- Email: [email protected]
Response to the editor
Letters to the Editor 1%
Contraception 1996;54:193-198
biases, the consistency of results between studies and lack of evidence of bias by those factors which the studies did address is remarkable. No quantitative evidence has been presented that the consistent observation of increased VTE risk in independent studies can be explained by bias. L&M’s recommendation that women who smoke or have a family history of stroke or myocardial infarction should in preference use third generation progestogen-containing OCs is brave since it is based on preliminary findings from a single study”-substantially less evidence than that available to suggest an excess VTE risk. Moreover, in that study there was no consistency in results between the different countries and an analysis restricted to United Kingdom from where the majority of cases arose showed no difference in risk between OC types. Women and their providers need to make a careful assessment based on personal circumstances and scientific knowledge of the risks and benefits of different contraceptive methods. To speculate that the recently published studies are all subject to bias without providing any evidence that this occurred suggests preconceived views which do not respond to evidence. The public must have confidence that the scientific community, providers and policy makers will seek evidence on the safety of contraceptive methods, and that such evidence will be evaluated, published and acted upon, even if it is uncomfortable.
5.
6. 7.
8. 9.
10. 11.
stiller HR, Vandenbroucke JP. Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing a thirdgeneration progestagen. Lancet 1995;346:1593-6. Spitzer WO, Lewis MA, Heinemann LAJ, Thorogood M, MacRae KD on behalf of Transnational Research Group on Oral Contraceptives and the Health of Young Women. Third generation oral contraceptives and risk of venous thromboembolic disorders: an international case-control study. BMJ 1996;312:83-8. Farmer R, Safety of oral contraceptives (Letter). Lancet 1996;347:259. Vandenbroucke JP, Koster T, Briet E, Retsma PH, Bertina RM, Rosendaal FR. Increased risk of venous thrombosis in oral contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994;344: 1453-7. Poulter NR, Farley TMM, Chang CL, Marmot MG, Meirik 0. Safety of combined oral contraceptive pills (Letter). Lancet 1996;347:547. Second European Conference on Sex Steroids and Metabolism. Consensus statement: Consensus development meeting 1995: combined oral contraceptives and cardiovascular disease. Gynecol Endocrinol 1996; 10: l-5. Speroff L, de Cherney A, and the Advisory Board for the New Progestins. Evaluation of a new generation of oral contraceptives. Obstet Gynecol 1993;81:1034-47. Lewis MA, Spitzer WO, Heinemann LAJ, MacRae KD, Bruppacher R, Thorogood M. Third generation oral contraceptives and risk of myocardial infarction: an international case-control study. BMJ 1996;312:88-90.
T.M.M. 0. Meirik,
Special Programme of Research Development and Research Training in Human Reproduction World Health Organization CH-1211 Geneva 27 Switzerland
References 1. Lidegaard 0, Milsom I. Oral contraceptives and thrombotic disease: impact of new epidemiological studies. Contraception 1996;53:135-9. 2. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Effect of different progestagens in low oestrogen oral contraceptives on venous thromboembolic disease. Lancet 199&346:1582-g. 3. Jick H, Jick SS, Gurewich V, Myers MW, Vasilakis C. Risk of cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet 1995; 346:1589-93. 4. Bloemenkamp KWM, Rosendaal FR, Helmerhorst FM,
Farley, Ph.D M.D., Ph.D.
N.R. Poulter, FRCP C.L. Chang, Msc M.G. Marmot, FFPHM Department
of Epidemiology
and Public Health University College London Medical School United Kingdom
PI1 SOOlO-7824(96)00166-7
RESPONSE TO THE EDITOR To the Editors: We wish to express our thanks to Farley, Poulter, Meirik, Chang and Marmot for their comments on
our guest editorial in Contraception.’ Our response follows the same succession as their comments. It is true that we have no proof that the differences in risk for venous thromboembolism (VTE) between
196
Letters to the Editor
Contraception
1996;54:193-198
users of oral contraceptives (OCs) with 2nd and 3rd generation progestins published in December 1995 and January 1996 are due to bias. The reason for this is primarily the lack of data in the published studies which could evaluate all important potential biases. However, as scientists and advisers we are obliged to evaluate potential biases and the probability that these may influence or explain the results. This obligation became especially apparent after the dramatic, and in our opinion, immature actions from health authorities in some countries, especially in Great Britain. In order to make an adequate confounder control, at least three circumstances should be fulfilled: l l
l
all relevant confounders should be considered; information about each confounder should be present for a high proportion of cases as well as controls; and the study should have an acceptable statistical power to conduct such a control.
The relevant confounders concerning the relationship between OC types and VTE are age, family history of VTE, body mass index (BMI), varicose veins, previous births, hypertension during any pregnancy, duration of OC use and referral practice. The WHO study did (in our opinion) control adequately for age and BMI, insufficiently for varicose veins and hypertension during pregnancy (due to missing information in a substantial part of their cases and controls), and not at all for family VTE, and referral practice. Thus, despite a well-planned, conducted, and described study, control for important confounders was also missing in this study.
Prescription
Bias
It has been substantially documented that the new OCs (correctly or not) have been marketed as safer than older OCs. This has been documented among the controls in an ongoing Danish case-control study on stroke and OCs (unpublished data, submitted for publication), and empirical support for preferential prescribing has also been found in Germany, France and Great Britain.’ The new OCs have by some workers been considered so safe that some women who previously would not have been prescribed OCs, now take them despite relative contraindications. These facts do not prove that the WHO results have been influenced by that potential bias, but preferential prescribing is a reality. We did not ignore the Leiden data. On the contrary, we stated that the circumstance that control for family VTE in that study did not change the OR between
2nd and 3rd generation products significantly was supportive of a causal relationship. This circumstance, however, doesn’t change the fact that missing control for other important confounders may also have influenced the results of the Leiden study. We postulate that in future studies there might be circumstances that could be difficult to control for, and which at the same time could influence the risk of VTE. For example, if a woman is especially concerned about thrombotic risks (without specific risk factors) such a woman is (or was) probably more likely to be prescribed a 3rd rather than a 2nd generation product. Such concerned women would probably be more aware of any symptoms of VTE, and therefore probably have a higher chance of being examined for VTE in case of discrete symptoms. But how do we take into account such a concern in future studies? In other words, one thing is the presence of a clear cut risk factor for VTE. Another thing is clinical circumstances that at the same time influence our recommendations and may influence the risk of VTE, and that are difficult to evaluate in observational epidemiological studies.
Diagnosis or Referral Bias In United Kingdom, more than two-thirds of patients with VTE are not hospitalized.3 Therefore, the study of VTE may be especially susceptible to referral bias and diagnosis bias. We agree that the design of the WHO study did not make it possible to control for that potential bias, but we disagree that this bias probably is without significance. One support that this bias is in effect is the fact that the AAH Meditel study,3 which included also non-hospitalized women with VTE, found smaller differences between 2nd and 3rd generation users than did the other four studies. Another support for such a bias is the fact that no difference in deaths from VTE was found between 2nd and 3rd generation product.4 Deaths are not susceptible to referral bias.
Lower Overall Incidence of VTE As the relative risk of VTE is independent of age, any altered age distribution of users of OCs should not influence the VTE risk of OCs by time. The incidence rate of VTE increases linearly with age (Figure 1). As estrogen dose was the same for the levonorgestrel products in the new and older studies, it is difficult to explain the reduced risk for identical products by other means than a changed selection of users of that product. The improved diagnostic facilities would tend to increase rather than decrease the risk in the new studies.
Letters to the Editor 197
Contraception 1996;54:193-198
lncidence1100,000/year.
been able to demonstrate differences between 2nd and 3rd generation products that can explain the epidemiological findings is more suggestive of selection bias than of a causal influence.
SW Cl indicated.
Conclusion
0
1 15-19
I 20-24
/ 25-29
! 30-34
I 35-39
I 40-44
Figure 1. Venous thromboembolism among young women in Denmark 1980-1993. Mean annual incidence rates according to age. Pregnant and puerperal women excluded.
Differential Patterns of OC Use According to Duration of Use Basically, we wonder how the WHO study on the one hand did not find any evidence of an influence from duration of use in their primary report5 (Table 6) and at the same time demonstrate a clear influence from duration in a later letter.6 Secondly, the Transnational group has found the risk of different brands to be dependent primarily on time of market introduction.2 How would the WHO group explain that the VTE risk of Mercilon is about twice the risk of Marvelon which contains 50% more estrogen than Mercilon and the same dose and type of desogestrel? We see only one possible explanation of this time dependency: a selection bias due to prescribing bias and recency of use. The same differences between these two products were found in the AAH Meditel study. Data on the relationship between market introduction and VTE risk have not been presented by the WHO group. These findings, in our opinion, strongly suggest that some kind of selection bias is in effect.
The most serious consequence of the actual situation is the apparent lack of comprehensive perspective in putting the new results in relation to other risks and benefits. For instance, we now have three independent studies that all demonstrate a decreased risk of AMI among users of 3rd compared with 2nd generation products. 7-9 Although the differences in none of the studies were significant at the 5% level, all indicated a rather large rate ratio. Despite the fact that VTE is more common among young women than AMI, the case-fatality rate of AM1 is higher than that for VTE resulting in identical mortality rates for these two diseases among young women (Figure 2). We are still awaiting the AM1 results from the WHO study but, so far, we find empirical support to recommend 3rd generation products for women with arterial risk factors. We agree that the decision on which OC to prescribe should be based on a careful assessment of personal circumstances and scientific knowledge. In considering risks and benefits of specific brands, it is in our opinion unjustly imbalanced to look at only one rare disease (VTE) and disregard numerous other factors relevant to the choice of OCs. Decisions grounded purely on such a limited aspect may lead (and probably have led) health authorities and the press to immature conclusions, with harmful effects on the population as one possible serious consequence. Deathslmiolyear. 20
95% Cl indicated
N,,,=:65
:
:
:
: -
:
NV,=64
:
]
:
:
:
1
15
10
5
Lack of Biological Excess Risk
Explanation
for the
It is true that a missing biological explanation doesn’t exclude a causal difference between 2nd and 3rd generation products. Nevertheless, when evaluating the probability of selection bias versus a causal influence, the circumstance that metabolic studies have not
0
15-19
20-24
25-29
30-34
35-39
40-44
Mean
Figure 2. Mortality rates from venous thromboembolism and myocardial infarction among young Danish women during 1980-1993.Pregnant and puerperal women excluded.
198
Letters to the Editor
References 1. Lidegaard 0, Milsom I. Oral contraceptives and thrombotic diseases:impact of new epidemiological studies. Contraception 1996;53:135-9. 2. ReekersH, Norpoth T, Michaels MA. Oral contraceptive use and venous thromboembolism: a consideration of the impact of bias and confounding factors on epidemiological studies. Eur J Contraception Reprod Health 1996; 1:2130. 3. Farmer R. (Letter). Lancet 1996;347:259. 4. Jick H, Jick SS, Gurewich V, Myers MW, Vasilakis C. Risk of ideopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet 1995;346:1589-93. 5. World Health Organization Collaborative Study on Cardiovascular Disease and Steroid Hormone Contraception. Venous thromboembolic diseaseand combined oral contraceptives: results of international multicentre casecontrol study. Lancet 1995;346:1575-82. 6. Poulter NR, Farley RMM, Chang CL, Marmot MG, Meirik 0. Safety of combined oral contraceptive pills (Letter). Lancet 1996;347:547. 7. Lewis MA, Spitzer WO, Heinemann LAJ, MacRae KD,
Contraception 1996;54:193-198
Bruppacher R, Thorogood M. Third generation oral contraceptives and risk of myocardial infarction: an international case-control study. BMJ 1996;312:88-90. 8. Jick H, Jick SS, Myers MW, Vasilakis C. Risk of acute myocardial infarction and low-dose combined oral contraceptives. (LetterJ. Lancet 1996;347:627-8. 9. Lidegaard 0, Edstrom B. Oral contraceptives and myocardial infarction. A case-control study. (Abstract). Eur J Contraception Reprod Health Care 1996;1:74.
Dr. Ojvind
Lidegaard
Department of OBlGYN Herlev Hospital University of Copenhagen DK-2 730 Herlev Denmark
Dr. Ian Milsom Dept. OBIGYN East Hospital University of G6teborg S-416 85 Gijteborg Sweden PI1 SOOlO-7824(96)00176-X
Contraception 1996;54:193-198
biases, the consistency of results between studies and lack of evidence of bias by those factors which the studies did address is remarkable. No quantitative evidence has been presented that the consistent observation of increased VTE risk in independent studies can be explained by bias. L&M’s recommendation that women who smoke or have a family history of stroke or myocardial infarction should in preference use third generation progestogen-containing OCs is brave since it is based on preliminary findings from a single study”-substantially less evidence than that available to suggest an excess VTE risk. Moreover, in that study there was no consistency in results between the different countries and an analysis restricted to United Kingdom from where the majority of cases arose showed no difference in risk between OC types. Women and their providers need to make a careful assessment based on personal circumstances and scientific knowledge of the risks and benefits of different contraceptive methods. To speculate that the recently published studies are all subject to bias without providing any evidence that this occurred suggests preconceived views which do not respond to evidence. The public must have confidence that the scientific community, providers and policy makers will seek evidence on the safety of contraceptive methods, and that such evidence will be evaluated, published and acted upon, even if it is uncomfortable.
5.
6. 7.
8. 9.
10. 11.
stiller HR, Vandenbroucke JP. Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing a thirdgeneration progestagen. Lancet 1995;346:1593-6. Spitzer WO, Lewis MA, Heinemann LAJ, Thorogood M, MacRae KD on behalf of Transnational Research Group on Oral Contraceptives and the Health of Young Women. Third generation oral contraceptives and risk of venous thromboembolic disorders: an international case-control study. BMJ 1996;312:83-8. Farmer R, Safety of oral contraceptives (Letter). Lancet 1996;347:259. Vandenbroucke JP, Koster T, Briet E, Retsma PH, Bertina RM, Rosendaal FR. Increased risk of venous thrombosis in oral contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994;344: 1453-7. Poulter NR, Farley TMM, Chang CL, Marmot MG, Meirik 0. Safety of combined oral contraceptive pills (Letter). Lancet 1996;347:547. Second European Conference on Sex Steroids and Metabolism. Consensus statement: Consensus development meeting 1995: combined oral contraceptives and cardiovascular disease. Gynecol Endocrinol 1996; 10: l-5. Speroff L, de Cherney A, and the Advisory Board for the New Progestins. Evaluation of a new generation of oral contraceptives. Obstet Gynecol 1993;81:1034-47. Lewis MA, Spitzer WO, Heinemann LAJ, MacRae KD, Bruppacher R, Thorogood M. Third generation oral contraceptives and risk of myocardial infarction: an international case-control study. BMJ 1996;312:88-90.
T.M.M. 0. Meirik,
Special Programme of Research Development and Research Training in Human Reproduction World Health Organization CH-1211 Geneva 27 Switzerland
References 1. Lidegaard 0, Milsom I. Oral contraceptives and thrombotic disease: impact of new epidemiological studies. Contraception 1996;53:135-9. 2. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Effect of different progestagens in low oestrogen oral contraceptives on venous thromboembolic disease. Lancet 199&346:1582-g. 3. Jick H, Jick SS, Gurewich V, Myers MW, Vasilakis C. Risk of cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet 1995; 346:1589-93. 4. Bloemenkamp KWM, Rosendaal FR, Helmerhorst FM,
Farley, Ph.D M.D., Ph.D.
N.R. Poulter, FRCP C.L. Chang, Msc M.G. Marmot, FFPHM Department
of Epidemiology
and Public Health University College London Medical School United Kingdom
PI1 SOOlO-7824(96)00166-7
RESPONSE TO THE EDITOR To the Editors: We wish to express our thanks to Farley, Poulter, Meirik, Chang and Marmot for their comments on
our guest editorial in Contraception.’ Our response follows the same succession as their comments. It is true that we have no proof that the differences in risk for venous thromboembolism (VTE) between
196
Letters to the Editor
Contraception
1996;54:193-198
users of oral contraceptives (OCs) with 2nd and 3rd generation progestins published in December 1995 and January 1996 are due to bias. The reason for this is primarily the lack of data in the published studies which could evaluate all important potential biases. However, as scientists and advisers we are obliged to evaluate potential biases and the probability that these may influence or explain the results. This obligation became especially apparent after the dramatic, and in our opinion, immature actions from health authorities in some countries, especially in Great Britain. In order to make an adequate confounder control, at least three circumstances should be fulfilled: l l
l
all relevant confounders should be considered; information about each confounder should be present for a high proportion of cases as well as controls; and the study should have an acceptable statistical power to conduct such a control.
The relevant confounders concerning the relationship between OC types and VTE are age, family history of VTE, body mass index (BMI), varicose veins, previous births, hypertension during any pregnancy, duration of OC use and referral practice. The WHO study did (in our opinion) control adequately for age and BMI, insufficiently for varicose veins and hypertension during pregnancy (due to missing information in a substantial part of their cases and controls), and not at all for family VTE, and referral practice. Thus, despite a well-planned, conducted, and described study, control for important confounders was also missing in this study.
Prescription
Bias
It has been substantially documented that the new OCs (correctly or not) have been marketed as safer than older OCs. This has been documented among the controls in an ongoing Danish case-control study on stroke and OCs (unpublished data, submitted for publication), and empirical support for preferential prescribing has also been found in Germany, France and Great Britain.’ The new OCs have by some workers been considered so safe that some women who previously would not have been prescribed OCs, now take them despite relative contraindications. These facts do not prove that the WHO results have been influenced by that potential bias, but preferential prescribing is a reality. We did not ignore the Leiden data. On the contrary, we stated that the circumstance that control for family VTE in that study did not change the OR between
2nd and 3rd generation products significantly was supportive of a causal relationship. This circumstance, however, doesn’t change the fact that missing control for other important confounders may also have influenced the results of the Leiden study. We postulate that in future studies there might be circumstances that could be difficult to control for, and which at the same time could influence the risk of VTE. For example, if a woman is especially concerned about thrombotic risks (without specific risk factors) such a woman is (or was) probably more likely to be prescribed a 3rd rather than a 2nd generation product. Such concerned women would probably be more aware of any symptoms of VTE, and therefore probably have a higher chance of being examined for VTE in case of discrete symptoms. But how do we take into account such a concern in future studies? In other words, one thing is the presence of a clear cut risk factor for VTE. Another thing is clinical circumstances that at the same time influence our recommendations and may influence the risk of VTE, and that are difficult to evaluate in observational epidemiological studies.
Diagnosis or Referral Bias In United Kingdom, more than two-thirds of patients with VTE are not hospitalized.3 Therefore, the study of VTE may be especially susceptible to referral bias and diagnosis bias. We agree that the design of the WHO study did not make it possible to control for that potential bias, but we disagree that this bias probably is without significance. One support that this bias is in effect is the fact that the AAH Meditel study,3 which included also non-hospitalized women with VTE, found smaller differences between 2nd and 3rd generation users than did the other four studies. Another support for such a bias is the fact that no difference in deaths from VTE was found between 2nd and 3rd generation product.4 Deaths are not susceptible to referral bias.
Lower Overall Incidence of VTE As the relative risk of VTE is independent of age, any altered age distribution of users of OCs should not influence the VTE risk of OCs by time. The incidence rate of VTE increases linearly with age (Figure 1). As estrogen dose was the same for the levonorgestrel products in the new and older studies, it is difficult to explain the reduced risk for identical products by other means than a changed selection of users of that product. The improved diagnostic facilities would tend to increase rather than decrease the risk in the new studies.
Letters to the Editor 197
Contraception 1996;54:193-198
lncidence1100,000/year.
been able to demonstrate differences between 2nd and 3rd generation products that can explain the epidemiological findings is more suggestive of selection bias than of a causal influence.
SW Cl indicated.
Conclusion
0
1 15-19
I 20-24
/ 25-29
! 30-34
I 35-39
I 40-44
Figure 1. Venous thromboembolism among young women in Denmark 1980-1993. Mean annual incidence rates according to age. Pregnant and puerperal women excluded.
Differential Patterns of OC Use According to Duration of Use Basically, we wonder how the WHO study on the one hand did not find any evidence of an influence from duration of use in their primary report5 (Table 6) and at the same time demonstrate a clear influence from duration in a later letter.6 Secondly, the Transnational group has found the risk of different brands to be dependent primarily on time of market introduction.2 How would the WHO group explain that the VTE risk of Mercilon is about twice the risk of Marvelon which contains 50% more estrogen than Mercilon and the same dose and type of desogestrel? We see only one possible explanation of this time dependency: a selection bias due to prescribing bias and recency of use. The same differences between these two products were found in the AAH Meditel study. Data on the relationship between market introduction and VTE risk have not been presented by the WHO group. These findings, in our opinion, strongly suggest that some kind of selection bias is in effect.
The most serious consequence of the actual situation is the apparent lack of comprehensive perspective in putting the new results in relation to other risks and benefits. For instance, we now have three independent studies that all demonstrate a decreased risk of AMI among users of 3rd compared with 2nd generation products. 7-9 Although the differences in none of the studies were significant at the 5% level, all indicated a rather large rate ratio. Despite the fact that VTE is more common among young women than AMI, the case-fatality rate of AM1 is higher than that for VTE resulting in identical mortality rates for these two diseases among young women (Figure 2). We are still awaiting the AM1 results from the WHO study but, so far, we find empirical support to recommend 3rd generation products for women with arterial risk factors. We agree that the decision on which OC to prescribe should be based on a careful assessment of personal circumstances and scientific knowledge. In considering risks and benefits of specific brands, it is in our opinion unjustly imbalanced to look at only one rare disease (VTE) and disregard numerous other factors relevant to the choice of OCs. Decisions grounded purely on such a limited aspect may lead (and probably have led) health authorities and the press to immature conclusions, with harmful effects on the population as one possible serious consequence. Deathslmiolyear. 20
95% Cl indicated
N,,,=:65
:
:
:
: -
:
NV,=64
:
]
:
:
:
1
15
10
5
Lack of Biological Excess Risk
Explanation
for the
It is true that a missing biological explanation doesn’t exclude a causal difference between 2nd and 3rd generation products. Nevertheless, when evaluating the probability of selection bias versus a causal influence, the circumstance that metabolic studies have not
0
15-19
20-24
25-29
30-34
35-39
40-44
Mean
Figure 2. Mortality rates from venous thromboembolism and myocardial infarction among young Danish women during 1980-1993.Pregnant and puerperal women excluded.
198
Letters to the Editor
References 1. Lidegaard 0, Milsom I. Oral contraceptives and thrombotic diseases:impact of new epidemiological studies. Contraception 1996;53:135-9. 2. ReekersH, Norpoth T, Michaels MA. Oral contraceptive use and venous thromboembolism: a consideration of the impact of bias and confounding factors on epidemiological studies. Eur J Contraception Reprod Health 1996; 1:2130. 3. Farmer R. (Letter). Lancet 1996;347:259. 4. Jick H, Jick SS, Gurewich V, Myers MW, Vasilakis C. Risk of ideopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet 1995;346:1589-93. 5. World Health Organization Collaborative Study on Cardiovascular Disease and Steroid Hormone Contraception. Venous thromboembolic diseaseand combined oral contraceptives: results of international multicentre casecontrol study. Lancet 1995;346:1575-82. 6. Poulter NR, Farley RMM, Chang CL, Marmot MG, Meirik 0. Safety of combined oral contraceptive pills (Letter). Lancet 1996;347:547. 7. Lewis MA, Spitzer WO, Heinemann LAJ, MacRae KD,
Contraception 1996;54:193-198
Bruppacher R, Thorogood M. Third generation oral contraceptives and risk of myocardial infarction: an international case-control study. BMJ 1996;312:88-90. 8. Jick H, Jick SS, Myers MW, Vasilakis C. Risk of acute myocardial infarction and low-dose combined oral contraceptives. (LetterJ. Lancet 1996;347:627-8. 9. Lidegaard 0, Edstrom B. Oral contraceptives and myocardial infarction. A case-control study. (Abstract). Eur J Contraception Reprod Health Care 1996;1:74.
Dr. Ojvind
Lidegaard
Department of OBlGYN Herlev Hospital University of Copenhagen DK-2 730 Herlev Denmark
Dr. Ian Milsom Dept. OBIGYN East Hospital University of G6teborg S-416 85 Gijteborg Sweden PI1 SOOlO-7824(96)00176-X