Results From a Multicenter Italian Cohort Over 20 Years Of Experience

Background/Purpose: Antiphospholipid antibodies (aPL) are risk factors for Adverse Pregnancy Outcome (APO). In particular, for aPL carriers (patients with aPL positivity with no thrombotic or obstetric history) pregnancy outcome and treatment are still not defined. Here we critically reviewed pregnancy outcome in a large multicenter cohort of aPL carriers patients, according to different serological profile and treatment protocols.

Methods: We reviewed 70 pregnancies in 62 patients, that were prospectively followed in 3 Italian centers over 20 years (1994-2015).  Patients with previous clinical events (thrombosis, any APO in previous pregnancies and also preterm birth <37 w for any reasons) or concomitant autoimmune diseases were excluded.  Patients with aPL positivity and non-criteria manifestations were included. aPL profile was defined as the combination of the 3 criteria tests for aPL (Lupus Anticoagulant, anti-cardiolipin, anti-Beta2 Glycoprotein I). APO was defined as at least one of the followings: miscarriage (<10^th week), fetal death (≥10^th week), severe preterm delivery (≤34^th week) with or without preeclampsia (PE), HELLP syndrome or perinatal death.

Results: Mean age at discovery of aPL was 31 years and mean age at pregnancy was 32 years.  Regarding aPL profile: 44 (63%) were single positive, 17 (24%) were double and 9 (13%) were triple. aPL non criteria manifestations were present in 6 (8%) and lupus-like manifestations in 5 (7%). Nine pregnancies had a combination treatment with prophylactic low molecular weight heparin (LMWH) plus low dose aspirin (LDA), 37 had LDA alone and 24 had no treatment. We observed 2 thrombotic events (3%), 1 deep venous thrombosis (6th week, in a single positive low titer, before the start of treatment) and 1 ischemic stroke (37th week, in a triple positive, already in treatment with combination therapy). We recorded 6 APO, all in spontaneous pregnancies: 3 fetal deaths and 3 pre-term birth ≤34^th week with PE. We then performed a univariate analysis comparing 8 complicated pregnancies (6 APO plus 2 thrombosis) with 62 non-complicated pregnancies (Table 1). Acquired risk factors (p:0.007), non-criteria aPL (p:0.017) and lupus-like manifestation (p:0.009), triple positive aPL profile (p:0.0005) were associated with APO. The combination treatment was also more frequent in APO pregnancies (p:0.007).

Conclusion:  Acquired risk factors, aPL profile (triple positivity), lupus-like and non-criteria aPL manifestations could represent risk factors for pregnancy complications and could determine failure even to conventional treatment with LDA plus prophylactic LMWH. These patients may deserve additional treatment, for example LMWH at higher/anti-coagulant dose or an immunomodulatory treatment to increase the probability of success during pregnancy, such as hydroxychloroquine, also considering its anti-platelet/anti-thrombotic effects.

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Table 1. Complicated pregnancies (APO and thrombosis) compared with non-complicated pregnancies – univariate analysis ^ Fisher’s exact test, except otherwise indicated; p significant <0.05 § Student’s T- test # Acquired risk factors. Obesity (BMI>30w), hypertension (>140/90), hyper-cholesterolemia, hyper-triglyceridemia, hyper-homocysteinemia, diabetes mellitus ° Non-criteria aPL manifestations were defined as the presence of at least one of the followings: (livaedo reticularis, thrombocytopenia, headache, hemolytic anemia, cardiac valvulopathy, epilepsy)