Besides thrombosis, aPL are known risk factors for a wide range of obstetric morbidity, such as recurrent pregnancy losses, late fetal losses, preeclampsia, placental abruption, and intrauterine growth restriction. The strength of association between aPL and single manifestations may vary from study to study, mainly for “methodological” problems: most of the data are derived from small case-control studies, often results are not conclusive, and there are no large controlled-randomized trials [42]. In any case, the management of aPL carriers should include prophylaxis, not only for pregnancy outcome itself but also for maternal protection, being pregnancy and puerperium as high-risk periods for the occurrence of thrombosis.

Pregnancy morbidity is not uncommon in the general population and can be due to multiple causes (anatomical defects, chromosomal aberrations, endocrine factors, subclinical infections, and, finally, immunological disturbances), but more than 50 % of the cases remain idiopathic after conventional investigations [43].

Antiphospholipid antibodies were shown to be pathogenic in several models of pregnancy wastage, both in vitro and in vivo [reviewed in [44, 45]. In particular, aPL specifically target the placenta by binding β2GPI, which is constitutively expressed on the trophoblast cell surface. This interaction may alter first-trimester human trophoblast modulating several cell biological pathways and, finally, causing unfavorable outcome [46, 47].

Suggested pathogenic mechanisms mediated by aPL are [2]:

A peculiar pathogenic model for aPL-induced pregnancy morbidity is preeclampsia. Preeclampsia is a vasospastic hypertensive disorders marked by abnormal maternal arteriolar reactivity to vasoactive agents such as prostacyclin, thromboxane A2, nitric oxide, and endothelins. Moreover, defective regulation of the complement system, allowing for excessive complement activation which leads to abnormal placental development and abnormal trophoblast invasion, placental damage, generalized endothelial activation, and release of antiangiogenic factors toxic to glomerular endothelium and liver sinusoids, seems to be involved in this complex model [50].

Association between aPL single test and pregnancy morbidity is not well defined, mainly because of lacking in randomized controlled trials and heterogeneity of design studies. Most studies are underpowered with high heterogeneity regarding association with aPL and pregnancy morbidity: there are only few studies which meet Sapporo/Sydney criteria and support association between clinical events and laboratory criteria [51, 52].

As previously discussed for the risk of thrombosis, also on the obstetric side, it is important to identify patients at high risk taking into account many variables. First of all, general obstetric risk should be assessed, taking into consideration age, concomitant autoimmune disease, previous thrombosis, family history (autoimmunity, thrombosis, abortions), hypertension, obesity, acquired thrombophilia, and so forth.

It is currently under discussion whether different aPL profiles confer the same degree of obstetric risk, and it is not easy to stratify patients into “risk classes.” Routine screening for aPL antibodies is not recommended in healthy pregnant women, because they occur infrequently, at low levels, and are rarely associated with adverse pregnancy outcome. An original report at the beginning of the 1990s found that greater than 50 % of such women will go on to have uncomplicated pregnancies without any additional treatment [53].

At the moment, it is recommended to test all three validated antibodies (aCL, anti-β2GPI, LA) included in the revised Sydney criteria. There are few studies evaluating a possible role of nonclassical aPL (anti-phosphatidylcholine, anti-phosphatidylethanolamine, anti-phosphatidylinositol, anti-phosphatidylserine, and anti-sphingomyelin) in obstetric complications. They seem not to be an independent risk factor in the prediction of miscarriage in women with recurrent pregnancy loss and to have no clinical significance in obstetric complications [54].

Available meta-analysis studies evaluating the association between different aPL tests and pregnancy morbidity showed divergent results. Opatrny et al. concluded that high-risk patients are those carrying LA and IgG aCL antibodies (especially at high titers) [55]. Abou-Nassar and coworkers concluded that the association between each single aPL test and placenta-mediated complications was inconsistent and debatable [52]. However, it should be considered that most of the studies included in the meta-analysis did not test for a complete aPL profile but rather for one or two aPL tests.

More recently, some studies took into consideration a complete aPL profile and its relationships with pregnancy outcome.

The PROMISSE study (Predictors of Pregnancy Outcome: BioMarkers In Antiphospholipid Syndrome and Systemic Lupus Erythematosus), a large, multicenter observational study on pregnancies of patients with APS and/or SLE, described the pregnancy outcome of 144 aPL-positive patients. Poor pregnancy outcome was observed mainly in LAC-positive women and in women with moderate- to high-titer IgG aCL; other aPL did not independently predict adverse pregnancy outcome [56].

Other studies found out that high-risk patients are those with aPL triple positivity (aCL, anti-β2GPI, LA) [51]. A multicenter European study showed that independent risk factors for pregnancy failure despite treatment were the presence of SLE or other autoimmune diseases, history of both thrombosis and pregnancy morbidity, and triple aPL positivity [57]. On the other hand, other authors observed unfavorable pregnancy outcome also in patients with a “low-risk” aPL profile (e.g., IgM isotype or medium to low aPL titers) [58, 59].

In our opinion, those risk factors identified in pregnancy failures despite treatment could be also considered as “red flags” to be applied in for primary prophylaxis. In other words, pregnant aPL carriers with either triple aPL positivity and/or a concomitant autoimmune disease should be considered at higher risk and provided with a more generous prophylaxis.

The main scenario in which aPL can be found incidentally is during workup for infertility. The role of aPL in infertility is controversial. aPL may interfere with several steps from implantation, placentation, to early embryonic development. At present, there is no evidence to support routine screening for aPL in patients with primary infertility, and no difference in the prevalence of aPL in women with unexplained infertility compared to fertile controls were found [51]. There is also no clear association between aPL positivity and implantation failure, clinical pregnancy, or live birth rates in women undergoing assisted reproduction.

The major point about assisted reproduction techniques is that ovarian stimulation protocols can be considered as high-risk situations for thrombosis because of artificially elevated estrogen levels [51]. One retrospective cohort study of ten APS patients who underwent 47 cycles of ovulation induction showed that no patients experienced thrombosis during treatment; all patients were treated with prophylactic LDA with or without heparin [60]. As a general measure, aPL-positive women, especially if high-risk profile, must be considered as a risk population, and so prophylactic treatment with LDA or LMWH should be considered during ovarian stimulation.

A key drug for primary obstetric prophylaxis is LDA. It is also indicated in women without aPL for the prevention of preeclampsia [61]. In clinical practice, many physicians are used to pregnant aPL carriers with LDA, in particular if the patients have already experienced one or two fetal losses or if maternal risk factors coexist (age, arterial hypertension, obesity, etc.). A large retrospective observational study showed that pregnancy outcome can be favorable without LDA in those patients with a low-risk profile [62]. According to another large cohort of pregnant aPL carriers, combination treatment of LDA and other drugs seems to be not necessary in asymptomatic pregnant aPL carriers, even in the presence of high antibody titers [63]. Nevertheless, the experts recommend the use of LMWH in addition to LDA in selected cases (older maternal age, high-risk aPL profile, assisted reproduction techniques) [64].

In our opinion, pregnant women with a high-risk aPL profile should be granted a generous prophylaxis for both maternal and fetal protection, while patients with a low-risk profile could be candidate to a less aggressive approach. However, the definitions of “high” and “low” risk from the obstetric point of view still need to be validated in properly designed studies.

Another point of concern is the puerperium. It is considered a high-risk period for thrombosis for all women. Usually APS patients are posed in primary prophylaxis with LMWH for a few weeks after delivery (generally 4–6 weeks). Regarding aPL carriers, experts believe that is important to protect these women with a similar management [64].

Recently, a role for HCQ was proposed. Recent studies have reported that HCQ reduces the binding of aPL-β2GPI complexes in trophoblast surface [65]. In a recent study by Albert and collaborators [66], authors studied a human first-trimester trophoblast cell line exposed to a β2GPI in presence or not of HCQ. HCQ was shown to partially antagonize aPL-induced inhibition of trophoblast migration, confirming the immunomodulatory properties of HCQ and suggesting beneficial effects on the placenta in patients with aPL positivity. At least from the experimental point of view, there may be a rationale for testing HCQ in clinical studies as a preventive treatment in aPL carrier’s pregnancies (Table 17.2).