Withdrawal bleeding and endometrial safety

of exacerbation-free when the analysis is groups whose exacerbations were verified

difference between the

subjects confined

across

patients according protocol. Although treatment to

proportions

treatment

to

with interferon beta-lb is associated with measurable clinical and magnetic-resonance-imaging (MRI) effects, statistics are no substitute for judgment. More widespread use of this now widely available drug should enable clinicians and patients to arrive at their own conclusions about practical value. However, it remains unclear how we are to determine the clinical significance of the interferon beta-lb treatment effect as measured by MRI activity. As I stated, "so far, there are still no convincing clinical data to support the notion that the reduction in new MRI activity observed in MS (multiple sclerosis) patients treated with interferon beta-lb translates into a reduction in measurable progression of sustained disability". It is difficult to envision how additional data from the interferon beta-lb study subjects with longer follow-up will convincingly address this question, since data from patients in the different treatment arms become increasingly difficult to compare as subjects have disproportionate attrition rates, use of corticosteroids, and institution of other disease-modifying

therapies. Donald E Goodkin

our knowledge, the first description of followed parapertussis by pertussis in the same individuals. The study shows that the two Bordetella species are immunologically different, that infection with B parapertussis does not protect against infection with B pertussis, and that serum antibodies against FHA do not protect against pertussis in the absence of pertussis toxin antibodies.

This is,

to

John Taranger, Birger Trollfors, Teresa Gunilla Zackrisson

Lagergård,

Departments of Paediatrics, Medical Microbiology and Immunology, and Clinical Bacteriology, Göteborg University, 41325 Göteborg, Sweden

1

2

3

4 5

Stehr K, Schmitt-Grohe S, et al. Clinical characteristics of illness caused by Bordetella pertussis compared with illness caused by Bordetella parapertussis. Pediatr Infect Dis J 1994; 13: 306-09. Khalef N, Danve B, Quentin-Millet M-J, Guiso N. Bordetella pertussis and Bordetella parapertussis: two immunologically distinct species. Infect Immun 1993; 61: 486-90. Robbins JB, Pittman M, Trollfors B, et al. Primum non nocere: a pharmacologically inert pertussis toxoid alone should be the next pertussis vaccine. Pediatr Infect Dis J 1993; 12: 795-807. Granström M, Askelöf P. Parapertussis: an abortive pertussis infection? Lancet 1982; ii: 1249-50. Zackrisson G, Arminjon P, Krantz I, et al. Serum antibody response to filamentous hemagglutinin in patients with clinical pertussis measured by an enzyme-linked immunosorbent assay. Eur J Clin Microbiol Infect Dis 1988; 7: 764-70.

Heininger U,

UCSF/Mount Zion Multiple Sclerosis Center, 1600 Divisadero, San Francisco, CA 94115, USA

Withdrawal 1

Food and Drug Administration. Minutes of the peripheral and central nervous system advisory committee meeting no 35. Washington DC: FDA, 1993: 44-71.

Parapertussis infection followed by pertussis infection SIR-Both Bordetella pertussis and Bordetella para pertussis prolonged cough. B parapertussis infections are much less common and less severe than B pertussis infections.The two organisms share several virulence factors (eg, filamentous haemagglutinin [FHA], pertactin, tracheal cytotoxin, and adenylate cyclase-haemolysin,2but only B pertussis produces pertussis toxin, an important virulence factor in pertussis).3 Because of similarities between the two organisms it was proposed that B para pertussis is not a distinct species but a non-toxigenic strain of B pertussis.4 However, studies show that the two organisms are genetically and immunologically different. We report four children with B parapertussis infection followed by B pertussis infection. Four healthy children, who were not vaccinated against pertussis, developed B para pertussis infections at ages 3 cause

months, and 2, 3, and 4

respectively. Three cases and the fourth by a positive parapertussis PCR and contact with a culture-verified parapertussis case. None of the children was treated with antibiotics. Their coughs lasted 3-4 weeks. One child had whooping attacks and vomiting for 2 days. The other three had neither whooping attacks nor vomiting. In convalescent sera obtained from the three oldest children, serum FHA IgG titres of the same magnitude as seen after pertussis5 were found. None of the sera had detectable pertussis toxin antibodies. 5-10 months after the onset of parapertussis, the children developed pertussis with positive cultures. The duration of cough was 5-9 weeks. All had whooping attacks and vomiting for 3-6 weeks. In new convalescent sera obtained from the three oldest children, high pertussis toxin antibodies were found. FHA antibodies remained high. were

verified

by culture

years,

bleeding and endometrial safety

SIR-Sturdee and colleagues (Oct 8, p 979) claim to have shown that the timing of withdrawal bleed in women using sequential hormone replacement therapy does not correlate with endometrial histology and cannot be used as a signpost to the possible presence of endometrial hyperplasia. They suggest that their findings contradict our study.’ I suggest that this conclusion is inaccurate and indeed cannot be drawn because of a failing in the study design. Padwick and co-workers’ study was a planned prospective blind study with one clinician and one histopathologist obtaining all information. The basis of this study was simple; endometrial biopsies were done on the sixth day of combined oestrogen/progestagen therapy at a time when progestational effect was expected to be greatest.2 Clearly, therefore, women whose endometrium still show proliferative activity at this phase of their treatment cycle are likely to be receiving suboptimum doses of progestagen, and this might increase the risk of hyperplasia and malignant disease. There was a close correlation with endometrial histology reported on biopsy specimens taken on day 6 and the first day of withdrawal bleeding. The major flaw in Sturdee’s report, which does not seem to be a prospectively planned study, is that all endometrial biopsies were done on a random basis. Consequently, biopsy specimens taken during the oestrogen-only phase or early phase of combined oestrogen/progestagen therapy tend to show proliferative endometrium whereas those obtained after 6 days of combined oestrogen/progestagen therapy tend to show secretory endometrium. However, to try and correlate these histological findings with the day of onset of withdrawal bleeding is clearly inappropriate. Other features of Sturdee and colleagues’ study are of concern, and could relate to the fact that this is a multicentre, multi-investigator study. Endometrial biopsy specimens were obtained by Pipelle, whereas we used Vabra curettage;l but this difference alone is unlikely to explain the up to 38-7% of uninterpretable biopsy specimens with histological comments of not assessable, atrophic, and menstrual. In our study only 14-6% of specimens were uninterpretable. Sturdee presents 244 women who fit the 1703

original criteria for bleeding pattern interpretation, but it is notable that 13 of these women had an onset of withdrawl bleed on day 5 of earlier, and I suggest that bleeding this early while on combined therapy should be regarded as abnormal. Sturdee and colleagues’ conclusion that the day of onset of withdrawal bleed does not predict pre-existing endometrial hyperplasia is interesting but, since only seven cases are presented, cannot be conclusive. We clearly showed that withdrawal bleeding patterns predict endometrial histology on day 6 of combined oestrogen/progestagen therapy and predict progestational activity within the endometrium. The dose of progestagen can therefore be varied to allow for this factor.

carcinoma,3,4 attractive

1

2

on

Trym,

Padwick ML, Pryse-Davies J, Whitehead MI. A simple method for determining the optimal dosage of progestin in post menopausal women receiving oestrogens. N Engl J Med 1986; 315: 930-34. Whitehead MI, Townsend PT, Pryse-Davies J, et al. Actions of progestins on the morphology and biochemistry of the endometrium of post menopausal women receiving low dose estrogen therapy. Am J Obstet Gynecol 1982; 142: 791-95.

Authors’

reply

SiR-We are surprised at Padwick’s response to our study and its conclusions, which we feel are wholly supported by the facts. Our study was planned as prospective and blind, and endometrial biopsies were not done at random. The protocol required that biopsy was done towards the end of the progestagen phase, which was achieved in most patients. In 18 patients in whom biopsy was undertaken during the oestrogen phase, there was proliferative endometrium as one would expect; but in 7, in whom biopsy was done on or after day 6 (as in Padwick’s study), proliferative endometrium was also seen, and 5 of these women bled after day 11. We acknowledge the potential disadvantages of a multiinvestigator study, but such studies do allow recruitment of many more patients. The main weaknesses of Padwick’s study were the small number of patients (96) and the fact that none had endometrial hyperplasia. Our study clearly shows that women with complex endometrial hyperplasia can have regular and apparently normal withdrawal bleeds after day 11 from the start of progestagen. According to Padwick, such a bleeding pattern should indicate a normal endometrium. 10 of our 11 cases of hyperplasia had regular bleeding on standard sequential regimens of oestrogen and progestagen, but only 7 were included in the figure for the day of onset of bleeding, since they fulfilled the arbitrary criteria in Padwick’s study and could thus be used for direct

comparison. The Pipelle endometrial biopsy technique has been well validated1,2and is now widely used as a simple and effective clinical investigation. In all similar studies of endometrial histology, there has been a high frequency of samples that were regarded as unassessable for histology. This variation could be partly due to different criteria by histopathologists (although we had only one histopathologist). Unassessable cases do not invalidate our conclusions drawn from women from whom sufficient endometrium was obtained to be assessed satisfactorily. The addition of progestagen in sequential hormone therapy is intended to prevent endometrial hyperplasia and carcinoma, and to produce a regular and predictable withdrawal bleed. Previous studies have shown that regular scheduled bleeding can occur even with hyperplasia or

1704

it is

perhaps surprising that Padwick’s unchallenged for so

has remained

long. David W Sturdee, David H

Barlow, Martin P Vessey

Solihull Hospital, Solihull, West Midlands B91 2JL, UK; and Nuffield Department of Obstetncs and Gynaecology, and Department of Public Health & Pnmary Care, University of Oxford, UK

1 2

3

Malcolm Padwick Department of Obstetrics and Gynaecology, Southmead Hospital, Westbury Bnstol BS10 5NB, UK

so

proposition

4

Eddowes HA. Pipelle: a more acceptable technique for outpatient endometrial biopsy. Br J Obstet Gynaecol 1990; 97: 961-62. Kaunitz AM, Masciello A, Ostrowski M, Rovira EZ. Comparison of endometrial biopsy with the endometrial Pipelle and Vabra aspirator. J Reprod Med 1988; 33: 427-31. Sturdee DW, Wade-Evans T, Paterson MEL, Thom MH, Studd JWW. Relations between bleeding pattern, endometrial histology and oestrogen treatment in menopausal women. BMJ 1978; 1: 1575-77. Paterson MEL,. Wade-Evans T, Sturdee DW, Thom MH, Studd JWW. Endometrial disease after treatment with oestrogens and progestogens in the climacteric. BMJ 1980; 280: 822-24.

Sumatriptan-induced

chest

pain

SIR-Houghton and colleagues (Oct 8, p 985) suggest that chest pain in association with sumatriptan can arise as a consequence of oesophageal motor dysfunction. The Australian Adverse Drug Reactions Advisory Committee (ADRAC) has received 114 reports of chest pain or tightness in association with sumatriptan in the 2 years since its Australian marketing in mid-1992. These reports are more common in female than male patients (F/M 84/18) and for the oral preparation (oral/subcutaneous 73/31); the median age of the patients is 40 years. These figures are believed to be related to the usage of the drug. In addition, ADRAC has received 28 reports of throat tightness during that period. Throat tightness is an unusual adverse reaction, and has been lately added to the terminology of the WHO Collaborating Centre for International Drug Monitoring in response to these reports with sumatriptan. Most reports use the description throat tightness or tightening, but the reaction has also been described as neck tightness or constriction or as a choking feeling in the throat. Patient characteristics were similar to those with chest pain, with most being female (F/M 26/2) and on an oral preparation (oral/subcutaneous 22/6), with a median age of 35. We have speculated about a relation between chest pain and throat tightness, but our reports seem to indicate that this adverse reaction is quite different from chest pain. Moreover, in at least 27 of the 114 reports of chest pain, the description of the reaction or reporting of doctor’s comments were highly consistent with ischaemic chest pain. Lloyd and colleagues’ recorded that ECGs were usually normal with sumatriptan-induced chest pain, and in our reports ECG was normal in all the 19 patients in whom it was documented, apart from 1 patient with pre-existing cardiac disease. However, with a median duration of chest pain of between 1 and 2 hours, many of these ECGs were measured after the reaction had abated. Stress tests were also done in 3 patients, and there were positive results in 2 of these 3 although the details are unknown. Also noteworthy, and suggestive of a dose relation, is the fact that in 2 patients, chest pain occurred with a whole 100 mg tablet but when the tablet was halved there was no reaction. Although most patients reported to ADRAC have recovered quickly, there have been 2 deaths. 1 patient, a 44year-old woman who had chest pain after sumatriptan, developed a fatal myocardial ischaemia after coronary artery dissection, but the causal relation between ingestion of sumatriptan and this event is unclear. The other patient, a 57-year-old woman with hypertrophic obstructive

Vol 344 • December 17, 1994