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Complete versus partial HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome
1120 Letters
May 1997 Am
a red blood cell volume of 1750 ml. If 12% were fetal in origin, a red blood cell volume of 210 ml would have to have come from the fetus. A 2785 gm fetus would have a total fetoplacental blood volume of about 350 ml (2.785 kg × 125 ml/kg); at a usual hematocrit of 45% the total red blood cell volume in this fetoplacental unit would be only 157 ml. It is hardly likely that the baby could have donated 133% o f its entire red blood cell volume and retained a hematocrit of 30%. Surely, however, some fetal bleeding could have occurred and probably did. As has been shown in other work, 1 stress in pregnancy can cause a regression of the marrow synthetic tendencies to a more primitive hemoglobin pattern. It is estimated that up to 25% of women carry fetal h e m o g l o b i n containing red blood cells in pregnancy that are of their own making and not of fetal origin. This severely stressful event may be one such case. Other observations in this case include a problem with interpreting serum values in the alternative system. A creatinine value of 188 ~ m o l / L does not ring a familiar bell to a U.S. reader. The conversion factors are not easily found. I gather that this is about 2.1 m g / d l in our reference values, but I am not sure. Can we not insist either on one standard set of units that are familiar to the majority of readers or require that values in competing systems both be presented? Keeping up is hard enough. As for autopsy data, the focal myocardial lesions are sometimes seen with aggressive use of inotropic agents. The rest of the findings are compatible with the suspected causation. The neonatal period was remarkable for the inability to achieve normoxemia even after 2 hours. The ability to time the injury to 30 hours a s opposed to 25 to 35 hours is challenged, and the probable contribution of persistently inadequate oxygen delivery to the neonatal organs is raised as an enhancing factor to the resultant damages observed at necropsy, unless great errors are present in the data presented in Table I. Are perhaps the oxygen and carbon dioxide tensions at 6 hours reversed? Richard P. Perkins, MD Department of Obstetrics, Gynecology, and Pediatrics, University of Nevada School of Medicine, 2040 W. CharlestonBlvd., Las Vegas, NV 89102
J Obstet Oynecol
morphonuclear response are time related to the acute complication. The absence of chronic neuropathologic features is in keeping with the conclusion that prior harm did not occur in this particular case. The Kleihauer-Betke test is regularly used in our hospital to establish the presence of fetal red blood cells in the maternal circulation. The possibly of a maternal origin of such cells is recognized. The procedure is our laboratory is to count approximately 2000 red blood cells and determine the percent of fetal ceils. Fetal cells of 12% is a striking increase in the experience of our laboratory, and in conjunction with a hematocrit of 30% in the newborn provided compelling evidence that a fetal hemorrhage into the maternal circulation did occur. The problem of interpretation of serum values in an alternate system is noted. "Uniform Requirements for Manuscripts Submitted to Biomedical Journals" recommends that all clinical chemistry- measurements should be reported in the metric system in terms of the International System of Units) Editors may request that alternative be added. However, such a request is not included in the Information for Authors. The conversion factor for serum creatinine is 88.4. Thus a serum creatinine of 188 ixmol is equivalent to 2.1 rag/100 Ixl, The possibility that newborn hypoxia may have contributed to the brain damage cannot be ruled out. The estimation of oxygen tension at 2 hours was in a capillary sample and therefore may be misleading. The observation is correct that the measures of oxygen and carbon dioxide tension at 6 hours are reversed. However, the fact that continuously recorded blood pressure was within a normal range until the last 2 hours is reassuring and suggests that newborn hypoxia-ischemia was not a contributing cause of the neuropathologic features observed. The timing of the asphyxial exposure accounting for brain damage present at postmortem examination is approximate. 2 Therefore we chose to state "approximately 30 hours" rather than define a precise range. J.A. Low, MD Department of Obstetrics and Gynaecology, Queen's University, Kingston, Ontario, Canada K7L 3N6
REFERENCES
1. Mollison PL. Blood transfusion in clinical medicine. Oxford: Blackwell Scientific Publications, 1983.
1. Uniform requirements for manuscripts submitted to biomedical journals. JAMA 1993;269:2282-6. 2. Norman MG. Perinatal brain damage. Perspect Pediatr Pathol 1978;4:41-92.
6/8/8O815
6/8/80814
REFERENCE
Reply To the Editors: We thank Perkins for his interest and comments on our case report. There is always a possibility in keeping with the generally held assumption that the majority of cases of cerebral palsy come from circumstances proximate to delivery that the harm may have occurred before the acute complication leading to delivery. However, the neuropathologic findings of neuronal necrosis and early poly-
Complete versus partial HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome To the Editors: I read with great interest the article by Audibert et al. (Audibert F, Friedman SA, Frangieh AY, Sibai BM. Clinical utility of strict diagnostic criteria for the HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. A m J Obstet Gynecol 1996;175:4604). Severe preeclampsia-eclampsia is c o m m o n in sub-
I_etters
Volume 176, Number 5 Am J Obstet Gynecol
T a b l e I. Comparison of cases of H E L L P syndrome with n o r m a l values
Partial HELLP syndrome (n = 9)
Normal laboratory values (n= 13)
29.7-+ 4.3 23.9 + 4.1 32.3 ± 3.7 31.0 -++6.0
21.6-+ 4.7 36.5 -+ 1.8
HELLP syndrome ( n : lo) Age (yr) Gestational age at delivery (wk) Birth weight (kg) Disseminated intravascular coagulation Acute renal failure Eclampsia Abruptio placentae Cesarean section rate Macerated stillborn Perinatal mortality rate
1 121
In our experience, with the exception of abruptio placentae (encountered only in patients with low platelets) there is no clear difference in the clinical features and complications between partial and complete HELLP syndrome. Louis-Jacques Van Bogaert, MD, PhD Department Of Obstetrics and Gynecology, University of Transhei, Faculty of Medicine and Health Sdences, Private Bag xO1, Umtata, Transkei, 5100, South Africa
REFERENCE 1.65 ± 0.70 1.80 + 0.97 3.03 -+ 0.45 1 (10.0%) --5 (50.0%) 2 (20.0%) --5 (50.0%) 5 (50.0%)
5 2 3 1 5 6
(55.6%) (22.2%) (33.3%) (11.1%) (55.6%) (66.7%)
-3 (23.1%) -3 (23.1%) 1 (7.7%) 3 (23.1%)
Saharan Africa; the true i n c i d e n c e of the H E L L P synd r o m e is m u c h less known. This is primarily attributable to suboptimal obstetric thcilities mostly with no pediatrician and limited laboratory services. In the latter circumstances the main thrust is at curtailing maternal morbidity and mortality; an excessively high perinatal mortality rate is often the price to pay. It is said that the m a n a g e m e n t of strictly defined HELLP syndrome should be the same as for severe preeclampsia remote from term I (i.e., termination of pregnancy). With partial HELLP syndrome conservatism is allowed. A review of 42 cases of severe preeclampsia-eclampsia, 10 with c o m p l e t e and 9 with partial H E L L P syndrome, c o m p a r e d with 13 cases with n o r m a l laboratory values is illustrated in Table I. T h e partial H E L L P syndrome cases comprised five with elevated liver enzymes and f o u r with low platelets. T h e similarities with the r e p o r t of A u d i b e r t et al. r e p o r t are the ratio of c o m p l e t e versus partial H E L L P syndrome, the prevalence of disseminated intravascular coagulation, and the relatively equal though h i g h e r distribution of eclampsia in each group. T h e main differences are the high prevalence of acute renal failure and o f abruptio placentae and the high perinatal mortality rate. Unless they were already in labor on admission (n = 9), in patients with features of H E L L P syndrome labor was i n d u c e d (n = 9). Eight were delivered within 24 hours and o n e within 48 hours after the vaginal a d m i n i s t r a t i o n of d i n o p r o s t o n e . All the patients, with or without HELLP syndrome, were put on a strict inputu t p u t intravenous fluid r e g i m e n with lactated Ringer's solution to c o m p e n s a t e urinary and n o n n r i n a r y losses. Acute renal failure, defined as a urine o u t p u t < 2 0 m l / h r with sermn creatinine values > 4 8 6 t~mol/L and u r e a values > 1 8 r e t o o l / L , o c c u r r e d in half the cases with either c o m p l e t e or partial HELLP syndrome. In all of them this was followed by a polyuric phase with no further evidence of p e r n l a n e n t renal damage. T h e r e was no maternal death. H a l f the fetal deaths was due to intrauterine fetal death present on admission.
1. Sibai BM, Ramadan MK. Preeclampsia. and eclampsia. In: SciarraJ, editor. Gynecology and obstetrics. Philadelphia: JB Lippincott; 1995. p. 1-17.
6/8/80757
Reply To the Editors: I thank Van Bogaert for his interest in our article and in the subject of severe preeclampsia. His findings are interesting and convincing. T h e differences in our findings and his may be related to differences in population, differences in the m a n a g e m e n t o f severe preeclampsia or, particularly, to sample size because they studied only 10 w o m e n with H E L L P (hemolysis, elevated fiver enzymes, /ow platelets) and 9 w o m e n with partial HELLP. Thanks again for this interest in our work. We are always pleased to engage in discourse on this exciting topic. Baha M. Sibai, J~iD Division of Material-Fetal Medicine, Universit~of Tennessee, Memphis, 853Jefferson Ave., Suite E102, Memphis, TN 58103 6/8/80756
Papillomavirus integration: Prognostic marker in cervical cancer? To the Editors: Many issues remain to be u n d e r s t o o d in the pathogenesis of cervical cancer. We would like to c o m m e n t on some aspects that may be relevant to the transition from transformed cell to invasive c a r c i n o m a and to the prognosis of this disease. Cervical carcinomas are associated with h u m a n papillomaviruses (HPV). 1 In HPV infections viral deoxyribonucleic acid (DNA) is present in an e x t r a c h r o m o s o m a l form. However, in carcinomas t h e viral DNA is integrated in the host cellular DNA. This viral DNA integration is a genetic alteration that results in deregulated expression of E6 and E7 genes. But it is also an irreversible cellular genetic alteration that m i g h t be a contributing factor to the cervical c a r c i n o m a phenotype. Therefore, if papillomavirus DNA integration is recurrent, t h e n it m i g h t be a marker for c h r o m o s o m e regions, as an alternative to translocations, containing genes linked to this t u m o r p h e n o t y p e and perhaps be of use in o t h e r types of carcinomas because they share c o m m o n phenotypic properties. In cervical carcinomas where integration sites have
May 1997 Am
a red blood cell volume of 1750 ml. If 12% were fetal in origin, a red blood cell volume of 210 ml would have to have come from the fetus. A 2785 gm fetus would have a total fetoplacental blood volume of about 350 ml (2.785 kg × 125 ml/kg); at a usual hematocrit of 45% the total red blood cell volume in this fetoplacental unit would be only 157 ml. It is hardly likely that the baby could have donated 133% o f its entire red blood cell volume and retained a hematocrit of 30%. Surely, however, some fetal bleeding could have occurred and probably did. As has been shown in other work, 1 stress in pregnancy can cause a regression of the marrow synthetic tendencies to a more primitive hemoglobin pattern. It is estimated that up to 25% of women carry fetal h e m o g l o b i n containing red blood cells in pregnancy that are of their own making and not of fetal origin. This severely stressful event may be one such case. Other observations in this case include a problem with interpreting serum values in the alternative system. A creatinine value of 188 ~ m o l / L does not ring a familiar bell to a U.S. reader. The conversion factors are not easily found. I gather that this is about 2.1 m g / d l in our reference values, but I am not sure. Can we not insist either on one standard set of units that are familiar to the majority of readers or require that values in competing systems both be presented? Keeping up is hard enough. As for autopsy data, the focal myocardial lesions are sometimes seen with aggressive use of inotropic agents. The rest of the findings are compatible with the suspected causation. The neonatal period was remarkable for the inability to achieve normoxemia even after 2 hours. The ability to time the injury to 30 hours a s opposed to 25 to 35 hours is challenged, and the probable contribution of persistently inadequate oxygen delivery to the neonatal organs is raised as an enhancing factor to the resultant damages observed at necropsy, unless great errors are present in the data presented in Table I. Are perhaps the oxygen and carbon dioxide tensions at 6 hours reversed? Richard P. Perkins, MD Department of Obstetrics, Gynecology, and Pediatrics, University of Nevada School of Medicine, 2040 W. CharlestonBlvd., Las Vegas, NV 89102
J Obstet Oynecol
morphonuclear response are time related to the acute complication. The absence of chronic neuropathologic features is in keeping with the conclusion that prior harm did not occur in this particular case. The Kleihauer-Betke test is regularly used in our hospital to establish the presence of fetal red blood cells in the maternal circulation. The possibly of a maternal origin of such cells is recognized. The procedure is our laboratory is to count approximately 2000 red blood cells and determine the percent of fetal ceils. Fetal cells of 12% is a striking increase in the experience of our laboratory, and in conjunction with a hematocrit of 30% in the newborn provided compelling evidence that a fetal hemorrhage into the maternal circulation did occur. The problem of interpretation of serum values in an alternate system is noted. "Uniform Requirements for Manuscripts Submitted to Biomedical Journals" recommends that all clinical chemistry- measurements should be reported in the metric system in terms of the International System of Units) Editors may request that alternative be added. However, such a request is not included in the Information for Authors. The conversion factor for serum creatinine is 88.4. Thus a serum creatinine of 188 ixmol is equivalent to 2.1 rag/100 Ixl, The possibility that newborn hypoxia may have contributed to the brain damage cannot be ruled out. The estimation of oxygen tension at 2 hours was in a capillary sample and therefore may be misleading. The observation is correct that the measures of oxygen and carbon dioxide tension at 6 hours are reversed. However, the fact that continuously recorded blood pressure was within a normal range until the last 2 hours is reassuring and suggests that newborn hypoxia-ischemia was not a contributing cause of the neuropathologic features observed. The timing of the asphyxial exposure accounting for brain damage present at postmortem examination is approximate. 2 Therefore we chose to state "approximately 30 hours" rather than define a precise range. J.A. Low, MD Department of Obstetrics and Gynaecology, Queen's University, Kingston, Ontario, Canada K7L 3N6
REFERENCES
1. Mollison PL. Blood transfusion in clinical medicine. Oxford: Blackwell Scientific Publications, 1983.
1. Uniform requirements for manuscripts submitted to biomedical journals. JAMA 1993;269:2282-6. 2. Norman MG. Perinatal brain damage. Perspect Pediatr Pathol 1978;4:41-92.
6/8/8O815
6/8/80814
REFERENCE
Reply To the Editors: We thank Perkins for his interest and comments on our case report. There is always a possibility in keeping with the generally held assumption that the majority of cases of cerebral palsy come from circumstances proximate to delivery that the harm may have occurred before the acute complication leading to delivery. However, the neuropathologic findings of neuronal necrosis and early poly-
Complete versus partial HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome To the Editors: I read with great interest the article by Audibert et al. (Audibert F, Friedman SA, Frangieh AY, Sibai BM. Clinical utility of strict diagnostic criteria for the HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. A m J Obstet Gynecol 1996;175:4604). Severe preeclampsia-eclampsia is c o m m o n in sub-
I_etters
Volume 176, Number 5 Am J Obstet Gynecol
T a b l e I. Comparison of cases of H E L L P syndrome with n o r m a l values
Partial HELLP syndrome (n = 9)
Normal laboratory values (n= 13)
29.7-+ 4.3 23.9 + 4.1 32.3 ± 3.7 31.0 -++6.0
21.6-+ 4.7 36.5 -+ 1.8
HELLP syndrome ( n : lo) Age (yr) Gestational age at delivery (wk) Birth weight (kg) Disseminated intravascular coagulation Acute renal failure Eclampsia Abruptio placentae Cesarean section rate Macerated stillborn Perinatal mortality rate
1 121
In our experience, with the exception of abruptio placentae (encountered only in patients with low platelets) there is no clear difference in the clinical features and complications between partial and complete HELLP syndrome. Louis-Jacques Van Bogaert, MD, PhD Department Of Obstetrics and Gynecology, University of Transhei, Faculty of Medicine and Health Sdences, Private Bag xO1, Umtata, Transkei, 5100, South Africa
REFERENCE 1.65 ± 0.70 1.80 + 0.97 3.03 -+ 0.45 1 (10.0%) --5 (50.0%) 2 (20.0%) --5 (50.0%) 5 (50.0%)
5 2 3 1 5 6
(55.6%) (22.2%) (33.3%) (11.1%) (55.6%) (66.7%)
-3 (23.1%) -3 (23.1%) 1 (7.7%) 3 (23.1%)
Saharan Africa; the true i n c i d e n c e of the H E L L P synd r o m e is m u c h less known. This is primarily attributable to suboptimal obstetric thcilities mostly with no pediatrician and limited laboratory services. In the latter circumstances the main thrust is at curtailing maternal morbidity and mortality; an excessively high perinatal mortality rate is often the price to pay. It is said that the m a n a g e m e n t of strictly defined HELLP syndrome should be the same as for severe preeclampsia remote from term I (i.e., termination of pregnancy). With partial HELLP syndrome conservatism is allowed. A review of 42 cases of severe preeclampsia-eclampsia, 10 with c o m p l e t e and 9 with partial H E L L P syndrome, c o m p a r e d with 13 cases with n o r m a l laboratory values is illustrated in Table I. T h e partial H E L L P syndrome cases comprised five with elevated liver enzymes and f o u r with low platelets. T h e similarities with the r e p o r t of A u d i b e r t et al. r e p o r t are the ratio of c o m p l e t e versus partial H E L L P syndrome, the prevalence of disseminated intravascular coagulation, and the relatively equal though h i g h e r distribution of eclampsia in each group. T h e main differences are the high prevalence of acute renal failure and o f abruptio placentae and the high perinatal mortality rate. Unless they were already in labor on admission (n = 9), in patients with features of H E L L P syndrome labor was i n d u c e d (n = 9). Eight were delivered within 24 hours and o n e within 48 hours after the vaginal a d m i n i s t r a t i o n of d i n o p r o s t o n e . All the patients, with or without HELLP syndrome, were put on a strict inputu t p u t intravenous fluid r e g i m e n with lactated Ringer's solution to c o m p e n s a t e urinary and n o n n r i n a r y losses. Acute renal failure, defined as a urine o u t p u t < 2 0 m l / h r with sermn creatinine values > 4 8 6 t~mol/L and u r e a values > 1 8 r e t o o l / L , o c c u r r e d in half the cases with either c o m p l e t e or partial HELLP syndrome. In all of them this was followed by a polyuric phase with no further evidence of p e r n l a n e n t renal damage. T h e r e was no maternal death. H a l f the fetal deaths was due to intrauterine fetal death present on admission.
1. Sibai BM, Ramadan MK. Preeclampsia. and eclampsia. In: SciarraJ, editor. Gynecology and obstetrics. Philadelphia: JB Lippincott; 1995. p. 1-17.
6/8/80757
Reply To the Editors: I thank Van Bogaert for his interest in our article and in the subject of severe preeclampsia. His findings are interesting and convincing. T h e differences in our findings and his may be related to differences in population, differences in the m a n a g e m e n t o f severe preeclampsia or, particularly, to sample size because they studied only 10 w o m e n with H E L L P (hemolysis, elevated fiver enzymes, /ow platelets) and 9 w o m e n with partial HELLP. Thanks again for this interest in our work. We are always pleased to engage in discourse on this exciting topic. Baha M. Sibai, J~iD Division of Material-Fetal Medicine, Universit~of Tennessee, Memphis, 853Jefferson Ave., Suite E102, Memphis, TN 58103 6/8/80756
Papillomavirus integration: Prognostic marker in cervical cancer? To the Editors: Many issues remain to be u n d e r s t o o d in the pathogenesis of cervical cancer. We would like to c o m m e n t on some aspects that may be relevant to the transition from transformed cell to invasive c a r c i n o m a and to the prognosis of this disease. Cervical carcinomas are associated with h u m a n papillomaviruses (HPV). 1 In HPV infections viral deoxyribonucleic acid (DNA) is present in an e x t r a c h r o m o s o m a l form. However, in carcinomas t h e viral DNA is integrated in the host cellular DNA. This viral DNA integration is a genetic alteration that results in deregulated expression of E6 and E7 genes. But it is also an irreversible cellular genetic alteration that m i g h t be a contributing factor to the cervical c a r c i n o m a phenotype. Therefore, if papillomavirus DNA integration is recurrent, t h e n it m i g h t be a marker for c h r o m o s o m e regions, as an alternative to translocations, containing genes linked to this t u m o r p h e n o t y p e and perhaps be of use in o t h e r types of carcinomas because they share c o m m o n phenotypic properties. In cervical carcinomas where integration sites have