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PAPERS: Herbert Kiss, Ljubomir Petricevic, and Peter Husslein Prospective randomised controlled trial of an infection screening programme to reduce the rate of preterm delivery BMJ 2004; 329: 371 [Abstract] [Full text]

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Implications for the economic evaluation of other screening programmes e.g. for chlamydia.

Woody Caan   (5 August 2004)

Ethical Approval?

James Crick   (23 August 2004)

Study design

HELMUT SCHUSTER   (25 August 2004)

The value of CONSORT in interpreting dramatic findings

Helen J Stokes-Lampard, Dr Jonathan Mant, Dr Angela Newnham, Dr Amanda Daley, Dr John Macleod and Dr Richard Mc Manus   (8 September 2004)

Does screening reduce preterm births?

Austin HN Ugwumadu, Phillip E. Hay   (9 September 2004)

Implications for the economic evaluation of other screening programmes e.g. for chlamydia. 5 August 2004
Woody Caan, Professor of public health APU, Chelmsford, Essex CM1 1SQ. Send response to journal: Re: Implications for the economic evaluation of other screening programmes e.g. for chlamydia.	It is good to see this promising example of an experimental public health intervention study in the BMJ [1]. Last year a review across multiple bibliographic databases found that no more than 0.4% of academic and research output was relevant to public health intervention research, including exploratory as well as experimental studies [2]. Kiss and co- authors do not describe which types of bacteria they detected in their Austrian cases of vaginal infection, but presumably these were common organisms like Gardnerella vaginalis. For each premature birth avoided by their screening and treatment they estimate a direct economic saving to healthcare services of over half a million pounds sterling, not to mention the non-financial, lifelong costs to child and parents resulting from physical or learning disabilities associated with a low birthweight. Could this have implications for another type of chronic bacterial infection? In Britain, Chlamydia is the most commonly diagnosed sexually transmitted infection, and the associated health burden is described in terms of a minority of cases who develop pelvic inflammatory disease (PID) and a minority of these women who become infertile [3]. For example, here in the East of England a test site (Norfolk) for an economic evaluation of opportunistic Chlamydia screening is using the treatment needs for PID as its main cost measure. But what about that 70-90% of infected women, who will never develop PID? Given that initial infection is mainly in their youth and that most will become pregnant at some time afterwards, could the really important outcome be the prevention of tiny, preterm deliveries in this fertile population? Multiple factors interact in determining intrauterine growth and maturity, but some authors claim that genito-urinary infection (including Chlamydia) [4] is the largest identifiable population risk associated with premature birth in a "developed" economy. We have found midwives increasingly willing to address sexually transmitted infections in a wide range of groups - even the population of rural Norfolk [5]. Is the time now ripe for an economic evaluation of the National Screening Programme [3] in relation to its impact on maternity services? 1 Kiss H, Petricevic L, Husslein P. Prospective randomised controlled trial of an infection screening programme to reduce the rate of preterm delivery. BMJ 2004; 0: bmj.38169.519653.EBv1-0 2 Millward LM, Kelly MP, Nutbeam D. Public health intervention research. The evidence. London: Health Development Agency, 2003. 3 Parliamentary Office of Science and Technology. Teenage sexual health. Postnote 2004; 217: 1-4. 4 Spencer N. Weighing the Evidence. How is birthweight determined? Abingdon: Radcliffe Medical Press, 2003. 5 Hillier D, Caan W. Researching the public health role of the midwife. British Journal of Midwifery 2002; 10: 545-547. Competing interests: None declared
Ethical Approval? 23 August 2004
James Crick, GP Registrar Eastfield Surgery, 1 Eastway, Eastfield. Scarborough. YO11 3LS Send response to journal: Re: Ethical Approval?	I read the above article with great interest, and some concern. I'm unsure as to how ethical approval for this study was granted. In the introduction, the authors state that "vaginal infections, particularly bacterial vaginosis, have consistently been shown in many longitudinal population studies to be associated with late miscarriage and preterm delivery." How were they then able to not treat those ladies in the control group who were shown to be carrying bacterial vaginosis? Surely, if bacterial vaginosis has been shown to be associated with these two outcomes, those involved in their care should be duty bound to treat them. I do note, from the commentary by Dr Alanen that treating BV made little impact in reducing the rate of pre-term delivery. However, this would not have been known at the time at which ethical approval would have been sought. Competing interests: None declared
Study design 25 August 2004
HELMUT SCHUSTER, Consultant Microbiologist Leeds Teaching Hospital NHS Trust Send response to journal: Re: Study design	Dear Sirs, Answering the question if vaginal colonisation/infection influences pregnancy outcomes is difficult and subject to ongoing investigations. In our times the need to use statistical tools to substantiate the evidence is paramount and I wondered if I could invite the author to comment on the design aspect of the study. The study was designed to show a 2% decrease of spontaneous preterm birth from an assumed population average of 7% to 5%. The alpha for the two-tailed chi-square test was set at 0.05 with a beta of 0.8. The sample size required to demonstrate any significant difference was approximately 2000 patients. Of the 2058 patients enrolled in the intervention group only 447 patients received any intervention because of an abnormal screening swab. The remaining 1611 patients in the “intervention group” were not treated with topical antimicrobials. This means that the required sample size for the study had not been met and the study is underpowered. Amongst the 447 patients in the “intervention” group who had received an antimicrobial 2.9% showed a spontaneous preterm birth rate (s. table 5). This rate did not differ from the remaining patients in the “intervention” group that had not been given any antimicrobials 48/1611 or 3% (s. table 4 and 5). On the other hand the spontaneous preterm birth rate of the “non-intervention” group was higher in those who had a normal vaginal flora 81/1656 or 4.9% (s. table 4 and 5) and was 31/441 or 7.0% in the group of patients with abnormal flora (s. Table 5). Competing interests: None declared
The value of CONSORT in interpreting dramatic findings 8 September 2004
Helen J Stokes-Lampard, Clinical Research Fellow & GP Principal Department of Primary Care & General Practice, University of Birmingham, UK, B15 2TT, Dr Jonathan Mant, Dr Angela Newnham, Dr Amanda Daley, Dr John Macleod and Dr Richard Mc Manus Send response to journal: Re: The value of CONSORT in interpreting dramatic findings	Sir, we read with great interest the paper by Kiss et al [1] and were struck by the dramatic difference in outcomes between the intervention and control arms. We did, however, notice that there was a difference in adverse outcomes in women who did not have infection present on screening and thus did not have any ‘active’ treatment as well as in women who did have infection. Tables 4 and 5 suggest that there were 81 pre-term births in women in the control group who without infection compared with 48 pre- term births in women without infection in the intervention group. It is unconvincing to attribute the differences to some non-specific effect of additional care as, in general, increased care does not seem to significantly affect obstetric outcomes. This implies that the difference in outcomes between the two groups may be due to other reasons that the study has not highlighted. We note that 68 patients were excluded after randomisation as they ‘did not fulfil inclusion criteria’ and 140 patients were lost to follow- up whilst these numbers are small compared to the study group they may have had a significant bearing on the outcomes. If those who failed the inclusion criteria were actually symptomatic of infection on closer questioning then the study results might be biased. A ‘consort’, style flow chart with information about the losses to follow up by treatment allocation would assist the reader in interpreting the results of this study, as would information about any intention to treat analysis[2]. We would value a response from the authors to our questions about what appears to be an interesting and thought provoking piece of research. Yours faithfully Dr Helen Stokes-Lampard, Dr Jonathan Mant, Dr Angela Newnham, Dr Amanda Daley, Dr John Macleod, Dr Richard Mc Manus References 1.Herbert Kiss, Ljubomir Petricevic, and Peter Husslein. Prospective randomised controlled trial of an infection screening programme to reduce the rate of preterm delivery BMJ 2004; 329: 371- 0 2 Begg C, Cho M, Eastwood S, Horton R, Moher D, Olkin I, et al. Improving the quality of reporting of randomized controlled trials: the CONSORT statement. JAMA 1996;276:637-9. Competing interests: None declared
Does screening reduce preterm births? 9 September 2004
Austin HN Ugwumadu, Consultant / Senior Lecturer in Obstetrics & Gynaecology St George’s Hospital, Blackshaw Road, London SW17 0QT, Phillip E. Hay Send response to journal: Re: Does screening reduce preterm births?	Kiss et al showed that screening for and treating asymptomatic lower genital tract infections reduced preterm delivery and low birth weight.1 Anna Alanen in her commentary, sub-analysed the findings of Kiss et al for the effects of treatment of individual infections such as bacterial vaginosis (BV), and concluded that the study’s results agreed with previous trials that showed no benefit of antenatal treatment of BV.2 This conclusion ignores the fundamental aim of the Kiss et al study. Firstly, Kiss and associates tested the hypothesis that a screening programme (including but not limited to BV) is effective in reducing preterm birth. Their study was not powered to show a difference between groups for the treatment of BV. Secondly, previous studies that failed to show benefit of treatment of BV introduced therapy late in pregnancy (after the risk of adverse outcome may have become irreversibly established),3 or used intravaginal medication4 (which may not eradicate organisms in the endometrial cavity) and / or tested short courses of metronidazole3 (which remains unproven in pregnancy and inactive against Mobiluncus and Mycoplasma species). Thirdly, Kiss et al screened for BV or intermediate flora but treated BV only, although intermediate flora is equally associated with late miscarriage and preterm birth. Furthermore, treatment failure in the study was high (29%) after therapy with clindamycin cream, and oral clindamycin was administered subsequently. The beneficial effect of treatment of candida found by the trial is intriguing and requires further studies. The 15 – 20% of BV-positive women who are truly at risk of adverse outcome may be better predicted in future by their higher vaginal sialidase but lower IL-8 concentrations,5 and the presence of genetic polymorphisms for excessive immune response against BV organisms.6 Austin Ugwumadu MRCOG Consultant / Senior Lecturer in Obstetrics & Gynaecology, St George’s Hospital, Blackshaw Road, London SW17 0QT Phillip Hay FRCP Senior Lecturer / Consultant in Genitourinary Medicine St George’s Hospital Medical School, Cranmer Terrace, London SW17 0RE Reference List 1. Kiss H, Petricevic L, Husslein P. Prospective randomised controlled trial of an infection screening programme to reduce the rate of preterm delivery. BMJ 2004;329:371-4. 2. Alanen A. Does screening reduce preterm births? BMJ 2004;329:374. 3. Carey JC, Klebanoff MA, Hauth JC, Hillier SL, Thom EA, Ernest JM et al. Metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis. N Engl J Med 2000;342:534-40. 4. Kekki M, Kurki T, Pelkonen J, Kurkinen R, Cacciatore B, Paavonen J. Vaginal clindamycin in preventing preterm birth and peripartal infections in asymptomatic women with bacterial vaginosis: a randomized, controlled trial. Obstet Gynecol 2001;97:643-8. 5. Cauci S, Guaschino S, de A, Driussi S, De S, Penacchioni P et al. Interrelationships of interleukin-8 with interleukin-1beta and neutrophils in vaginal fluid of healthy and bacterial vaginosis positive women. Mol Hum Reprod 2003;9:53-8. 6. Macones GA, Parry S, Elkousy M, Clothier B, Ural SH, Strauss JF, III. A polymorphism in the promoter region of TNF and bacterial vaginosis: preliminary evidence of gene-environment interaction in the etiology of spontaneous preterm birth. Am J Obstet Gynecol 2004;190:1504-8. Competing interests: Austin Ugwumadu – was invited by Professor Herbert Kiss as the guest speaker to the Annual Austrian Society of Obstetricians and Gynaecologists meeting held in Pathos Cyprus, in September 2003. Phillip Hay – has received payments for lectures and consultancy from 3M, Osmetech, and Pharmacia and Upjohn and has received funding for trials and to attend conferences from these companies.