Repeated fetal losses associated with antiphospholipid antibodies: A collaborative randomized trial comparing prednisone with low-dose heparin treatment

doi:10.1016/0002-9378(92)91596-3

American Journal of Obstetrics and Gynecology

Volume 166, Issue 5, May 1992, Pages 1318-1323

https://doi.org/10.1016/0002-9378(92)91596-3 Get rights and content

OBJECTIVE: We attempted to compare the use of low-dose heparin with a standard dose of 40 mg prednisone daily (both plus low-dose aspirin) for treatment of pregnant women with antiphospholipid antibody—associated recurrent fetal loss with respect to maternal and perinatal morbidity and efficacy in prevention of fetal death.

STUDY DESIGN: A multicenter randomized trial included 20 patients. Generalizability of results from randomized patients was evaluated by means of additional data from 13 women refusing and 12 women ineligible for randomization. Data from study groups were compared with Fisher's exact test, and generalizability was evaluated with a χ2 test for trend.

RESULTS: Live birth rates were the same (75%) with either treatment, but “serious” maternal morbidity and the frequency of preterm delivery were significantly higher among women randomly assigned to prednisone (p = 0.02 vs p = 0.006). Preterm delivery among prednisone-treated women was usually associated with premature rupture of the membranes or preeclampsia. These results could be generalized to the other groups of women ascertained during the course of the study.

CONCLUSIONS: Low-dose heparin should be preferred to prednisone when treatment is indicated for high-risk pregnant women with antiphospholipid antibodies.

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A prospective, single-center randomized trial included 14 patients who were alternately assigned to treatment. Each patient had a history of recurrent miscarriage diagnosed with antiphospholipid syndrome. 5 accepted the treatment of aspirin alone, 5 accepted the combination treatment of aspirin + prednisone, and 4 accepted the combination therapy of aspirin + heparin. Data were compared by the One-way ANOVA test using IBM SPSS stats 19.
There were no significant differences in patient outcome data, obstetric complications, and gestational age at delivery in live births between the 3 groups (P > 0.05). However, treatment with aspirin + heparin increased neonatal weight (P < 0.05).
Our data demonstrate the non-superiority one on each other of the three different regimens, except in terms of neonatal weight when aspirin + heparin were used. These findings raise questions about the need for therapies such as heparin and corticosteroids for women with antiphospholipid antibody syndrome, especially in resource-limited settings similar to Syria.
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Citation Excerpt :
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MEDLINE, Scopus, CINAHL, the Cochrane Library, and Ovid were searched from study inception to May 2022.
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Pregnant individuals who agreed to participate in randomized controlled trials had no difference in outcomes compared with those who decline participation. Pregnant individuals should be provided with this reassuring information when offered to participate in a randomized controlled trial. Moreover, this information may improve patient recruitment into randomized controlled trials.
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As part of the non-criteria clinical manifestations, postural orthostatic tachycardia syndrome (POTS), a multisystem autonomic dysfunction, can co-exist with antiphospholipid syndrome (APS). Several pieces of evidence hint on the autoimmune basis of POTS, and its possible association with several autoimmune diseases, including APS. Indeed, the evidence exists in the etiologies, symptomatology, and treatment options. Although infections, viral ones in particular, stress, and pregnancy are etiologies to both POTS and APS, the exact pathophysiological connection is still to be studied taking into consideration the activity of cytokines in both diseases. Nevertheless, certain immunomodulatory treatments used for the catastrophic or obstetrical forms of APS, such as intravenous immunoglobulins (IVIG) and steroids, have been also used for the treatment of POTS resistant to classical treatments. Therefore, our review aims to highlight the association between POTS and APS, shedding light on the common etiologies explaining the pathophysiology of the two disorders, the diagnostic approach to POTS as a possible clinical criterion of APS, and the treatment of APS in the context of treating POTS.
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Rheumatologic diseases are autoimmune disorders that have a high prevalence amongst reproductive-aged women. The alterations in the immune system during pregnancy can cause changes in rheumatic disease activity, and rheumatic diseases themselves can influence reproductive outcomes. In general, rheumatoid arthritis improves during pregnancy, whereas systemic lupus erythematosus tends to worsen. Systemic sclerosis disease activity is not impacted by pregnancy. An obstetrical antiphospholipid syndrome is manifested by recurrent pregnancy losses, particularly once the embryo becomes a fetus and is dependent on the placenta for growth. Neonatal lupus, caused by anti-Ro (SSA) and anti-La (SSB) antibodies, can be a self-limited neonatal disorder with skin, liver, and hematologic abnormalities or can be more severe as these antibodies can interfere with the developing cardiac system. These antibodies are the etiology of 95% of congenital complete heart block.
Heparin for preventing adverse obstetrical outcomes in pregnant women with antiphospholipid syndrome, a systematic review and meta-analysis
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We performed a systematic review and meta-analysis to assess the efficacy and safety of heparin for preventing adverse obstetrical outcomes in pregnant women with antiphospholipid syndrome (APS).
We reviewed randomized controlled trials from CENTRAL, EMBASE, MEDLINE, and Web of science (inception to November 5th 2019), and relevant article reference lists. Two reviewers independently screened and extracted data from trials investigating heparin, including Low Molecular Weight Heparin (LMWH) and unfractionated heparin (UFH) at any dose, associated or not with aspirin, compared to any comparator group in pregnant women with APS. Internal validity was assessed in duplicate using the Cochrane Risk of Bias tool. The strength of evidence was assessed in duplicate using the Grading of Recommendations Assessment, Development and Evaluation framework. Our primary outcome was live birth rate. Secondary outcomes included preeclampsia, preterm birth, intra-uterine growth restriction (IUGR) and thromboembolism. Safety outcomes included maternal or neonatal bleedings, heparin-induced thrombocytopenia and allergy. Subgroup analyses were conducted to explore heterogeneity.
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Antiphospholipid syndrome is one of the more common acquired causes of hypercoagulability. Its major presentations are thrombotic (arterial, venous, or microvascular) and pregnancy morbidity (miscarriages, late intrauterine fetal demise, and severe pre-eclampsia). Classification criteria include 3 different antiphospholipid antibodies: lupus anticoagulant, anticardiolipin, and anti-beta 2 glycoprotein I. Management includes both preventive strategies (low-dose aspirin, hydroxychloroquine) and long-term anticoagulation after thrombosis.

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^*: Supported by grant ROI HD 21657 from the National Institutes of Health.

^a: From the Departments of Medicine and Obstetrics and Gynecology

^b: Greenfield Research Center, Department of Family Medicine

^c: Jefferson Medical College, the Department of Obstetrics and Gynecology, Yale University School of Medicine

^d: Department of Obstetrics and Gynecology, University of Utah School of Medicine

^e: Department of Obstetrics and Gynecology, Medical College of Georgia.

^f: A complete list of participating institutions and contributors appears at the end of the article.

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Repeated fetal losses associated with antiphospholipid antibodies: A collaborative randomized trial comparing prednisone with low-dose heparin treatment*

AmJ Obstet Gynecol

AmJ Obstet Gynecol

Am J Obstet Gynecol

Lancet

Lancet

AmJ Obstet Gynecol

Blood

Am J Obstet Gynecol

Antibody to cardolipin as a predictor of fetal distress or death in pregnant patients with systemic lupus erythematosus

N Engl J Med

Thrombosis, recurrent fetal loss, and thrombocytopenia

Arch Intern Med

Antiphospholipid antibodies and recurrent pregnancy loss

AmJ Reprod Immunol

Antibody to cardiolipin, lupus anticoagulant, and fetal death

J Rheumatol