**6.1 Management of refractory/high-risk pregnancies**

Even if current recommendations are carefully followed [83], 20–30% of pregnancies fail [92], and these are the so-called refractory pregnancies and/or high-risk pregnancies. High-risk pregnancies are pregnancies of APS patients with one or more laboratory or clinical risk factors who may or may not have experienced adverse pregnancy outcomes despite treatment with heparin/LDA [8]. Experts in the field believe that women should receive additional treatments when the risk of having pregnancy complications is elevated based on their antibody profile and certain clinical characteristics [93] as this will improve these women's live birth rate and/or reduce their pregnancy complications. Various therapeutic options, such as low-dose prednisolone, intravenous immunoglobulins, hydroxychloroquine, plasmapheresis alone or in combination have been used in an attempt to achieve a better pregnancy outcome [94–104]. Usually, these treatments were administered in conjunction with conventional heparin/LDA therapy. An Experts' Consensus [8] following a systematic review of the literature recently suggested that hydroxychloroquine and low-dose steroids, alone or in combination, may be an option for

pregnant APS women whose previous pregnancies were not successful despite receiving conventional therapy. Intravenous immunoglobulins (IVIG) and plasma exchange (PE), alone or in combination, could be considered in refractory high-risk APS pregnancies. Furthermore, a recent systematic literature review [9] analyzed 313 refractory/high-risk pregnancies from 14 studies comprising 134 (42.8%) pregnancies refractory to conventional treatment, and 179 (57.2%) high-risk/refractory pregnancies. The findings from this review suggest introducing low-dose IVIG (< 2 g/kg/month) or HCQ 400 mg/day before pregnancy in women with APS refractory to conventional therapy, and high-dose IVIG (2 g/kg/month) in combination with PE or alone in those with high risk/refractory APS with both approaches leading to improved pregnancy outcome. It should be noted that, drug related sideeffects were observed in 3/313 (0.9%) of pregnancies, and none of which required hospitalization.

Although statins appear to be a potential therapy in the treatment of APS refractory pregnancies, as suggested by murine studies [105] and a small case-control study of the use of pravastatin for placental dysfunction/pre-eclampsia in patients with APS [106], they have not yet been routinely used to date. Pravastatin was administered to 11 women with obstetric APS and preeclampsia/IUGR at the time of diagnosis of the complication (range 22–30 weeks) in addition to standard of care; they were compared with 10 control patients with preeclampsia/IUGR who did not receive pravastatin. The pravastatin group achieved a 100% rate of live births (34–36 week of gestation) and rapid improvement in uterine artery hemodynamics was observed, while the control group had a 50% rate of live births, all of which were delivered preterm (26–32 week of gestation). An ongoing multicenter study, the StAmP trial, is testing pravastatin for the prophylaxis of preeclampsia (double-blind, randomized and placebo-controlled) in the general population [107]. However, several concerns remain about their use, as they are classified as FDA category X. However, no congenital abnormalities have been reported in the pilot studies to date.

## **7. Future perspectives**

Much has been done over the past three decades to understand the pathogenesis of aPL-mediated obstetric injury and to diagnose and treat obstetric APS. However, much remains to be done to provide the best diagnostic and therapeutic approach to our patients.

Future research should be conducted to evaluate the intracellular signaling pathways that are affected by aPLs and lead to trophoblastic dysfunction. Identification of these mechanisms could lead to identification of potential therapeutic targets in the future.

The redefinition of the classification criteria is currently under evaluation and should provide a valuable tool for future clinical trials of APS. It is important to include in these studies the concept of risk stratification according to aPLs profile and clinical features. The possible inclusion of new autoantibodies such as antidomain I and aPS/PT in the new classification criteria could be helpful in improving the diagnosis of obstetric APS, especially in cases where conventional antibodies are not detectable.

Clinical trials of new therapeutic approaches for refractory obstetric APS syndrome are currently underway. Two randomized clinical trials (NCT04275778 and NCT04624269) and two prospective studies [108, 109] are evaluating the effect of HCQ in addition to standard treatment to prevent pregnancy morbidity in APS patients. According to a recent prospective case series, the use of TNF-alpha

### *Obstetric Antiphospholipid Syndrome DOI: http://dx.doi.org/10.5772/intechopen.101804*

inhibitors in addition to standard treatment seems to be a promising treatment for refractory obstetric APS [10]. If these findings are confirmed by the ongoing IMPACT Study: IMProve Pregnancy in APS with certolizumab (NCT03152058), the TNF-alfa inhibitors may constitute a valid second-line treatment for refractory and/ or high-risk APS pregnancies in the near future.
