Hydroxychloroquine in obstetric antiphospholipid syndrome: rationale and results of an observational study of refractory cases
In women with antiphospholipid syndrome (APS) during pregnancy, also known as obstetric APS, conventional treatment involves the use of low-dose aspirin plus low molecular weight heparin (LMWH) or unfractionated heparin.
Unfortunately this treatment is not always effective despite anticoagulation failing to produce a live birth in 20 to 30% of cases or reduce the incidences of pregnancy complications (preeclampsia and foetal growth restriction).
Hydroxychloroquine (HCQ) is an existing immunomodulator, used to treat malaria and systemic lupus erythematosus (SLE), that interferes with the production of several pro-inflammatory cytokines.
To date our understanding of HCQ effects in women with antiphospholipid antibodies is only from animal experiments and in vitro models.
Originally 217 women from 2013 to 2020 with antiphospholipid antibodies and obstetric morbidities were observed following conventional treatment (low dose aspirin ± LMWH).
Of these 217 women, 150 (69.1%) had successful live births and 67 (30.9%) had failed pregnancies due to obstetric and thrombotic complications. These 67 women were then offered conventional treatment plus HCQ.
In total 41 of these women agreed to the low dose aspirin (100mg/day) plus LMWH (4000 anti-Xa) and HCQ (400mg/day) treatment protocol from the day of a positive pregnancy test.
In 2013 at the beginning of the study these 41 women had 113 previous pregnancies, without anticoagulants or HCQ, that resulted in;
- 56 foetal loss (49.5%) before 10 weeks
- 14 foetal loss (12.4%) at 10-20 weeks
- 21 still birth (18.5%)
- 11 viable preterm deliveries (9.7%)
- 11 unreported presumed live births (9.7%)
Following low dose aspirin and LMWH only treatment, from 2013 to 2017, these 41 women had another 43 pregnancies that resulted in;
- 7 foetal loss (16.3%) before 10 weeks
- 3 foetal loss (6.9%) at 10-20 weeks
- 2 still birth (4.6%)
- 3 viable preterm deliveries (6.9%)
- 29 successful live births (67.4%)
From 2017 onwards these 41 women (median age 37} tried again with HCQ added to their treatment resulting in 41 pregnancies (34 with 400mg HCQ, 7 with 200mg HCQ) of which 4 was via IVF. Of these 41 pregnancies there was;
- 7 foetal loss (17.1%) before 10 weeks
- 1 foetal loss (2.4%) at 10-20 weeks
- 1 non-viable preterm delivery (2.4%)
- 32 successful live births (78%)
Secondary analysis of low dose aspirin plus LMWH and HCQ showed a significant reduction in fetal growth restriction (4.9% vs. 11.6%) and a slight (nonsignificant) reduction in the incidence of preeclampsia.
There was no incidences of placental abruption, thrombotic complications or congenital anomalies observed. The addition of HCQ also had no apparent side effects and was found to decrease anti-b2GPI titer (-35%) and aCL (-22%) levels considered important for improved pregnancy outcomes in women with APS.
The authors concluded that, irrespective of these findings, there is still insufficient evidence to support routine use of HCQ in women with obstetric APS, although it should be considered in selected patients following failed pregnancy with conventional treatment.
The results of two ongoing clinical trials (HYPATIA, HIBISCUS) should clarify further which women with APS may benefit the most with the addition of HCQ.
SUMMARY: Current antiphospholipid (APS) pregnancy treatment
In this small study, current antiphospholipid treatment of low-dose aspirin plus low molecular weight heparin (LMWH) during pregnancy in women with APS had improved pregnancy outcomes following the addition of hydroxychloroquine, with 78% of pregnancies cumulating in live births.
- Observational study design.
- Small study size.
This research was supported by the First I.M. Sechenov Moscow State Medical University
Use of anticoagulant drugs to reduce the risk of the formation of blood clots..
A large group of proteins, peptides or glycoproteins that are secreted by specific cells of immune system.
A drug or substance that has an effect on the immune system.
An experiment performed outside the living organism usually within a laboratory.
Belizna C, et al. (2018). HIBISCUS: Hydroxychloroquine for the secondary prevention of thrombotic and obstetrical events in primary antiphospholipid syndrome. https://doi.org/10.1016/j.autrev.2018.05.012
Torigoe M, et al. (2018). Hydroxychloroquine efficiently suppresses inflammatory responses of human class-switched memory B cells via Toll-like receptor 9 inhibition. https://doi.org/10.1016/j.clim.2018.07.003
Schreiber K, et al. (2017). HYdroxychloroquine to improve pregnancy outcome in women with AnTIphospholipid Antibodies (HYPATIA) protocol: a multinational randomized controlled trial of hydroxychloroquine versus placebo in addition to standard treatment in pregnant women with antiphospholipid syndrome or antibodies. https://doi.org/10.1055/s-0037-1603359
Albert C R, et al. (2014). Effect of hydroxychloroquine on antiphospholipid antibody induced changes in first trimester trophoblast function. https://doi.org/10.1111/aji.12184
Marchetti T, et al. (2014). Hydroxychloroquine restores trophoblast fusion affected by antiphospholipid antibodies. https://doi.org/10.1111/jth.12570
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