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Obstetric Implications of Antiphospholipid Antibodies: Pregnancy Loss and Other Complications

2001; Lippincott Williams & Wilkins; Volume: 44; Issue: 1 Linguagem: Inglês

10.1097/00003081-200103000-00002

1532-5520

W. P. Geis, D. Ware Branch,

Parvovirus B19 Infection Studies

A relation between antiphospholipid antibodies (aPL) and pregnancy loss has been formally recognized for nearly 20 years. It is now well accepted that aPL are a treatable "cause" of fetal loss and probably of recurrent preembryonic and embryonic loss. The growing interest in aPL and reproductive failure has encouraged investigation, prompted international symposia, and involved numerous medical specialists; however, this exciting field has also spawned plenty of controversy. This review describes the evolution of our understanding of aPL and pregnancy loss and critically examines the important questions in the field. A possible association between aPL and pregnancy loss was first suggested in case reports by Nilsson et al 1 in 1975 and by Soulier and Boffa 2 in 1980. Subsequent case series by Lubbe et al, 3 Lockshin et al, 4 and Branch et al 5 confirmed this association. By the mid-1980s, the clinical criteria for the newly named antiphospholipid syndrome (APS) were established, and pregnancy loss was included as one of the clinical features of the disorder. In Harris' 1987 proposal 6 entitled The Syndrome of the Black Swan, Harris identified the APS pregnancy loss criterion as "fetal loss." Since that time, definitions and criteria have been expanded, with the 1999 clinical and laboratory criteria proposed at the International Antiphospholipid Symposium in Sapporo, Japan, identifying current consensus. The criteria include three types of pregnancy loss as clinical criteria for APS: 1) one or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, with normal morphology documented by ultrasound or direct examination of the fetus; 2) one or more premature births at or before the 34th gestational week as a consequence of severe preeclampsia or placental insufficiency; or 3) three or more consecutive spontaneous abortions before the 10th gestational week, with maternal anatomic and hormonal abnormalities, maternal and paternal chromosomal abnormalities, and other known causes for the miscarriages excluded. 7 Nomenclature and Classification of Pregnancy Loss Occasional (sporadic) pregnancy loss is a common condition, with a majority of losses unrecognized and causation often unidentified. An estimated 50% of conceptions result in pregnancy failure. 8 Frequently, a woman is unaware of the pregnancy and often unaware of the loss. 9 Clinically, pregnancy loss becomes a medical and emotional issue when the pregnancy is known and identified, usually having progressed beyond the next expected menstrual period. Of these recognized pregnancies, approximately 10–12% end in spontaneous abortion at or before the 14th gestational week and are usually (>80%) preembryonic or embryonic losses in which the conceptus does not survive beyond the ninth week of gestation. Another 5% of all known pregnancies end in pregnancy loss from 14 weeks to term, including fetal and neonatal deaths. 10–12 Approximately 1% of women will experience recurrent pregnancy loss, usually defined as three or more consecutive losses. Recurrent losses are also most commonly preembryonic or embryonic, with recurrent fetal death much less common. Women experiencing two or three successive embryonic or preembryonic losses are at a similar or equivalent risk (approximately 25–30%) of recurrent loss. 13–15 Interestingly, however, when one fetal death has occurred, the risk of subsequent fetal deaths increases five-fold to 20-fold. 16,17 Clinical criteria are important in classifying, understanding, and investigating pregnancy loss. A traditional stance has been to classify losses before the 20th gestational week as "abortions" and death thereafter as "stillbirth." This traditional classification, however, ignores developmental stages of biology and confuses specific causes and processes affecting these distinct periods of development and the nature of pregnancy loss. Pregnancy loss, when possible, should be identified as preembryonic, embryonic, fetal, and neonatal. The preembryonic period covers the duration from conception through the fourth week of gestation, as determined by the first day of the last menstrual cycle. During this period, the trophoblast differentiates into tissue different from that of the embryo itself, and implantation occurs within the endometrium. Further differentiation occurs as the embryo progresses from a bilaminar to a trilaminar disc of cells, and alterations occur identifying the cranial end neural axis of the preembryo. Oxygen and nutrients are supplied primarily by diffusion across maternal tissues. The embryonic period encompasses the fifth through ninth weeks of gestation and proceeds through folding of the trilaminar disc cylindrically, followed-up by identification of the head and tail regions, segmentation, cardiac formation, establishment of circulation through the umbilical cord and placenta, and subsequent development of all organs (organogenesis). The fetal period then proceeds from the 10th week of gestational age until delivery. This period is characterized by substantial growth and differentiation with little organogenesis. One must recognize that the clinical presentation of pregnancy loss, however, is not necessarily so easily classified into different developmental periods. Most commonly, demise of the conceptus precedes pregnancy loss, and even symptoms of such a loss, by days or weeks. In turn, this discrepancy can cloud the diagnosis of embryonic versus fetal demise. Conversely, fetal death may not always precede a loss, as in cases of cervical incompetence, when frequently the fetus is alive at presentation. Nevertheless, the previously mentioned criteria offer greater definition to and developmental consideration of pregnancy loss. Ober et al 18 were able to use such criteria successfully in a large, randomized, controlled, treatment trial studying unexplained recurrent miscarriage. They demonstrated 59 recurrent miscarriages in 131 women attaining pregnancy, with greater than half of these losses preembryonic, 28% embryonic, and only 10% fetal. Loss after 15 weeks was rare. Pregnancy Loss and Antiphospholipid Antibodies WHAT TYPE OF PREGNANCY LOSS IS ASSOCIATED WITH ANTIPHOSPHOLIPID ANTIBODIES Although virtually all authorities agree that aPL are associated with and may cause pregnancy loss, several controversies remain. One such debate entails the type of loss most closely associated with aPL. A review of the literature before 1990 found 30–40% of allegedly antiphospholipid-related pregnancy losses were fetal deaths occurring in the second or early third trimesters. 19 More recently published case series are similar with regard to the type of pregnancy loss, showing that 41% of 131 previous pregnancies in women identified as having APS were fetal deaths. 20 In 1996, Oshiro et al 21 performed a retrospective study of 366 women with two or more consecutive pregnancy losses, 79 were noted to have lupus anticoagulant (LA) or ≥20 GPL units of anticardiolipin antibody, and 290 did not. Both groups had similar rates of pregnancy loss (84%); however, those with APS had 50% fetal deaths compared with 95th percentile). 31 Others have included such patients in treatment studies that found a favorable response to heparin therapy. 30 However, Silver et al 32 showed no greater risk for antiphospholipid events in women with low IgG antibody levels than those who tested negative. In contrast, the risk for antiphospholipid-associated complications was significantly greater in the women with LA or IgG anticardiolipin antibodies ≥20 GPL units. Might two different populations of patients with antibody levels be found? This debate is not resolved, but the International Consensus Criteria 7 require that patients with >20 units of anticardiolipin antibody or LA be identified as having definite APS. Whether isolated IgM or IgA aPL (in the absence of IgG aCL or LA) are clinically important is also controversial. A number of experts in the field believe that there are very few cases in which an isolated IgM or IgA antiphospholipid antibody is clinically relevant. The original published criteria for APS disregarded isolated IgM antibodies altogether. 6 Silver et al 32 showed no greater risk for antiphospholipid events in women with isolated IgM antibodies than in those who tested negative. In contrast, a modest percentage of patients in some studies of women with antiphospholipid antibodies and previous pregnancy loss had only IgM aCL antibodies (without LA). 33–35 Women with isolated IgM antiphospholipid antibodies have been included in treatment studies, but outcomes for them cannot be separated from those of others. 36 There are too little data available from patients with isolated IgA results to make a comment (see review by Pierangeli et al in this symposium). The International Consensus Criteria 7 allow that patients with >20 MPL units of IgM anticardiolipin antibody be identified as having definite APS. Another area of debate centers on whether aPL other than aCL and LA are relevant. During the last decade, many investigators have attempted to link antibodies to other phospholipid antigens to recurrent pregnancy loss, including antibodies to phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylglycerol, phosphatidylcholine, and phosphatidic acid antibodies. 28,31,37 Some studies, however, have shown that these other aPL do not add to the diagnosis of APS. 29,38 The final answer to this debate will require standardization of these other antiphospholipid assays, establishment of meaningful cut-offs between normal and abnormal levels, and demonstration of an efficacious treatment. Antibodies to phospholipid mixtures or to protein–phospholipid complexes or neoepitopes created by these complexes may be important because they may represent the most relevant antigen and may increase the specificity of antiphospholipid antibody testing. The favorite protein antigens or coantigens are β2-glycoprotein I, prothrombin, and annexin V. To date, antiβ2-glycoprotein I antibodies have been most extensively studied. Lee et al 39 found that testing for this antibody did not enhance the diagnosis of APS among patients with recurrent miscarriages or patients with fetal death. Franklin et al 40 found that standard antiphospholipid assays were more sensitive than assays for anti-β2-glycoprotein I in women with recurrent pregnancy loss. It should be emphasized that the number of times a patient is required to test positive before a diagnosis is made influences the final diagnosis. In one series of 500 consecutive recurrent patients who had miscarriage, more than 25% of women tested positive for aPL initially, but less than 15% repeated positive for the same antibody. 41 Many studies, especially those before the mid-1990s, did not specifically require that women with APS diagnosed should test repeatedly positive for antiphospholipid antibodies. The International Consensus Criteria are clear on this point: at least two tests, 6 to 8 weeks apart, are required for the diagnosis of definite APS. To fully understand the significance of low levels of IgG aCL antibodies, isolated IgM aCL antibodies, or phospholipid binding autoantibodies other than LA and aCL, the individuals studied must be meticulously characterized from a clinical standpoint and their levels of aPL carefully determined in a way that allows comparison between studies. The inclusion of appropriate controls is crucial. Obstetric Complications Other Than Pregnancy Loss In addition to pregnancy loss, APS is associated with a number of potential serious obstetric complications, including thrombosis, severe preeclampsia, utero-placental insufficiency, fetal distress, and iatrogenic preterm birth. These complications have significant maternal consequences, and they also may contribute individually or collectively to fetal loss. Yet, because of differences in patient selection and aPL required for inclusion, the rates of these complications vary from one study to another. Numerous studies demonstrate an unusually high rate of preeclampsia in patients with well-defined APS. 4,5,20,42,43 The two largest of these studies found rates of preeclampsia of 18% and 48%, respectively. Likewise, several studies of patients with preeclampsia identify significant levels of aPL in 11.7–17% of subjects. 44–47 Two prospective studies of unselected obstetric patients confirmed the association of aPL and preeclampsia, 48,49 whereas a third was unable to do so. 50 Two prospective treatment studies found that no more than 10% of women with aPL had preeclampsia develop during a treatment trial. 30,36 Placental insufficiency, as reflected by fetal growth impairment and fetal distress, occurs in approximately 30% of women with APS. 5,42,43,51 Even in women with only IgG or IgM aCL or antiphosphatidyl serine antibodies and no LA, fetal growth impairment occurs in 15%. 35 Another prospective study found that 12% of infants were growth-restricted, compared with 2% in the normal control population, 49 whereas two additional prospective studies demonstrated no relation. 48,50 Preeclampsia and fetal distress may necessitate preterm delivery. Preterm delivery occurs frequently in APS patients. Case series find that approximately one-third of treated APS pregnancies result in preterm delivery. 43,51 In a prospective study of women with IgG or IgM aCL antibodies and no LA, preterm delivery occurred in 13% of patients. 35 In another prospective (observational) study of unselected obstetric patients, 12% of 60 women testing positive for IgG aCL antibodies were delivered early, compared with 4% of those testing negative. 49 Finally, women with APS are at an increased risk for thrombosis during pregnancy. Women with APS and LA or medium-to-high levels of aCL antibodies have a 5–12% risk of thrombosis or embolism. 43,51 This risk presumably is lessened by appropriate use of anticoagulant therapy during pregnancy. Women without LA or with low levels of aCL antibodies appear to be at much lower-risk of thrombosis. 35 Differences in the reported rates of preeclampsia, fetal growth restriction, and other complications are almost certainly because of differences in patient selection. As described in the preceding paragraphs, women with low levels of aPL or those without a history of LA, fetal demise, or thrombosis who have recurrent preembryonic or embryonic loss seem to have much reduced risks of the pregnancy complications. A review of two recent studies is instructive. In one well-designed study, 35 women with a history of thrombosis, systemic lupus erythematosus, or LA were excluded, criteria that would exclude from study at least 40% of the patients that we and others have examined. 43,51 Women with aCL antibodies of either isotype or the less well-accepted antiphosphatidylserine antibodies were included. Most patients had recurrent preembryonic or embryonic loss, not fetal deaths; by comparison, we have found that more than 50% of our patients with APS have a history of fetal death. Yet, as with APS patients, the use of heparin treatment in the patients selected by Kutteh was associated with a dramatic improvement in successful pregnancy rates. But unlike the patients we and others have studied, the patients studied by Kutteh did not have high rates of preeclampsia (10%) or premature birth (13%) caused by obstetric complications, and no patient had a thrombosis. 43,51 In a randomized study, Rai et al 30 selected a population of women with aPL and predominantly recurrent preembryonic and embryonic loss for treatment with heparin versus no heparin. Once again, women with a history of thrombosis or systemic lupus erythematosus were not included, and no more than one-third of patients had a history of fetal death. Most of the patients had LA by a sensitive assay, but only 10% had aCL antibodies. Thus, the population comprised a different population of patients with APS than typically would be identified in most laboratories. 52 None of the patients had a thrombosis. The patients treated with heparin had much better pregnancy outcomes than those who were not treated with heparin. The findings of a recent well-designed trial deserve consideration. 53 Experienced investigators in New Zealand included 50 women with predominantly preembryonic or embryonic losses and with LA or aCL at any positive level in their trial. Women with previous thrombosis or SLE were excluded. The women were randomized to receive either low-dose aspirin or a placebo; no heparin was administered. Live birth rates were more than 80% in both the aspirin and placebo-treated women! The rate of serious obstetric or medical complication was low. Though nearly 25% of the women included in this trial had LA, more than half of the women had only low levels of IgG or IgM aCL and thus did not qualify as having APS. Nonetheless, the authors appropriately emphasize that some women labeled as having antiphospholipid-related recurrent pregnancy loss do not require heparin treatment to have successful pregnancy. One can easily see how clinicians may be confused about the comparability of the respective patient populations in different studies. Clinical studies to better-define the risks of different patients with aPL are desperately needed. Conclusion and Recommendations Antiphospholipid antibodies have been linked to obstetric complications for nearly 20 years. The association with pregnancy loss was the first to be formally recognized, but the type of pregnancy loss most specific for APS is somewhat controversial. In some case series, other obstetric complications, such as preeclampsia and placental insufficiency, are prominent. But in other studies, these complications are relatively infrequent. The disparate observations are likely because of the nature of patients selected for study. Perhaps a spectrum of antiphospholipid-related disease exists, or perhaps different investigators are describing fundamentally different patients. For further research and clinical analysis, we suggest a classification system for women with aPL such as: 1. Definite, or classic, APS: Patients with LA or medium-to-high levels of IgG or IgM aCL antibodies and fetal death, recurrent preembryonic or embryonic pregnancy loss, thrombosis, or neonatal death after delivery for severe preeclampsia or fetal distress. 7 Further research will be required to determine if isolated IgM aCL antibodies have the same clinical implications as LA and/or IgG aCL antibodies. 2. Syndrome of low levels of IgG or IgM aCL antibodies associated with fetal death or recurrent preembryonic or embryonic pregnancy loss. Currently available data do not support the treatment of these patients with heparin or other medications. 3. Syndrome of aPL other than LA and aCL antibodies associated with fetal death or recurrent preembryonic or embryonic pregnancy loss. The appropriate treatment for these patients is unknown. Obstetric risks other than pregnancy loss are also unknown.