- Email: [email protected]
Drug prescribing for thromboembolic disease during pregnancy
784 Correspondence
tiple of the median; so the use of a 0.3 multiple of the median cutoff could potentially lead to poor detection efficiency. Additionally, since the incidence of Down syndrome increases substantially with age, failure to incorporate age in determining risk will result in mis interpretation of low values of a-fetoprotein.* With regard to Kazazian et al.'s Case 2, the patient's weight-adjusted multiple of the median is 0.34. Inas much as 0.34 multiple of the median is higher than the authors' 0.3 multiple of the median cutoff, we are un clear as to why their laboratory alerted clinicians to the need for further evaluation in this case. Kazazian et a!. concluded by stating that the Mary land State Health Department has not missed an open neural tube defect because of maternal weight adjust ment and, on the contrary, has avoided many unnec essary amniocenteses. They did not reveal, however, (1) the mathematical basis for their weight adjustment system, (2) the number of cases on which it is based, (3) how many pregnancies either (a) avoided further testing or (b) were directed to go on for further testing because of weight adjustment, or (4) their overall pro gram detection efficiency for open neural tube defects. All information concerning weight adjustments pub lished by others to date presents a concept that is based on estimates and assumptions but fails to present em pirical data to demonstrate the beneficial effects of this statistical adjustment. The data presented in our October 1986 maternal weight article illustrate our point concerning a negative effect on detection efficiency. Finally, we share with Kazazian et a!. an interest in empirical data from other screening programs related to their experience with weight adjustment of maternal serum a-fetoprotein values. james N. Macri, Ph.D. Ramana V. Kasturi, B.E., M.S. David A. Krantz, B.S. Kevin E. Koch, B.S. Mannshya G. Hu, Ph.D. Research Division Neural Tube Defect Laboratories 383 Old Country Road Carle Place, New York 11514 *We disagree with the use of the multiple of the median statistical parameter for reporting and decision making. Patient-specific risk reporting is clinically preferable. 5· 6
REFERENCES l. Macri JN, Kasturi RV, Krantz DA, Koch KE. Maternal se
rum a-fetoprotein screening, maternal weight, and detec tion efficiency. AMJ 0BSTET GYNECOL 1986;155:758-60. 2. Palomaki GE, Knight GJ, Kloza EM, Haddow ]E. Maternal weight adjustment and low serum a-fetoprotein values. L ancet 1985; 1:468. 3. Wald N, Cuckle H, Bareham], et al. The effect of maternal weight on maternal serum alpha-fetoprotein levels. Br ] Obstet Gynaecol 1981;88:1094. 4. Knight GJ, Haddow JE, Palomaki G. An external labora tory quality control program to help ensure reliability for
September 1987 Am J Obstet Gynecol
maternal serum alpha-fetoprotein screening. Scarborough, Maine: Foundation for Blood Research, 1985. 5. Adams MJ, Windham GC, James LM, et al. Clinical inter pretation of maternal serum a-fetoprotein concentrations. AM] 0BSTET GYNECOL 1984;148:241. 6. ACOG Technical Bulletin: Prenatal detection of neural tube defects. Washington DC: The American College of Obstetricians and Gynecologists, December 1986, no. 99.
Drug prescribing for thromboembolic disease during pregnancy To the Editors: Drs. Rayburn and Lavin have done obstetricians a great service in summarizing the current treatment of common disorders complicating pregnancy (Rayburn WF, Lavin JP Jr. Drug prescribing for chronic medical disorders during pregnancy: an overview. AM J OB STET GYNECOL 1986; 155:565-9). Their protocol for treating thromboembolic disease assumes physicians have a reliable heparin assay available. Unfortunately, most hospitals do not offer tests of heparin levels al though they do provide reliable activated partial throm boplastin time determinations. We have a simplified approach to the treatment of thromboembolic diseases such as deep venous throm bosis or pulmonary embolism. Our regimen, modified from the protocol of Hull eta!.,' utilizes the activated partial thromboplastin time. The initial treatment in the hospital with intravenous heparin is the same; how ever, after at least 7 days of therapy patients are switched to heparin administered subcutaneously every 12 hours. The initial daily subcutaneous dose used is two thirds of the total intravenous dose required during 24 hours to maintain a therapeutic activated partial thromboplastin time. The daily subcutaneous dose is divided into two doses given every 12 hours. Thus, if a patient requires intravenous heparin at 1000 units/hr, the total daily intravenous dose is 24,000 units. The patient receives two thirds of this dose (16,000 units) divided into 8000 units subcutaneously every 12 hours. The activated partial thromboplastin time is measured 6 hours after the subcutaneous heparin dose, and the heparin dose is adjusted until a therapeutic activated partial thromboplastin time is achieved (one and a half to two times control). This regimen has proved satisfactory in our hospital in more than 50 cases of deep vein thrombosis. Physicians who do not have a heparin assay available at their hospitals may find our approach acceptable. The treatment of pregnant patients with prosthetic heart valves who require anticoagulation is much more controversial. A recent consensus conference recom mended that these patients be treated during preg nancy with subcutaneous heparin every 12 hours in a dose that prolongs the activated partial thromboplastin time to the therapeutic range (one and a half to two times control) 6 hours after the injection! It is recog nized that adequate clinic studies to support this rec ommendation are lacking.
Volume 157 Number 3
There are not adequate data to be certain that sub cutaneous heparin is the optimal regimen. Oakley and Doherty3 reported a case of thrombosis of a Hammersmith-Alvarez prosthetic mitral valve in a pa tient treated with "full anticoagulant doses of heparin subcutaneously." Despite the risk that heparin will fail to prevent some thromboembolic complications, the alternative, cou marin, is unacceptable. In their classic review, Hall et al. 4 showed that pregnancies exposed to coumarin derivatives had the following outcomes: abnormal live birth, V6; abortion or stillbirths; V6; and apparently nor mal births; %. Iturbe-Alessio et aP recently reported an even higher incidence of coumarin embryopathy: 25% (two of eight) in pregnancies exposed from conception to the seventh to eleventh week and 29.6% (eight of 27) in pregnancies treated with acenocoumarol during all three trimesters. Other anticoagulant regimens that are ineffective or complicated by hemorrhage include minidose hep arin and continuous subcutaneous heparin infusions. Minidose heparin (5000 units subcutaneously every 12 hours) has no place in the prevention of thromboem bolism in pregnant patients with prosthetic heart valves requiring anticoagulation. Four of 10 patients treated by Chen et al. 6 had thromboembolism during preg nancy while being treated with minidose heparin. The use of continuous subcutaneous heparin infusion for anticoagulation during pregnancy was associated with major bleeding complications requiring transfusion in four of six patients treated.' These regimens should be abandoned. There is a need to collect information on the out come of pregnancy in patients with prosthetic heart valves requiring anticoagulation, who are treated with adjusted-dose subcutaneous heparin. jeffrey S. Greenspoon, M.D. Martin Montara, M.D. Department of Obstetrics and Gynecology Women's Hospital 1240 North Mission Road Los Angeles, California 90033 REFERENCES l. Hull R, Delmore T, Carter C, et al. Adjusted subcutaneous heparin versus warfarin sodium in the long-term treatment of venous thrombosis. N Englj Med 1982;306:189-94. 2. Levine HJ, Pauker SG, Salzman EW. Antithrombotic ther apy in valvular heart disease. Chest 1986;89:36S-45S. 3. Oakley CM, Doherty P. Pregnancy in patients after heart valve replacement. Br Heart J 1976;38: ll40-8. 4. HallJG, Pauli RM, Wilson KM. Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med 1980; 68:122-40. 5. Iturbe-Alessio I, del Carmen Fonseca M, Mutchinik 0, et al. Risks of anticoagulant therapy in pregnant women with artificial heart valves. N Eng! J Med 1986;315: 1390-3. 6. Chen WWC, Lee PK, Wang RYC, Wong VWC. Pregnancy in patients with prosthetic heart valves: an experience with 45 pregnancies. QJ Med 1982;51:358-65.
Correspondence
785
7. Barss VA, Schwartz PA, Greene MF, Phillippe M, Saltz man D, Frigoletto FD. Use of the subcutaneous heparin pump during pregnancy. J Reprod Med 1985;30:899-90 l.
Lymphocyte-reactive antibodies and recurrent early pregnancy failure To the Editors: It was with interest that we read the latest report by Unander and Lindholm on the use of leukocyte-rich erythrocyte concentrate transfusions in women with re current early pregnancy failure (Unander AM, Lind holm A. Transfusions of leukocyte-rich erythrocyte concentrates: a successful treatment in selected cases of habitual abortion. AM J 0BSTET GYNECOL 1986; 154: 516-20). Recognizing the risks associated with trans fusion for viral transfer (human immunovirus, hepa titis, and cytomegalovirus)' as well as detrimental sensitization (blood groups, platelet and classical his tocompatibility or HLA antigens), these authors ret rospectively identified some individuals with recurrent unexplained abortions who would not benefit from leu kocyte transfusions. Although limited variables were reported, it was concluded that women without "block ing" antibodies are the women who benefit from third party transfusions. Because Unander and Lindholm's study was not randomized, they failed to acknowledge the 20% to 60% of subjects that may have been able to carry a pregnancy to term without transfusion treat ment. Antipaternal cytotoxic antibodies were not stud ied as a criterion of those who would not benefit from transfusions, as only 20% to 50% of multiparous women have such antibodies. In contrast, the presence of antipaternal cytotoxic antibodies was a major exclu sion criterion used by Mowbray et al! in their "con trolled trial" of women with recurrent spontaneous abortion immunized with paternal cells. In trying to clarify those subjects who may not require immunotherapy, data concerning the expected fre quency of blocking antibodies in women with primary and secondary abortion would have been elucidating. After the report by Mowbray et al., we set out to define an expected frequency for the presence of cytotoxic antibodies in women who are recurrent spontaneous aborters. We chose to study nulliparous women with (1) three or more elective abortions and (2) three or more spontaneous abortions, without a viable preg nancy progressing beyond 12 weeks in both groups. Venous blood was obtained from these women at 4 to 12 weeks after their last elective abortion. Serum lymphocytotoxic antibody was assessed at room tem perature by complement-dependent lysis against a panel of 30 individuals' peripheral blood lymphocyte5 in a 1 V2-hour two-stage technique at 22° C. 3 Only om of 23 (4%) "recurrent elective aborters" exhibited lym phocytotoxic antibodies. For comparison, the incidenn of antibody observed in the sample of primary recur rent spontaneous aborters was 8/63 (13%). We recognize that our control population may no
tiple of the median; so the use of a 0.3 multiple of the median cutoff could potentially lead to poor detection efficiency. Additionally, since the incidence of Down syndrome increases substantially with age, failure to incorporate age in determining risk will result in mis interpretation of low values of a-fetoprotein.* With regard to Kazazian et al.'s Case 2, the patient's weight-adjusted multiple of the median is 0.34. Inas much as 0.34 multiple of the median is higher than the authors' 0.3 multiple of the median cutoff, we are un clear as to why their laboratory alerted clinicians to the need for further evaluation in this case. Kazazian et a!. concluded by stating that the Mary land State Health Department has not missed an open neural tube defect because of maternal weight adjust ment and, on the contrary, has avoided many unnec essary amniocenteses. They did not reveal, however, (1) the mathematical basis for their weight adjustment system, (2) the number of cases on which it is based, (3) how many pregnancies either (a) avoided further testing or (b) were directed to go on for further testing because of weight adjustment, or (4) their overall pro gram detection efficiency for open neural tube defects. All information concerning weight adjustments pub lished by others to date presents a concept that is based on estimates and assumptions but fails to present em pirical data to demonstrate the beneficial effects of this statistical adjustment. The data presented in our October 1986 maternal weight article illustrate our point concerning a negative effect on detection efficiency. Finally, we share with Kazazian et a!. an interest in empirical data from other screening programs related to their experience with weight adjustment of maternal serum a-fetoprotein values. james N. Macri, Ph.D. Ramana V. Kasturi, B.E., M.S. David A. Krantz, B.S. Kevin E. Koch, B.S. Mannshya G. Hu, Ph.D. Research Division Neural Tube Defect Laboratories 383 Old Country Road Carle Place, New York 11514 *We disagree with the use of the multiple of the median statistical parameter for reporting and decision making. Patient-specific risk reporting is clinically preferable. 5· 6
REFERENCES l. Macri JN, Kasturi RV, Krantz DA, Koch KE. Maternal se
rum a-fetoprotein screening, maternal weight, and detec tion efficiency. AMJ 0BSTET GYNECOL 1986;155:758-60. 2. Palomaki GE, Knight GJ, Kloza EM, Haddow ]E. Maternal weight adjustment and low serum a-fetoprotein values. L ancet 1985; 1:468. 3. Wald N, Cuckle H, Bareham], et al. The effect of maternal weight on maternal serum alpha-fetoprotein levels. Br ] Obstet Gynaecol 1981;88:1094. 4. Knight GJ, Haddow JE, Palomaki G. An external labora tory quality control program to help ensure reliability for
September 1987 Am J Obstet Gynecol
maternal serum alpha-fetoprotein screening. Scarborough, Maine: Foundation for Blood Research, 1985. 5. Adams MJ, Windham GC, James LM, et al. Clinical inter pretation of maternal serum a-fetoprotein concentrations. AM] 0BSTET GYNECOL 1984;148:241. 6. ACOG Technical Bulletin: Prenatal detection of neural tube defects. Washington DC: The American College of Obstetricians and Gynecologists, December 1986, no. 99.
Drug prescribing for thromboembolic disease during pregnancy To the Editors: Drs. Rayburn and Lavin have done obstetricians a great service in summarizing the current treatment of common disorders complicating pregnancy (Rayburn WF, Lavin JP Jr. Drug prescribing for chronic medical disorders during pregnancy: an overview. AM J OB STET GYNECOL 1986; 155:565-9). Their protocol for treating thromboembolic disease assumes physicians have a reliable heparin assay available. Unfortunately, most hospitals do not offer tests of heparin levels al though they do provide reliable activated partial throm boplastin time determinations. We have a simplified approach to the treatment of thromboembolic diseases such as deep venous throm bosis or pulmonary embolism. Our regimen, modified from the protocol of Hull eta!.,' utilizes the activated partial thromboplastin time. The initial treatment in the hospital with intravenous heparin is the same; how ever, after at least 7 days of therapy patients are switched to heparin administered subcutaneously every 12 hours. The initial daily subcutaneous dose used is two thirds of the total intravenous dose required during 24 hours to maintain a therapeutic activated partial thromboplastin time. The daily subcutaneous dose is divided into two doses given every 12 hours. Thus, if a patient requires intravenous heparin at 1000 units/hr, the total daily intravenous dose is 24,000 units. The patient receives two thirds of this dose (16,000 units) divided into 8000 units subcutaneously every 12 hours. The activated partial thromboplastin time is measured 6 hours after the subcutaneous heparin dose, and the heparin dose is adjusted until a therapeutic activated partial thromboplastin time is achieved (one and a half to two times control). This regimen has proved satisfactory in our hospital in more than 50 cases of deep vein thrombosis. Physicians who do not have a heparin assay available at their hospitals may find our approach acceptable. The treatment of pregnant patients with prosthetic heart valves who require anticoagulation is much more controversial. A recent consensus conference recom mended that these patients be treated during preg nancy with subcutaneous heparin every 12 hours in a dose that prolongs the activated partial thromboplastin time to the therapeutic range (one and a half to two times control) 6 hours after the injection! It is recog nized that adequate clinic studies to support this rec ommendation are lacking.
Volume 157 Number 3
There are not adequate data to be certain that sub cutaneous heparin is the optimal regimen. Oakley and Doherty3 reported a case of thrombosis of a Hammersmith-Alvarez prosthetic mitral valve in a pa tient treated with "full anticoagulant doses of heparin subcutaneously." Despite the risk that heparin will fail to prevent some thromboembolic complications, the alternative, cou marin, is unacceptable. In their classic review, Hall et al. 4 showed that pregnancies exposed to coumarin derivatives had the following outcomes: abnormal live birth, V6; abortion or stillbirths; V6; and apparently nor mal births; %. Iturbe-Alessio et aP recently reported an even higher incidence of coumarin embryopathy: 25% (two of eight) in pregnancies exposed from conception to the seventh to eleventh week and 29.6% (eight of 27) in pregnancies treated with acenocoumarol during all three trimesters. Other anticoagulant regimens that are ineffective or complicated by hemorrhage include minidose hep arin and continuous subcutaneous heparin infusions. Minidose heparin (5000 units subcutaneously every 12 hours) has no place in the prevention of thromboem bolism in pregnant patients with prosthetic heart valves requiring anticoagulation. Four of 10 patients treated by Chen et al. 6 had thromboembolism during preg nancy while being treated with minidose heparin. The use of continuous subcutaneous heparin infusion for anticoagulation during pregnancy was associated with major bleeding complications requiring transfusion in four of six patients treated.' These regimens should be abandoned. There is a need to collect information on the out come of pregnancy in patients with prosthetic heart valves requiring anticoagulation, who are treated with adjusted-dose subcutaneous heparin. jeffrey S. Greenspoon, M.D. Martin Montara, M.D. Department of Obstetrics and Gynecology Women's Hospital 1240 North Mission Road Los Angeles, California 90033 REFERENCES l. Hull R, Delmore T, Carter C, et al. Adjusted subcutaneous heparin versus warfarin sodium in the long-term treatment of venous thrombosis. N Englj Med 1982;306:189-94. 2. Levine HJ, Pauker SG, Salzman EW. Antithrombotic ther apy in valvular heart disease. Chest 1986;89:36S-45S. 3. Oakley CM, Doherty P. Pregnancy in patients after heart valve replacement. Br Heart J 1976;38: ll40-8. 4. HallJG, Pauli RM, Wilson KM. Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med 1980; 68:122-40. 5. Iturbe-Alessio I, del Carmen Fonseca M, Mutchinik 0, et al. Risks of anticoagulant therapy in pregnant women with artificial heart valves. N Eng! J Med 1986;315: 1390-3. 6. Chen WWC, Lee PK, Wang RYC, Wong VWC. Pregnancy in patients with prosthetic heart valves: an experience with 45 pregnancies. QJ Med 1982;51:358-65.
Correspondence
785
7. Barss VA, Schwartz PA, Greene MF, Phillippe M, Saltz man D, Frigoletto FD. Use of the subcutaneous heparin pump during pregnancy. J Reprod Med 1985;30:899-90 l.
Lymphocyte-reactive antibodies and recurrent early pregnancy failure To the Editors: It was with interest that we read the latest report by Unander and Lindholm on the use of leukocyte-rich erythrocyte concentrate transfusions in women with re current early pregnancy failure (Unander AM, Lind holm A. Transfusions of leukocyte-rich erythrocyte concentrates: a successful treatment in selected cases of habitual abortion. AM J 0BSTET GYNECOL 1986; 154: 516-20). Recognizing the risks associated with trans fusion for viral transfer (human immunovirus, hepa titis, and cytomegalovirus)' as well as detrimental sensitization (blood groups, platelet and classical his tocompatibility or HLA antigens), these authors ret rospectively identified some individuals with recurrent unexplained abortions who would not benefit from leu kocyte transfusions. Although limited variables were reported, it was concluded that women without "block ing" antibodies are the women who benefit from third party transfusions. Because Unander and Lindholm's study was not randomized, they failed to acknowledge the 20% to 60% of subjects that may have been able to carry a pregnancy to term without transfusion treat ment. Antipaternal cytotoxic antibodies were not stud ied as a criterion of those who would not benefit from transfusions, as only 20% to 50% of multiparous women have such antibodies. In contrast, the presence of antipaternal cytotoxic antibodies was a major exclu sion criterion used by Mowbray et al! in their "con trolled trial" of women with recurrent spontaneous abortion immunized with paternal cells. In trying to clarify those subjects who may not require immunotherapy, data concerning the expected fre quency of blocking antibodies in women with primary and secondary abortion would have been elucidating. After the report by Mowbray et al., we set out to define an expected frequency for the presence of cytotoxic antibodies in women who are recurrent spontaneous aborters. We chose to study nulliparous women with (1) three or more elective abortions and (2) three or more spontaneous abortions, without a viable preg nancy progressing beyond 12 weeks in both groups. Venous blood was obtained from these women at 4 to 12 weeks after their last elective abortion. Serum lymphocytotoxic antibody was assessed at room tem perature by complement-dependent lysis against a panel of 30 individuals' peripheral blood lymphocyte5 in a 1 V2-hour two-stage technique at 22° C. 3 Only om of 23 (4%) "recurrent elective aborters" exhibited lym phocytotoxic antibodies. For comparison, the incidenn of antibody observed in the sample of primary recur rent spontaneous aborters was 8/63 (13%). We recognize that our control population may no