Treating unexplained recurrent pregnancy loss based on lessons learned from obstetric antiphospholipid syndrome and inherited thrombophilia: a propensity-score adjusted retrospective study

Antiphospholipid syndrome (APS) comprises persistently high titers of antiphospholipid antibodies (aPL), vascular thrombosis and/or obstetrical complications (O-APS), such as miscarriages or late pregnancy complications related to placental insufficiency (Miyakis et al., 2006). The main target of aPL is β2-glycoprotein I (β2GPI), a plasma protein that binds to anionic phospholipids. aPL recognition of phospholipid-bound β2GPI leads to activation of the coagulation cascade and of the cellular and humoral arms of the innate immune response, most importantly activating the complement cascade (Garcia and Erkan, 2018). Complement activation in turn leads to the generation of anaphylatoxins with further recruitment of inflammatory cells and placental injury. Depending on the extent of the damage pregnancy loss, intrauterine fetal death or fetal growth restriction ensue (Girardi et al., 2003).

The therapeutic efficacy of low molecular weight heparin (LMWH) is well-established in patients with O-APS, even if the precise molecular mechanisms associated with clinical benefit are not known (Hamulyák et al., 2020). LMWH limits aPL-induced activation of the complement cascade, evidenced by elevated plasma C3a levels and decidual deposition of C3 (Girardi et al., 2004) and impacts on other events that are critical for placental injury, such as neutrophil activation and generation of neutrophil extracellular traps (NETs) (Manfredi et al., 2017). Recurrent Pregnancy Loss (RPL) is defined as the loss of either two or three clinical pregnancies, either consecutive or not depending on the definition taken into consideration (“Definitions of infertility and recurrent pregnancy loss,” 2013; “Recurrent Miscarriage, Investigation and Treatment of Couples (Green-top Guideline No. 17),” n.d.; The ESHRE Guideline Group on RPL et al., 2018). RPL occurs in around 1% of couples, when three miscarriages are considered (American College of Obstetricians and Gynecologists, 2002). Prevalence rises to 5% if we consider two miscarriages (Stirrat, 1990). The etiology is complex and several factors may contribute including chromosomal abnormalities, coagulation anomalies, endocrine disorders, autoimmune diseases and anatomic abnormalities (Branch, 2010). Even after thorough investigations, the etiology of RPL is identified in only half of the patients (Rai and Regan, 2006).

When no abnormality is encountered at screening, RPL is defined as “unexplained”. Empiric therapies may be administered, among which heparin has gained increasing importance in recent years. Numerous studies addressing this question have provided non-conclusive results (Badawy et al., 2008, Clark et al., 2010, de Jong et al., 2014, Dolitzky et al., 2006, Fawzy et al., 2008, Kaandorp et al., 2010, Lin et al., 2019, Skeith et al., 2016). Many studies however included RPL patients affected by any kind of thrombophilia (Brenner et al., 2005, Carp et al., 2003, Karadağ et al., 2017, Shen et al., 2016). Evidence against the use of LMWH in U-RPL patients is provided by a recent meta-analysis (Lin et al., 2019) based on three small randomized, controlled trials. As we discussed previously (Scarrone et al., 2021), the results of such meta-analysis might have however been confounded by the inclusion of studies with a very high prevalence of overweight women, for whom a standard dose of daily subcutaneous 40 mg of enoxaparin might be underdosed during pregnancy (Boban et al., 2017). On the other hand, two randomized control trials that supported the therapeutic efficacy of heparin in reducing the rate of miscarriage in U-RPL patients were excluded from the meta-analysis, in one case because of lack of placebo administration in the control group (Badawy et al., 2008) and in one case for no clear reason (Fawzy et al., 2008). In addition, a more recent registry study (Grandone et al., 2021) and a recent meta-analysis (Wang et al., 2021) also confirmed a beneficial effect of LMWH on live-birth rates and miscarriage rates in women with U-RPL. The objective of our study was therefore to provide further evidence to assess whether LMWH administration from the beginning of pregnancy affect rates of miscarriage and late obstetrical complications in U-RPL patients as well as in O-APS and thrombophilia patients.

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