Antiphospholipid Antibody Syndrome. Rare Diseases of the Immune System

7. Obstetric APS

Micaela Fredi  and Angela Tincani 


Rheumatology and Clinical Immunology, Spedali Civili, University of Brescia, Piazzale Spedali Civili, 1, Brescia, 25123, Italy

Micaela Fredi


Angela Tincani (Corresponding author)



Antiphospholipid antibodiesPregnancyFetal lossAntibody profileRecurrent miscarriagesPreeclampsia

7.1 Antiphospholipid Syndrome and Pregnancy Loss

Antiphospholipid syndrome (APS) was first described in patients with obstetric morbidity, in particular midtrimester fetal losses [1], enlightening the impact of the obstetric manifestations in this condition.

When classification criteria of APS were defined in 1999 [2] and revised in 2006 [3], the obstetric manifestations were considered as one out of the two clinical aspects characterizing the syndrome. From a practical point of view, the right identification of the APS-related obstetric complications and the consequent application of an appropriate management had the greatest impact on the quality of life of these patients, returning to them, in the majority of cases, the possibility of having children.

The definition of obstetric APS (Table 7.1) includes different pathological manifestations: recurrent early pregnancy loss (REPL), fetal death, early severe preeclampsia with placental insufficiency and growth restriction, and even the HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets), classified within the microangiopathic manifestations of APS [4]. In a multicenter prospective cohort of 1,000 patients with primary and secondary antiphospholipid syndrome followed for 10 years, the most frequent fetal complications were REPL, followed by fetal death and premature birth, whereas the most common maternal manifestations were preeclampsia, followed by eclampsia and abruptio placentae [5]. The wide spectrum of APS pregnancy complications implies that several pathogenic mechanisms might be involved, perhaps reflecting several possible interactions between antiphospholipid antibodies (aPL) and the uteroplacental unit (see Chap.​ 4). The observation that pregnancy losses tend to recur in a relevant percentage of the patients despite careful management and despite a treatment based on the actual guidelines suggests that part of aPL-mediated pregnancy damage remains still undefined and therefore not adequately prevented.

Table 7.1

Classification criteria for definite obstetric antiphospholipid syndrome proposed during the 11th International Congress on aPL held in Sydney in 2004

Criteria for obstetric APS

1. One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, with normal fetal morphology documented by ultrasound or by direct examination of the fetus

2. One or more premature birth of a morphologically normal neonate before the 34th week of gestation because of eclampsia or severe preeclampsia or recognized features of placental insufficiency

3. Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomic causes excluded

From Miyakis et al. [3]

An additonal aspect that has to be considered is the clinical setting of patients with obstetric APS. The presence of aPL in a patient with a well-defined systemic autoimmune disease (mainly systemic lupus erythematosus) and obstetrical morbidity seems to be a different condition from that occurring in a patient with aPL and REPL or fetal death in the absence of other medical problems. It seems that these two conditions are hardly comparable and that the recurrence rate is probably higher in the first one [6]. Another well-established risk factor for recurrences is a previous history of thromboembolism that requires, beside a specific management during pregnancy, a careful prophylaxis not only to protect fetal well-being but also to avoid possible thrombotic events in the mother [7].

Antiphospholipid antibody profile has been also investigated as possible risk factor for pregnancy loss recurrence. A recent collaborative Italian study demonstrated that triple positivity of aPL antibodies (LA, aCL, and anti-β2GPI) is an independent risk factor for pregnancy poor outcome despite conventional treatment [6]. Conversely a multicenter American study enlightened the role of LA as primary predictor of adverse pregnancy outcome after 12 weeks of gestation in the pregnancies of aPL-positive mothers; in this study positivity for aCL and anti-β2GPI, if LA is not also present, did not predict adverse pregnancy outcome [6].

The aPL titer (aCL and anti-β2GPI) is also considered in the frame of aPL profile. According to international recommendation [8] IgG isotype at medium high titer is considered a higher risk factor for APS clinical manifestations compared to low titer and IgM isotype. In fact low titer is not recognized as formal classification criteria.

Nevertheless in obstetric APS also low titers were suggested to be of significance [910] being associated with poor obstetric outcome. This particular aspect is still debated; a study from Israel showed a good pregnancy outcome in 77 % of patients with low aPL titers, compared to 35 % of good outcomes reported in patients with high aPL titers [9]. Instead a French study described poor pregnancy outcomes in untreated mothers with low aPL titers that were not significantly different from those observed in patients with medium-high titers [10]. Furthermore an English study showed that over 50 % of women with pure obstetric APS had low titer aCL and/or anti-β2GPI in the absence of LA. Approximately 27 % of these patients had clinical features of high-risk obstetric APS [11]. Indeed the impression is that in obstetric APS also low titer aPL may play a notable role. Accordingly, low titer aCL were already described to be of clinical significance for women with purely obstetric APS in a large prospective cohort of European patients [12] as well as in women with stillbirth in a recent collaborative report [13].

In addition to classical aPL antibodies, increasing evidence demonstrates that several other autoantibodies, such as antibodies against phosphatidylethanolamine (aPE), anti-annexin 5, antiprothrombin (aPT), and/or anti-phosphatidylserine/prothrombin complex (aPT/PS), can be found associated with pregnancy loss. Starting in the 1990s Yetman et al. reported non-criteria aPL, including aPE, in 10.1 % of women with REPL [14]. Further studies confirmed an increased incidence of aPE in patients with REPL, in fetal death, and in infertile women with recurrent implantation failures [1516]. However, aPE was not shown to be an independent risk factor for further miscarriage in patients with REPL [17], but the combinations of IgG aPE with other aPL detected by tests included in the Classification Criteria can be useful predictors of severe pregnancy-induced hypertension, with a 30.8 % sensitivity and a 99.2 % specificity [17].

The association of antiprothrombin antibodies and pregnancy morbidity is still not clear also because of the known difference between antibody binding to prothrombin alone (aPT) and antibodies binding to phosphatidylserine/prothrombin complex (aPS/PT). Several groups found that women with REPL, either idiopathic or within APS, display higher frequency of aPT compared to normal subjects [18]. Recently the prevalence of aPT was investigated in a cohort of patients negative for classical aPL with previous uteroplacental insufficiency complications, including severe preeclampsia, HELLP syndrome, placental abruption, and fetal death. A significantly 10-fold higher prevalence of aPT IgG was reported in cases compared to controls (OR, 95 % CI: 10.92, 4.52–26.38); the strongest statistical association was reached with fetal death [19]. The association between the aPS/PT antibodies and pregnancy morbidity is also still matter of discussion, with studies that have found low rate of aPS/PT positivity in patients with REPL without APS [20], while a recent paper reported high rate of antibodies against aPS/PT in patient with APS (with or without SLE) [21]. The authors reported that aPS/aPT antibodies were the strongest independent risk factor for obstetric complications in their cohort.

High rate of anti-annexin 5 antibodies was found in several retrospective studies [22]. However, in a large prospective cohort study, the detection of anti-annexin 5 at the beginning of pregnancy was not related to the occurrence of pregnancy loss [23]. In women with obstetric APS characterized by REPL, a higher prevalence of anti-annexin 5 antibodies has been observed compared to aPL-negative women with the same obstetrical complications or to general obstetric population [24]. Therefore, it is actually suggested that anti-annexin 5 antibodies do not represent an independent risk factor for REPL, while they could represent an additional risk factor possibly contributing to the disruption of the annexin 5 crystal shield [25].

To achieve a successful outcome in APS pregnancy, an optimal management strategy is required. This includes a proper treatment (as enlighten in the Chap.​ 16), but the experience has thought us that pharmacological treatment by itself is not sufficient. Success, defined as fetal survival, is the result of careful obstetric monitoring, proper delivery timing, and skilful neonatal care [26]. The careful surveillance conducted by a multidisciplinary team (obstetricians, rheumatologists, and neonatologists) and the progress in neonatal intensive care are as important as drugs to achieve a good obstetric outcome and to reduce the possible adverse consequences of premature delivery.

7.2 Nomenclature

A major problem in comparing the published data of obstetric APS has been and still is the lack of uniform definitions for pregnancy loss and pregnancy complications. Therefore, in the interest of the readers, we think important to share common definitions.

The nomenclature used for the definition of pregnancy loss can be quite outdated, and in this case it does not reflect the modern understanding of reproductive biology. Traditionally pregnancy loss occurring at less than 20 weeks of gestation have been grouped together as spontaneous abortions, while those occurring after 20 weeks gestation have been defined stillbirths. More recently nomenclature that accurately reflects our current knowledge of the developmental process and that is more aligned with pathophysiology or causes of pregnancy loss has been proposed [27]; these definitions are outlined in Table 7.2.

Table 7.2

Proposed nomenclature

Proposed nomenclature


Previous nomenclature

Developmental stage

Early pregnancy loss (04+0–09+6weeks of gestation)


Early spontaneous abortion


 Death of a conceptus measuring up to 29 mm in crown-rump length

 Sonographic documentation of a dead conceptus consistent with a gestational age up to 9 weeks and 6 days gestation (crown-rump length up to 29 mm)

The embryo must be identified by ultrasound to rule out anembryonic pregnancy

Fetal death (10+0–19+6 weeks of gestation)


Spontaneous abortion


 Passage of a conceptus measuring at least 30 mm in crown-rump length or

(a) Early fetal death (10+0–15+6weeks gestation)

 Sonographic documentation of a dead conceptus with crown-rump length consistent with a gestational age at least 10 weeks gestation

(b) Late fetal death (16+0–19+6weeks of gestation)

 Loss of the conceptus after documented fetal cardiac activity at or beyond 10 weeks gestational age The fetus is dead at the time of delivery with Apgar scores of zero at one and 5 min.

Neonatal death

Death of a formed fetus alive at birth in the first 28 days of life

Neonatal death


Stillbirth (at least 20 weeks of gestation)

Fetus at least 20 weeks of gestation that is dead at the time of delivery with Apgar scores of zero at one and 5 min.




Increased blood pressure associated with proteinuria in pregnancy Diagnostic blood pressures include either a systolic blood pressure ≥140 mmHg or a diastolic blood pressure ≥90 mmHg on at least two occasions (at least 4 h apart) Proteinuria is defined as the excretion of 300 mg of protein or greater in a 24-h specimen



Early (<33 weeks)

Late (≥34 weeks of gestation)


An acute and life-threatening complication of pregnancy characterized by the appearance of tonic–clonic seizures (convulsions)



HELLP syndrome

Hemolysis, elevated liver enzymes, and low platelet

HELLP syndrome


Modified from Silver et al. [27]

In the following pages we try to apply the new terminology; however, some of the reported data were published before its definition; therefore, we had to deal with various descriptions of pregnancy complications and adverse outcomes and some imprecision has to be taken into account.

7.3 Recurrent Early Pregnancy Loss

In a general obstetric population, 10–15 % of pregnancies end in spontaneous abortion, mainly occurring during the pre-embryonic (up to 5+6 weeks of gestation) or embryonic period (up to 9+6 weeks of gestation), while the rate of fetal death, after 10 weeks of gestation, is very low. In addition, the recurrence of early miscarriages in the general population is not unusual, being recorded in about 1 % of them. A recent critical review, including only four prospective studies performed on general population with REPL, reported aPL positivity in about 2 % of the women [28]. The selection of the included papers was limited to the studies including details allowing to verify the reliability of the findings and therefore might be near to the real picture.

The attribution of early recurrent miscarriages to aPL-mediated damage implies the exclusion of several other possible causes:





The need for at least three REPL in the first 10 weeks of gestation to fulfill the classification criteria of APS is probably based on these observations and allows to exclude most of the losses due to genetic abnormalities that can confuse the clinical picture.

Nevertheless, REPL, often misdiagnosed because of their frequency in the general obstetric population, can be considered to be the most frequently occurring pregnancy losses associated with aPL. In fact according to a recent report of the 10-year follow-up of 1,000 APS patients [5], 188 pregnancies in 127 women were observed and despite prophylactic treatment, REPL occurred in 16.5 % of pregnancies, while fetal death in 5 %.

Many published studies reports a positive association between aPL and REPL, but they are highly heterogeneous concerning clinical events (number of previous pregnancy losses, gestational age of pregnancy losses, inclusion of early miscarriage, and late fetal death in the same analysis) and laboratory criteria (different cutoffs, inclusion of patients with low titers, and lack of confirmatory testing). A recent meta-analysis [29] tried to evaluate the previous papers that have analyzed this association in patients without systemic autoimmune disease. The authors underlined that the comparison between studies was difficult due to many methodological causes: poor standardization of assays testing for aPL, heterogeneity of studies regarding the definitions of cases (minimum number of consecutive losses required), and controls (not matched for parity, few studies with appropriate controls). No studies were found examining the association between lupus anticoagulant (LA) and anticardiolipin (aCL) IgM with pregnancy loss before 13 weeks of gestation, and the association between anti-β2 glycoprotein-I (aβ2GPI) and recurrent abortion before 13 weeks was not statistically significant. Instead they reported a positive association between low and moderate-high titers aCL IgG and REPL occurring at less than 13 weeks of gestation; however, only two studies, including 907 patients, could be evaluated in this analysis.

The recent report of the antiphospholipid antibodies taskforce [30] included only studies recording losses occurring within 10 weeks of gestation. Forty-six original studies investigating the frequency of positive aPL tests in patients with REPL were identified and included in the analysis. High percentage (nearly 80 %, 27 out of 34) of the case-control studies found a significant association of aPL and REPL. Results of LA and aCL antibodies were available in most of the studies, with only a small number of papers analyzing anti-β2GPI. Fourteen out of 27 studies reporting a positive association between aPL and REPL included a significant number of patients (>100). Conversely, a number of studies found no association between aPL and REPL. Notably, some of them published in the 1990s did not include the evaluation of patients by all the three tests. Panton et al. described a higher prevalence of aCL IgG among 177 women with REPL compared to 254 healthy blood donors [31], but the finding was not statistically significant. Two large studies [1532] published in the 2000s found no association between aPL and REPL. In the first LA and aCL IgG were studied in 273 patients [15], while the other considered aβ2GPI IgG and IgM in 172 patients [32]; data from both the works showed no significant difference in the frequency of aPL in patients compared to healthy controls. Finally a very recent reported no significant association between aCL or LA and REPL in 52 Pakistani women [33].

The heterogeneous results of the studies mentioned above can be partially explained by different inclusion criteria and definitions of positive laboratory tests. Many papers (26/46) investigating aPL in patients with REPL were published before the first international consensus on aPL [2] and most of them did not use the criteria currently accepted to classify patients with APS. More than three pregnancy loss was the criteria used only in two third of the studies (30/46), and the majority of the published studies did not mention if patients had consecutive pregnancy loss; only four papers [3437] strictly followed the pregnancy morbidity criteria for REPL described in Sapporo/Sidney consensus (“Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation”). The gestational age of the pregnancy loss used as inclusion criteria was also various among the publications with several studies including patients with both first and second trimester loss. Also the use of different cutoff in the diagnostic tests appears to have contributed to the discrepant findings, and the confirmation of aPL positivity was performed in only 8 out of 46 studies, increasing the risk of misclassification due to momentary aPL.

However the a majority of published studies identifie a positive association between aPL and REPL, they are highly heterogeneous concerning clinical events and laboratory criteria.

Evidence arising from clinical experience and the few relevant publications suggests that while the recurrent early pregnancy loss may be the most sensitive manifestations of obstetric APS, the specificity is uncertain because of the difficulty in excluding other known or suspected causes.

7.4 Fetal Death

Historically, repeated fetal deaths were the first pregnancy complication reported in patients with aPL with or without thrombosis [138]. In the general population fetal death is a rare event, and only about 2 % of pregnancy losses seem to occur between 10 and 20 weeks of gestation [39]. It is estimated that up to 5 % of normal pregnancies end in loss during both fetal and neonatal periods [40].

However, in women with aPL positivity, late pregnancy failures are a frequent issue and represent one of the clinical classification criteria for APS; in the work of Cervera et al. [5], fetal death occurred in 16.9 % of the patients at time of the inclusion, and in nearly 5 % a recurrence despite treatment was reported during the 10 years of follow-up.

Among the formal classification criteria, fetal death is considered the most specific symptom defining obstetric APS [41]. In patients suffering recurrent pregnancy loss, the specificity of fetal death for the presence of aPL was shown to be up to 76 % compared with only 6 % for two or more pre-embryonic pregnancy losses [42]. Today, according to what is known about the biological development of the embryo, the fetal period is defined as starting at the 10th week of gestation and lasting until delivery.

Fetal damage may be reasonably due to the presence of aPL only after exclusion of other possible causes such as cervical insufficiency and infections. In this respect the role of heritable thrombophilia defects such as factor V or factor II Leiden mutation, antithrombin, and protein C or protein S deficiency is still debated. In fact heritable thrombophilia defects have been associated with fetal losses, but their role in the fetal damage is still unclear [43].

The association between fetal death and aPL has been evaluated in several studies, and a systematic review has been recently released [44]. According to this systematic review, fetal death, considered after 10 weeks of gestation, was shown to be associated with LA in 4 case-control studies and 3 cohort studies, aCL antibodies in 7 case control studies and 5 cohort studies, and anti-β2GPI in 2 cohort studies. However, the authors of this paper underlined several limitations of their work. First of all many studies included a small number of patients, so they were considerably underpowered to detect significant associations between aPL and fetal deaths. This observation is certainly pertinent from a methodological point of view, but does not consider that fetal death is rarer than early pregnancy loss and that APS is also un uncommon disease. Indeed, case control studies could include no more than 200–300 events of placenta-mediated complications (including but not limited to fetal deaths), and prospective studies on the pregnancy of general obstetric population could identify only few cases of fetal death. An additional limitation comes from the definition of fetal death itself that resulted to be widely different in the included studies. In fact, some cohorts called fetal death events occur after 8 weeks of gestations while others after 24. However, an association was found between aPL and both stillbirth (>20 weeks of gestation) and fetal death (>10 weeks of gestation), suggesting that antibody-mediated damage can similarly affect different pregnancy periods. Moreover wide methodological variability in aPL assays has been observed, as expected because of the well-known difficulties in the performance of aPL antibody tests. In the ELISA-based papers, the cutoff values applied to the different assays displayed significant variability, and frequently IgG- and IgM-positive values were merged, making impossible to evaluate isotypes separately. Lastly few papers included all the three criteria tests and the confirmation of positive results, as recommended by the international consensus [3]. After this systematic review a more recent large, multicenter, multiethnic prospective population-based study focused on the association between aPL and stillbirth [13], and this study showed that elevated levels of aCL and anti-β2GPI antibodies were associated with a 3- to 5-fold increased odds of stillbirth. Strengths of this study were the inclusion of a great number cases and the centralization of aCL and anti-β2GPI testing for homogeneous assessment of positive results. However, the lack of LA testing and the absence of any confirmation of aPL persistence are major limitations that do not allow the precise identification of the true-positive patients.

7.5 Preeclampsia and Placental Insufficiency

Pregnancy in women with positive aPL can also be complicated by uteroplacental insufficiency inducing intrauterine growth restriction (IUGR), premature delivery [45], and early preeclampsia; the early-onset, severe preeclampsia complicated by hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome) was also reported in APS pregnant patients.

As already detailed elsewhere (Chap.​ 4), poor placentation has been demonstrated to impair the physiological change of spiral arteries into low-resistance vessels during the first half of pregnancy. The absence of this remodeling impairs uteroplacental blood flow and consequently does not allow a physiological fetal growth.

Preeclampsia (defined in Table 7.2) is a major obstetric problem leading to substantial maternal and perinatal morbidity and mortality worldwide. Maternal and perinatal outcomes in preeclampsia depend on one or more of the following situations: gestational age at time of onset, severity, presence or absence of preexisting medical disorders, and quality of management.

Preeclampsia generally affects 2–8 % of the pregnancies in general obstetric population [46], while in pregnant women with APS (with or without SLE), it is reported in 20–50 % of cases [47]. In particular there is a higher rate of early (<34 weeks of gestation) severe preeclampsia, whereas the late preeclampsia (near term), as seen in general population, is not associated with the presence of aPL [4849].

The association between severe preeclampsia at or before 34 weeks’ gestation and aPL was first observed in 1989 [50], but the real linkage between aPL and preeclampsia is still debatable [47]. Several studies report high frequency of preeclampsia in patients with primary or secondary APS, and in the obstetric population with preeclampsia, aPL antibodies are often observed to confirm the linkage between these conditions [47]. This topic was recently revised by two meta-analysis: the main finding of the first [51] was the observation of an association between aPL and severe preeclampsia in pregnant patients without autoimmune disease, but again significant methodological limitations of the included studies were underlined. In the second meta-analysis [44] that focus on late fetal loss, preeclampsia, and IUGR, the authors conclude that only fetal loss are significantly associated with aPL.

IUGR is defined as a fetus with an abdominal circumference below the 5th percentile according the gestational age (assessed with ultrasound), and it is an established cause of perinatal mortality and severe morbidity in surviving infants. This complication is common in APS pregnancies, occurring in approximately 30 % of the women [455253], while it is usually observed in only 3–10 % of the general obstetric population. In women without a prior diagnosis of APS, the presence of IUGR in the setting of preeclampsia may increase the likelihood of a positive test for aPL [47].

Regarding the association between aPL and IUGR, few studies have specifically addressed this issue. Positive tests for aPL occur in 25 % of women delivering IUGR fetuses [54], and aPL has been associated with IUGR in pregnancies complicated by preeclampsia [55]. In a prospective study conducted by Yasuda et al. [56], 12 % of women from a general obstetric population testing positive for aCL had infants who were small for gestational age, compared to 2 % of women testing negative. However, in two other prospective studies, investigators found no correlation between aPL and IUGR [5758].

7.6 Conclusion

Since the first description of obstetric APS, in the 1980s, great improvement has been achieved in the practical approach to pregnancy. However, after nearly 30 years from the identification of the syndrome and nearly 15 years from the publication of the clinical and laboratory criteria, uncertainties still abound regarding the association of each of the current clinical obstetric criteria for APS and aPL antibodies. New and more informative studies could be drawn taking into account the modern definitions of the events, the use of the three diagnostic tests, and the need to confirm the serological positivity. Nevertheless we have to admit that it will be always difficult to draw large trials in these relatively rare pregnancy complications or losses.

Despite these considerations, the key role of aPL in the occurrence of pregnancy morbidity is well established in the “real life.” Today, the identification of an appropriate treatment and strict multidisciplinary management before and during pregnancy has allowed to achieve a good pregnancy outcome approximately by 80 % of the women. A precise classification of the events will allow the development of more targeted treatments possibly helping the 20 % of patients with obstetric APS that still have fetal losses regardless the current treatments.



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