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Comment on Lefkou et al.

Submitter: Lionel Carbillon | lionel.carbillon@aphp.fr

Authors: Lionel Carbillon

Assistance Publique-Hôpitaux de Paris, Paris 13 University

Published August 31, 2016

I read with great interest the article by Lefkou et al (1) who found that pravastatin may improve pregnancy outcomes in women with “refractory” obstetric antiphospholipid syndrome (APS) when taken at the onset of preeclampsia (PE) or intra uterine growth restriction (IUGR) until the end of pregnancy. The higher risk of PE, IUGR and placenta-mediated complications in patients with obstetric APS despite conventional treatment with low-dose aspirin plus low–molecular weight heparin (LDA+LMWH) is a crucial issue (2, 3), and the possible effectiveness of pravastatin in this occurrence is exciting. However, in this study (1) the pravastatin and control groups are not really similar. Indeed, patients 12, 13, 14, 17, 19, 20, 21 (6 among the 11 patients in the pravastatin group) had no clinical criteria of APS in their history and met the criteria for obstetric APS only during the current pregnancy, while all patients in the control group had adverse obstetric events in their history with a true refractory APS. Besides, blood pressure (mmHg) of the patients 13, 16 and 19 before pravastatin were 130/90, 130/92 and 138/90 respectively, i.e. just over the threshold achievement set by the authors.

References:

1. Lefkou E et al. Pravastatin improves pregnancy outcomes in obstetric antiphospholipid syndrome refractory to antithrombotic therapy. J Clin Invest. 2016;126(8):2933-40.
2. Bouvier S, et al. Comparative incidence of pregnancy outcomes in treated obstetric antiphospholipid syndrome: the NOH-APS observational study. Blood. 2014;123(3):404–413.
3. Carbillon L et al. Treated pregnant patients with antiphospholipid syndrome are particularly susceptible to pre-eclampsia and fetal growth retardation. J Reprod Immunol. 2005;65(1):89-90.

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Response to Carbillon

Submitter: Guillermina Girardi | guillermina.girardi@kcl.ac.uk

Authors: Guillermina Girardi

King's College London

Published August 31, 2016

All the patients in the pravastatin-treated group, met APS criteria at the time of the study when preeclampsia or severe IUGR was detected and pravastatin therapy was started (1). Because the classification criteria for APS was not set for diagnostic/treatment purposes and the clinical manifestations of APS are broad and many clinical manifestations of APS are not covered within the criteria (e.g. infertility, frequently observed in women with aPL antibodies), all patients were treated with antithrombotic therapy from the beginning of pregnancy. While having 2 or 3 miscarriages is relevant to meet criteria for research purposes, there is no rationale to wait for a 3^rd miscarriage or another adverse pregnancy outcome to treat women with APS. Other authors share our point of view and recommend early treatment without meeting full criteria (2).   Even more, the fact that antithrombotic therapy was started from the first positive pregnancy test and did not prevent placental insufficiency, emphasizes the fact that standard antithrombotic therapy is not sufficient to prevent pregnancy complications in women with antiphospholipid antibodies. At the moment pravastatin was given in this study, all patients met the clinical criteria for APS and received antithrombotic therapy from the beginning of pregnancy comparable to the control group.

Thank you for this opportunity to clarify the evaluation of efficacy of treatment in this study. This study focused on the prevention with pravastatin of two placental insufficiency derived-pregnancy complications: preeclampsia and IUGR. The threshold of 130/90 mmHg for blood pressure (BP) was set to evaluate treatment efficacy in the preeclampsia group. Patients 13, 16 and 19 showed severe IUGR but did not show preeclampsia (1). However, these patients showed BP values slightly increased compared to control values. Time of threshold achievement for patients 13, 16 and 19 in Table 2 (1) indicates the time after pravastatin treatment at which BP diminished to normal values and remained within those values. Efficacy of treatment in the patients with IUGR was also evaluated by acceleration of fetal weight gain along with improved fetal and maternal Doppler measurements. In the control group, patients 2, 3 , 6 and 9 showed similar phenotypic characteristics (no preeclampsia, severe IUGR and abnormal Doppler measurements). These patients that continued on standard therapy showed adverse pregnancy outcomes: still births (patients 2 and 6) and very low birth weight and developmental abnormalities in the surviving neonates (1).

References:

1. Lefkou E et al. Pravastatin improves pregnancy outcomes in obstetric antiphospholipid syndrome refractory to antithrombotic therapy. J Clin Invest. 2016;126(8):2933-40.
2. Arachchillage DR et al. Diagnosis and management of non-criteria obstetric antiphospholipid syndrome. Thromb Haemost. 2015; 113(1): 13-19