- Email: [email protected]
Postnatal outcome depends on prenatal history
Letters
Volume 165 Number 4, Part 1
localized in the intraductal space of the mammary gland would support the notion that the milk antigen may be synthesized and secreted by the breast, just as antigen appears to be synthesized and secreted by both the apocrine sweat glands and the endometrial glands, Leakage of this antigen into the maternal circulation, thereby contributing to the postpartum serum levels, is possible but unlikely unless access of the CA 125 antigen through the endothelium to the circulation can be accounted for. The likelihood that serum antigen is the source of the CA 125 in colostrum also is unlikely because of the great disparity in concentrations between serum CA 125 and colostrum CA 125, Nonetheless, we believe that paired concurrent assays of CA 125 in colostrum and serum in the postpartum period would be useful in the support or denial of these conclusions. Timothy J. O'Brien, PhD Department of Obstetrics and Gynecology, University of Arkansas for Medical Sciences, 4301 West Markham, Mail Slot 518, Little Rock, AR 72205-7199
REFERENCES 1. Fuith LC, Daxenbichler G, Marth C. CA 125 in human
milk and serum. Gynecol Obstet Invest 1989;28: 1-3. 2. Itahashi K, Inaba N, Fukazawa I, Takamizawa H. Immunoradiometrical measurement of tissue polypeptide antigen (TPA) and cancer antigen 125 (CAI25) in pregnancy and at delivery. Arch Gynecol Obstet 1988;243:191-7. Risk of open spina bifida To the Editors: Genetic counselors try to provide couples with the best estimate of their risk of birth defects. With the implementation of maternal serum u-fetoprotein (AFP) screening programs, patients with elevated maternal serum AFP levels are referred to ultrasonography specialists to look for fetal open spina bifid a and other lesions. Ultrasonographic examinations will show most of these patients to have normal fetuses. The revised numerical risk of a fetus having open spina bifida calculated on the basis of its mother's maternal serum AFP level plus normal results on ultra so nographic examination is important information that patients may want to use in deciding whether to accept the risk of amniocentesis. The figures presented by Thornton et al. (ThorntonJG, Lilford I\J, Newcombe RG. Tables for estimation of individual risks of fetal neural tube and ventral wall defects, incorporating prior probability, maternal serum u-fetoprotein levels, and ultrasonographic examination results. AM J OBSTET GYNECOL 1991;164:154-60) are therefore potentially very useful. My initial inspection of Tables II through IV focused on the upper of the three lines for each particular maternal serum AFP level. Each figure in this line "assumes that ultrasonography provides no information beyond maternal serum AFP" level. In other words, I presume the risk would be calculated solely on the basis of the maternal serum AFP level. If the population incidence of open spina bifid a is 1 in 1000, my reading of the tables indicates that a patient with a maternal serum AFP level of 2.0 multiples of
1159
the median would have a risk of fetal open spina bifida of 1 in 1800. If the ultrasonographic information is excluded, how can a patient with an elevated maternal serum AFP level end up with a lower risk than the risk that existed before the screening test was performed? Douglas W. Hershey, MD Prenatal Genetic Services, Sutter Center for Women's Health, 5275 F St., Sacramento, CA 95819
Reply To the Editors: I thank Dr. Hershey for his interest in our paper. At first sight it is indeed surprising that a woman with a maternal serum AFP level of 2.0 multiples of the median should have a lower risk of open spina bifid a than if she had had no test at all. It is nevertheless correct. The posterior odds of open spina bifida are increased only when the maternal serum AFP likelihood ratio rises above unity. This happens when the curves of the maternal serum AFP probability distributions for affected and unaffected pregnancies cross. Fig. 1 in our article, a hand-drawn plot of the probability distributions, was only intended to illustrate the derivation of the likelihood ratio; the curves were drawn (inaccurately) to cross at 2.0 multiples of the median. The curves should cross at a maternal serum AFP level between 2.0 and 2.5 multiples of the median. Nevertheless it is easy to see from Fig. 1 that a maternal serum AFP level of 1.5 multiples of the median gives a likelihood ratio of < 1.0; if the curves were drawn correctly, it would be clear that the likelihood ratio for a maternal serum AFP level of 2.0 multiples of the median is also < 1.0. The assumption that the risk of open spina bifida automatically increases if the maternal serum AFP is > 1.0 multiples of the median is an error resulting from intuitionist thought. Dr. Hershey used the "representativeness" heuristic to calculate risk ' ; because raised levels of maternal serum AFP are "representative" of open spina bifida, he assumed that the risk was raised. The truth is sometimes counterintuitive, but our tables should prevent this mistake in future. James C. Thornton, MD Department of Obstetrics and Gynecology, St. James University Hospital, Leeds, England LS9 7TF
REFERENCE 1. Tversky A, Kahnemann D. Judgement under uncertainty: heuristics and biases. Science 1974; 185: 1124-31.
Postnatal outcome depends on prenatal history To the Editors: We read attentively the article by Lipper et al. (Lipper EG, Ross GS, Auld PAM, Glassman MB. Survival and outcome of infants weighing <800 grams at birth. AMJ OBSTET GYNECOL 1990; 163: 146-50), and we wish to express the opinion that this study has no scientific meaning. In particular, the weight of the fetus at birth is for obstetricians a topic of great importance and interest, and we should not forget to differentiate the weight of an appropriate-for-gestational-age newborn from the
1160
Letters
October 1991 Am J Obstet Gynecol
weight of a growth-retarded fetus. All of the modern literature differentiates the postnatal outcome according to the prenatal history of the fetus. The study of Lipper et aI. brings confusion at a time when pediatrics and obstetrics are beginning to agree on the definitions of the terms. A knowledge of the outcome of a fetus <800 gm is of no utility if we are not acquainted with the gestational period in which the infant was born. Your JOURNAL usually is rightly critical in selecting studies coming from non-English-speaking authors, and we are astonished that it publishes with such simplicity data so barely scientific. Claudio Ciorlandino, MD 49 Viale Liegi, 00198 Rome, Italy
Reply
To the Editors: Although it is an important practice in neonatology to differentiate appropriate-for-gestational-age from small-for-gestational-age infants, our study only reported on survival and outcome of infants weighing between 500 and 799 gm at birth whose mean gestational age was 25.5 ± 1.8 weeks (see Table I of our article). Within this narrow range of birth weight and gestational age intrauterine growth retardation could not be a factor relating to outcome, as suggested by Dr. Giorlandino. Evelyn C. Lippa, MD Perinatology Center, The New York Hospital-Cornell Medical Center, 525 East 68th St., New York, NY 10021
Anticomplementary activity in serum and abortion
To the Editors: We read with interest the article by Quinn and Petric (Quinn PA, Petric M. Anticomplementary activity in serum of women with a history of recurrent pregnancy loss. AMJ OBSTET GYNECOL 1988;158:36872). We would like to present our similar study of habitual abortions, preeclampsia, spontaneous abortions, endometriosis, and normal pregnancies. We performed complement fixation tests with cardiolipin antigen and tested the anticomplementary activity of the sera of these patients. Card.iolipin is a negatively charged phos-
pholipid abundant in mitochondrial membranes. The mitochondria are one type of activator of the complement cascade through the classic pathway. I Autoantibodies against cardiolipin cause extensive placental thrombosis and subsequent fetallosses. 2 • 3 Anticardiolipin antibodies have been detected in recurrent fetal losses, preeclampsia, and endometriosis. Thus it is possible for antibodies that form immune complexes with cardiolipin to activate the complement system and have an anticomplementary effect, as was shown by Quinn and Petric. We had 50 patients with histories of habitual abortion (three or more abortions), 22 patients with histories of spontaneous abortion (fewer than three abortions), 6 patients with histories of late intrauterine fetal death, 26 patients with histories of severe preeclampsia, and 58 patients with histories of endometriosis. As control groups we had 26 women with histories of uneventful gestations and deliveries, 28 prepubertal girls, and 10 men. Anticomplementary activity was found in 19 (38%) of the 50 women with habitual abortions, in 4 (18%) of the 22 women with spontaneous abortions, in 7 (27%) of the 26 women with preeclampsia, and in 13 (22%) of 58 women with endometriosis. None of the patients who had had intrauterine deaths showed anticomplementary activity. Only 2 of 28 serum samples in the prepubertal-girls control group showed anticomplementary activity. Anticardiolipin antibody tests were done in all of the groups with enzyme-linked immunoadsorbent assay. The results of the serologic tests are shown in Table I. Autoimmune abnormalities are thought to have a role in the pathogenesis of these disorders. There are two possible explanations for the anticomplementary activity seen. First, immune complexes or antigens such as cardiolipin can nonspecifically fixate complement and cause an anticomplementary effect. Second, patients with circulating immune complexes can also have autoantibodies against complement components. Sibel Erguven, PhD, and Ekrem Culmezoglu, MD Department of Microbiology, Hacettepe University, Ankara, Turkey
A. Metin Culmezoglu, MD
Ankara Maternity Hospital, Ankara, TUTkey
Table I. Serologic tests in patient and control groups Anticardiolipin IgM+
IgG+ No.
Habitual abortion Spontaneous abortion Intrauterine death Severe preeclampsia Endometriosis Normal pregnancy and delivery Prepubertal girls Men
10 4 1 1 9 2
I
%
No.
20 18.2 16.6 3.8 15.5 7.7
8 4 3 3 1 2
IgG, Immunoglobulin G; IgM, immunoglobulin M; +, positive.
I
%
Anticomplementary activity
16 18.2
19 4
38.0 18.2
11.5
7 13
26.9 22.4
2
7.1
1.7 7.7
Volume 165 Number 4, Part 1
localized in the intraductal space of the mammary gland would support the notion that the milk antigen may be synthesized and secreted by the breast, just as antigen appears to be synthesized and secreted by both the apocrine sweat glands and the endometrial glands, Leakage of this antigen into the maternal circulation, thereby contributing to the postpartum serum levels, is possible but unlikely unless access of the CA 125 antigen through the endothelium to the circulation can be accounted for. The likelihood that serum antigen is the source of the CA 125 in colostrum also is unlikely because of the great disparity in concentrations between serum CA 125 and colostrum CA 125, Nonetheless, we believe that paired concurrent assays of CA 125 in colostrum and serum in the postpartum period would be useful in the support or denial of these conclusions. Timothy J. O'Brien, PhD Department of Obstetrics and Gynecology, University of Arkansas for Medical Sciences, 4301 West Markham, Mail Slot 518, Little Rock, AR 72205-7199
REFERENCES 1. Fuith LC, Daxenbichler G, Marth C. CA 125 in human
milk and serum. Gynecol Obstet Invest 1989;28: 1-3. 2. Itahashi K, Inaba N, Fukazawa I, Takamizawa H. Immunoradiometrical measurement of tissue polypeptide antigen (TPA) and cancer antigen 125 (CAI25) in pregnancy and at delivery. Arch Gynecol Obstet 1988;243:191-7. Risk of open spina bifida To the Editors: Genetic counselors try to provide couples with the best estimate of their risk of birth defects. With the implementation of maternal serum u-fetoprotein (AFP) screening programs, patients with elevated maternal serum AFP levels are referred to ultrasonography specialists to look for fetal open spina bifid a and other lesions. Ultrasonographic examinations will show most of these patients to have normal fetuses. The revised numerical risk of a fetus having open spina bifida calculated on the basis of its mother's maternal serum AFP level plus normal results on ultra so nographic examination is important information that patients may want to use in deciding whether to accept the risk of amniocentesis. The figures presented by Thornton et al. (ThorntonJG, Lilford I\J, Newcombe RG. Tables for estimation of individual risks of fetal neural tube and ventral wall defects, incorporating prior probability, maternal serum u-fetoprotein levels, and ultrasonographic examination results. AM J OBSTET GYNECOL 1991;164:154-60) are therefore potentially very useful. My initial inspection of Tables II through IV focused on the upper of the three lines for each particular maternal serum AFP level. Each figure in this line "assumes that ultrasonography provides no information beyond maternal serum AFP" level. In other words, I presume the risk would be calculated solely on the basis of the maternal serum AFP level. If the population incidence of open spina bifid a is 1 in 1000, my reading of the tables indicates that a patient with a maternal serum AFP level of 2.0 multiples of
1159
the median would have a risk of fetal open spina bifida of 1 in 1800. If the ultrasonographic information is excluded, how can a patient with an elevated maternal serum AFP level end up with a lower risk than the risk that existed before the screening test was performed? Douglas W. Hershey, MD Prenatal Genetic Services, Sutter Center for Women's Health, 5275 F St., Sacramento, CA 95819
Reply To the Editors: I thank Dr. Hershey for his interest in our paper. At first sight it is indeed surprising that a woman with a maternal serum AFP level of 2.0 multiples of the median should have a lower risk of open spina bifid a than if she had had no test at all. It is nevertheless correct. The posterior odds of open spina bifida are increased only when the maternal serum AFP likelihood ratio rises above unity. This happens when the curves of the maternal serum AFP probability distributions for affected and unaffected pregnancies cross. Fig. 1 in our article, a hand-drawn plot of the probability distributions, was only intended to illustrate the derivation of the likelihood ratio; the curves were drawn (inaccurately) to cross at 2.0 multiples of the median. The curves should cross at a maternal serum AFP level between 2.0 and 2.5 multiples of the median. Nevertheless it is easy to see from Fig. 1 that a maternal serum AFP level of 1.5 multiples of the median gives a likelihood ratio of < 1.0; if the curves were drawn correctly, it would be clear that the likelihood ratio for a maternal serum AFP level of 2.0 multiples of the median is also < 1.0. The assumption that the risk of open spina bifida automatically increases if the maternal serum AFP is > 1.0 multiples of the median is an error resulting from intuitionist thought. Dr. Hershey used the "representativeness" heuristic to calculate risk ' ; because raised levels of maternal serum AFP are "representative" of open spina bifida, he assumed that the risk was raised. The truth is sometimes counterintuitive, but our tables should prevent this mistake in future. James C. Thornton, MD Department of Obstetrics and Gynecology, St. James University Hospital, Leeds, England LS9 7TF
REFERENCE 1. Tversky A, Kahnemann D. Judgement under uncertainty: heuristics and biases. Science 1974; 185: 1124-31.
Postnatal outcome depends on prenatal history To the Editors: We read attentively the article by Lipper et al. (Lipper EG, Ross GS, Auld PAM, Glassman MB. Survival and outcome of infants weighing <800 grams at birth. AMJ OBSTET GYNECOL 1990; 163: 146-50), and we wish to express the opinion that this study has no scientific meaning. In particular, the weight of the fetus at birth is for obstetricians a topic of great importance and interest, and we should not forget to differentiate the weight of an appropriate-for-gestational-age newborn from the
1160
Letters
October 1991 Am J Obstet Gynecol
weight of a growth-retarded fetus. All of the modern literature differentiates the postnatal outcome according to the prenatal history of the fetus. The study of Lipper et aI. brings confusion at a time when pediatrics and obstetrics are beginning to agree on the definitions of the terms. A knowledge of the outcome of a fetus <800 gm is of no utility if we are not acquainted with the gestational period in which the infant was born. Your JOURNAL usually is rightly critical in selecting studies coming from non-English-speaking authors, and we are astonished that it publishes with such simplicity data so barely scientific. Claudio Ciorlandino, MD 49 Viale Liegi, 00198 Rome, Italy
Reply
To the Editors: Although it is an important practice in neonatology to differentiate appropriate-for-gestational-age from small-for-gestational-age infants, our study only reported on survival and outcome of infants weighing between 500 and 799 gm at birth whose mean gestational age was 25.5 ± 1.8 weeks (see Table I of our article). Within this narrow range of birth weight and gestational age intrauterine growth retardation could not be a factor relating to outcome, as suggested by Dr. Giorlandino. Evelyn C. Lippa, MD Perinatology Center, The New York Hospital-Cornell Medical Center, 525 East 68th St., New York, NY 10021
Anticomplementary activity in serum and abortion
To the Editors: We read with interest the article by Quinn and Petric (Quinn PA, Petric M. Anticomplementary activity in serum of women with a history of recurrent pregnancy loss. AMJ OBSTET GYNECOL 1988;158:36872). We would like to present our similar study of habitual abortions, preeclampsia, spontaneous abortions, endometriosis, and normal pregnancies. We performed complement fixation tests with cardiolipin antigen and tested the anticomplementary activity of the sera of these patients. Card.iolipin is a negatively charged phos-
pholipid abundant in mitochondrial membranes. The mitochondria are one type of activator of the complement cascade through the classic pathway. I Autoantibodies against cardiolipin cause extensive placental thrombosis and subsequent fetallosses. 2 • 3 Anticardiolipin antibodies have been detected in recurrent fetal losses, preeclampsia, and endometriosis. Thus it is possible for antibodies that form immune complexes with cardiolipin to activate the complement system and have an anticomplementary effect, as was shown by Quinn and Petric. We had 50 patients with histories of habitual abortion (three or more abortions), 22 patients with histories of spontaneous abortion (fewer than three abortions), 6 patients with histories of late intrauterine fetal death, 26 patients with histories of severe preeclampsia, and 58 patients with histories of endometriosis. As control groups we had 26 women with histories of uneventful gestations and deliveries, 28 prepubertal girls, and 10 men. Anticomplementary activity was found in 19 (38%) of the 50 women with habitual abortions, in 4 (18%) of the 22 women with spontaneous abortions, in 7 (27%) of the 26 women with preeclampsia, and in 13 (22%) of 58 women with endometriosis. None of the patients who had had intrauterine deaths showed anticomplementary activity. Only 2 of 28 serum samples in the prepubertal-girls control group showed anticomplementary activity. Anticardiolipin antibody tests were done in all of the groups with enzyme-linked immunoadsorbent assay. The results of the serologic tests are shown in Table I. Autoimmune abnormalities are thought to have a role in the pathogenesis of these disorders. There are two possible explanations for the anticomplementary activity seen. First, immune complexes or antigens such as cardiolipin can nonspecifically fixate complement and cause an anticomplementary effect. Second, patients with circulating immune complexes can also have autoantibodies against complement components. Sibel Erguven, PhD, and Ekrem Culmezoglu, MD Department of Microbiology, Hacettepe University, Ankara, Turkey
A. Metin Culmezoglu, MD
Ankara Maternity Hospital, Ankara, TUTkey
Table I. Serologic tests in patient and control groups Anticardiolipin IgM+
IgG+ No.
Habitual abortion Spontaneous abortion Intrauterine death Severe preeclampsia Endometriosis Normal pregnancy and delivery Prepubertal girls Men
10 4 1 1 9 2
I
%
No.
20 18.2 16.6 3.8 15.5 7.7
8 4 3 3 1 2
IgG, Immunoglobulin G; IgM, immunoglobulin M; +, positive.
I
%
Anticomplementary activity
16 18.2
19 4
38.0 18.2
11.5
7 13
26.9 22.4
2
7.1
1.7 7.7