Meta-analysis of randomized controlled trials of antibiotic prophylaxis in abdominal hysterectomy E. W. Wttewaall-Evelaar
Introduction Post-operative infections comprise a major portion of the morbidity experienced in gynaecologic o p e r a t i o n s and m a y lead to increased cost of medical care. This was the impetus to the search f o r - n e w methods to decrease post-operative morbidity. The results of several clinical studies to justify the prophylactic use of antibiotics to reduce the incidence of infection, use of therapeutic antibiotics and length of hospitalization for vaginal, but not for abdominal h y s t e r e c t o m y [1-8]. While a large n u m b e r of studies have been examined, the use of prophylactic antibiotics in elective abdominal hysterectomy, m u c h controversy remains. Some studies [9-12] h a v e evidence for a statistically significant decrease in postoperative infectious morbidity, while others have failed to d e m o n s t r a t e a beneficial effect [13-16]. The: difference in study outcome m a y be due to several factors, but most i m p o r t a n t is the insufficient sample size of the individual trials, leading t o a lack of significance [17]. The method by which empirical research has been assessed in the literature of clinical medicine h a s been the n a r r a t i v e review, based on reports of r a n d o m observations and therefore served to describe a state of art. More objective conclusions can be obtained by using a new method, t e r m e d meta-analysis [18]. We conducted such a analysis to assess the value of antibiotic prophylaxis in elective abdominal hysterectomy. In this article, we discuss how to t a k e advantage of meta-anatysis in clinical medicine, illustrated by a clinical example, without describing some details of the meta-analysis t h a t we" performed. Methods Meta-analysis includes [17 t8]: - defining a research question (objectives); - searching and retrieving r e l e v a n t literature; - defining inclusion and exclusion criteria and screening the r e l e v a n t literature;
- describing and analysing the data; reporting and interpreting results. -
Research question A clearly defined research question is the foundation on which any meta-analysis is built [17]. All subsequent steps are necessarily related to the specific goal for meta-analysis. Our objective was: "Define the value of antibiotic prophylaxis in elective abdominal hysterectomy." Literature search Relevant data is retrieved, using keywords relating to the research question. The literature search includes: - c o n d u c t i n g a search of the M E D L I N E data base; - searching m a n u a l l y through the list of references of previously retrieved literature (reviews and books); - c o n t a c t i n g a professional librarian for published (current contents) and unpublished information (abstracts); - using a registry or inventory of clinical trials. We conducted a l i t e r a t u r e search from 1966 to 1988, using the keywords abdominal, hysterectomy and prophylaxis. Inclusion and exclusion criteria Inclusion and exclusion criteria are dependent on the research question and investigator predispositions and m u s t be consistent [17-19]. We included studies of patients undergoing elective abdominal hysterectomy which were prospective, randomized, and placebo-controlled. Trials describing abdominal hysterectomy for oncologic reasons and papers of retrospective n a t u r e (reviews) were excluded. The following end-points were chosen as p a r a m e t e r s for post-operative morbidity: wound infection, pelvic infection, urin a r y tract infection, febrile morbidity, antibiotic t h e r a p y and hospital stay. To avoid potential bias, literature retrieval should be performed under coded conditions and
Wttewaall-Evelaar EW. Meta-analysis of randomized controlled trials of antibiotic prophylaxis in abdominal hysterectomy. Pharm Weekbl [Sci] 1990;12(6A):296-9. Keywords Antibiotics Hysterectomy Literature Meta-analysis Pre-operative care Dr. E. W. WttewaaIl-Evelaar: Department of Gynaecology and Obstetrics, Diakonessen Hospital, Bosboomstraat 1, 3582 KE Utrecht, the Netherlands.
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Abstract The value of antibiotic prophylaxis in abdominal hysterectomy was reviewed by meta-analysis. Two independent literature searches (1986-1988) yielded 150 relevant papers, however, only 17 (11.3%) papers met our inclusion criteria. The selected papers described prospective, randomized, blinded, placebo-controlled studies of patients undergoing elective abdominal hysterectomy. In 14 of 17 (82%) trials, first- or second-generation cephalosporins were used. Results pooled confirm that antibiotic prophylaxis will reduce infectious morbidity following elective abdominal hysterectomy. Hospital stay is little affected and significant levels of infectious morbidity remain. Accepted 2 November 1990.
P h a r m a c e u t i s c h Weekblad Scientific edition
12(6A) 1990
each paper, blinded for source, should be reviewed and assessed by two separate observers. Disagreements should be resolved by consensus
[18]. Thus, papers accepted for meta-analysis that included data at the same well-defined endpoints can be tabulated, pooled and used for further analysis. Analytic methods Event rates of each end-point of all studies should be measured and judged for homogeneity [18 19]. This technique is based on the ratio of the outcome frequencies in the two patient groups, the treatment and the control group: i.e. the relative risk = Pt/Pc [18]. Statistical significance can be tested by the Mantel-Haenszel estimation of the combined relative risk, and by pooling the difference and its standard error in each trial (all two-tailed tests) [18 20]. Results 150 Papers were retrieved from the medical literature using the keywords described; 39 (26.0%) met our initial inclusion criteria. 111 Papers (75.0%) were excluded for the following reasons: retrospective nature, oncology patients only, lack of randomization, controls or vaginal hysterectomy cases. In addition, 22 papers (14.7%) were excluded because of unacceptable methods of randomization (not under coded conditions), selection of patients or controls, lack of defined end-points. 17 Reports (11.3%) described prospective, randomized, blinded, placebo-controlled studies of patients undergoing elective abdominal hysterectomy and were used for the final analysis [1014 21-33]. Selection of patients was uniform in all studies. Although not every study was required to have all end-points, the end-points used had to be well-defined. In 14 of 17 studies (82%) first- or second-generation cephalosporins were used. The sample sizes of the individual trials were usually too small to detect a statistical significance. The studies were published between 1972 and 1986 and after revealing the source, it appeared that these studies had been published in journals of a high scientific level. The control and treatment groups were summed across the 17 studies and numbered 961 and 1,134 patients, respectively. The difference in number is due to the fact that
Table 1 Pooled data (% morbidity): control versus treatment [21-33]
Post-operative event
Placebo (n=961) (%)
Prophylaxis P (n=1134) (%)
Wound infection Pelvic infection Urinary infection Febrile episodes Antibiotic therapy Hospital stay
71 (7.4%) 117 (12.1%) 139 (13.5%) 257 (26.7%) 148 (15.4%) 8.7 days
32 2.8%) 74 6.5%) 58 5.1%) 208 18.3%) 106 9.3%) 7.7 days
12(6A) 1990
< 0.001