Contraception
46:349-357,
1992
ORAL CONTRACEPTIVES AND PREGNANCY IN RELATION TO PEPTIC ULCER Martin P. Vessey, M.D., Laurence Villard-Mackintosh, Ph.D. Rosemary Painter, D.Phil. Department of Public Health and Primary Care, Radcliffe Infirmary, Oxford, OX2 6HE, England ABSTRACT There is evidence in the scientific literature that peptic ulceration occurs less frequently during pregnancy than at other times. This encouraged us to examine the pattern of hospitalisation for peptic ulcer in the Oxford-Family Planning Association contraceptive study. In total, 175 women in the study had been hospitalised for peptic ulcer; 105 had duodenal disease, 55 had gastric disease and 22 had disease of unspecified site (some had disease at more than one location). Hospitalisation for peptic ulcer increased with age, parity and cigarette smoking. In addition, hospitalisation was at a low rate during pregnancy and was not seen at all during the 12 months following delivery. There was no relationship between hospitalisation for peptic ulcer and total duration of oral contraceptive use. Likewise, there was no significant relationship with recency of oral contraceptive use, but the lowest rate of hospitalisation was in current users of the pill. INTRODUCTION The development of active peptic ulceration during pregnancy is uncommon and, in the case reports which have been published, ulcer activity tended to occur close to the time of delivery (l-3). Furthermore, pregnancy is believed to have a beneficial effect on the course of pre-existing acute peptic ulceration (4). These observations led one of us, a number of years ago, to undertake a case-control study to see if oral contraceptives might reduce the risk of peptic ulceration (5). A negative association was indeed found, but this was judged to be an artefact consequent upon the study design and therefore no conclusions could be drawn. A large quantity of data on peptic ulceration, collected prospectively, has now accumulated in the Oxford-Family Planning Association (Oxford-FPA) contraceptive study. Accordingly, we decided to look again at the peptic ulcer-oral contraceptive question using the information from this investigation. METHODS A detailed description of the methods used in the Oxford-FPA study has been given elsewhere (6). In brief, 17,032 women were recruited at 17 large family planning clinics in England and Scotland during 1968-74. At the time of recruitment, each of these women had to be aged 25-39 years, married, a white British subject, willing to participate, and Submitted for publication June 2, 1992 Accepted for publication July 16, 1992 CopyrightQ1992Buttetworth-Heinemann
Contraception
350
either a current user of oral contraceptives with at least five months use or a current user of a diaphragm or an intrauterine device with at least five months use without previous exposure to the pill. During follow-up, each woman is questioned at return visits to the clinic by a doctor or a nurse and certain items of information are recorded on a special form, including details of pregnancies and their outcome, changes in contraceptive practices and reasons for referral to hospital. Women who stop attending the clinic are sent a postal version of the questionnaire and, if this is not returned, are interviewed on the telephone or at a home visit. Each hospital admission is followed-up by writing to the consultant concerned and a copy of the relevant discharge summary is obtained. The work in each clinic is coordinated by a parttime research assistant and follow-up has been maintained with an annual loss rate because of withdrawal of cooperation or loss of contact of only about 0.3%. When women reach the age of 45 years, they are divided into three groups: those who have never used the pill, those with eight or more years use of the pill, and the remainder. Only the women in the first two of these groups are subsequently followed-up intensively in the way described above. As already indicated, the Oxford-FPA study collects information only about illnesses reauirina referral to hosoital. This imolies that the women with a first'attack of peptic ulcer'included in the analysis are likely to be those with persistent and severe symptoms for whom management in general practice failed. In deciding whether or not a woman had a first attack of peptic ulcer, we relied on the diagnosis in the discharge summary for those admitted to hospital and on the woman's own statement for those managed as outpatients (often supplemented by the woman's report on the outcome of barium studies or endoscopy). Of the 175 with peptic ulcer included in our analysis, 65 (37%) underwent inpatient treatment. Although the inpatient diagnoses in our study must be more reliable than the outpatient diagnoses, analysis showed the two series of cases to have similar characteristics and we have therefore considered them jointly throughout. The analysis is based on the computation of woman-years of observation in the various groups compared. First hospital referral rates for peptic ulcer within these groups are standardised by the indirect method as described by Vessey u.(6). RESULTS Of the total of 175 women with peptic ulcer, 105 had duodenal disease, 55 had gastric disease and 22 had disease of unspecified site (some women had disease at more than one location). This split approximates well to that expected in the general female population. Preliminary analyses showed significant relationships between peptic ulcer and age, parity and cigarette smoking. They also showed a nonsignificant relationship with pregnancy and interval since last pregnancy. All these variables have been taken into account in standardising rates. The relationship with age is shown in Table I. It is stronger for gastric ulcer than for duodenal ulcer, but taking all ulcers together,
351
Contraception there is almost a three-fold increase in the rate of first hospital referral from ages 25-29 to ages 50 or more. Table I.
Age
Duodenal ulcer No. Rate/ cases TWY
Peptic ulcer and age Gastric ulcer No. Rate/ TWY cases
All peptic ulcers No. Rate/ TWY cases
25-29
2
0.11
3
0.20
5
0.30
30-34
17
0.38
7
0.16
24
0.54
35-39
32
0.44
8
0.11
45
0.62
40-44
21
0.27
16
0.20
44
0.56
45-49
24
0.61
12
0.30
37
0.93
9
0.38
9
0.37
20
0.84
5ot
x2 trend = 2.1 P = 0.1
x2 trend = 5.4 P = 0.02
x2 trend = 7.6 P = 0.006
TWY = thousand woman-years Rates adjusted for parity (0, l-2, 3t births), smoking (never, ex, 1-14, 15t cigs/day) and pregnancy/interval since last pregnancy (never pregnant, unknown, pregnant, last pregnant up to 12 months ago, last pregnant more than 12 months ago).
Table II shows the relationship between ulcer and parity. Taking all ulcers together, women of high parity are about a third more likely to experience hospital referral than those of low parity. Table III concentrates on cigarette smoking. Here, the relationship is clear and unequivocal for both duodenal and gastric ulcer. Considered together, there is a near doubling of the hospital referral rate in contrasting those who have never smoked with those who were smoking 15 or more cigarettes per day on entry to the study. The relationship between peptic ulcer on the one hand and pregnancy and interval since last pregnancy on the other is shown in Table IV. Some of the data fall into an unknown category because the dates of spontaneous and induced abortions and ectopic pregnancies (as opposed to the dates of stillbirths and livebirths) were not recorded prior to entry
352
Contraception Table II.
Parity
Peptic ulcer and parity
Duodenal ulcer No. Rate/ TWY cases
Gastric ulcer No. Rate/ cases TWY
All peptic ulcers No. Ratej cases TWY
7
0.38
2
0.17
9
0.60
l-2
55
0.33
29
0.17
94
0.55
3t
43
0.49
24
0.26
72
0.80
Nulliparous
x2 trend = 2.5 P = 0.1
trend = 2.2 P = 0.1
x2
x2
trend = 4.1 P = 0.04
TWY = thousand woman-years Rates adjusted for age (6 groups), smoking (4 groups), pregnancy/ interval since last pregnancy (5 groups). Table III. Cigarettes smoked per day
Peptic ulcer and smoking
Duodenal ulcer No. Rate/ cases TWY
Gastric ulcer No. Rate/ cases TWY
All peptic ulcers No. Rate/ cases TWY
51
0.32
21
0.13
80
0.51
9
0.28
4
0.12
18
0.56
1-14
24
0.49
20
0.40
44
0.89
15t
21
0.57
10
0.27
33
0.89
Never Ex
x2 trend = 5.8 P = 0.02
x2 trend = 9.4
P = 0.002
X2 trend = 11.8 P = 0.001
TWY = thou:and woman-years Rates adjusted for age (6 groups), parity (3 groups), pregnancy/ interval since last pregnancy (5 groups). to the study; only information on the number of such events was noted. Nonetheless, it will be apparent that most of the woman-years in the unknown category will not have accumulated during pregnancy or in close proximity to pregnancy.
Contraception
353
The overall data in Table IV show a remarkable uniformity of rates in all categories, save for a low rate in the pregnancy category and a zero rate in the up to 12 months since last pregnant category. These differences are not formally significant, but they are clearly compatible with the findings reported in the introduction. Table IV.
Pregnancy/interval since last pregnancy
Never pregnant
Peptic ulcer in relation to pregnancy/ interval since last pregnancy Duodenal ulcer No. Rate/ cases TWY
Gastric ulcer No. Rate/ cases TWY
All peptic ulcers No. Rate/ cases TWY
6
0.39
2
0.24
8
0.67
Not known
13
0.36
8
0.21
26
0.71
Pregnant
1
0.26
0
0.00
1
0.29
-12
0
0.00
0
0.00
0
0.00
13-24
4
0.60
1
0.15
5
0.76
25-48
2
0.13
5
0.35
8
0.54
49-72
6
0.32
3
0.18
11
0.62
73-96
11
0.51
3
0.16
16
0.78
97-120
8
0.35
5
0.26
13
0.59
54
0.42
28
0.20
87
0.65
Interval since last pregnancy (mths):-
120+
x2 trend = 0.9 P = 0.3
x2 trend = 0.0 P = 1.0
X2 heterogeneity 7.8, P = 0.6
x2
heterogeneity 4.3, P = 0.9
X2
trend = 0.0 P = 0.9
x2 heterogeneity 6.3, P = 0.7
TWY = thousand woman-years Rates adjusted for age (6 groups), parity (3 groups), smoking (4 groups). In Table V, the relationship between peptic ulcer and total duration of oral contraceptive use is examined. The data show random variation only and there is no hint of a protective effect of the pill.
Contraception
354 Table V.
Overall duration of oral contraceptive use (mths) Non user
Peptic ulcer and overall duration of oral contraceptive use
Duodenal ulcer No. Rate/ TWY cases
Gastric ulcer No. Rate/ cases TWY
All peptic ulcers No. Rate/ TWY cases
46
0.41
26
0.22
78
0.68
-12
2
0.25
1
0.13
3
0.38
13-24
5
0.49
3
0.31
10
1.00
25-48
12
0.47
4
0.16
18
0.71
49-72
5
0.16
5
0.19
12
0.41
73-96
14
0.52
6
0.27
22
0.87
97+
21
0.34
10
0.15
32
0.50
x2 trend = 0.4 P = 0.5
x2 trend
= 0.6 P = 0.4
x2 trend = 1.1 P = 0.3
TWY = thousand woman-years Rates adjusted for age (6 groups), parity (3 groups), smoking (4 groups) pregnancy/interval since last pregnancy (5 groups).
Table VI considers the relationship between peptic ulcer and recency of oral contraceptive use. None of the differences within the columns is statistically significant and there are no significant trends in the table. However, it is of some interest that both for duodenal ulcer and for all ulcers combined, the lowest rate is among the current users of oral contraceptives. The data are clearly compatible with some protective effect of current oral contraceptive use, but the numbers available for the present analysis do not permit any more definite statement than that. Examination of oral contraceptive type was unhelpful as is usually the case in the Oxford-FPA study in which some 75% of all oral contraceptive exposure is to pills containing 50 pg oestrogen.
355
Contraception Table VI.
Peptic ulcer and recency of oral contraceptive use
Interval between last use of oral contraceptives & hospital referral for peptic ulcer
Duodenal ulcer No. cases
Gastric ulcer
All peptic ulcers
Rate/ TWY
No.
Rate/ TWY
No.
Rate/ TWY
Non-user
46
0.41
26
0.22
78
0.68
Current user
I1
0.22
9
0.20
20
0.42
-12
9
0.62
0
0.00
9
0.67
13-24
3
0.27
1
0.11
25-48
12
0.57
0
0.00
13
0.64
49-72
10
0.52
8
0.43
21
1.09
73-96
7
0.41
4
0.23
10
0.58
97+
7
0.23
7
0.19
19
0.58
X2 trend = 0.02 P = 0.9 x2
heterogeneity 11.0, P=O.l
X2 trend = 0.0 P = 1.0 x2
heterogeneity 11.8, P=O.l
0.47
x2 trend = 0.1 P = 0.7 x2
heterogeneity 10.8, P=O. 1
TWY = thousand woman-years Rates adjusted for age (6 groups), parity (3 groups), smoking (4 groups), pregnancy/interval since last pregnancy (5 groups).
DISCUSSION Peptic ulcer disease is known to increase with age (7) and with cigarette smoking (8) and our findings on pregnancy and interval since last pregnancy seem to fit in with existing evidence (l-4). We are, however, unaware of any previous evidence linking risk to parity. This should be a simple enough hypothesis to test in another data set now that we have drawn attention to the possibility. The theoretical background to the present analysis was summarised in the Introduction and will not be repeated here. In addition to the previous study of one of us (5) which led to an inconclusive result, data on peptic ulcer and oral contraceptives have been published from the
356
Contraception
Royal College of General Practitioners (9) study and from the Walnut Creek Study (10). The first of these studies included only 16 cases of gastric ulcer, too few to analyse. There were, however, 76 cases of duodenal ulcer with a deficit amongst current pill users and an excess among ex-users. Although the results did not reach statistical significance, they are very carefully discussed by the authors who come to the conclusion that the low incidence of duodenal ulcer in current users is due to selection rather than a protective effect. In the Walnut Creek Study, there were 19 cases of gastric ulcer and 18 of duodenal ulcer, an unexpected ratio. Not surprisingly with such small numbers, the authors concluded that "no clear pattern of risk" was apparent in their data. Our present findings, which represent the largest data set to be reported so far, take matters a little further. First, there is no sign of any relationship between peptic ulcer and overall duration of oral contraceptive use. Secondly, there are no significant differences in risk in the table relating to recency of oral contraceptive use and it would be reasonable to leave matters like that. However, there is just a suggestion of a lower rate in the current user group than in other groups and this must still leave doubt about the possibility of some small protective effect in women using the pill. To investigate this further would require an extremely large study of very careful design and we suspect that, like the possible minimal protective effect of oral contraceptives against thyroid disease (ll), the issue will remain undecided. ACKNOWLEDGEMENTS We thank Mrs. P. Brown, Mrs. D. Collinge, Mrs. J. Winfield, and the research assistants, doctors, nurses and administrative staff working at the participating clinics for their hard work and loyal support. We are also grateful to the Medical Research Council, the Imperial Cancer Research Fund and the Knott Family Trust for financial support. REFERENCES 1.
Sandweiss DJ, Saltzstein HC, Farbman AA. The relation of sex hormones to peptic ulcer. Am J Dig Dis 1939; 6:6-12.
2.
Jones
3.
Rider JA, Kirsner JB, Palmer WL. Active duodenal ulcer in pregnancy. Gastroenterology 1953; 24:357-68.
4.
Clark DH.
5.
Glober G, Doll R, Fairbairn AS, Vessey MP. Peptic ulceration and the use of oral contraceptives: A negative correlation attributable to the disease? Br J Prev Sot Med 1971; 25:144-46.
FA. Haematemesis and melaena with special reference to bleeding peptic ulcer. Br Med J 1947; 2:441-46.
Peptic ulcer in women.
Br Med J 1953; 1:1254-57.
Contraception
357
6.
Vessey M, Doll R, Peto R, Johnson 8, Wiggins P. A long-term follow-up study of women using different methods of contraception an interim report. J Biosoc Sci 1976; 8~373-427.
7.
Schoon I-M, Mellstrom D, Oden A, Ytterberg B-O.
8.
Sol1 AH. therapy.
9.
Royal College of General Practitioners. Oral Contraceptives and Health. London: Pitman Medical, 1974.
10.
The Walnut Creek Contraceptive Drug Study. Bethesda, 1981.
11.
Vessey M, Villard-Mackintosh L, McPherson K, Yeates D. Thyroid disorders and oral contraceptives. Br J Fam Planning 1987; 13:12427.
peptic ulcer in Gothenberg 1985.
Incidence of Br Med J 1989; 299:1131-34.
Pathogenesis of peptic ulcer and implications for N Engl J Med 1990; 322:909-16.
Vol III.
NIH,
46:349-357,
1992
ORAL CONTRACEPTIVES AND PREGNANCY IN RELATION TO PEPTIC ULCER Martin P. Vessey, M.D., Laurence Villard-Mackintosh, Ph.D. Rosemary Painter, D.Phil. Department of Public Health and Primary Care, Radcliffe Infirmary, Oxford, OX2 6HE, England ABSTRACT There is evidence in the scientific literature that peptic ulceration occurs less frequently during pregnancy than at other times. This encouraged us to examine the pattern of hospitalisation for peptic ulcer in the Oxford-Family Planning Association contraceptive study. In total, 175 women in the study had been hospitalised for peptic ulcer; 105 had duodenal disease, 55 had gastric disease and 22 had disease of unspecified site (some had disease at more than one location). Hospitalisation for peptic ulcer increased with age, parity and cigarette smoking. In addition, hospitalisation was at a low rate during pregnancy and was not seen at all during the 12 months following delivery. There was no relationship between hospitalisation for peptic ulcer and total duration of oral contraceptive use. Likewise, there was no significant relationship with recency of oral contraceptive use, but the lowest rate of hospitalisation was in current users of the pill. INTRODUCTION The development of active peptic ulceration during pregnancy is uncommon and, in the case reports which have been published, ulcer activity tended to occur close to the time of delivery (l-3). Furthermore, pregnancy is believed to have a beneficial effect on the course of pre-existing acute peptic ulceration (4). These observations led one of us, a number of years ago, to undertake a case-control study to see if oral contraceptives might reduce the risk of peptic ulceration (5). A negative association was indeed found, but this was judged to be an artefact consequent upon the study design and therefore no conclusions could be drawn. A large quantity of data on peptic ulceration, collected prospectively, has now accumulated in the Oxford-Family Planning Association (Oxford-FPA) contraceptive study. Accordingly, we decided to look again at the peptic ulcer-oral contraceptive question using the information from this investigation. METHODS A detailed description of the methods used in the Oxford-FPA study has been given elsewhere (6). In brief, 17,032 women were recruited at 17 large family planning clinics in England and Scotland during 1968-74. At the time of recruitment, each of these women had to be aged 25-39 years, married, a white British subject, willing to participate, and Submitted for publication June 2, 1992 Accepted for publication July 16, 1992 CopyrightQ1992Buttetworth-Heinemann
Contraception
350
either a current user of oral contraceptives with at least five months use or a current user of a diaphragm or an intrauterine device with at least five months use without previous exposure to the pill. During follow-up, each woman is questioned at return visits to the clinic by a doctor or a nurse and certain items of information are recorded on a special form, including details of pregnancies and their outcome, changes in contraceptive practices and reasons for referral to hospital. Women who stop attending the clinic are sent a postal version of the questionnaire and, if this is not returned, are interviewed on the telephone or at a home visit. Each hospital admission is followed-up by writing to the consultant concerned and a copy of the relevant discharge summary is obtained. The work in each clinic is coordinated by a parttime research assistant and follow-up has been maintained with an annual loss rate because of withdrawal of cooperation or loss of contact of only about 0.3%. When women reach the age of 45 years, they are divided into three groups: those who have never used the pill, those with eight or more years use of the pill, and the remainder. Only the women in the first two of these groups are subsequently followed-up intensively in the way described above. As already indicated, the Oxford-FPA study collects information only about illnesses reauirina referral to hosoital. This imolies that the women with a first'attack of peptic ulcer'included in the analysis are likely to be those with persistent and severe symptoms for whom management in general practice failed. In deciding whether or not a woman had a first attack of peptic ulcer, we relied on the diagnosis in the discharge summary for those admitted to hospital and on the woman's own statement for those managed as outpatients (often supplemented by the woman's report on the outcome of barium studies or endoscopy). Of the 175 with peptic ulcer included in our analysis, 65 (37%) underwent inpatient treatment. Although the inpatient diagnoses in our study must be more reliable than the outpatient diagnoses, analysis showed the two series of cases to have similar characteristics and we have therefore considered them jointly throughout. The analysis is based on the computation of woman-years of observation in the various groups compared. First hospital referral rates for peptic ulcer within these groups are standardised by the indirect method as described by Vessey u.(6). RESULTS Of the total of 175 women with peptic ulcer, 105 had duodenal disease, 55 had gastric disease and 22 had disease of unspecified site (some women had disease at more than one location). This split approximates well to that expected in the general female population. Preliminary analyses showed significant relationships between peptic ulcer and age, parity and cigarette smoking. They also showed a nonsignificant relationship with pregnancy and interval since last pregnancy. All these variables have been taken into account in standardising rates. The relationship with age is shown in Table I. It is stronger for gastric ulcer than for duodenal ulcer, but taking all ulcers together,
351
Contraception there is almost a three-fold increase in the rate of first hospital referral from ages 25-29 to ages 50 or more. Table I.
Age
Duodenal ulcer No. Rate/ cases TWY
Peptic ulcer and age Gastric ulcer No. Rate/ TWY cases
All peptic ulcers No. Rate/ TWY cases
25-29
2
0.11
3
0.20
5
0.30
30-34
17
0.38
7
0.16
24
0.54
35-39
32
0.44
8
0.11
45
0.62
40-44
21
0.27
16
0.20
44
0.56
45-49
24
0.61
12
0.30
37
0.93
9
0.38
9
0.37
20
0.84
5ot
x2 trend = 2.1 P = 0.1
x2 trend = 5.4 P = 0.02
x2 trend = 7.6 P = 0.006
TWY = thousand woman-years Rates adjusted for parity (0, l-2, 3t births), smoking (never, ex, 1-14, 15t cigs/day) and pregnancy/interval since last pregnancy (never pregnant, unknown, pregnant, last pregnant up to 12 months ago, last pregnant more than 12 months ago).
Table II shows the relationship between ulcer and parity. Taking all ulcers together, women of high parity are about a third more likely to experience hospital referral than those of low parity. Table III concentrates on cigarette smoking. Here, the relationship is clear and unequivocal for both duodenal and gastric ulcer. Considered together, there is a near doubling of the hospital referral rate in contrasting those who have never smoked with those who were smoking 15 or more cigarettes per day on entry to the study. The relationship between peptic ulcer on the one hand and pregnancy and interval since last pregnancy on the other is shown in Table IV. Some of the data fall into an unknown category because the dates of spontaneous and induced abortions and ectopic pregnancies (as opposed to the dates of stillbirths and livebirths) were not recorded prior to entry
352
Contraception Table II.
Parity
Peptic ulcer and parity
Duodenal ulcer No. Rate/ TWY cases
Gastric ulcer No. Rate/ cases TWY
All peptic ulcers No. Ratej cases TWY
7
0.38
2
0.17
9
0.60
l-2
55
0.33
29
0.17
94
0.55
3t
43
0.49
24
0.26
72
0.80
Nulliparous
x2 trend = 2.5 P = 0.1
trend = 2.2 P = 0.1
x2
x2
trend = 4.1 P = 0.04
TWY = thousand woman-years Rates adjusted for age (6 groups), smoking (4 groups), pregnancy/ interval since last pregnancy (5 groups). Table III. Cigarettes smoked per day
Peptic ulcer and smoking
Duodenal ulcer No. Rate/ cases TWY
Gastric ulcer No. Rate/ cases TWY
All peptic ulcers No. Rate/ cases TWY
51
0.32
21
0.13
80
0.51
9
0.28
4
0.12
18
0.56
1-14
24
0.49
20
0.40
44
0.89
15t
21
0.57
10
0.27
33
0.89
Never Ex
x2 trend = 5.8 P = 0.02
x2 trend = 9.4
P = 0.002
X2 trend = 11.8 P = 0.001
TWY = thou:and woman-years Rates adjusted for age (6 groups), parity (3 groups), pregnancy/ interval since last pregnancy (5 groups). to the study; only information on the number of such events was noted. Nonetheless, it will be apparent that most of the woman-years in the unknown category will not have accumulated during pregnancy or in close proximity to pregnancy.
Contraception
353
The overall data in Table IV show a remarkable uniformity of rates in all categories, save for a low rate in the pregnancy category and a zero rate in the up to 12 months since last pregnant category. These differences are not formally significant, but they are clearly compatible with the findings reported in the introduction. Table IV.
Pregnancy/interval since last pregnancy
Never pregnant
Peptic ulcer in relation to pregnancy/ interval since last pregnancy Duodenal ulcer No. Rate/ cases TWY
Gastric ulcer No. Rate/ cases TWY
All peptic ulcers No. Rate/ cases TWY
6
0.39
2
0.24
8
0.67
Not known
13
0.36
8
0.21
26
0.71
Pregnant
1
0.26
0
0.00
1
0.29
-12
0
0.00
0
0.00
0
0.00
13-24
4
0.60
1
0.15
5
0.76
25-48
2
0.13
5
0.35
8
0.54
49-72
6
0.32
3
0.18
11
0.62
73-96
11
0.51
3
0.16
16
0.78
97-120
8
0.35
5
0.26
13
0.59
54
0.42
28
0.20
87
0.65
Interval since last pregnancy (mths):-
120+
x2 trend = 0.9 P = 0.3
x2 trend = 0.0 P = 1.0
X2 heterogeneity 7.8, P = 0.6
x2
heterogeneity 4.3, P = 0.9
X2
trend = 0.0 P = 0.9
x2 heterogeneity 6.3, P = 0.7
TWY = thousand woman-years Rates adjusted for age (6 groups), parity (3 groups), smoking (4 groups). In Table V, the relationship between peptic ulcer and total duration of oral contraceptive use is examined. The data show random variation only and there is no hint of a protective effect of the pill.
Contraception
354 Table V.
Overall duration of oral contraceptive use (mths) Non user
Peptic ulcer and overall duration of oral contraceptive use
Duodenal ulcer No. Rate/ TWY cases
Gastric ulcer No. Rate/ cases TWY
All peptic ulcers No. Rate/ TWY cases
46
0.41
26
0.22
78
0.68
-12
2
0.25
1
0.13
3
0.38
13-24
5
0.49
3
0.31
10
1.00
25-48
12
0.47
4
0.16
18
0.71
49-72
5
0.16
5
0.19
12
0.41
73-96
14
0.52
6
0.27
22
0.87
97+
21
0.34
10
0.15
32
0.50
x2 trend = 0.4 P = 0.5
x2 trend
= 0.6 P = 0.4
x2 trend = 1.1 P = 0.3
TWY = thousand woman-years Rates adjusted for age (6 groups), parity (3 groups), smoking (4 groups) pregnancy/interval since last pregnancy (5 groups).
Table VI considers the relationship between peptic ulcer and recency of oral contraceptive use. None of the differences within the columns is statistically significant and there are no significant trends in the table. However, it is of some interest that both for duodenal ulcer and for all ulcers combined, the lowest rate is among the current users of oral contraceptives. The data are clearly compatible with some protective effect of current oral contraceptive use, but the numbers available for the present analysis do not permit any more definite statement than that. Examination of oral contraceptive type was unhelpful as is usually the case in the Oxford-FPA study in which some 75% of all oral contraceptive exposure is to pills containing 50 pg oestrogen.
355
Contraception Table VI.
Peptic ulcer and recency of oral contraceptive use
Interval between last use of oral contraceptives & hospital referral for peptic ulcer
Duodenal ulcer No. cases
Gastric ulcer
All peptic ulcers
Rate/ TWY
No.
Rate/ TWY
No.
Rate/ TWY
Non-user
46
0.41
26
0.22
78
0.68
Current user
I1
0.22
9
0.20
20
0.42
-12
9
0.62
0
0.00
9
0.67
13-24
3
0.27
1
0.11
25-48
12
0.57
0
0.00
13
0.64
49-72
10
0.52
8
0.43
21
1.09
73-96
7
0.41
4
0.23
10
0.58
97+
7
0.23
7
0.19
19
0.58
X2 trend = 0.02 P = 0.9 x2
heterogeneity 11.0, P=O.l
X2 trend = 0.0 P = 1.0 x2
heterogeneity 11.8, P=O.l
0.47
x2 trend = 0.1 P = 0.7 x2
heterogeneity 10.8, P=O. 1
TWY = thousand woman-years Rates adjusted for age (6 groups), parity (3 groups), smoking (4 groups), pregnancy/interval since last pregnancy (5 groups).
DISCUSSION Peptic ulcer disease is known to increase with age (7) and with cigarette smoking (8) and our findings on pregnancy and interval since last pregnancy seem to fit in with existing evidence (l-4). We are, however, unaware of any previous evidence linking risk to parity. This should be a simple enough hypothesis to test in another data set now that we have drawn attention to the possibility. The theoretical background to the present analysis was summarised in the Introduction and will not be repeated here. In addition to the previous study of one of us (5) which led to an inconclusive result, data on peptic ulcer and oral contraceptives have been published from the
356
Contraception
Royal College of General Practitioners (9) study and from the Walnut Creek Study (10). The first of these studies included only 16 cases of gastric ulcer, too few to analyse. There were, however, 76 cases of duodenal ulcer with a deficit amongst current pill users and an excess among ex-users. Although the results did not reach statistical significance, they are very carefully discussed by the authors who come to the conclusion that the low incidence of duodenal ulcer in current users is due to selection rather than a protective effect. In the Walnut Creek Study, there were 19 cases of gastric ulcer and 18 of duodenal ulcer, an unexpected ratio. Not surprisingly with such small numbers, the authors concluded that "no clear pattern of risk" was apparent in their data. Our present findings, which represent the largest data set to be reported so far, take matters a little further. First, there is no sign of any relationship between peptic ulcer and overall duration of oral contraceptive use. Secondly, there are no significant differences in risk in the table relating to recency of oral contraceptive use and it would be reasonable to leave matters like that. However, there is just a suggestion of a lower rate in the current user group than in other groups and this must still leave doubt about the possibility of some small protective effect in women using the pill. To investigate this further would require an extremely large study of very careful design and we suspect that, like the possible minimal protective effect of oral contraceptives against thyroid disease (ll), the issue will remain undecided. ACKNOWLEDGEMENTS We thank Mrs. P. Brown, Mrs. D. Collinge, Mrs. J. Winfield, and the research assistants, doctors, nurses and administrative staff working at the participating clinics for their hard work and loyal support. We are also grateful to the Medical Research Council, the Imperial Cancer Research Fund and the Knott Family Trust for financial support. REFERENCES 1.
Sandweiss DJ, Saltzstein HC, Farbman AA. The relation of sex hormones to peptic ulcer. Am J Dig Dis 1939; 6:6-12.
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Jones
3.
Rider JA, Kirsner JB, Palmer WL. Active duodenal ulcer in pregnancy. Gastroenterology 1953; 24:357-68.
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Clark DH.
5.
Glober G, Doll R, Fairbairn AS, Vessey MP. Peptic ulceration and the use of oral contraceptives: A negative correlation attributable to the disease? Br J Prev Sot Med 1971; 25:144-46.
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Vessey M, Doll R, Peto R, Johnson 8, Wiggins P. A long-term follow-up study of women using different methods of contraception an interim report. J Biosoc Sci 1976; 8~373-427.
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Schoon I-M, Mellstrom D, Oden A, Ytterberg B-O.
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Sol1 AH. therapy.
9.
Royal College of General Practitioners. Oral Contraceptives and Health. London: Pitman Medical, 1974.
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The Walnut Creek Contraceptive Drug Study. Bethesda, 1981.
11.
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