Charles J Lockwood, MD
Peter H Schur, MD
Susan M Ramin, MD
Vanessa A Barss, MD
INTRODUCTION — The antiphospholipid syndrome (APS) refers to a syndrome characterized by arterial or venous thrombosis or specific pregnancy complications in women with laboratory evidence of antibodies to proteins bound to anionic phospholipids. Pregnancy complications that have been associated with APS include pregnancy-related maternal thrombosis, late fetal death, early severe preeclampsia, fetal growth restriction, and recurrent pregnancy loss . The two main types of antiphospholipid antibodies (aPL) of concern to obstetricians are lupus anticoagulants (LA) and anticardiolipin antibodies (aCL) , although detection of anti-beta-2-glycoprotein-1 antibodies may be a risk for later miscarriages and/or thromboembolic complications .
Pregnancy-related complications associated with APS will be discussed in this review. The evaluation, treatment and monitoring of pregnancies complicated by aPL and general issues related to APS in the nonpregnant population are reviewed separately:
- (See “Management of pregnant women with antiphospholipid antibodies or the antiphospholipid syndrome”.)
- (See “Clinical manifestations of the antiphospholipid syndrome”.)
- (See “Diagnosis of the antiphospholipid syndrome”.)
- (See “Treatment of the antiphospholipid syndrome”.)
- (See “Pathogenesis of the antiphospholipid syndrome”.)
PATHOGENESIS OF ADVERSE PREGNANCY OUTCOME — The role of aPL as a causal factor in pregnancy loss was demonstrated in experiments in which aPL from women with fetal loss was injected into the peritoneal cavity of pregnant mice and caused fetal death . Initially, aPL was believed to cause obstetrical complications primarily by inducing thrombosis in the uteroplacental circulation. Thrombosis could be induced by a variety of pathways [5-12]; as an example, aPL can reduce the levels of trophoblast-associated annexin V, thereby promoting placental villus thrombosis [13-19]. In a murine model, APS appears to increase monocytic expression of tissue factor, the major initiator of coagulation in vivo . If true in humans, this may also play a role in thrombosis and adverse pregnancy outcome . Eicosanoid imbalance and cross reactivity with glycosaminoglycans are other possible prothrombotic mechanisms. Further investigation is required, and studies in humans need to be performed.
Although thrombosis may be one mechanism for adverse pregnancy outcome, not all affected placentas have signs of thrombosis or infarction. Experimental models suggest that additional factors are responsible for adverse pregnancy outcomes [8,21-25]. As an example, complement activation is a critical component of APS-related adverse pregnancy outcomes [26-28]. APL-induced neutrophil tissue factor expression has been linked to induction of placental bed inflammation in an experimental murine model . Interleukin-3 (IL-3), which is an important factor for embryo implantation and placental development, is decreased in pregnant women with APS compared with controls without APS, and in animal models of APS. Mice with APS and low IL-3 have high rates of pregnancy loss that can be partially prevented by treatment with IL-3 . In addition, aPL appears to have a direct effect on human placental trophoblast, inhibiting the expression of human chorionic gonadotrophin, inducing apoptosis, decreasing trophoblast fusion, altering expression of adhesion molecules, limiting trophoblast invasiveness, and inhibiting decidualization of cultured endometrial stromal cells [30-34]. Thus, the association of APS and pregnancy complications may not be just an epiphenomenon occurring after antecedent endothelial injury [4,24,35]. (See “Pathogenesis of the antiphospholipid syndrome”.)
PREVALENCE OF aPL IN PREGNANT WOMEN — The reported prevalence of aCL in women with uncomplicated pregnancies ranges from 0 to 11 percent, with a median value of about 2 percent [36-44].
Definitions — An international committee proposed the following criteria for defining adverse pregnancy outcomes in the diagnosis of APS :
- Abortion is the delivery of a pregnancy, either spontaneously (miscarriage) or electively, before 20 weeks of gestation. A first trimester abortion occurs up to 13 weeks of gestation, a second trimester abortion occurs between 14 and 20 weeks.
- Recurrent pregnancy loss (also known as recurrent abortion) refers to two or more spontaneous abortions (the abortions do not have to be in consecutive pregnancies).
- Preembryonic loss occurs from conception through the end of the fourth week of gestation.
- Embryonic loss occurs from the fifth through the ninth week of gestation.
- Preterm delivery constitutes a live birth or stillbirth after 20 and before 37 weeks of gestation. After this, the birth is considered a term delivery.
- A fetal demise refers to an intrauterine death at anytime after 10 weeks of gestation. Stillbirth refers to a demise after 20 weeks of gestation.
These definitions were proposed because fetal loss and pregnancy loss are imprecise terms used in different ways by different investigators. Fetal loss may be used to refer to an abortion or fetal death at a gestational age defined by the investigator (eg, only after 10 weeks of gestation, only in the second or third trimester). Pregnancy loss can mean an abortion, fetal death at any gestational week, or delivery of an infant of any gestational age that does not survive. The broad usage of these terms for case selection in studies of adverse pregnancy outcome has contributed to variable, and often conflicting, results.
Adverse outcomes — Adverse pregnancy outcomes attributed to the presence of aPL include :
- Late fetal death
- Early, severe preeclampsia/eclampsia
- Fetal growth restriction
- Pregnancy-related maternal thromboembolic disease (venous or arterial)
- Recurrent pregnancy loss. This a controversial area; many investigators believe aPL antibodies are not a cause of embryonic loss before 10 weeks [39,45,46].
Pregnancy complications such as preeclampsia and fetal growth restriction often lead to preterm delivery, which places the neonate at risk of complications of prematurity. (See “Short-term complications of the premature infant” and “Long-term complications of the premature infant”.)
There is no good evidence of an association between aPL and primary infertility [47-51]. Although some studies have reported an increased incidence of in vitro fertilization failure in women with aPL [36,52], a meta-analysis failed to confirm this association .
Difficulties with causality — Since aPL can be found in normal asymptomatic individuals, it is sometimes unclear whether there is a causal relationship between these antibodies and a clinical event in any one individual, particularly when the adverse obstetrical outcome is relatively common (eg, spontaneous abortion before 10 weeks). Additional explanations for the poor predictive value of a given positive LA or aCL result include the following:
- Reliance upon non-standardized assays for aPL and failure to use internationally recognized standards
- Failure to control for the severity of co-existing diseases (eg, systemic lupus erythematosus [SLE], diabetes, renal disease, hypertension, and infections) known to cause adverse obstetrical outcomes
- Failure to recognize co-existing inherited coagulopathies (see “Inherited thrombophilias in pregnancy”)
- Inclusion of patients with low positive aPL levels among patients considered positive
- Broad definitions for case selection in series involving pregnancy wastage (preembryonic versus later loss)
- The variable thrombogenic potential of a given patient’s aPL
- Population heterogeneity in concentrations of clotting, anti-clotting, and fibrinolytic proteins
- Population heterogeneity with respect to the clinical phenotype of APS, which may be recurrent early pregnancy loss, late pregnancy loss, thrombosis, or premature birth before 34 weeks of gestation because of eclampsia, preeclampsia, or placental insufficiency .
Recurrent abortion and fetal loss — There is good evidence that aPL are associated with late fetal loss (10 or more weeks of gestation), and that subsequent pregnancies are at increased risk of recurrent fetal loss [33,55,56]. There appears to be a correlation between the level of IgG aCL and the risk of pregnancy loss . Although many women with aPL also have systemic lupus erythematosus (SLE), the risk of pregnancy loss appears to be independent, at least in part, of their underlying autoimmune disease. A review of 10 studies involving 554 women with SLE found fetal loss was more common among those with than among those without aPL (38 to 59 percent versus 16 to 20 percent), LA (36 versus 13 percent), or aCL (39 versus 18 percent) .
In addition, a meta-analysis including 2000 women without autoimmune disease found a significant association between aPL and pregnancy loss before 13 and before 24 weeks of gestation; this association was stronger for LA (OR 13) than for Ig-G aCL (OR 3.6) or Ig-M aCL (OR 5.6) .
Some studies suggest there is also an association between aPL and preembryonic (less than 6 weeks of gestation) and embryonic (6 through 9 weeks of gestation) loss [33,46,59,60], while other studies fail to establish a link . Causality is difficult to establish since there are many disorders associated with recurrent pregnancy loss. (See “Definition and etiology of recurrent pregnancy loss”.)
The risk of aPL and fetal loss was examined in a cohort of 491 patients with a history of adverse pregnancy outcomes . These women were evaluated for both aCL and LA, as well as inherited thrombophilias. The presence of a maternal thrombophilia was found to be protective of recurrent losses at <10 weeks of gestation (OR 0.55, 95% CI 0.33-0.92), but was associated with a modestly increased risk of loss >10 weeks (OR 1.76, 95% CI 1.05-2.94). Women who experienced only euploid losses were not more likely to have an identified thrombophilia than women who experienced only aneuploid losses (OR 1.03; 95% CI 0.38-2.75).
The paradoxical observation that maternal thrombophilias, including aPL, might be protective of early loss is not unexpected . Early pregnancy is normally associated with a low oxygen environment, trophoblast plugging of the intervillous space, and low Doppler flow of the uteroplacental circulation [62,63]. Thus, the early pregnancy environment may be relatively immune to the effects of aPL.
Fetal growth restriction — The best evidence of an association between aPL and growth restriction derives from a prospective study of 860 unselected Japanese women evaluated for aCL in the first trimester . The rate of fetal growth restriction was significantly higher among the 60 aCL positive than the 800 aCL negative women (12 versus 2 percent) .
Among patients with symptomatic APS, the frequency of growth restriction approaches 30 percent, which is significantly higher than the rate of 10 percent or less observed in the general population [65,66].
Preeclampsia/HELLP — Systematic reviews have concluded there is a significant association between the development of preeclampsia and the presence of aCL [33,67], and possibly LA . For aCL, the odds ratios were 2.73 (95% CI 1.65-4.51)  and 2.86 (95% CI 1.37-5.98)  and, for LA, the odds ratio was 1.45 (95% CI 0.70-4.61) . Severe preeclampsia and HELLP syndrome (Hemolysis, Elevated Liver function enzymes, and Low Platelet count) are particular concerns in this population [64,67-73], while mild or near term/term preeclampsia does not appear to be strongly associated with aPL .
Maternal thrombosis — Pregnancy and the puerperium are associated with an increased incidence of thromboembolic disease, including stroke. The risk of thromboembolism among aPL positive patients is highly variable and is exacerbated by co-existent hereditary coagulopathies (eg, factor V Leiden) [65,74], but aPL is likely to increase the risk of pregnancy-related venous thrombosis [72,75]. In a cohort study, 24 percent of thrombotic events in women with aPL occurred in association with pregnancy . In a prospective study, the risk of thrombosis during pregnancy was 5 percent among women with known APS (compared with 0.025 to 0.10 percent in the general obstetrical population) . (See “Deep vein thrombosis and pulmonary embolism in pregnancy: Epidemiology, pathogenesis, and diagnosis”.)
Risk in unselected populations — Whether asymptomatic women with aPL and no prior adverse pregnancy outcome (no thrombotic event or pregnancy complication) have an increased risk of complications during pregnancy is unclear.
Some studies show little or no increase in risk:
- Among 1449 healthy pregnant women, positive aCL tests occurred infrequently and were rarely associated with adverse pregnancy outcome .
- An elegant study comparing women with spontaneous abortion or fetal death with pregnant controls also found no association between aPL and an adverse pregnancy outcome . Among 331 women with spontaneous abortion or fetal death and 993 control women, no increased risk of miscarriage was observed in first pregnancies in women with aPL. This study concluded that routine screening of women with one pregnancy loss for aPL was not indicated.
In contrast, a prospective study of asymptomatic nulliparas with normal pregnancies reported a higher rate of fetal loss in women found to have high-titer IgG aCL before 25 weeks of gestation than in those who were aCL negative (28 versus 7 percent) .
NEONATAL APS — Neonatal APS is defined by the same criteria as APS in other populations: presence of at least one type of aPL in serum and the occurrence of at least one clinical feature such as venous or arterial thromboses or thrombocytopenia . A confounding factor, however, is that aPL in the neonate results from placental transfer of maternal antibody, and thus may not have the same significance as endogenously produced antibody. Passively acquired aPL completely disappears by 6 to 12 months of age .
Neonatal APS is rare to nonexistent. Studies reporting neonatal outcome of maternal APS have not described any cases of neonatal APS among 277 neonates [79-84]; a registry that collects outcome data on pregnancies complicated by APS also has not recorded any cases of neonatal APS . However, a literature review found 16 case reports of thrombosis in infants born to women with aPL, and 12 of these infants met criteria for neonatal APS (for the other four infants, aPL was detected only in the mother) . Causality related to aPL has not been established, as almost all of these infants had additional risk factors for arterial or venous thrombosis (eg, asphyxia, sepsis, indwelling vascular catheters, cardiac disease, inherited thrombophilia, antenatal disorders [preeclampsia, growth restriction]).
WHEN TO EVALUATE FOR ANTIPHOSPHOLIPID ANTIBODIES — Given the confusion surrounding causality and association with adverse outcomes, the population that should be evaluated for aPL because of obstetrical complications is controversial.
- The American College of Obstetricians and Gynecologists recommends testing women with “appropriate medical or obstetrical histories” for APS .
- The American College of Chest Physicians Evidence-Based Clinical Practice Guidelines recommend that women with recurrent early pregnancy loss (three or more miscarriages) be tested for the presence of LA and aCL antibodies . They also suggest screening women with severe or recurrent preeclampsia or fetal growth restriction, while acknowledging that there is less evidence supporting this approach. Since they consider late fetal death an appropriate indication for treatment with anticoagulants, women with otherwise unexplained late fetal loss should be screened for aPL.
If the initial screening test is positive, it should be repeated in 12 weeks to determine whether the aPL is transient or persistent. (See “Diagnosis of the antiphospholipid syndrome”.)
Evaluation for aPL is also indicated in nonpregnant women and women with no history of pregnancy complications if other clinical manifestations of APS are present or if they have SLE. (See “Clinical manifestations of the antiphospholipid syndrome”.)
SUMMARY AND RECOMMENDATIONS
- Thrombus formation, infarction, and vasculopathy are assumed to account for many of the clinical manifestations of the APS, but additional factors, such as direct effects on trophoblast, may also play a role in adverse pregnancy outcomes. (See ‘Pathogenesis of adverse pregnancy outcome’ above.)
- We suggest that patients with the following pregnancy complications be tested for the presence of LA and aCL antibodies:
- One or more fetal losses after 10 weeks of gestation
- Unexplained intrauterine growth restriction
- Early, severe preeclampsia
- Pregnancy-related maternal thrombosis
(See ‘When to evaluate for antiphospholipid antibodies’ above.)
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