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Discriminatory human chorionic gonadotropin zone “demilitarized”
Yolume 160 Number 5, Part 1
Reply To the Edtlors:
We appreciate the comments of Dr, Pastorek and will attempt to allay his reservations with regard to our study's design, The study group's patients-pregnant women with idiopathic premature contractions-were carefully selected to eliminate any possible known etiologic factor that might cause premature contractions, Thus we excluded all women with various medical problems that are known to provoke premature contractions, and by so doing we hoped to focus on chlamydia as a possible cause of premature contractions, Women with no history of pelvic inflammatory disease were placed in the control group to minimize the possibility of chlamydial infection, Therefore, it is logical to compare the study group with the control groups and to draw the conclusion that chlamydia probably has no role in premature contractions, With regard to Dr. Pastorek's second point, we direct his attention to Guderian and Trobough'sl statement that chlamydial salpingitis may be subclinical in approximately two thirds to three fourths of cases, and that it may persist indefinitely as chronic intrapelvic infection until appropriate antibiotic therapy is administered, They also claim that chlamydial cultures and smears are of little benefit in the diagnosis of chronic upper tract chlamydial infection. It is quite possible that the pregnant women with asymptomatic persistent pelvic infection might have recurrent asymptomatic exacerbations. At the same time, it has been hypothesized that asymptomatic genitourinary tract infections may stimulate the onset of preterm labor.2 Patients with premature rupture of the membranes were excluded from the present study because they were the target of a different project. We are hopeful that we will publish the results of that project in the near future. Ilan Cohen, AID Moshe Fejgin, MD Department of Obstetrics and Gynecology "A" Meir General Hospital Sapir Medical Center Kfar Saba 44281. Israel
REFERENCES
I. Guderian AM, Trobough GE. Residues of pelvic inflammatory disease in intrauterine device users: a result of the intrauterine device or Chlam~dta trachomatlS infection? AM J OBSTET GYNECOL 1986;154:497-503. 2, MacDonald P, Alexander D. Summary of a workshop on antenatal genitourinary infections and the outcome of pregnancy. J Infect Dis 1983; 147:596-604.
Correspondence
1255
Discriminatory human chorionic gonadotropin zone "demilitarized" To the Editors: We would like to comment on the article (Bernaschek G, Rudelstorfer R, Csaicsich P. Vaginal sonography versus serum human chorionic gonodotropin in early detection of pregnancy. AM J OBSTET GYNECOL 1988; 158:608-12) in which several references were made to earlier work by us and to a supposedly ongoing dispute between ourselves and Nyberg et al.I We do so because we believe there is a danger that the discriminatory human chorionic gonadotropin (hCG) zone, which has been shown repeatedly to be useful in the ultrasonographic evaluation for ectopic pregnancy, will lose its clinical relevance as far as practicing gynecologists are concerned by virtue of its being unnecessarily embroiled in a pseudoscientific controversy. First, there is no genuine controversy between ourselves and Nyberg et al.I In our opinion, these investigators made what should have been a useful contribution to the literature by defining the discriminatory hCG zone for assays standardized against the Second International Standard (2nd-IS) (they used three different assays to generate their data), inasmuch as the discriminatory hCG zone was originally derived with the use of an assay standardized against the International Reference Preparation (IRP). Contrary to what seems to be believed, it is not meaningful to use a single conversion factor to derive an equivalence between readings obtained against these two standards in different assays. (The use of such a conversion factor would be valid only for the comparison of readings obtained against the two standards in the same assay, which one would never wish to do in practice.) For example, Rasor et aJ.2 analyzed 10 different commercially available hCG assays and found that the IRP gave readings 1.75 to 3.5 higher than the 2nd-IS. Furthermore, the standard curves of different assays were usually not parallel, which makes it impossible to use a single conversion factor even for two specific assays. In short, the conversion factor of 2.2 quoted by Bernaschek et al. is valid for their assay but is not necessarily valid for any other assay. Nyberg et al.'s results may appear different than ours. However, this is in no small part attributable to the different RCG standard used to calibrate their assays. They have espoused the view that there is an intimate relationship between the resolution of the ultrasonographic equipment used and the value obtained for the discriminatory hCG zone. Obviously, when major improvements in resolution occur, as with the vaginal probe, the value of the discriminatory hCG zone will be reduced. Indeed, several groups are gathering data to determine the discriminatory heG zone for the vaginal probe. Some of these data are in press and show values considerably higher than those reported by Ber-
1256 Correspondence
naschek et al. However, Nyberg et al.'s view was different. Their comments implied that in their view there was a graded relationship between the resolution of the sonar equipment and the value of the discriminatory heG zone, a relationship that constituted a continuum. To the best of our knowledge, the scientific evidence to support this contention is not available. The reasons why we hold this viewpoint have been outlined elsewhere." 4 Second, Bernaschek et al., like Nyberg et al. before them, devote considerable space to the question of when it is first possible to detect the gestational sac of an intrauterine pregnancy ultrasonographically. However, it should be stressed that the heG value above which one can detect the gestational sac of an intrauterine pregnancy may not be the same heG value above which failure to detect a gestational sac has a very high predictive value for ectopic pregnancy. Whether these respective heG values coincide is a matter of pure serendipity. As we have pointed out, it may be deduced a priori that there must be an heG value below which the sac of an intrauterine pregnancy can never be ultrasonographically detected, a value above which it can always be detected, and intervening values at which a sac can sometimes be detected and sometimes not." The most appropriate way to determine the probability of detecting a gestational sac above a certain heG value is by subjecting a set of data to probit or logit analysis, which has not been done. We were residents when our original work on the discriminatory heG zone was carried out, and unfortunately at that time we were not familiar with the principles of regression analysis as applied to quantal data (the classic pro bit or the now more usual, but equivalent, logit analysis). We did, however, carry out an exact statistical test that showed the probability that a discriminatory heG zone did not exist in the heG range of 4000 to 8500 mIU/ml (IRP) was 1.211000. 3 It would be useful if Bernaschek et al. could carry out regression analysis on their data and derive statistically appropriate fiducial limits. Whereas the question as to which heG value corresponds to the upper fiducial limit of the discriminatory heG zone is a purely statistical one, the question as to whether such a threshold value is of any practical use is not a statistical, but a pragmatic, issue. It is vital that readers understand this distinction. In other words, the heG value at which a gestational sac can be detected in 99% of intrauterine pregnancies may not be the value above which failure to detect a gestational sac implies ectopic pregnancy ~95% of the time, as was the case of our discriminatory heG zone. In our data most cases of threatened or missed abortions were associated with a gestational sac either above or below our discriminatory heG zone, or no gestational sac below the zone." 6 If the failure to detect a gestational sac at heG levels that are above a particular statistically derived zone were to be a common finding in cases of
May 1989 Am J Obstet Gynecol
spontaneous abortion, then the practical use of that zone for the diagnosis of ectopic pregnancy would be severely limited. From the data provided by Bernaschek et al., it is not possible to determine the predictive value for an ectopic pregnancy of failure to detect a gestational sac by a vaginal probe above an heG value of 750 (2nd-IS). In summary, other investigators may legitimately wish to pose a number of questions about the correlation of serum heG and sonar findings. Among these might be how the gestational sac increases with serum heG and at what heG level a gestational sac can first be detected by sonar. These issues are unrelated both to the early diagnosis of ectopic pregnancy by the combined use of heG and sonar and to the usefulness of the discriminatory heG zone when the resultant findings are interpreted. We hope we can persuade our colleagues not to confuse their research interests with what has been repeatedly shown to be a useful test. When they have convincingly defined better diagnostic criteria for ectopic pregnancy (i.e., criteria that enable an earlier diagnosis to be reached with the same predictive value), everyone should embrace those criteria, but not until then. We would like to ask the authors, parenthetically, how they measure sac diameter. Nzcholas Kadar, MD Department of Obstetrics and Gynecology Albert Einstein Medical Center 410 Klem Building 5501 Old York Road Philadelphia, PA 19141 Roberto Romero, MD Department of Obstetrics and Gynecology Yale-New Haven Hospital 333 Cedar Street New Haven, CT 06510 REFERENCES I. Nyberg DA, Filly RA, Mahony BS, Monroe S, Laing FC, Jeffrey RB. Early gestation: correlation of hCG levels and sonographic identification. Am J Roentgenol 1985; 144: 951-4. 2. Rasor JL, Farber S, Braunstein GD. An evaluation of 10 kits for determination of human choriogonadotropin in serum. Clin Chern 1983;29:1828-31. 3. Romero R, Kadar N. Reply to Drs. Pittaway, Nyberg, et al. Obstet Gynecol 1986;68:441-2. 4. Kadar N, Romero R. hCG standardization. Fertil Steril 1987;47:722-3. 5. Kadar N, DeVore G, Romero R. Discriminatory hCG zone: its use in the sonographic evaluation for ectopic pregnancy. Obstet Gynecol 1981 ;58: 156-61. 6. Romero R, Kadar N, Jeanty P, Copel FA, Chervenak FA, DeCherney AH, Hobbins JC. A prospective study of the value of the discriminatory hCG zone in the diagnosis of ectopic pregnancy. Obstet Gynecol 1985;66:357-60.
Reply To the Editors: Dr. Kadar's arguments have been published in different journals. l We agree that one should always be aware that dif-
Reply To the Edtlors:
We appreciate the comments of Dr, Pastorek and will attempt to allay his reservations with regard to our study's design, The study group's patients-pregnant women with idiopathic premature contractions-were carefully selected to eliminate any possible known etiologic factor that might cause premature contractions, Thus we excluded all women with various medical problems that are known to provoke premature contractions, and by so doing we hoped to focus on chlamydia as a possible cause of premature contractions, Women with no history of pelvic inflammatory disease were placed in the control group to minimize the possibility of chlamydial infection, Therefore, it is logical to compare the study group with the control groups and to draw the conclusion that chlamydia probably has no role in premature contractions, With regard to Dr. Pastorek's second point, we direct his attention to Guderian and Trobough'sl statement that chlamydial salpingitis may be subclinical in approximately two thirds to three fourths of cases, and that it may persist indefinitely as chronic intrapelvic infection until appropriate antibiotic therapy is administered, They also claim that chlamydial cultures and smears are of little benefit in the diagnosis of chronic upper tract chlamydial infection. It is quite possible that the pregnant women with asymptomatic persistent pelvic infection might have recurrent asymptomatic exacerbations. At the same time, it has been hypothesized that asymptomatic genitourinary tract infections may stimulate the onset of preterm labor.2 Patients with premature rupture of the membranes were excluded from the present study because they were the target of a different project. We are hopeful that we will publish the results of that project in the near future. Ilan Cohen, AID Moshe Fejgin, MD Department of Obstetrics and Gynecology "A" Meir General Hospital Sapir Medical Center Kfar Saba 44281. Israel
REFERENCES
I. Guderian AM, Trobough GE. Residues of pelvic inflammatory disease in intrauterine device users: a result of the intrauterine device or Chlam~dta trachomatlS infection? AM J OBSTET GYNECOL 1986;154:497-503. 2, MacDonald P, Alexander D. Summary of a workshop on antenatal genitourinary infections and the outcome of pregnancy. J Infect Dis 1983; 147:596-604.
Correspondence
1255
Discriminatory human chorionic gonadotropin zone "demilitarized" To the Editors: We would like to comment on the article (Bernaschek G, Rudelstorfer R, Csaicsich P. Vaginal sonography versus serum human chorionic gonodotropin in early detection of pregnancy. AM J OBSTET GYNECOL 1988; 158:608-12) in which several references were made to earlier work by us and to a supposedly ongoing dispute between ourselves and Nyberg et al.I We do so because we believe there is a danger that the discriminatory human chorionic gonadotropin (hCG) zone, which has been shown repeatedly to be useful in the ultrasonographic evaluation for ectopic pregnancy, will lose its clinical relevance as far as practicing gynecologists are concerned by virtue of its being unnecessarily embroiled in a pseudoscientific controversy. First, there is no genuine controversy between ourselves and Nyberg et al.I In our opinion, these investigators made what should have been a useful contribution to the literature by defining the discriminatory hCG zone for assays standardized against the Second International Standard (2nd-IS) (they used three different assays to generate their data), inasmuch as the discriminatory hCG zone was originally derived with the use of an assay standardized against the International Reference Preparation (IRP). Contrary to what seems to be believed, it is not meaningful to use a single conversion factor to derive an equivalence between readings obtained against these two standards in different assays. (The use of such a conversion factor would be valid only for the comparison of readings obtained against the two standards in the same assay, which one would never wish to do in practice.) For example, Rasor et aJ.2 analyzed 10 different commercially available hCG assays and found that the IRP gave readings 1.75 to 3.5 higher than the 2nd-IS. Furthermore, the standard curves of different assays were usually not parallel, which makes it impossible to use a single conversion factor even for two specific assays. In short, the conversion factor of 2.2 quoted by Bernaschek et al. is valid for their assay but is not necessarily valid for any other assay. Nyberg et al.'s results may appear different than ours. However, this is in no small part attributable to the different RCG standard used to calibrate their assays. They have espoused the view that there is an intimate relationship between the resolution of the ultrasonographic equipment used and the value obtained for the discriminatory hCG zone. Obviously, when major improvements in resolution occur, as with the vaginal probe, the value of the discriminatory hCG zone will be reduced. Indeed, several groups are gathering data to determine the discriminatory heG zone for the vaginal probe. Some of these data are in press and show values considerably higher than those reported by Ber-
1256 Correspondence
naschek et al. However, Nyberg et al.'s view was different. Their comments implied that in their view there was a graded relationship between the resolution of the sonar equipment and the value of the discriminatory heG zone, a relationship that constituted a continuum. To the best of our knowledge, the scientific evidence to support this contention is not available. The reasons why we hold this viewpoint have been outlined elsewhere." 4 Second, Bernaschek et al., like Nyberg et al. before them, devote considerable space to the question of when it is first possible to detect the gestational sac of an intrauterine pregnancy ultrasonographically. However, it should be stressed that the heG value above which one can detect the gestational sac of an intrauterine pregnancy may not be the same heG value above which failure to detect a gestational sac has a very high predictive value for ectopic pregnancy. Whether these respective heG values coincide is a matter of pure serendipity. As we have pointed out, it may be deduced a priori that there must be an heG value below which the sac of an intrauterine pregnancy can never be ultrasonographically detected, a value above which it can always be detected, and intervening values at which a sac can sometimes be detected and sometimes not." The most appropriate way to determine the probability of detecting a gestational sac above a certain heG value is by subjecting a set of data to probit or logit analysis, which has not been done. We were residents when our original work on the discriminatory heG zone was carried out, and unfortunately at that time we were not familiar with the principles of regression analysis as applied to quantal data (the classic pro bit or the now more usual, but equivalent, logit analysis). We did, however, carry out an exact statistical test that showed the probability that a discriminatory heG zone did not exist in the heG range of 4000 to 8500 mIU/ml (IRP) was 1.211000. 3 It would be useful if Bernaschek et al. could carry out regression analysis on their data and derive statistically appropriate fiducial limits. Whereas the question as to which heG value corresponds to the upper fiducial limit of the discriminatory heG zone is a purely statistical one, the question as to whether such a threshold value is of any practical use is not a statistical, but a pragmatic, issue. It is vital that readers understand this distinction. In other words, the heG value at which a gestational sac can be detected in 99% of intrauterine pregnancies may not be the value above which failure to detect a gestational sac implies ectopic pregnancy ~95% of the time, as was the case of our discriminatory heG zone. In our data most cases of threatened or missed abortions were associated with a gestational sac either above or below our discriminatory heG zone, or no gestational sac below the zone." 6 If the failure to detect a gestational sac at heG levels that are above a particular statistically derived zone were to be a common finding in cases of
May 1989 Am J Obstet Gynecol
spontaneous abortion, then the practical use of that zone for the diagnosis of ectopic pregnancy would be severely limited. From the data provided by Bernaschek et al., it is not possible to determine the predictive value for an ectopic pregnancy of failure to detect a gestational sac by a vaginal probe above an heG value of 750 (2nd-IS). In summary, other investigators may legitimately wish to pose a number of questions about the correlation of serum heG and sonar findings. Among these might be how the gestational sac increases with serum heG and at what heG level a gestational sac can first be detected by sonar. These issues are unrelated both to the early diagnosis of ectopic pregnancy by the combined use of heG and sonar and to the usefulness of the discriminatory heG zone when the resultant findings are interpreted. We hope we can persuade our colleagues not to confuse their research interests with what has been repeatedly shown to be a useful test. When they have convincingly defined better diagnostic criteria for ectopic pregnancy (i.e., criteria that enable an earlier diagnosis to be reached with the same predictive value), everyone should embrace those criteria, but not until then. We would like to ask the authors, parenthetically, how they measure sac diameter. Nzcholas Kadar, MD Department of Obstetrics and Gynecology Albert Einstein Medical Center 410 Klem Building 5501 Old York Road Philadelphia, PA 19141 Roberto Romero, MD Department of Obstetrics and Gynecology Yale-New Haven Hospital 333 Cedar Street New Haven, CT 06510 REFERENCES I. Nyberg DA, Filly RA, Mahony BS, Monroe S, Laing FC, Jeffrey RB. Early gestation: correlation of hCG levels and sonographic identification. Am J Roentgenol 1985; 144: 951-4. 2. Rasor JL, Farber S, Braunstein GD. An evaluation of 10 kits for determination of human choriogonadotropin in serum. Clin Chern 1983;29:1828-31. 3. Romero R, Kadar N. Reply to Drs. Pittaway, Nyberg, et al. Obstet Gynecol 1986;68:441-2. 4. Kadar N, Romero R. hCG standardization. Fertil Steril 1987;47:722-3. 5. Kadar N, DeVore G, Romero R. Discriminatory hCG zone: its use in the sonographic evaluation for ectopic pregnancy. Obstet Gynecol 1981 ;58: 156-61. 6. Romero R, Kadar N, Jeanty P, Copel FA, Chervenak FA, DeCherney AH, Hobbins JC. A prospective study of the value of the discriminatory hCG zone in the diagnosis of ectopic pregnancy. Obstet Gynecol 1985;66:357-60.
Reply To the Editors: Dr. Kadar's arguments have been published in different journals. l We agree that one should always be aware that dif-