| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan.
Address reprint requests to: Koji Kanazawa, MD, PhD, Department of Obstetrics and Gynecology, University of the Ryukyus, Faculty of Medicine, 207 Uehara Nishihara-Machi, Nakagami-Gun, Okinawa, Japan
 |
Abstract |
|---|
Top
 Abstract Materials and MethodsResultsDiscussionReferences |
|---|
Methods: Thirty-six women with antiphospholipid antibodies who had three or more repeated miscarriages were enrolled. Intravenous heparin was used for each of the first pregnancies after referral. Changes in antibody status were investigated with relation to outcomes of the index and subsequent pregnancies.
Results: Eighteen of 23 pregnancies in 36 antibody-positive women treated with heparin resulted in term or preterm deliveries with live-born infants, and five ended in abortions. Antibodies cleared in ten of 12 term pregnancies, in five of six preterm pregnancies, and in one of five abortions. There was a statistically significant difference between the term pregnancy and abortion groups (P < .05). Eleven second and third pregnancies in nine women in whom antibodies cleared resulted in term or preterm deliveries of live-born infants, without heparin therapy. The second and third pregnancies in one woman whose antibodies persisted ended in miscarriages despite repeated heparin administration.
Conclusion: Antiphospholipid antibodies cleared spontaneously in some pregnant women treated with heparin. Subsequent pregnancies among women in whom antibodies cleared were managed successfully without medication, whereas pregnancies in women with persistent antibodies required treatment.
Lupus anticoagulant and anticardiolipin antibodies, originally described in patients with autoimmune diseases, are overlapping subsets of antiphospholipid antibodies.1,2 It is well known that antiphospholipid antibodies can be associated with fetal and maternal complications,3–5 which might be explained by observations that antibodies induce thrombosis in the utero-placental vasculature, leading to placental insufficiency, and impair trophoblast function, leading to defective implantation and invasion in the decidua.6–8 Therapeutic approaches, including cortisol and heparin, have been used for prophylaxis of those complications. There is little literature on the long-term natural history of antibodies during and especially after pregnancy. Lubbe et al,9 Out et al,10 and Kwak et al11 reported that serum levels of antibodies decreased significantly in women treated with prednisone during pregnancy. Lynch et al12 and Topping et al13 observed that positivity of antibodies varied considerably in untreated women during pregnancy.
We treated pregnant women with antiphospholipid antibodies with heparin, a drug without immunosuppressive activity and not prednisone. The objectives of this prospective study were to characterize the natural history of serum antibodies in women treated with heparin during and after pregnancy and to identify any association between changes in antibody status and outcomes of subsequent pregnancies.
|
Materials and Methods |
|---|
|
Top
AbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Diluted prothrombin time (PT) and diluted activated partial thromboplastin time (PTT) were measured for detection of lupus anticoagulant according to the conventional method. An elevated coagulation time was considered positive when women’s values were higher than the threshold mean of normal controls for PT and twofold greater than the mean of normal controls for activated PTT. Those results were confirmed by a neutralization test with hexagonal (II) phospholipid (STAGO, Asnieres-Sur-Seine, France). Enzyme-linked immunosorbent assay (ELISA) was used to quantify immunoglobulin (Ig) G and M class anticardiolipin antibody according to international standard methodology, with an IgG level and an IgM level of at least 1.0 unit/mL considered positive. Testing for antibodies was done bimonthly or trimonthly during pregnancy, and at 1 month, 3–6 months, and 12 months after pregnancy.
Heparin therapy was used for each of the first pregnancies after referral and was initiated immediately after confirmation of a potentially viable pregnancy (ultrasonographic documentation of embryo or fetal heart movement) and continued to 34 or 35 weeks’ gestation; it was stopped at miscarriage. Heparin was given intravenously (IV) with a portable continuous injection pump. The dose of heparin was 10,000 IU/day initially and was adjusted thereafter to obtain an activated PTT of 1.2–1.3 times the control value. Ultrasonographic monitoring of retroplacental bleeding was done serially (usually at least weekly). If heparin-related hemorrhagic events occurred, the dose of heparin was reduced. If retroplacental hematoma was suspected, heparin was discontinued.
Among women in whom antiphospholipid antibodies cleared during or after first pregnancies, heparin therapy was not used for their subsequent pregnancies, but they were observed closely. In women with persistent antibodies, heparin was given during subsequent pregnancies.
Fisher exact test was used to assess the difference among clearance rates of antibodies in term pregnancy, preterm pregnancy, and abortion groups. P < .05 was considered statistically significant.
|
Results |
|---|
|
Top
AbstractMaterials and MethodsResultsDiscussionReferences |
|---|
. Mean age was 34.1 years with a range of 21–42 years. Six had histories of preterm pregnancies and three had histories of fetal growth restriction (FGR). Lupus anticoagulant and anticardiolipin antibody were positive in 17(47.2%) and 25 (69.4%) of 36 women, respectively. Immunoglobulin subclasses of anticardiolipin antibodies were IgG in nine women (mean level 1.8 unit/mL, range 1.0–3.2 unit/mL) and IgM in 18 women (mean level 1.3 unit/mL, range 1.0–2.2 unit/mL).
|
), of whom 12 (52.2%) had term deliveries of 11 appropriate for gestational age (AGA) infants and one small for gestational age (SGA) infant. Six pregnancies (26.1%) resulted in preterm deliveries of four AGA infants and two SGA infants, one of whom died extremely preterm. Thus, the live birth rate was 78.3% (18 of 23 pregnancies). Five pregnancies (21.7%) ended in abortions (four embryo-fetal deaths and one partial hydatidiform mole coexisting with a live fetus). The results of chromosomal analysis of trophoblasts in three of four embryo-fetal deaths were trisomy 9, trisomy 21, and a normal karyotype of 46,XX. In the hydatidiform molar pregnancy, the karyotype of molar trophoblasts was identical to morphologically normal trophoblasts, 46,XY. Live-birth rates among women with both lupus anticoagulant and anticardiolipin antibody, with lupus anticoagulant alone, and with anticardiolipin alone, were five of six, six of six, and seven of 11, respectively. Live-birth rates by Ig classes of anticardiolipin antibody, were four of seven in the IgG anticardiolipin antibody group and eight of 12 in the IgM anticardiolipin antibody group. There were no statistically significant differences among groups categorized according to status of antibodies.
|
). Lupus anticoagulant and anticardiolipin antibody ceased to be detectable in most women who had those antibodies. The clearance rate was ten of 12 in term pregnancies, five of six in preterm pregnancies, and one of five in abortions. There was a statistically significant difference between the rates of the term pregnancy and abortion groups (P = .028) but not between preterm pregnancy and abortion groups (P = .08).
Subsequent second and third pregnancies occurred in nine of 16 women in whom antibodies cleared and in one of seven women with persistent antibodies (Table 2). The 11 pregnancies in the former group resulted in term or preterm deliveries of AGA infants, with no heparin therapy. Those women had no reappearance of antibodies at their last follow-up visits. In contrast, the second and third pregnancies in one woman with persistent antibodies, during which heparin therapy was used, ended in abortions; she had persistent IgM anticardiolipin antibody. The chromosomal analyses of both aborted trophoblasts showed normal karyotypes of 46,XX. In that woman IgM anticardiolipin antibody had not cleared at her last visit.
Three patients had mild nasal or gingival bleeding that was controlled by decreasing their heparin doses. One woman had transient microscopic hematuria. There were no significant findings in bone mineral density of lumbar spine in six women postpartum. No retroplacental hematoma was documented in women in this series in whom it was initially suspected.
|
Discussion |
|---|
|
Top
AbstractMaterials and MethodsResultsDiscussionReferences |
|---|
There are few data from long-term follow-up studies that show the natural history of antiphospholipid antibodies during pregnancy or postpartum. Lubbe et al,9 Out et al,10 and Kwak et al11 reported that levels of antibodies fluctuated or decreased significantly in women treated with prednisone and aspirin during pregnancy. In their studies, pregnant women were given high-dose prednisone of 40–60 mg/day and aspirin of 75–80 mg/day, which resulted in successful suppression of antibodies and live-born infants. In those studies, suppression of antibodies was a down-regulation of antibody production induced with high-dose exogenous cortisol, not a natural shift of antibody status in pregnancy. Lynch et al12 and Topping et al13 reported that the positivity of antibodies varied considerably during nontreated pregnancies. They observed that some women changed from positive antibody profiles at first visits to negative profiles at delivery, whereas other women changed from negative to positive profiles. Those findings suggest that a considerable shift in antibody status throughout pregnancy might occur. In the present study, antibodies cleared in 16 of 23 women (70%) treated with heparin alone. Heparin has an anticoagulative function through its complex formation with antithrombin III but does not have immunoinhibitory activity. Accordingly, we speculate that the clearance of antibodies might be associated with pregnancy-induced maternal immune suppression. That speculation appears to be supported by findings that the clearance rate of antibodies was significantly higher in term or preterm pregnancies than in abortions, because suppressed maternal immune status might be longer and deeper in the former than the latter. It should also be noted that antibodies cleared more frequently postpartum than during pregnancy. Those data suggest that antiphospholipid antibodies might clear or decrease spontaneously even in pregnancies successfully treated by nonimmunoinhibitory drug therapy. This appears to mimic the finding that in pregnancies complicated by systemic lupus erythematosus, the disease often improves spontaneously.
There is a paucity of information on a subset of women whose antiphospholipid antibodies clear, with regard to treatment and outcome of their subsequent pregnancies. In the present study, 11 subsequent pregnancies occurred in nine women in whom antibodies had cleared in their first pregnancies, resulting in term or preterm deliveries of live-born AGA infants despite no heparin therapy. None of those nine women had reappearance of antibodies at their last follow-up visits. Second and third pregnancies of one woman in whom IgM anticardiolipin antibody was persistent ended in abortions, with normal chromosomal analyses of trophoblasts. Her IgM anticardiolipin antibody had not cleared at her last visit. Those findings are clinically informative for identifying a subset of women with pregnancies complicated by antibodies who need therapeutic intervention. In women in whom antibodies cleared, subsequent pregnancies might not require medication, but in women with persistent antibodies, medication will likely be necessary.
|
Footnotes |
|---|
Received July 31, 2000. Received in revised form November 13, 2000. Accepted November 22, 2000.
|
References |
|---|
|
Top
AbstractMaterials and MethodsResultsDiscussionReferences |
|---|
2. Hughes GRV. The antiphospholipid syndrome: Ten years on. Lancet 1993;342:341–4.[Medline]
3. Polzin WJ, Kopeman N, Robinson RD, Read JA, Brady K. The association of antiphospholipid antibodies with pregnancies complicated by fetal growth restriction. Obstet Gynecol 1991;78:1108–11.
4. Pattison NS, Chamley LW, McKay EJ, Liggins GC, Butler WS. Antiphospholipid antibodies in pregnancy: Prevalence and clinical associations. Br J Obstet Gynaecol 1993;100:909–13.[Medline]
5. Rai RS, Clifford K, Cohen H, Regan L. High prospective fetal loss rate in untreated pregnancies of women with recurrent miscarriage and antiphospholipid antibodies. Hum Reprod 1995;10:3301–4.
6. Lyden TW, Vogt E, Ng AK, Johnson PM, Rote NS. Monoclonal antiphospholipid antibody reactivity against human placental trophoblast. J Reprod Immunol 1992;22:1–14.[Medline]
7. Sthoeger ZM, Mozes E, Tartakovsky B. Anticardiolipin antibodies induce pregnancy failure by impairing embryonic implantation. Proc Natl Acad Sci U S A 1993;90:6464–7.
8. Nayar R, Lage JM. Placental changes in a first trimester abortion in maternal systemic lupus erythematosus with antiphospholipid syndrome: A case report and review of the literature. Hum Pathol 1996;27:201–6.[Medline]
9. Lubbe WF, Butler WS, Palmer S, Liggins GC. Fetal survival after prednisone suppression of maternal lupus-anticoagulant. Lancet 1983;2:1361–3.[Medline]
10. Out HJ, Bruinse HW, Christiaens GCML, van Vliet M, de Groot PG, Nieuwenhuis HK, et al. A prospective, controlled multicenter study on the obstetric risks of pregnant women with antiphospholipid antibodies. Am J Obstet Gynecol 1992;167:26–32.[Medline]
11. Kwak JYH, Barini R, Gilman-Sachs A, Beaman KD, Beer AE. Down-regulation of maternal antiphospholipid antibodies during early pregnancy and pregnancy outcome. Am J Obstet Gynecol 1994;171:239–46.[Medline]
12. Lynch A, Marlar R, Murphy J, Davila G, Santos M, Rutledge J, et al. Antiphospholipid antibodies in predicting adverse pregnancy outcome. Ann Intern Med 1994;120:470–5.
13. Topping J, Quenby S, Farquharson R, Malia R, Greaves M. Marked variation in antiphospholipid antibodies during pregnancy: Relationships to pregnancy outcome. Hum Reprod 1999; 14:224–8.
14. Rosove MH, Tabsh K, Wasserstrum N, Howard P, Hahn BH, Kalunian KC. Heparin therapy for pregnant women with lupus anticoagulant or anticardiolipin antibodies. Obstet Gynecol 1990; 75:630–4.
15. Cowchock FS, Reece EA, Balaban D, Branch DW, Plouffe L. Repeated fetal losses associated with antiphospholipid antibodies: A collaborative randomized trial comparing prednisone with low-dose heparin treatment. Am J Obstet Gynecol 1992; 166:1318–23.[Medline]
16. Branch DW, Silver RM, Blackwell JL, Reading JC, Scott JR. Outcome of treated pregnancies in women with antiphospholipid syndrome: An update of the Utah experience. Obstet Gynecol 1992;80:614–20.
17. Hasegawa I, Takakuwa K, Goto S, Yamada K, Sekizuka N, Kanazawa K, et al. Effectiveness of prednisolone/aspirin therapy for recurrent aborters with antiphospholipid antibody. Hum Reprod 1992;7:203–7.
18. Kwak JYH, Quilty EA, Gilman-Sachs A, Beaman KD, Beer AE. Intravenous immunoglobulin infusion therapy in women with recurrent spontaneous abortions of immune etiologies. J Reprod Immunol 1995;28:175–88.[Medline]
19. Rai R, Cohen H, Dave M, Regan L. Randomized controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ 1997;314:253–7.
20. Silver RK, MacGregor SN, Sholl JS, Hobart JM, Neerhof MG, Ragin A. Comparative trial of prednisone plus aspirin versus aspirin alone in the treatment of anticardiolipin antibody-positive obstetric patients. Am J Obstet Gynecol 1993;169:1411–7.[Medline]
21. Casele HL, Laifer SA. Hemorrhagic complication of anticoagulation during pregnancy in a woman with lupus anticoagulant. Obstet Gynecol 1997;90:646–7.[Abstract]
22. Laskin CA, Bombardier C, Hannah ME, Mandel FP, Ritchie JWK, Farewell V, et al. Prednisone and aspirin in women with autoantibodies and unexplained recurrent fetal loss. N Engl J Med 1997;337:148–53.
23. Backos M, Rai R, Baxter N, Chilcott IT, Cohen H, Regan L. Pregnancy complications in women with recurrent miscarriage associated with antiphospholipid antibodies treated with low dose aspirin and heparin. Br J Obstet Gynecol 1999;106:102–7.[Medline]
This article has been cited by other articles:
|
|
 |
|
  R. D. Franklin and W. H. Kutteh Effects of Unfractionated and Low Molecular Weight Heparin on Antiphospholipid Antibody Binding In Vitro Obstet. Gynecol., March 1, 2003; 101(3): 455 - 462. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J Balasch and R Cervera Reflections on the management of reproductive failure in the antiphospholipid syndrome--the clinician's perspective Lupus, August 1, 2002; 11(8): 467 - 477. [Abstract] [PDF]
|
|
|
|
|
|
J. A. McIntyre, D. R. Wagenknecht, W. P. Faulk, H. Masamoto, T. Toma, K. Sakumoto, and K. Kanazawa Clearance of Antiphospholipid Antibodies in Pregnancies Treated With Heparin Obstet. Gynecol., July 1, 2001; 98(1): 162 - 162. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
