trials reported being double blind, about twice as many could have been. Of the 31 trials only eight (26%) provided information on the protection of the allocation schedule and only five (16%) provided some written assurance of successful implemention of double blinding. Of 38 trials in which the authors provided sufficient information for readers to infer that no exclusions after randomisation had occurred, six (16%) reported adequate allocation concealment and none stated that an intention to treat analysis had been performed. That compared with 14 (27%) and six (12%), respectively, for the 52 trials that reported exclusions. Conclusions: Investigators could have double blinded more often. When they did double blind, they reported poorly and rarely evaluated it. Paradoxically, trials that reported exclusions seemed generally of a higher methodological standard than those that had no apparent exclusions. Exclusions from analysis may have been made in some of the trials in which no exclusions were reported. Editors and readers of reports of randomised trials should understand that flawed reporting of exclusions may often provide a misleading impression of the quality of the trial. Key messages Key messages Poor reporting of methods used for double blinding raises concerns about how effective blinding was in many of the studies Some investigators may have excluded some patients from the analysis but not reported these exclusions in their published paper Given the apparent failure to report exclusions, some of the more biased trials may be mistaken as unbiased and vice versa Investigators must pay more attention to executing and reporting their approaches to blinding and the handling of exclusions

Local versus general anesthesia: Which is safer for performing suction curettage abortions?

The relative safety of suction curettage abortions performed with either local or general anesthesia has not been clearly established. To compare the safety of these two anesthetic techniques, we studied 36,430 women who received local anesthetics and 17,725 who received general anesthetics for this operation in the United States from 1971 through 1975. The aggregated major complication rates for the two groups were similar, but there were significant differences between local and general anesthesia for specific complications and treatments. Local anesthesia was associated with higher rates of febrile and convulsive morbidity; however, general anesthesia was associated with higher rates of hemorrhage, cervical injury, and uterine perforation. Both anesthetic techniques appear to be safe, with similar degrees of overall safety, although each is associated with a different spectrum of complications.

Maternal Health and Child Survival: Opportunities to Protect Both Women and Children from the Adverse Consequences of Reproductive Tract Infections

Although AIDS, human papilloma virus infection, and other newly identified sexually transmitted diseases (STDs) are attracting much attention, we must remain vigilant to the serious sequelae of conventional STDs, especially in areas where traditional “venereal diseases” have not been controlled. The problems currently associated with syphilis and gonorrhea during pregnancy in various parts of the world are strikingly reminiscent of those faced by the Western world in the early 1900s. Particularly compelling is the need to control fetal wastage, prematurity, and complications in neonates caused by reproductive tract infections (RTIs), especially in Third World countries.

Urea-prostaglandin versus hypertonic saline for instillation abortion

Authorities have suggested use of a combination of hyperosmolar urea and low-dose prostaglandin F2 alpha as a second-trimester intra-amniotic abortifacient to avoid the disadvantages of hypertonic saline solution. To examine the safety and efficacy of urea-prostaglandin compared with the instillation of saline solution, we analyzed data from a prospective multicenter study conducted in the United States between 1975 and 1978. Both agents were highly effective in producing an abortion. However, urea-prostaglandin had a significantly lower rate of serious complications when compared with saline solution (1.03 versus 2.18 per 100 abortions; p less than 0.001). Urea-prostaglandin also had a significantly shorter induction-to-abortion time (14.2 versus 25.6 hours; p less than 0.001). Urea-prostaglandin, therefore, appears to be superior to hypertonic saline solution as an abortifacient.

Coagulopathy and induced abortion methods: rates and relative risks.

n The relative risks of coagulopathy from suction curettage, dilatation and evacuation (D and E), and saline instillation were examined using the records of all women obtaining abortions at the Inglewood Hospital in California from February 1980-September 1981. Abortion-related coagulopathy cases were defined as those having both clinical evidence of nonclotting hemorrhage and laboratory confirmation of lower than expected fibrinogen levels (200 mg/dl). During the study period, 13,272 abortions were done by suction curettage, 2619 by D and E, and 304 by saline instillation. 8 cases of coagulopathy were identified. 1 case was associated with suction curettage, 2 with saline instillation, and 5 with D and E. The rates for coagulopathy/100,000 procedures were 8 for suction curettage, 191 for D and E, and 658 for saline instillation. Compared with that of suction curettage, the relative risk of coagulopathy associated with D and E was 25 and of saline instillation, 87, both statistically significant. The relative risk associated with saline instillation versus D and E was 3.4, not statistically significant. The study presents the experience of a single institution with a single group of similarly trained physicians, and uses uniform diagnostic criteria for coagulopathy, but the findings were based on the experience of a limited patient population and the demographic characteristics of the 16,195 women were unavailable, so that potential confounders such as age and parity could not be controlled. Large series are required to define more precisely the risk of coagulopathy for the various abortion methods.n

Methods of midtrimester abortion: which is safest?

In the United States, the three principal methods of abortion for patients at 13 or more menstrual weeks gestation are intraamniotic instillation of saline or prostaglandin F2α (PGF2α) and dilatation and evacuation (D&E). The relative safety of these methods, however, has not been established. This report compares the three methods using data on 17467 abortions collected by the Joint Program for the Study of Abortion under the auspices of the Center for Disease Control (JPSA/CDC). Abortion by D&E was found to be significantly safer than abortion by saline instillation (p<0.001), and abortion by saline instillation was significantly safer than by PGF2α (p<0.01). Moreover, midtrimester D&E is both safe and practical; it is a direct and rapid procedure which can be performed on an outpatient basis. Although PGF2α accelerated the time required for abortion, it also significantly increased serious morbidity.

Identifying neonatal risk factors and predicting neonatal deaths in Georgia

A predictive model which identifies 38% of the neonatal deaths by isolating only 11% of the births was formulated. It utilized existing vital records data for 230,585 single live births which occurred in Georgia for the period 1974-1976, to describe factors recorded on the birth certificate which are determinants of neonatal mortality on a statewide basis. Maternal age, race, premature birth, spontaneous abortion or stillbirth, complications related to pregnancy, complications not related to pregnancy, and type of birth (multiple gestation) were found to be statistically significant. It is proposed that private physicians evaluate patients on the basis of this model to facilitate estimates of risk of a neonatal death. In addition, public health physicians could utilize this model to make informed decisions in regard to the management of public health programs directed at the care of pregnant women.

Sample size and statistical power in reproductive research

The calculation of sample size should be an integral part of the planning stages of all research projects to avoid wasting time, money, and valuable resources. The necessary information for sample size calculations includes the alpha (type I) error level, the beta (type II) error, delta (or the difference you would like to be able to detect), and, for continuous variables, the variance. We review these terms and outline their importance in the calculation of sample size and statistical power. When necessary, the investigator should seek expertise and advice to perform these calculations.

Oxytocin augmentation of second-trimester abortion: Safe or hazardous?

The role of oxytocin in augmenting the uterine activity of second-trimester instillation abortions is controversial. To evaluate the efficacy and safety of oxytocin augmentation, we studied 10,013 women who underwent hypertonic saline instillation procedures and 1,241 women who underwent prostaglandin F2a (PGF2a) instillation procedures in the United States in the period 1971 through 1975. Data were obtained through the Joint Program for the Study of Abortion under the auspices of the Center for Disease Control, a multi-center, prospective, cohort study. We found that concurrent administration of oxytocin was associated with a significantly shorter instillation-to-abortion time for hypertonic saline, but with a significantly longer time for PGF2a. For hypertonic saline, use of concurrent oxytocin did not affect either the success rate or the major complication rate; however, it did not affect the specific type of complication that occurred. For PGF2a, use of concurrent oxytocin was associated with a lower success rate and a higher major complication rate than when PGF2a was used alone; however, the relatively small number of observations and limitations in our study design may have affected our results. When we compared the 2 main abortifacients, even when we controlled for concurrent oxytocin augmentation, unaugmented PGF2a had higher major complication rates than hypertonic saline.