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Anticardiolipin antibodies
ANTICARDlOLlPIN ANTIBODIES A Review of the Literature
Lyneite A. Ament, CNM,MSN,
RNC
ABSTRACT Repeatedfekl lass may be a result of a varietyof causes.Immunologtalfactorshave beentmpticated in fetalImr. intrauteiinegrowthretardation.preedampria. andthrombacytopenk.Anttcardioltpinantibodies(ACM belongto a fan,&, of autoantibodies knwm B antlphosphobpid an!Jbcdks.Plateletagwgalion andincreasedcoaguktion watts from the ,x-c* of these an8badies.andis believedto conhlbuteto the fetal complkations.Thii articlek a reviewof the physiotqica,imptications of AcAr. SCTPP”. tngcxiterkfor the presenceof A’.%, pfevaience rates,dkgnnttc measures~ treatment Opaons,and posriblepostpartu~~, effectsof ACAs When womenwith rec’wrentpteg. nannykobesprexnt for care.the nurw-midwifeneedsto be ableto dkass pxsible -, aspectsof dkgnmis. andtreatmentoptionsavailableWith a betterunderstandingofwhat theseare.the nurse-mtdtifewill bebetterabk to pkn carethatwill promote a positiveplqlancy outcome.
Repeated fetal loss, de&d as the loss of three consecutive prqnanc+es pliorto2Swek5,mayboarewltof a valiety of causes (1). Sane causes that have bean identified include genetic anomalies. infectfons, uterine anomabes. luteal phase deficiency. and ~mmuno!agkelcauses Immun+ k&al factors have a!so been in+ caed in olher adverse pregnancy outcomes, such as intrauterine growth retardatton. preeclampsia. and thmmbocytopenia. Antfcardiolfpfn antibodfes, which belong to a family of autoantibcdles known as antfphos+UPfd an%adks, are immun~ns that have been linked to repeatedfetal less. The pupasa of thk artkle k to r&au the recent Uteraiwe on .nucoTdioupin antibodies, specifically as regards diagnosis, treatm+nL and associatedoutcomes.
PHYSlOLOGKAL tMFiKATlONS OF ANllCARDlOLIPlN ANTIBODIES Antkardioliiin anti&dies are aq immuncglobulin of the IgG or IgM ckss, with anticoagulantactivfty considered to result from ik interference with the activation of the pfothmmhill activator cumplex (2). Patients with anticardiolfpin antibody usuauy exhibt a tendency toward thmmtosk. The biolcgfc mechanism(s) by which this o&s k not known (2): It has been suggested that antiphaphofipid antibodies. the fam& of autoanttbodles to which anacardfolipin antibodies belong, prevent pmstacyclin pmductfon. Pmstacydn, which k a patent vasadilatorand inhibitor of platelet aggregation. is pDduced hy vaxular iksues. It is a natural antagunkt to thmmlmxane, a potent vasoconstitor and plateletaggregation-inducing pmstaglandin that is rekared hy aggre@ing platelets. Pmductton of prcstacyclin hy
the endothelfal cells k considered an important mechanism in protecting the vascular wal! from the deposition of platelet aggw_gatesand subsequent thrombosis. Thus the inhibftion of pro?.tacyclin would favor dxcmhazis (3). Anticadtolipin antibodies also bind to phapholiiid ant&ens of the placentalvesek, inducin4 bental inhuction (4). It k the aggqation and increased m?lgu!anonthat are Nmlked to co”bibute to fetal death (1).
platelet
SCREENINGCRllERIA FOR ANTlCARDIOLlPlN ANllBODfES vadous expetk 0” the topicof anticadfoiiptn antIbodies recommend an anay of saeentng ctitetfa. Mfllkz and cd!eague$ (4) recommend that tesk for the deteztion of anticardfolipin antihodks during pregnancy should be performed for multiparous .&amen with hypertemi~n or a hktory of intrauterine fetal growth reta-
19 w9131-7.w
d&ion. Reece and colleagues(2) recommend screening for the presence of antibodies not only in the presence of intrauterine growth retardation, but also in cases of une@ained recurrent snontaneous abortions or stillbirth. ihcy also state screening should be considered for indications such as suspicion of lupus erythematceus, unexplained thrombocytopenta or hypoprothrombinemia, the presenceof positive anttnuckar antibodies. or a persistent false-posittve VDRL. Antibodies to cardiolipin can give dse to biolcgtc false-positive VDRLs becausethe serolwic tests use phospholipid ahstr& (2). Lubbe and colleaoues (51 found the FTA-abs end T&pmemo pallidurn hem&utination to be negat&e when the reason for a false-positive VDFtL to be the oresence of anticardiolipin antibodies. Giano~oulos 161 recommends screenins women tith a histoy of thrombosis or pulmonary embolism, early atypical kypertension in pregnancy, and patients with abruptio placenta. Lakwocd and colleagues (7) studted the prevalenceand signif~mnceof antiphospholipid antibodies in a low-risk obstetdc population and found a statistically significant relationship between elevated anticardiolipin antibodies, preterrn delivery, and low birth weight. Carp et al (1) recommend Screeningfor antibodieri on!y after all other possible explanations for recurrent fetal loss have been ruled out. Lynetle A. Amen! receiveda poshrwstefs cerrpcoteh nurse-midwfleyjmm the University oj Illinois-Chicago.She is cumnIly LI dwtoml candidate fn nuafngat the “niuersily “J Wisconsin-hfilwoukee. She is en ersiskmtpmfersor et Bamt College andLlnivasiiy of He& SctenceslChicngo Mediml School in North Chicago,Illinois, and in clinical ~recticeot Sinai Sam&en Hosoital m
PRNALENCE OF ANT,CARDlOLIPINANTIRODIES Anticardlolipin antibodies occur with high frequency in women with e dim agnosis of systemic lupus eythematosus. High titers of anticardioltpin antibodies have occasionally been found in obstetric patients without systemic lupus eyth*matosus and in patients with current thromboembolit episodes (8). Anlieardiolipin an& bodies are rarefy foonnd.in Sealthy populations. and they can occasion& be found in patients with acute infections (8). In cases of infection, however, the andcardioliptnantibodies seem to occur only tempaarily
@I.
Unander and colleagues(81 inwtigated rhe occurrenceof anticardiolipin antibodies in 99 women referred to them because of recurrent fetal loss, defined as at least three consecutive at&tons. Increasedanticardiolipin antibody levels were found in 42 of the women. Cardtolipin antibodies exclusively of the IgM class were found in seven women; IgG anttbodies were found in 35 of the women. The authors did not examine outcomes based on the influence of the IgM and fgG antibodies togetha; instead they chcee to report the IgG anticardiolipin antibody levels, because these were more prevalent. None of the women were considered to have s+emic lupus eythematosus. They also found that the anticardiolipin antibody levels remained constant and independent of pregnancy and steroid therapy. ockwood zmd colleaques (7) studied the prevalenceof a&ardio: lipin antibodies in a low-risk obstehtc population. Patients with a hlstw 01 three consecutivespontaneous l0sw or sttllbirths were excluded. The total population consisted of 737 women with a median gestational age of 16 weeks. Of these 737 low-risk women. onlv 2.2% exhibtted anticardiolipin anti&ies. The mean maternal age was 22.7 years and the median gravtdity was three. There were
I
maternal age
no differences in or parity between women with elevatedanticardiolipin antibodies compared with those with no elevation. Millie2 and colleagues (41 examined the prevalenceof autoantibodies durhw third-himester preqnancv complica~d by hypertension or idi;nathic fetal “row& retardation. Tr;;j bundred p;egnant women were weened; none “i the p&en& had systemic lupus eryihematosus or any other documented autoimmune di.ease. Rfty percent, or loo women, were witho”t compllcauons of pregnancyto form the mntml Population. Twenty-five percent of the sample women had fetal growth retardation and 25% had pregnancies compltrated by hypertenston. Among the 100 normal pregnancies and those with fetal growth retardation, none had antlcardiolipin antibodies. Among the women with hypertension during preegnancy, only 4% had elevated anticardtolipln antibodies. Thus, in this sample the only risk factor associated with elevated levels was hypertension during pregnancy. Harrisand Spinnato 191examined 1,449 pregnant women for the plwalence of anticardtoliptn antlbodks Although thtt study did not control for the frequency of aspirin. coxticosteroids, or other immunosuppressive therapy, the frequency of women with elevated IgG lewls was 1.79% and the frequency of v.anen with elevated I&f levek was 4.3%. On the basis findings, they recommend that for anticardiolipin antibodies not be done to ween otherwise hea!!hy v~**>en. One interesting Rnding from their study is that pasittve antlcardioUptn results remalned pwiave for peitods of up to three months’ postparium for a majority of the women.
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DIAGNOSISOF .ANncARDnwm
ANTBODIES
Anticardiolipin antibodies can be quantified by enzyme-linked immunosorbent assay @LISA) levek and
binding activity of IgG and IgM anticardiolfpin preparations. Experts are not in agreement es to which laboraton/ tesk are the most accurate i” diagnosing anticardiolipin antibodies, nor are they in agreement e5 to cutoff values for the various tests (see Table 1). Unander and colleagues (8) co” sider IgG and IgM vafues above or equal to three standard deviation units as pathologic. I” their study, 42 of 99 vane” with habitual abortion demonstrated increased andcardie lfpin an&fly kvefs. Sew” women had IgM values between three to seven unik and 35 of these 42 had IgG antibodies against cardiolipin equal to or greater than 10 “nib. They found that, in most cases. the antibody activity of IgM VJes lower the” that of I&; in other words, IgG wes a more accurate dfeg”ostk test. Rote et al (10) fou:id that IgG Macardtoftpin annbodk?s were greater the” 5.8 standard deviation units in 58% of their sample of 47 women, of whom had at least hue consecutive preg”ancy f#sses. The assay for fgM antkardiofipin anttbodtes had the !awst freque”cy, witf. 36% of the sample having a median of 1.2 stenderd deviation unik Mtllkz and ml!wJgues (41 used a fowr cutoff point and defined a positive value as grater then Awe sIa”dard deviation unfts above the “lee” contmf value. and IgM vakles. Two articles discussed the activated parttal thmmboplasttn time (APTT) es a dieg”ostic tool (2. 9).
TABLE1 LXESiU&dACA
Llnander et al (8) Rote et al (10)
l’be rationale for using the AF’lT k to “11e out the presence of the lupus a”ticoagulant &us anticardiol&i” antibody es the causative agent with adveE-2 pregnancy outcomes. A5 mentioned previously both the lupus anticoagule~t and the anticardiolipin antibody belong to the more general group of antiphcspholipid antibodizs. Although the majority of patients with lupus a”ticoa&nt alw have anticxdiolipin antibodies, the presence of anticardiolipin aniibcdies are a better predictor of adverse prep “ancy outcomes. The difference between the two an&dies, according to some a”!“on, 1s with treatment: luws a”(icow,ulant is easier to suep&s (2). Tl&, if anttrardioliiin antibodies are present. the ApIT may be used to determine the presence of the lupu.-like aniicoa@nt. Reece and colleagues (2) state that if plasma co”tai”s high levels of the lupus-llke anttcoagant, the par&l thrombockstin time @ITI and occaSioMuy & pmthrombin time (PT) are prolonged. but that in general the PIT is the more sensitive measurement Because there is also a tendency toward thrombosis, there may else be a prolonged APTT. Reece et al evaiuate a prolonged AF’TT by mking the patient’s plasma with “amalpbsme;iftheAPlTiscorrected by thk mWng of bled. a clotting iactar deficiency should be suspected (2). If the APl-r 15not corrected wtb the mixing. the presence of circufating anticoegufenk such es the lupusltke anttcoegulant should be mnstdered (2).
Although Rote et el (10) still WCommend screenino for APTf’ beca.we clinicians a& more familiar with it and the test is widely available, they believe that the Ml-r may be less sensitive than other screening tests plimaily for two wasonc The test is prone to the effects of &red levels of normal coagufation factors Wiih may be elevated during preg“ancy) and the co”te”t of procoegulatoy phospholipids (which may vary considerably among conunercielly available preparanOns of par8al thrombopfastin). In addition; they state that the APlT is cumbersome. arid the qwifcity and class of the antibody that prolongs coagulation cannot be readily identified. It is espekally recommended for weentng women who are not currently pregKM, as the pro&m of pRg,,Fa”Cyassociatedekzvaiionsin the levels of coagufatio” factors can be atided. For the AFfT they consider a coagufatin time of longer than 45 setends es abnomxel.
lREATMEI?T OF
Rosowetellll)treated13women who had one or more abnormal pregnancy outcomes and positive anticardldlpln antfbodies with hepari” therapy. Hepad” therapy was used due to their coiz-zem regard&g @ucocorticoid side effects. and bec&lee pf%cental thrombosis “lay be e fector that detelmhles fetal outco”le. The gestational age when hep ad” beatment bega” was 10.3 weeks and continued for the remainder of the woqnancy. Heraad” was qive” sub&&eousiy e&y 12 hours, and dasage was based on elevated AFll’ values. In patients with normal AFfTs, the dosage was adjusted to obtain a mid-internal clotting time of 1.5 to 2.0 times the control value. Tlw mea” total dalfy hepaiin dcag-a was 24,700 units. Heparin was discontinued briefly at delivay and then resumed for vatable periods
Ninety-three percent of these pregnancies resulted in live births at a mean gestational age of 36.1 weeks. Five (36%) of the placentas were n-&nknaUyinfarcted on gross examination: this 1sa decrease from 56% with thesubjects’ prior second- and third-trimester losses. Recorted hew ark-a&ted problems included inj&tion ‘?e bruises. three minor instancesof epistaxis,and one instance of hemaiuda at delivers. There was no control group duting this study of untreated subjects. The only control was the subjects’prior pregnancy histories: an increase from 3% live births prior to treabnent to 93% with treatment
DISCUSSIONS REGARDING TREATMENT Lockshin et al (12) evaluated 25 asymptomatic wmnen with high anticardioli~in antibodv titers (levels were noi reporiedj &ho had been treated during pregnancy. The women were managed In one of four ways: no treatment, aspirin 80 mgl day, aspirin plus prednisone 30 mg/ day for at least four weeks and then continued or tapered to a lower dtxe, or prednisone 60 mglday for four weeks and continued at reduced doses until delivery. Women were not randomized into treatment protoc&z watment was based on bath the patient’s and physician’s request. These authors feel that their results were less than optimistic. For women with a hqh anticardiolipin antibody titer and prlor fetal death, 67% of their current pregnancies were not successful.For women with a high anticadiolipin antibody titer but no prior fetal death, 33% of the pregnandes ended in fetal death. In those women with prior fetal death, treatment with prednisone worsened the prcgnasis (P - .Ol); in women without prior fetal death there was no effect of either therapy, and prognosis was generaljy gad even in untreated patients. Reece and colleagues (2) achieved
14 (77.8%) live births among 18 women with high anticardfolfpin antibodies and prior pregnancy losses treated with prednisone or low-dose aspirin during pregnancy. They also observed an associationtieen the number of pdor fetal losses,the anticardiolipin antibody titer, and the fetal survival rate after the varying therapies. Two or more prior fetal lossesand high autoantibody titer resulted in a fetal sunrival rate of 50% to 75% with varying therapeutic regimens and dosages. A fetal survival rate of 75% to 100% occurred with fewer than hvo prior fetal lows and low to mid-anticardiolipin antibody titer with the same therapies. The authors conclude their article by stating that because matemal and fetal cornplications have been reported In patients who receive therapy, such as severe thrombwfs, extreme caution must be exercised. They recommend further studies to deterine the optimum therapu~c regimens, dosages, timing. and duration of theraw Unander and colleagw (8) found that even the occurrence of high Ievels (greater than 10 units) of anticardialipin/antiphospholipid antibody could result in successfulpregnancies without any theraw aimed at diminishing the~autoir&me aberration. Those authors recommend keatment be considered in those women in whom the sera dudng a long period of time constantly dlsp!ay very elevated anttcardloli~in levels and prolongation of All?. This recom&nd&ion is based an their treatment protocol results: Treatment with prednlsone and aspirin resulted In live bbths and decreased AFIT mlues, but the antkxdlo!Jpln !a& remained relatively high. This is cons& tent with the prior findings, as noted in the section regarding dlagnosls. Thus the question arisesas to whether the practfttcmer is really twating the anticardiolipin antibodies, sane other underlying problem, or achlw lng results that would have been achieved without treatment Maier (13) has questioned the
study results of Rosove et al (111, which was discussedearlier in this review. His first question relates to the timing of treatment initiation relative to of the woman’s previous pregnancy losses. How many uorrlen began lxe&lent l&l than the date of their previous pregnancy losses? He argues that if treahnent was started after the date of all the previous losses, then it could certainly nol be said that the treatment prevented a recurrence of the pmblem. Other questionsrelate to the frequency of anticardiolipin measurements. Was treatment based on only one measurement or were studiesrepeated? Rosove et al responded that treatment started at or before the time of orevicus Ias9 In 14 of the 15 women; and repeat anticardiolipin measurements often showed that there was variability in the degree of anticardiolipin positivity. Yet Ret al state in their aticle that weatn-lent was based 0” APT-r values. and they do nd menUon treatment based on anticardiolipin antibody values (11).
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ANTlPHOSPHOLIpmANTlBOD~ AND WSTPARNJM COURSE one article reported case audies of three women with a poetpamun syndrome of plewqauknonay dlwase, fever, and cardiac manlfesiatfons (14). Each woman had either lupus anncoagu!ant or antlcardwdpn &Ibodies or both. Evaluation of the wmen f&d to demonstrate pulmonary embolism or infection as the cause. These authrmr suggesta postpaturn autolmmuno syndronw asscciated with antiphospholipid annbodles. It most likely mnts an exacerbancln of a preexisting, &lcJfnkxl autoimmune process Theso authors also suggest that pregnant patients known to have antiphosphdipid anitbodies be camfuUy monitored in the postpamm p&xl for early agns or symptom5 of pjeumpulmonary or cardiac disease or thrombotic epfsoda, and when such paatpamun complications occur. autoimmune
causes should be co”sidered if pulmonary embolus and infection have bee” ruled out. OTHERRELATED
FtNDINGS
Rec.&y a group of physicians SWulated that anticmdiolipin antibodies may be responsible for intrauterine thromboembolic stroke (15). They identify three mechanisms that could explain fetal strokesseconday to cir c&&q maternal anticardiolipin antibody. The antibody #couldlead to thrombosis within the fetoplacental vasculature, IgG antibody could crossthe placenta and enter the fetal drculation. and, !astly. the antibodies could damage the placenta. They recommend a pmspxKw evaluation of early neonatal brain images and cord antibody levels of infants born to mothers with antifardiolipin antibody to determine the importance of the antibody in infant neurologic nwrbidKy. Doherty and colleagues (16) PXamined the relationship between white bled cell immunization for the treabnent of InferKiity for recurrent spontaneousabmtions and imxeased andlcardidptn anbibody. Serum was collected from 24 “onpregnant women before and six to seven we& after immunimOn with their husbands’ white blood c&s. Postimmu”fzati” IgG levels were slgniflcantiy lower than preinvnunization !wels, and there was no SigrKExant diffen?“ce I” a”ncmdt+i” IgM levels preimmunirsaon and pc&nmu“izatiml. These resuhswere ineonslstert with the Rndi”gs of Mo”cay0 and c&agues (17). who did Bnd incwasedh?velsofa”&ardidiplna”tibodfes after hnmtmwdon. Two group of researchers have shxw the prevatence of antlcardiolipin an&dies in women with hu“la” tm”lunodeAdeney %i”Js wlw and their effect on PlogMncy outcomes (18, 19). Vrscarello and cdleagues (18) shtdied 32 preegnant women semposlKve for HIV. Their co”cluwJ” ts that preg”ant women
infected with HIV-1 have a high prevalence of anttcardiolipin anibodies. but this elevation is not related to maternal disease status, adverse pregnilncy *“*come. or panatal kansmission of HIV-l. .!ohnstone and colleagues (191 studied 55 pregnancies in 46 HN-infected women. Twenty-four percent of this group had elevated anKcardioli”in anKbo& ice. Their conclusion was consistent with Viscarello et al 118) that this eleation explain adverse prep “ancy outcome. Johnstone et al’s other conclusion, though, presents a leap in gener&aKon: HIV should b-e considered in the differenaal diagno. sis of women found to have tired anticardioliiin antibodies (191.
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IMF’LICATtONS FOR NURSE-MIDWIVES Recunent pregnancy loss Is devastatlng to the families it affects. Eve” today, as the 21st century looms ahead, causes are not known: yet there continues to be research into the etiology and treatment, which is replete with controversy. When a woman with recurrent pregnancy tossespressnts for care, the cerKfled nurse-midwife (CNMI needs to be able to discuss posdbh causes, aspects of dkzgnmjs.and treabnent op ttons avat!able. With a better understanding of what these are, the CNM will be able to promote a positive preg”ancy outcmne for these clients thmugh co4labom~vecare in consultation and referral with physldans The data in this article. although technical in nature, will assistnursemidwives In their care of these women. Although it may not be within nome-midwifery’s domain to diagnose a” immunological cause such as the wzse”ce of ankatdioiipfn an&&s in a woman with reepeated preglMnw loss CNMs “lay &nan&pre&ant women who are “?cetti”g a treatnlent regi”Ie”. As evidenced here, treatment re$mens and their successrates vary. Discussion continues to ensue as to exact
definitions of abnormal valuesrequirmngtreabnent, which treaknent regime” is best, and even whether treatment is “ecesurry. Equipped with this knowkdse, nurse-midwives may serve woTnen as their advocates in the medical @e”~ and assist them toward the goal of positive pregnancy outconws. This is the perfect time. as Shah states (20). to listen to the woman herself to determine areas in need of further investigation. It is the role of CNM as pdmay care provider.
REFERENCES 1. Carp H. Tcder V, Mashiach S. N&l L. Sen I). Recunentmiscaniago: a rwiew of current concepts. imm”“e m~hanisms. and resulk of keahnen,. ObstetGynffol SUN 199Q45z657-69. 2. Reece E, GabrieUi S. Cults” M, ZhengX HobhinsJ, Hmis E. Recurrent adverse prsgnancy outcome and anb_phcuphoXpM anKbod& Am J Ot&t G,,wcol 15%163:162-V. 3 BranchD, ScottJ. KochenourN. Her&-&d E Obstetriccomplicahans as. scc!&edwith the hrpls a”tkoa&nt N Engl .l Med 1985:3111322-6. 4. MKKezJ.Ldong F, &,=,ni M. Jan. “et D. Medisdj!m.Latpur H. et al. The prevalence of autoantibodies during third-um.mef pqprancyo=“*tiby hypertensiona idiDpathicfetal growth retudaKc.o.Am J ObsIet Gymcal 1991; 165516. 5. Lubbs W, Ratter W. Palmer S. L@ns G. Lupus anKcoa@nt in mw.ncy. Bx J Obstet Gyrwcd 1984;91: 35763. 6. Giatwpcuhx J. AnKcardiob@n anUw and ropmduc~vefailure. presmted at me nfteentb Annual rnd of Dimes Perinatal Nursing Conference, Chii, u. 1990. 7. Lockwmd C, Romem R, Feinbsm R. Clvw L, Caster B. Hohbim J. Thopovd;lrce and blok& &mikarxe of lupls a”ticoag&nt and a”ticxdio6pi” anliba&s in a generaloktea% pop& tto”. Am J Obstet GymxOr 19S%161: 369-73. 8. Unander P, No&erg R. Hahn L, A&s L. AnbZarcKoli#na”Kbc&s and
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in ti”ety-“se women v&h babs,ml &anon. Am J Obotet Gynecd 19!37;156:11&9. 9. Hanis E. Spinnato J. Should anticardio”pin tests be pprfmmed in dherwisehealmypregrrantwamen?AmJObste, Gyxcol1991;165:1272-7. 10. Rote N, Johnson D, Branch D. Antipborphollpfd antibodies and recurrent pregnancy loss: cmre1.6on between the activated pat%?.1lhmmbopbmn time and antibodies against phosphatidyl.wine and cardiolfpln Am J Obstet Gyw?col199o,163:57%34. 11. Rorove M. Tabsh K, W+ssersfmm N, Howard P, Hahn B, Kalunfcm K. Hqai” tbeqy lor pregnant women with kpus antima@ant or antlcardfollpin antibcdles. Obstet Gynecol1990;75:~. 12. Loc!shin M. Dnxfn M. Qamar T. complement
Prednisone dops not pmwenf recux”t fetal death in women with anttphmpholipid antibody. Am J Obstet Gynecol 1989;16043%43. 13. Mder D. Letter to lbe editor. Ob*et Gynec0l1990;76:7345. 14. Kochenwr N. Branch D. Rote N. Scoti J. A new pa&urn syndrome as tiated with antiphosphdipfd an&cdies. obsfet Gynecoll93769:46w7. 15. Silver R, MacGregor S, Pastemak J, NeolyD. Fetal eke assaiated with elevated maternal anticxdlolfpin antibodies. Obstet Gynecol199%Xk497-9. 16. Doherty R. Stubblefield P. Dcefal. Johnson D, Day G. White blocd cell Immunuatkm and anticardldpfn anlibcdy levels in women with recurrent mixardata. Fed Stedl1992:58:19%201. i7. tefoncayo R. Moncayo H. Sleffens
18. Vi-Uo R. Williams C, D&nnaor N, Hobbfna J. &valence and pmgntic @nificanee of anticmdiolipbl antibodies in prqnandes complicated by human immunod&iency virus-1 infw+ion. Am J Obstet Gynewl1992;167:1CZXX 19. Johnstone F. Kilpatik D. BUM S. Anticardfolipin antibodies and preg nancu outcome In women wlfh human imm;nodsnciency virusklfecuon. o&a Gwev.s11992;30:92-6. 20. Shah M. The nurse-midwifeasmfmary care provider. J Nurse Mfdwfiew 1993g81~7.
39th Annual Meeting of the American College of Nurse-Mldwives April 2228.1994 Nashville. Tennessee Featuring “Nurse-Midwifery: Ageless put--New Technology”
24
humal
cd Nuue.Mihuikry
. Vol. 39. No. 1. January-
1994
Lyneite A. Ament, CNM,MSN,
RNC
ABSTRACT Repeatedfekl lass may be a result of a varietyof causes.Immunologtalfactorshave beentmpticated in fetalImr. intrauteiinegrowthretardation.preedampria. andthrombacytopenk.Anttcardioltpinantibodies(ACM belongto a fan,&, of autoantibodies knwm B antlphosphobpid an!Jbcdks.Plateletagwgalion andincreasedcoaguktion watts from the ,x-c* of these an8badies.andis believedto conhlbuteto the fetal complkations.Thii articlek a reviewof the physiotqica,imptications of AcAr. SCTPP”. tngcxiterkfor the presenceof A’.%, pfevaience rates,dkgnnttc measures~ treatment Opaons,and posriblepostpartu~~, effectsof ACAs When womenwith rec’wrentpteg. nannykobesprexnt for care.the nurw-midwifeneedsto be ableto dkass pxsible -, aspectsof dkgnmis. andtreatmentoptionsavailableWith a betterunderstandingofwhat theseare.the nurse-mtdtifewill bebetterabk to pkn carethatwill promote a positiveplqlancy outcome.
Repeated fetal loss, de&d as the loss of three consecutive prqnanc+es pliorto2Swek5,mayboarewltof a valiety of causes (1). Sane causes that have bean identified include genetic anomalies. infectfons, uterine anomabes. luteal phase deficiency. and ~mmuno!agkelcauses Immun+ k&al factors have a!so been in+ caed in olher adverse pregnancy outcomes, such as intrauterine growth retardatton. preeclampsia. and thmmbocytopenia. Antfcardiolfpfn antibodfes, which belong to a family of autoantibcdles known as antfphos+UPfd an%adks, are immun~ns that have been linked to repeatedfetal less. The pupasa of thk artkle k to r&au the recent Uteraiwe on .nucoTdioupin antibodies, specifically as regards diagnosis, treatm+nL and associatedoutcomes.
PHYSlOLOGKAL tMFiKATlONS OF ANllCARDlOLIPlN ANTIBODIES Antkardioliiin anti&dies are aq immuncglobulin of the IgG or IgM ckss, with anticoagulantactivfty considered to result from ik interference with the activation of the pfothmmhill activator cumplex (2). Patients with anticardiolfpin antibody usuauy exhibt a tendency toward thmmtosk. The biolcgfc mechanism(s) by which this o&s k not known (2): It has been suggested that antiphaphofipid antibodies. the fam& of autoanttbodles to which anacardfolipin antibodies belong, prevent pmstacyclin pmductfon. Pmstacydn, which k a patent vasadilatorand inhibitor of platelet aggregation. is pDduced hy vaxular iksues. It is a natural antagunkt to thmmlmxane, a potent vasoconstitor and plateletaggregation-inducing pmstaglandin that is rekared hy aggre@ing platelets. Pmductton of prcstacyclin hy
the endothelfal cells k considered an important mechanism in protecting the vascular wal! from the deposition of platelet aggw_gatesand subsequent thrombosis. Thus the inhibftion of pro?.tacyclin would favor dxcmhazis (3). Anticadtolipin antibodies also bind to phapholiiid ant&ens of the placentalvesek, inducin4 bental inhuction (4). It k the aggqation and increased m?lgu!anonthat are Nmlked to co”bibute to fetal death (1).
platelet
SCREENINGCRllERIA FOR ANTlCARDIOLlPlN ANllBODfES vadous expetk 0” the topicof anticadfoiiptn antIbodies recommend an anay of saeentng ctitetfa. Mfllkz and cd!eague$ (4) recommend that tesk for the deteztion of anticardfolipin antihodks during pregnancy should be performed for multiparous .&amen with hypertemi~n or a hktory of intrauterine fetal growth reta-
19 w9131-7.w
d&ion. Reece and colleagues(2) recommend screening for the presence of antibodies not only in the presence of intrauterine growth retardation, but also in cases of une@ained recurrent snontaneous abortions or stillbirth. ihcy also state screening should be considered for indications such as suspicion of lupus erythematceus, unexplained thrombocytopenta or hypoprothrombinemia, the presenceof positive anttnuckar antibodies. or a persistent false-posittve VDRL. Antibodies to cardiolipin can give dse to biolcgtc false-positive VDRLs becausethe serolwic tests use phospholipid ahstr& (2). Lubbe and colleaoues (51 found the FTA-abs end T&pmemo pallidurn hem&utination to be negat&e when the reason for a false-positive VDFtL to be the oresence of anticardiolipin antibodies. Giano~oulos 161 recommends screenins women tith a histoy of thrombosis or pulmonary embolism, early atypical kypertension in pregnancy, and patients with abruptio placenta. Lakwocd and colleagues (7) studted the prevalenceand signif~mnceof antiphospholipid antibodies in a low-risk obstetdc population and found a statistically significant relationship between elevated anticardiolipin antibodies, preterrn delivery, and low birth weight. Carp et al (1) recommend Screeningfor antibodieri on!y after all other possible explanations for recurrent fetal loss have been ruled out. Lynetle A. Amen! receiveda poshrwstefs cerrpcoteh nurse-midwfleyjmm the University oj Illinois-Chicago.She is cumnIly LI dwtoml candidate fn nuafngat the “niuersily “J Wisconsin-hfilwoukee. She is en ersiskmtpmfersor et Bamt College andLlnivasiiy of He& SctenceslChicngo Mediml School in North Chicago,Illinois, and in clinical ~recticeot Sinai Sam&en Hosoital m
PRNALENCE OF ANT,CARDlOLIPINANTIRODIES Anticardlolipin antibodies occur with high frequency in women with e dim agnosis of systemic lupus eythematosus. High titers of anticardioltpin antibodies have occasionally been found in obstetric patients without systemic lupus eyth*matosus and in patients with current thromboembolit episodes (8). Anlieardiolipin an& bodies are rarefy foonnd.in Sealthy populations. and they can occasion& be found in patients with acute infections (8). In cases of infection, however, the andcardioliptnantibodies seem to occur only tempaarily
@I.
Unander and colleagues(81 inwtigated rhe occurrenceof anticardiolipin antibodies in 99 women referred to them because of recurrent fetal loss, defined as at least three consecutive at&tons. Increasedanticardiolipin antibody levels were found in 42 of the women. Cardtolipin antibodies exclusively of the IgM class were found in seven women; IgG anttbodies were found in 35 of the women. The authors did not examine outcomes based on the influence of the IgM and fgG antibodies togetha; instead they chcee to report the IgG anticardiolipin antibody levels, because these were more prevalent. None of the women were considered to have s+emic lupus eythematosus. They also found that the anticardiolipin antibody levels remained constant and independent of pregnancy and steroid therapy. ockwood zmd colleaques (7) studied the prevalenceof a&ardio: lipin antibodies in a low-risk obstehtc population. Patients with a hlstw 01 three consecutivespontaneous l0sw or sttllbirths were excluded. The total population consisted of 737 women with a median gestational age of 16 weeks. Of these 737 low-risk women. onlv 2.2% exhibtted anticardiolipin anti&ies. The mean maternal age was 22.7 years and the median gravtdity was three. There were
I
maternal age
no differences in or parity between women with elevatedanticardiolipin antibodies compared with those with no elevation. Millie2 and colleagues (41 examined the prevalenceof autoantibodies durhw third-himester preqnancv complica~d by hypertension or idi;nathic fetal “row& retardation. Tr;;j bundred p;egnant women were weened; none “i the p&en& had systemic lupus eryihematosus or any other documented autoimmune di.ease. Rfty percent, or loo women, were witho”t compllcauons of pregnancyto form the mntml Population. Twenty-five percent of the sample women had fetal growth retardation and 25% had pregnancies compltrated by hypertenston. Among the 100 normal pregnancies and those with fetal growth retardation, none had antlcardiolipin antibodies. Among the women with hypertension during preegnancy, only 4% had elevated anticardtolipln antibodies. Thus, in this sample the only risk factor associated with elevated levels was hypertension during pregnancy. Harrisand Spinnato 191examined 1,449 pregnant women for the plwalence of anticardtoliptn antlbodks Although thtt study did not control for the frequency of aspirin. coxticosteroids, or other immunosuppressive therapy, the frequency of women with elevated IgG lewls was 1.79% and the frequency of v.anen with elevated I&f levek was 4.3%. On the basis findings, they recommend that for anticardiolipin antibodies not be done to ween otherwise hea!!hy v~**>en. One interesting Rnding from their study is that pasittve antlcardioUptn results remalned pwiave for peitods of up to three months’ postparium for a majority of the women.
otthelr
tailng
DIAGNOSISOF .ANncARDnwm
ANTBODIES
Anticardiolipin antibodies can be quantified by enzyme-linked immunosorbent assay @LISA) levek and
binding activity of IgG and IgM anticardiolfpin preparations. Experts are not in agreement es to which laboraton/ tesk are the most accurate i” diagnosing anticardiolipin antibodies, nor are they in agreement e5 to cutoff values for the various tests (see Table 1). Unander and colleagues (8) co” sider IgG and IgM vafues above or equal to three standard deviation units as pathologic. I” their study, 42 of 99 vane” with habitual abortion demonstrated increased andcardie lfpin an&fly kvefs. Sew” women had IgM values between three to seven unik and 35 of these 42 had IgG antibodies against cardiolipin equal to or greater than 10 “nib. They found that, in most cases. the antibody activity of IgM VJes lower the” that of I&; in other words, IgG wes a more accurate dfeg”ostk test. Rote et al (10) fou:id that IgG Macardtoftpin annbodk?s were greater the” 5.8 standard deviation units in 58% of their sample of 47 women, of whom had at least hue consecutive preg”ancy f#sses. The assay for fgM antkardiofipin anttbodtes had the !awst freque”cy, witf. 36% of the sample having a median of 1.2 stenderd deviation unik Mtllkz and ml!wJgues (41 used a fowr cutoff point and defined a positive value as grater then Awe sIa”dard deviation unfts above the “lee” contmf value. and IgM vakles. Two articles discussed the activated parttal thmmboplasttn time (APTT) es a dieg”ostic tool (2. 9).
TABLE1 LXESiU&dACA
Llnander et al (8) Rote et al (10)
l’be rationale for using the AF’lT k to “11e out the presence of the lupus a”ticoagulant &us anticardiol&i” antibody es the causative agent with adveE-2 pregnancy outcomes. A5 mentioned previously both the lupus anticoagule~t and the anticardiolipin antibody belong to the more general group of antiphcspholipid antibodizs. Although the majority of patients with lupus a”ticoa&nt alw have anticxdiolipin antibodies, the presence of anticardiolipin aniibcdies are a better predictor of adverse prep “ancy outcomes. The difference between the two an&dies, according to some a”!“on, 1s with treatment: luws a”(icow,ulant is easier to suep&s (2). Tl&, if anttrardioliiin antibodies are present. the ApIT may be used to determine the presence of the lupu.-like aniicoa@nt. Reece and colleagues (2) state that if plasma co”tai”s high levels of the lupus-llke anttcoagant, the par&l thrombockstin time @ITI and occaSioMuy & pmthrombin time (PT) are prolonged. but that in general the PIT is the more sensitive measurement Because there is also a tendency toward thrombosis, there may else be a prolonged APTT. Reece et al evaiuate a prolonged AF’TT by mking the patient’s plasma with “amalpbsme;iftheAPlTiscorrected by thk mWng of bled. a clotting iactar deficiency should be suspected (2). If the APl-r 15not corrected wtb the mixing. the presence of circufating anticoegufenk such es the lupusltke anttcoegulant should be mnstdered (2).
Although Rote et el (10) still WCommend screenino for APTf’ beca.we clinicians a& more familiar with it and the test is widely available, they believe that the Ml-r may be less sensitive than other screening tests plimaily for two wasonc The test is prone to the effects of &red levels of normal coagufation factors Wiih may be elevated during preg“ancy) and the co”te”t of procoegulatoy phospholipids (which may vary considerably among conunercielly available preparanOns of par8al thrombopfastin). In addition; they state that the APlT is cumbersome. arid the qwifcity and class of the antibody that prolongs coagulation cannot be readily identified. It is espekally recommended for weentng women who are not currently pregKM, as the pro&m of pRg,,Fa”Cyassociatedekzvaiionsin the levels of coagufatio” factors can be atided. For the AFfT they consider a coagufatin time of longer than 45 setends es abnomxel.
lREATMEI?T OF
Rosowetellll)treated13women who had one or more abnormal pregnancy outcomes and positive anticardldlpln antfbodies with hepari” therapy. Hepad” therapy was used due to their coiz-zem regard&g @ucocorticoid side effects. and bec&lee pf%cental thrombosis “lay be e fector that detelmhles fetal outco”le. The gestational age when hep ad” beatment bega” was 10.3 weeks and continued for the remainder of the woqnancy. Heraad” was qive” sub&&eousiy e&y 12 hours, and dasage was based on elevated AFll’ values. In patients with normal AFfTs, the dosage was adjusted to obtain a mid-internal clotting time of 1.5 to 2.0 times the control value. Tlw mea” total dalfy hepaiin dcag-a was 24,700 units. Heparin was discontinued briefly at delivay and then resumed for vatable periods
Ninety-three percent of these pregnancies resulted in live births at a mean gestational age of 36.1 weeks. Five (36%) of the placentas were n-&nknaUyinfarcted on gross examination: this 1sa decrease from 56% with thesubjects’ prior second- and third-trimester losses. Recorted hew ark-a&ted problems included inj&tion ‘?e bruises. three minor instancesof epistaxis,and one instance of hemaiuda at delivers. There was no control group duting this study of untreated subjects. The only control was the subjects’prior pregnancy histories: an increase from 3% live births prior to treabnent to 93% with treatment
DISCUSSIONS REGARDING TREATMENT Lockshin et al (12) evaluated 25 asymptomatic wmnen with high anticardioli~in antibodv titers (levels were noi reporiedj &ho had been treated during pregnancy. The women were managed In one of four ways: no treatment, aspirin 80 mgl day, aspirin plus prednisone 30 mg/ day for at least four weeks and then continued or tapered to a lower dtxe, or prednisone 60 mglday for four weeks and continued at reduced doses until delivery. Women were not randomized into treatment protoc&z watment was based on bath the patient’s and physician’s request. These authors feel that their results were less than optimistic. For women with a hqh anticardiolipin antibody titer and prlor fetal death, 67% of their current pregnancies were not successful.For women with a high anticadiolipin antibody titer but no prior fetal death, 33% of the pregnandes ended in fetal death. In those women with prior fetal death, treatment with prednisone worsened the prcgnasis (P - .Ol); in women without prior fetal death there was no effect of either therapy, and prognosis was generaljy gad even in untreated patients. Reece and colleagues (2) achieved
14 (77.8%) live births among 18 women with high anticardfolfpin antibodies and prior pregnancy losses treated with prednisone or low-dose aspirin during pregnancy. They also observed an associationtieen the number of pdor fetal losses,the anticardiolipin antibody titer, and the fetal survival rate after the varying therapies. Two or more prior fetal lossesand high autoantibody titer resulted in a fetal sunrival rate of 50% to 75% with varying therapeutic regimens and dosages. A fetal survival rate of 75% to 100% occurred with fewer than hvo prior fetal lows and low to mid-anticardiolipin antibody titer with the same therapies. The authors conclude their article by stating that because matemal and fetal cornplications have been reported In patients who receive therapy, such as severe thrombwfs, extreme caution must be exercised. They recommend further studies to deterine the optimum therapu~c regimens, dosages, timing. and duration of theraw Unander and colleagw (8) found that even the occurrence of high Ievels (greater than 10 units) of anticardialipin/antiphospholipid antibody could result in successfulpregnancies without any theraw aimed at diminishing the~autoir&me aberration. Those authors recommend keatment be considered in those women in whom the sera dudng a long period of time constantly dlsp!ay very elevated anttcardloli~in levels and prolongation of All?. This recom&nd&ion is based an their treatment protocol results: Treatment with prednlsone and aspirin resulted In live bbths and decreased AFIT mlues, but the antkxdlo!Jpln !a& remained relatively high. This is cons& tent with the prior findings, as noted in the section regarding dlagnosls. Thus the question arisesas to whether the practfttcmer is really twating the anticardiolipin antibodies, sane other underlying problem, or achlw lng results that would have been achieved without treatment Maier (13) has questioned the
study results of Rosove et al (111, which was discussedearlier in this review. His first question relates to the timing of treatment initiation relative to of the woman’s previous pregnancy losses. How many uorrlen began lxe&lent l&l than the date of their previous pregnancy losses? He argues that if treahnent was started after the date of all the previous losses, then it could certainly nol be said that the treatment prevented a recurrence of the pmblem. Other questionsrelate to the frequency of anticardiolipin measurements. Was treatment based on only one measurement or were studiesrepeated? Rosove et al responded that treatment started at or before the time of orevicus Ias9 In 14 of the 15 women; and repeat anticardiolipin measurements often showed that there was variability in the degree of anticardiolipin positivity. Yet Ret al state in their aticle that weatn-lent was based 0” APT-r values. and they do nd menUon treatment based on anticardiolipin antibody values (11).
thetime
ANTlPHOSPHOLIpmANTlBOD~ AND WSTPARNJM COURSE one article reported case audies of three women with a poetpamun syndrome of plewqauknonay dlwase, fever, and cardiac manlfesiatfons (14). Each woman had either lupus anncoagu!ant or antlcardwdpn &Ibodies or both. Evaluation of the wmen f&d to demonstrate pulmonary embolism or infection as the cause. These authrmr suggesta postpaturn autolmmuno syndronw asscciated with antiphospholipid annbodles. It most likely mnts an exacerbancln of a preexisting, &lcJfnkxl autoimmune process Theso authors also suggest that pregnant patients known to have antiphosphdipid anitbodies be camfuUy monitored in the postpamm p&xl for early agns or symptom5 of pjeumpulmonary or cardiac disease or thrombotic epfsoda, and when such paatpamun complications occur. autoimmune
causes should be co”sidered if pulmonary embolus and infection have bee” ruled out. OTHERRELATED
FtNDINGS
Rec.&y a group of physicians SWulated that anticmdiolipin antibodies may be responsible for intrauterine thromboembolic stroke (15). They identify three mechanisms that could explain fetal strokesseconday to cir c&&q maternal anticardiolipin antibody. The antibody #couldlead to thrombosis within the fetoplacental vasculature, IgG antibody could crossthe placenta and enter the fetal drculation. and, !astly. the antibodies could damage the placenta. They recommend a pmspxKw evaluation of early neonatal brain images and cord antibody levels of infants born to mothers with antifardiolipin antibody to determine the importance of the antibody in infant neurologic nwrbidKy. Doherty and colleagues (16) PXamined the relationship between white bled cell immunization for the treabnent of InferKiity for recurrent spontaneousabmtions and imxeased andlcardidptn anbibody. Serum was collected from 24 “onpregnant women before and six to seven we& after immunimOn with their husbands’ white blood c&s. Postimmu”fzati” IgG levels were slgniflcantiy lower than preinvnunization !wels, and there was no SigrKExant diffen?“ce I” a”ncmdt+i” IgM levels preimmunirsaon and pc&nmu“izatiml. These resuhswere ineonslstert with the Rndi”gs of Mo”cay0 and c&agues (17). who did Bnd incwasedh?velsofa”&ardidiplna”tibodfes after hnmtmwdon. Two group of researchers have shxw the prevatence of antlcardiolipin an&dies in women with hu“la” tm”lunodeAdeney %i”Js wlw and their effect on PlogMncy outcomes (18, 19). Vrscarello and cdleagues (18) shtdied 32 preegnant women semposlKve for HIV. Their co”cluwJ” ts that preg”ant women
infected with HIV-1 have a high prevalence of anttcardiolipin anibodies. but this elevation is not related to maternal disease status, adverse pregnilncy *“*come. or panatal kansmission of HIV-l. .!ohnstone and colleagues (191 studied 55 pregnancies in 46 HN-infected women. Twenty-four percent of this group had elevated anKcardioli”in anKbo& ice. Their conclusion was consistent with Viscarello et al 118) that this eleation explain adverse prep “ancy outcome. Johnstone et al’s other conclusion, though, presents a leap in gener&aKon: HIV should b-e considered in the differenaal diagno. sis of women found to have tired anticardioliiin antibodies (191.
cannot
IMF’LICATtONS FOR NURSE-MIDWIVES Recunent pregnancy loss Is devastatlng to the families it affects. Eve” today, as the 21st century looms ahead, causes are not known: yet there continues to be research into the etiology and treatment, which is replete with controversy. When a woman with recurrent pregnancy tossespressnts for care, the cerKfled nurse-midwife (CNMI needs to be able to discuss posdbh causes, aspects of dkzgnmjs.and treabnent op ttons avat!able. With a better understanding of what these are, the CNM will be able to promote a positive preg”ancy outcmne for these clients thmugh co4labom~vecare in consultation and referral with physldans The data in this article. although technical in nature, will assistnursemidwives In their care of these women. Although it may not be within nome-midwifery’s domain to diagnose a” immunological cause such as the wzse”ce of ankatdioiipfn an&&s in a woman with reepeated preglMnw loss CNMs “lay &nan&pre&ant women who are “?cetti”g a treatnlent regi”Ie”. As evidenced here, treatment re$mens and their successrates vary. Discussion continues to ensue as to exact
definitions of abnormal valuesrequirmngtreabnent, which treaknent regime” is best, and even whether treatment is “ecesurry. Equipped with this knowkdse, nurse-midwives may serve woTnen as their advocates in the medical @e”~ and assist them toward the goal of positive pregnancy outconws. This is the perfect time. as Shah states (20). to listen to the woman herself to determine areas in need of further investigation. It is the role of CNM as pdmay care provider.
REFERENCES 1. Carp H. Tcder V, Mashiach S. N&l L. Sen I). Recunentmiscaniago: a rwiew of current concepts. imm”“e m~hanisms. and resulk of keahnen,. ObstetGynffol SUN 199Q45z657-69. 2. Reece E, GabrieUi S. Cults” M, ZhengX HobhinsJ, Hmis E. Recurrent adverse prsgnancy outcome and anb_phcuphoXpM anKbod& Am J Ot&t G,,wcol 15%163:162-V. 3 BranchD, ScottJ. KochenourN. Her&-&d E Obstetriccomplicahans as. scc!&edwith the hrpls a”tkoa&nt N Engl .l Med 1985:3111322-6. 4. MKKezJ.Ldong F, &,=,ni M. Jan. “et D. Medisdj!m.Latpur H. et al. The prevalence of autoantibodies during third-um.mef pqprancyo=“*tiby hypertensiona idiDpathicfetal growth retudaKc.o.Am J ObsIet Gymcal 1991; 165516. 5. Lubbs W, Ratter W. Palmer S. L@ns G. Lupus anKcoa@nt in mw.ncy. Bx J Obstet Gyrwcd 1984;91: 35763. 6. Giatwpcuhx J. AnKcardiob@n anUw and ropmduc~vefailure. presmted at me nfteentb Annual rnd of Dimes Perinatal Nursing Conference, Chii, u. 1990. 7. Lockwmd C, Romem R, Feinbsm R. Clvw L, Caster B. Hohbim J. Thopovd;lrce and blok& &mikarxe of lupls a”ticoag&nt and a”ticxdio6pi” anliba&s in a generaloktea% pop& tto”. Am J Obstet GymxOr 19S%161: 369-73. 8. Unander P, No&erg R. Hahn L, A&s L. AnbZarcKoli#na”Kbc&s and
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in ti”ety-“se women v&h babs,ml &anon. Am J Obotet Gynecd 19!37;156:11&9. 9. Hanis E. Spinnato J. Should anticardio”pin tests be pprfmmed in dherwisehealmypregrrantwamen?AmJObste, Gyxcol1991;165:1272-7. 10. Rote N, Johnson D, Branch D. Antipborphollpfd antibodies and recurrent pregnancy loss: cmre1.6on between the activated pat%?.1lhmmbopbmn time and antibodies against phosphatidyl.wine and cardiolfpln Am J Obstet Gyw?col199o,163:57%34. 11. Rorove M. Tabsh K, W+ssersfmm N, Howard P, Hahn B, Kalunfcm K. Hqai” tbeqy lor pregnant women with kpus antima@ant or antlcardfollpin antibcdles. Obstet Gynecol1990;75:~. 12. Loc!shin M. Dnxfn M. Qamar T. complement
Prednisone dops not pmwenf recux”t fetal death in women with anttphmpholipid antibody. Am J Obstet Gynecol 1989;16043%43. 13. Mder D. Letter to lbe editor. Ob*et Gynec0l1990;76:7345. 14. Kochenwr N. Branch D. Rote N. Scoti J. A new pa&urn syndrome as tiated with antiphosphdipfd an&cdies. obsfet Gynecoll93769:46w7. 15. Silver R, MacGregor S, Pastemak J, NeolyD. Fetal eke assaiated with elevated maternal anticxdlolfpin antibodies. Obstet Gynecol199%Xk497-9. 16. Doherty R. Stubblefield P. Dcefal. Johnson D, Day G. White blocd cell Immunuatkm and anticardldpfn anlibcdy levels in women with recurrent mixardata. Fed Stedl1992:58:19%201. i7. tefoncayo R. Moncayo H. Sleffens
18. Vi-Uo R. Williams C, D&nnaor N, Hobbfna J. &valence and pmgntic @nificanee of anticmdiolipbl antibodies in prqnandes complicated by human immunod&iency virus-1 infw+ion. Am J Obstet Gynewl1992;167:1CZXX 19. Johnstone F. Kilpatik D. BUM S. Anticardfolipin antibodies and preg nancu outcome In women wlfh human imm;nodsnciency virusklfecuon. o&a Gwev.s11992;30:92-6. 20. Shah M. The nurse-midwifeasmfmary care provider. J Nurse Mfdwfiew 1993g81~7.
39th Annual Meeting of the American College of Nurse-Mldwives April 2228.1994 Nashville. Tennessee Featuring “Nurse-Midwifery: Ageless put--New Technology”
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humal
cd Nuue.Mihuikry
. Vol. 39. No. 1. January-
1994