The so-called antiphospholipid syndrOIne may be responsible for repeated spontaneous abortion and fetal loss. We examined the plasma of 61 women with either reproductive failure or abruptio placentae for the presence of lupus anticoagulant and anticardiolipin antibodies in an attempt to assess the prevalence of this condition. No patient had haematological abnormalities consistent with the presence of lupus anticoagulant. However, 6 women had anticardiolipin antibodies with normal coagulation tests. The clinical profile together with this laboratory finding allows us to diagnose the antiphospholipid syndrome in these patients. Our incidence is considerably lower than that reported in many other studies but does suggest a place for screening for this condition in patients with recurrent complications ofpregnancy.S Afr Med J 1993; 83: 319-32

Bird, AR

Bruce, C

Lindow, SW

Van Der Spuy, ZM

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_---- ..319The prevalence of antiphospholipid antibodies in womenwith reproductive failure or major abruptio placentaez. M. VAN DER SPUY, A. R. BIRD, S. W. LINDOW, C. BRUCEAbstract The so-called antiphospholipid syndrOIne may beresponsible for repeated spontaneous abortion andfetal loss. We examined the plasma of 61 womenwith either reproductive failure or abruptio pla-centae for the presence of lupus anticoagulant andanticardiolipin antibodies in an attempt to assessthe prevalence of this condition.No patient had haematological abnormalitiesconsistent with the presence of lupus anticoagu-lant. However, 6 women had anticardiolipin anti-bodies with normal coagulation tests. The clinicalprofile together with this laboratory finding allowsus to diagnose the antiphospholipid syndrome inthese patients.Our incidence is considerably lower than thatreported in many other studies but does suggest aplace for screening for this condition in patientswith recurrent complications ofpregnancy.SAfrMedJ1993; 83: 319-321.~e lupus anticoagulant (LA) is a spontaneouslyacquired anticoagulant initially described inpatients with systemic lupus erythematosus(SLE) _1 It has subsequently been reported in patientswith other auto-immune disorders, in association withdrugs or neoplasia and in the normal population. TheLA is an immunoglobulin (Ig),either IgG or IgM, thatacts by inhibiting phospholipid activity in clotting reac-tions. Characteristically, the anticoagulant prolongs theactivated partial thromboplastin time (APIT) and failsto correct upon mixing with equal volumes of normalplasma. The prothrombin time (PTT) is only slightlyprolonged when measured with undiluted thrombo-plastin.'The LA is not associated with a haemorrhagic ten-dency, unless there is a concomitant qualitative or quan-titative platelet or clotting factor abnormality.' Para-doxically, an increase in thrombo-embolic events and ahigh rate of spontaneous fetal loss have been observed inpatients with this laboratory abnormality.4-9 This is par-ticularly so in patients with SLE and LA.There have been a number of reports of the presenceof LA or anticardiolipin antibodies or both in womenwho have suffered repeated spontaneous abortion andfetal loss. The prevalence of antiphospholipid antibodiesin this group of patientS varies considerably in the dif-ferent srudies and ranges from 7% to 50%.10 Becausetherapy with aspirin and glucocorticoids is often suc-cessful in treating this condition, it has been recom-mended that all women presenting with reproductivefailure should be screened for LA and anticardiolipinantibodies. 11In order to srudy this condition in our patient popu-lation we examined plasma samples for the presence ofLA and anticardiolipin antibodies in women with a his-DepartInents of Obstetrics and Gynaecology and Haematology,Groote Schuur Hospital and University of Cape TownZ. M. VAN DER SPUY, M.B. CH. B., PH. D., F.R.C.O.G.A. R. BIRD, M.B. CH. B., M.MED. (pATH.)S. W. UNDOW, M.MED., F.C.O.G., M.R.C.O.G.C. BRUCE, M.B. CH.B.Accepted 28 Apr 1992.tory of reproductive failure (recurrent spontaneousabortions, unexplained stillbirth or intra-uterine growthretardation) and women who had suffered severe abrup-tio placentae.Patients and methodsConsent to perform this sntdy was obtained from theEthics and Research Committee of the University ofCape Town Medical School. Informed consent wasgiven by all patients and controls srudied.PatientsThree groups of women with no clinical evidence ofSLE-related collagen disorders or other illnesses knownto cause abnormalities in haemostasis tests were investi-gated.Abruptio placentaeThirty women with a history of major abruptio placen-tae in a recent pregnancy were studied. They wererecalled for assessment 1 - 3 years after the index preg-nancy and there was thus no likelihood of the coagula-tion problems associated with abruptio placentae affect-ing the laboratory srudies.Reproductive failureThirty-one women attending the reproductive failureclinic at Groote Schuur Hospital were included in thisstudy. Women attending this clinic had all had 2 ormore spontaneous abortions and possibly other forms ofreproductive failure such as unexplained stillbirth orsevere intra-uterine growth retardation. The subjectsstudied had been fully investigated and no cause fortheir reproductive problems had been found. All sero-logical tests for syphilis were negative.Control subjectsA group of 20 normal adult women and 20 normaladult men served as the control group to establish thereference range for the tests described below, whichwere used to detect the LA.Laboratory methodsFull blood and platelet counts were performed on allpatients. PTT, APTT, kaolin clotting time (KCT),Russell viper venom time CRvvn were measured in allthe subjects, who were also assessed for the presence ofanticardiolipin antibodies.Blood was taken by venepuncture into a 0,1 volumeof 3,8% trisodium citrate. Platelet-rich plasma (PRP)was prepared by centrifuging of blood at 200 g for 20minutes at room temperature. Platelet-poor plasma(PPP) was prepared by centrifuging of the blood at3 000 g for 15 minutes at room temperature. The PPPwas further filtered through 0,22 IJffi cellulose acetate fil-ters in stainless steel assemblies (Millipore Filter, typeG5), in order to extract as many platelets as possible;this reduced the platelet phospholipid content in anattempt to enhance the sensitivity for the LA. I2 Allhaemostatic tests were performed by means of both fil-tered and unfiltered plasma. The APTT was carried Outby means of the Automated APTT Reagent on the_3_2_0....J _DiscussionTABLE 11.Numbers of normal and abnormal laboratory results inpatientsSix of our patients had positive anticardiolipin anti-bodies. However, despite the use of a wide battery ofcoagulation screening tests, none of the women studiedhad evidence to suggest the presence of LA, namely:(1) prolongation of the APTT, KCT or simlar test;(li) failure of 1:1 mixture with normal plasma to correctTwo women in the reproductive failure group hadisolated results « 1,0 seconds) outside the controlgroup reference values for the filtered APPT and RVVTrespectively, while 1 patient in the abruptio placentaegroup had a similar mild prolongation of the filteredAPTT test. All these corrected fully after administrationof a 1:1 mixture with normal plasma. Three women ineach group had anticardiolipin antibodies, but none ofthese women had any coagulation test abnormalities.CoIlagen vascular screens were performed on all thepatients with reproductive failure and none had sero-logical evidence to suggest an underlying auto-immunedisease.In the reproductive failure group, women who hadundergone a positive serological test for syphilis or whohad aknown cause for abortion were excluded from thisstudy. Of the 3 women with positive anticardiolipinantibodies, 2 had had 3 and 8 abortions respectively andno successful pregnancies; the third woman had deliv-ered 2 live healthy children and had subsequently had 3abortions.The 3 women with abruptio placentae who werefound to have anticardiolipin antibodies had negativeresults on serological testing for syphilis. The abruptioplacentae occurred in their first, third and seventh preg-nancies respectively; all the babies were stillborn andweighed 700, 1 700 and 4 000 g respectively. Thewoman in her seventh pregnancy had also had a pre-vious stillbirth of unknown cause.3ol'2'162531Reproductivefailure group4o1o3o3026Abruptioplacentae groupNo. of patientsPatients with allresults normalPatients withabnormal resultsAbnormal resultsAPTTFiltered APTTRVVTAnti-cardiolipinantibodiesCollagen screen• 1 patient had 2 abnormal results.APTT; acitvated partial thromboplastin time.RVVT; Russell viper venom time.Reproductive failure groupThe age range of the patients was 19 - 33 years. The 31women studied had had a total of 157 pregnancies.Twenty-three were pregnant at the time of the study.The remaining 135 pregnancies had resulted in 23 live-births (5 of these infants had been severely growthretarded), 13 stillbirths, 3 ectopic pregnancies and 96abortions. Eighty of these abortions had occurred .at lessthan 12 weeks, 13 at 13 - 20 weeks and the remaining 3at 21 - 28 weeks. In addition there had been 4 neonataldeaths and 2 paediatric deaths among the liveborninfants.Coag-a-mate X2 (General Diagnostics, New Jersey).The PTT was calculated on the Clotek IT (Hyland) andthe Automated Coagulation Laboratory (Instrumen-tation Laboratories, Milan, Italy) by means of undilutedacetone-dried human brain thromboplastin. '3 The KCTwas measured as previously described and the diluteRVVT was assessed according to the method ofThiagarajan el al." Enzyme-linked immunosorbentassay (EUSA) was used to detect plasma cardiolipinantibodies (personal communication - R. Cooper).Laboratory resultsThe full blood and platelet counts were within normalranges in all the women. The means and ranges of theresults of haematological tests in the control group areoutlined in Table 1. The means for all the tests, apartfrom the PTTs, were significantly greater with filteredplasma. The assay for cardiolipin antibodies was con-sidered positive when more than 5 units of IgG anti-bodies were found. Since practically all the assays weresingle, as opposed to serial, tests, IgM results wereignored in cases of nonspecific cross-reactions withother antibodies. In the spontaneous abortion grouponly 1 of the 30 patients had a result outside the rangeof the control group in more than one coagulation test,namely an isolated mild prolongation of the APTT inboth filtered and unfiltered PPP, which corrected towithin 4 seconds of the control with a 1:1 mixture ofnormal plasma. Assays of factor VIII, IX, XI and XIIwere normal with no dilutional effect. The results forthe two groups ofpatients are summarised in Table IT.ResultsAbruptio placentae groupThe age range of these patients was 17 - 38 years. In 28of the 30 women a retroplacental clot had been found atdelivery. Nine infants survived, 2 suffered early neonataldeaths and the remaining 19 were stillborn. The birth-weight varied from 550 g to 4 600 g and the gestationalage from 24 weeks to 40 weeks with a mean (± SD) of34, 7 ± 4 weeks. Twenty-five of the patients were multi-parous and the remaining 5 were primigravidas. Of the30 women, 15 were hypertensive either before or aftertheir delivery and 14 had proteinuria. The records of 2patients' postpartum blood pressure were missing.TABLE!.Means and ranges for the screening tests in 40 control subjects*APPT (seconds) KCT (seconds) RVVT (seconds)Pre-filter Post-filter Pre-fiIter Post-filter Pre-filter Post-filterP< 0,0001 P<O,0001 P<O,001Mean ± SOReference range (± SO)Comparison of pre- andpost-filter results(paired t-test)29,8 ± 2,924-35,631,7 ± 3,325,1 - 38,380,9 ± 13,254,5 -107,3145,7 ± 34,377,1 -214,328,6 ± 2,623,4 -33,829,4 ± 2,424,4 - 34,4• The mean and range for the prothrombin time was 13,7 sand 12,6 • 15,2 s respectively - no significant difference was seen between filtered and unfiltered plasma.____________________________-----'_'-3_2_1__-/a prolonged APTT to within 4 seconds of the control;(iiz) decrease in at least two factors (VIII, IX, XI or XII)by one-stage assay; and (iv) a sensitivity to dilution."One patient with a clearly prolonged APTT correctedon a 1: 1 normal plasma mix and had normal levels ofthe intrinsic pathway factors. We have not been able toobtain further follow-up specimens and can thereforeonly surmise that she may have had a deficiency of oneof the other factors involved in contact activation, e.g.high molecular weight kininogen. The 3 other patientshad isolated mild abnormalities « 1,0 second outsidecontrol reference values) which similarly did not fulfilthe criteria for the LA, and probably represent a normallevel just outside the 95% confidence limits used for thereference values.Hams'o has suggested guidelines for the diagnosis of'antiphospholipid' syndrome. Patients should have atleast one clinical and one serological feature of this syn-drome at some time in their disease course. The clinicalfeatures mentioned by Hams are venous thrombosis,anerial thrombosis and recurrent fetal loss, while thethree serological findings of imponance are IgG anticar-diolipin antibodies, positive LA tests and IgM anticar-diolipin antibody plus positive LA test. 10,16 According tothese criteria, 6 of our patients had the antiphospholipidsyndrome.Our finding of a low incidence of antiphospholipidsyndrome in this group of women with pregnancy loss iscontrary to the results of most previous studies, in whichthe incidence ranged from 7% to 51,6%,10,1l,17 It isunlikely that our coagulation screening tests are less sen-sitive than those in previous studies since we used awide spectrum of tests previously reponed to be sensi-tive to the LA. As mentioned earlier, in an attempt toheighten the sensitivity we filtered the PPP to remove asmany platelets as possible, thereby reducing to a mini-mum the masking effect of platelet phospholipids.'2Although the findings in our study demonstrate aconsiderably lower incidence of anticardiolipin anti-bodies than usual in a group of women with abruptioplacentae or recurrent fetal loss, the incidence is justunder 10% and we suggest that it is advisable to screenpatients who present with fetal loss or a previous historyof abruptio placentae.Lubbe et al. J8 and Partison et al. 19 originally describedthe presence of the LA ± anticardiolipin antibodiesin women with recurrent fetal loss. They successfullytreated these patients with low-dose aspirin andimmunosuppressive doses of corticosteroids. The aim oftheir therapy was to normalise the clotting factors andmany of their patients subsequently delivered livehealthy children.20 A very high prevalence of antiphos-pholipid antibodies in patients with high fetal wastage -recurrent abortion, growth retardation and unexplainedstillbinhs was, however, reponed. lI ,19 Other workershave confirmed their work. Howard et al. J7 reponed a48% prevalence of LA in women with recurrent miscar-riage who did not have SLE. In another study, Deleze etal. 21 studied patients with SLE who had been investi-gated for recurrent fetal loss and compared them withhealthy women who had suffered recurrent abortionsand a group of healthy women who had had at least 3successful pregnancies. The prevalence of antiphospho-lipid antibodies was high in the patients with SLE andjust under 10% in the women with recurrent fetal loss.None of the women with a normal obstetric history hadevidence of these antibodies. The prevalence in their'study therefore is in the same range as ours,In conclusion, there have been reports of vascu-lopathies, placental infarction and the development ofhypenension in pregnancy in patients who have anti-phospholipid antibodies. 22-24 Recurrent early pregnancyloss is possibly just one aspect of pregnancy compromisein these patients and we should be alen to the possibleassociation of the antiphospholipid syndrome and otherpregnancy complications.Given the ease of therapy and the good results whichhave been reponed to date, we suggest that patients whopresent with recurrent fetal loss, unexplained stillbirth,previous abruptio placentae or gestational proteinurichypenension should be screened for antiphospholipidantibodies and that, where appropriate, aspirin and pos-sible steroid therapy should be initiated. It should benoted however, that in some women these antibodiesonly appear during pregnancy and disappear thereafter.A negative result in the non-pregnant patient needs fur-ther follow-up during pregnancy and patients should beappropriately counselled.We gratefully acknowledge the assistance of DrRosemary Cooper of Tygerberg Hospital and theUniversity of Stellenbosch Medical School, who performedthe cardiolipin antibody assays, and thank Mr BarryKossew of Groote Schuur Hospital, who did the coagula-tion tests. This study was funded by a grant from theHarold Crossley Fund of the University of Cape TownResearch Committee.REFERENCESI. Coniey CL, Hanman RC. A hemorrhagic ctisorder caused by circu-lating anticoagulant in patients with dissseminated lupus erythe-matosus. J Clin Invest 1952; 31: 621-622.2. Elan PM, Marrin SE. The lupus anticoagulant. Arch Parhol LabMed 1982; 111: 113-114.3. Shapiro S, Thaigarajan P. Lupus anticoagulant. Prog HemosrThromb 1982; 6: 263-285.4. Mueh JR, Herbst KD, Rapaport SI. Thrombosis in patients withthe lupus anticoagulant. Ann Imem Med 1980; 92: 156-159.5. Asherson RA, Mackay IR, Harris EN. Myocardial infarction in ayoung man with systemic lupus erythematosus, deep vein thrombo-sis and antibocties to phospholipids. Br Heal1J 1986; 56: 190-193.6. Feinstein DI. Lupus anticoagulant, thrombosis and fetal loss. NEnglJ Med 1985; 313: 1348-1350.7. Branch D\V, Scon JR, Kochenour NK, Hershgold E. Obstetriccomplications associated with the lupus anticoagulant. N Engl JMed 1985; 313: 1322-1326.8. Gleicher N, Friberg J. I~M gammopathy and the lupus anticoagu-lant syndrome in habitual aborrers. JAMA 1985; 253: 3278-3281.9. Finnazi G, Cortelazzo S, Viero P, er al. IgM garnmopathy and thelupus anticoagulant in habitual aborters. JAMA 1986; 225: 39.10. Harris EN. Clinical and immunological significance of antiphos-pholipid antibocties. In: Beard RW, Sharp F, eds. Early PregnancyLoss. Mechanisms and Treamlenr. London: Springer-Verlag, 1985:43-65.11. Lubbe WF, Liggins Gc. Lupus anticoagulant and pregnancy. Am JObsret Gyneco11985; 153: 322-327.12. Exner T. Comparison of two simple tests for the lupus anticoagu-lant. Am J Clin Parho11985; 83: 215-218.13. Bird AR, Kossew B, Mulligan TP, Jacobs P. Regional thrombo-plastin standardisation using a human brain extract. S AIr Med J1989; 75: 538-540.14. Thiagarajan P, Pengo V, Shapiro SS. The use of the ctilute RussellViper venom time for the diagnosis of lupus anticoagulants. Blood1986; 68: 869-874.15. Green D, Hougie C, Kazmier FJ, er at. Report of the working partyon acquired inhibitors of coagulation: studies of the lupus anticoag-ulant. Thromb Haemosr 1983; 49: 144-146.16. Hughes GRV, Harris l'-.TN, Gharavi AE. The anticardiolipin syn-drome. J RheumalOl1986; 13: 486-489.17. Howard MA, Firkin BG, Healy DL, Choong SCC. Lupus antico-agulant in women with mulriple spontaneous miscarriage. Am JHemarcll987; 26: 175-178.18. Lubbe WF, Butler WS, Palmer SJ, Liggins Gc. Lupus anticoagu-lant in pregnancy. Br J Obsret Gynaecol 1984; 91: 357-363.19. Partison NS, McKay EJ, Liggins GC, Lubbe WE Anticardiolipinantibodies: their presence as a marker for lupus anticoagulant inpregnancy. NZ MedJ 1987; lOO: 61-63.20. Lubbe WF, Butler WS, Palmer SJ, Liggins Gc. Fetal survival afterprednisone suppression of maternal lupus-anticoagulant. Lancet1983; 1: 1361-1363.21. Deleze M, A1arc6n-Segovia D, Valdes-Macho E, aria CV, de LeonSP. Relationship between anti-phospholipid antibodies and recur-rent fetal loss in patients with systemic lupus erythematosus andapparently healthy women. J Rheuma1011989; 16: 768-772.22. Branch DW, Andres R, Digre KB, Rote NS, Scon JR. The associa-tion of antiphospholipid antibodies with severe preeclampsia. ObsterGynecol1989; 73: 541-545.23. Khong TY, De Wolf F, Robertson WB, Brosens I. Inadequatematernal vascular response to placenration in pregnancies compli-cated by pre-eclampsia and by small-for-gestational-age infants. BrJ Obsrer Gynaeco11986; 93: 1049-1059.24. De WolfF, Carreras La, Moermann P, Vermylen J, Van Assche A,Renaer M. Decidual vasculopathy and extensive placental infarc-tion in a patient with repeated thromboembolic accidents, recurrentfetal loss and a lupus anticoagulant. Am J Obster Gyneco11982; 142:829-834.

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The prevalence of antiphospholipid antibodies in women with reproductive failure or major abruptio placentae

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The prevalence of antiphospholipid antibodies in women with reproductive failure or major abruptio placentae

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