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SAN DIEGO – Low molecular weight heparin does not appear to reduce the risk of recurrent placenta-mediated pregnancy complications in women with prior such complications, according to Marc Rodger, MD.
“It’s time to put the needles away for pregnant patients,” he said at the biennial summit of the Thrombosis & Hemostasis Societies of North America.
The pathophysiology of placenta-mediated pregnancy complications includes placental thrombosis. Thrombophilias predispose to the development of thrombosis in slow-flow circulation of the placenta. “It’s possible that the etiology mix of placental-mediated pregnancy complications includes thrombophilias, and by extension, that anticoagulants would prevent these complications,” said Dr. Rodger, a senior scientist at the hospital and professor at the University of Ottawa.
In a study from 1999, researchers demonstrated that patients with pregnancy-mediated placental complications were 8.2 times more likely to develop thrombophilia, compared with controls (N Engl J Med. 1999;340:9-13). “But as with positive initial case-control studies, subsequent work downplayed this association,” Dr. Rodger said. “Now, we’re at a point where we recognize that thrombophilias are weakly associated with recurrent early loss, late pregnancy loss, and severe preeclampsia ([odds ratio] of about 1.5-2.0 for all associations), while thrombophilias are not associated with nonsevere preeclampsia and small for gestational age.”
Currently, low-molecular-weight heparin (LMWH) is the preferred pharmacoprophylaxis in pregnancy. Unfractionated heparin, meanwhile, requires b.i.d. or t.i.d. injections, and has a 10-fold higher risk of heparin-induced thrombocytopenia and a greater than 10-fold higher risk of osteoporotic fracture. Warfarin is teratogenic antepartum and inconvenient postpartum, while direct oral anticoagulants cross the placenta and enter breast milk.
Downsides of LMWH include the burden of self-injections and costs of over $10,000 per antepartum period, Dr. Rodger said. Common side effects include minor bleeding and elevated liver function tests, and it complicates regional anesthetic options at term. Uncommon side effects include major bleeding, skin reactions, and postpartum wound complications, while rare but serious complications include heparin-induced thrombocytopenia and osteoporotic fractures.
He offered a hypothetical case. A 32-year-old woman with prior severe preeclampsia who delivered at 32 weeks asks you, “Should I be treated with LMWH in my next pregnancy?” What should you tell her? To answer this question, Dr. Rodger and his associates conducted a study-level meta-analysis of six randomized controlled trials that included 848 pregnant women with prior placenta-mediated pregnancy complications (Blood. 2014;123[6]:822-8). The primary objective was to determine the effect of LMWH in preventing placenta-mediated pregnancy complications in women with prior late placenta-mediated pregnancy complications. This included patients with or without thrombophilia who were treated with or without LMWH. The primary outcome was a composite of preeclampsia, birth of an SGA newborn, placental abruption, or pregnancy loss greater than 20 weeks. Overall, 67 (18.7%) of 358 of women being given prophylactic LMWH had recurrent severe placenta-mediated pregnancy complications, compared with 127 (42.9%) of 296 women with no LMWH (relative risk reduction, 0.52; P = .01, indicating moderate heterogeneity). They identified similar relative risk reductions with LMWH for individual outcomes, including any preeclampsia, severe preeclampsia, SGA below the 10th percentile, SGA below the 5th percentile, preterm delivery less than 37 weeks, and preterm delivery less than 34 weeks with minimal heterogeneity. They concluded that LMWH “may be a promising therapy for recurrent, especially severe, placenta-mediated pregnancy complications, but further research is required.”
At the meeting, Dr. Rodger noted that the positive studies in the analysis were single-center trials, “which are generally acknowledged to be of a lesser methodologic quality, and the majority of patients in these single-center trials are from a small area in the south of France. Multicenter trials don’t show an effect, so is it single-centeredness or is it something else? The other feature that’s distinct is that the positive trials recruited patients with prior severe complications only, while the negative trials included patients with nonsevere complications. So maybe LMWH works in patients who have a very strong phenotype that have had very bad prior complications. We can’t tease that out with a study-level meta-analysis because we’re getting average effects over heterogeneous groups of patients.”
To expand on the study-level meta-analysis, Dr. Rodger and his associates conducted a systematic review and individual patient data meta-analysis of eight randomized trials of 963 patients conducted between 2000 and 2013 of LMWH to prevent recurrent placenta-mediated pregnancy complications (Lancet. 2016;388:2629-41). “In this approach you get individual patient data from the trials, and you create a new randomized, controlled data set,” he explained. “That way we could tease out the patients who have had the prior severe complications and whether their mild or severe outcomes are being prevented or not.”
The study’s composite primary outcome was one or more of the following: early-onset or severe preeclampsia, SGA newborn below the 5th percentile, late pregnancy loss (over 20 weeks), or placental abruption. Dr. Rodger and his associates found that LMWH did not significantly reduce the risk of recurrent placenta-mediated pregnancy complications, compared with patients who did not receive LMWH (14% vs. 22%, respectively; P = .09). In subgroup analyses, however, LMWH in multicenter trials reduced the primary outcome in women with previous abruption (P = .006) but not in any of the other subgroups of previous complications. “There were small numbers of patients in this subgroup, though, so I would use caution,” Dr. Rodger said. Two recent randomized, controlled trials from separate investigators further support the overall null findings of the individual patient data meta-analysis (Obstet Gynecol. 2016;128[5]:1053-63 and Am J Obstet Gynecol. 2017 Mar;216[3]:296.e1-296.e14).
Revisiting the hypothetical case of a 32-year-old woman with prior severe preeclampsia who delivered at 32 weeks, Dr. Rodger said that he would “definitely not” recommend LMWH during her next pregnancy.
He acknowledged limitations of the systematic review, including the limited numbers of patients in subgroups and the large differences between single-center and multicenter trials. “We still can’t explain this, and it remains an open question that bugs me,” he said. “This has been seen in many disease areas. Empirically, single-centeredness leans toward positivity.”
He called for more research in women with recurrent pregnancy loss. Dr. Rodger reported having no financial disclosures.
SAN DIEGO – Low molecular weight heparin does not appear to reduce the risk of recurrent placenta-mediated pregnancy complications in women with prior such complications, according to Marc Rodger, MD.
“It’s time to put the needles away for pregnant patients,” he said at the biennial summit of the Thrombosis & Hemostasis Societies of North America.
The pathophysiology of placenta-mediated pregnancy complications includes placental thrombosis. Thrombophilias predispose to the development of thrombosis in slow-flow circulation of the placenta. “It’s possible that the etiology mix of placental-mediated pregnancy complications includes thrombophilias, and by extension, that anticoagulants would prevent these complications,” said Dr. Rodger, a senior scientist at the hospital and professor at the University of Ottawa.
In a study from 1999, researchers demonstrated that patients with pregnancy-mediated placental complications were 8.2 times more likely to develop thrombophilia, compared with controls (N Engl J Med. 1999;340:9-13). “But as with positive initial case-control studies, subsequent work downplayed this association,” Dr. Rodger said. “Now, we’re at a point where we recognize that thrombophilias are weakly associated with recurrent early loss, late pregnancy loss, and severe preeclampsia ([odds ratio] of about 1.5-2.0 for all associations), while thrombophilias are not associated with nonsevere preeclampsia and small for gestational age.”
Currently, low-molecular-weight heparin (LMWH) is the preferred pharmacoprophylaxis in pregnancy. Unfractionated heparin, meanwhile, requires b.i.d. or t.i.d. injections, and has a 10-fold higher risk of heparin-induced thrombocytopenia and a greater than 10-fold higher risk of osteoporotic fracture. Warfarin is teratogenic antepartum and inconvenient postpartum, while direct oral anticoagulants cross the placenta and enter breast milk.
Downsides of LMWH include the burden of self-injections and costs of over $10,000 per antepartum period, Dr. Rodger said. Common side effects include minor bleeding and elevated liver function tests, and it complicates regional anesthetic options at term. Uncommon side effects include major bleeding, skin reactions, and postpartum wound complications, while rare but serious complications include heparin-induced thrombocytopenia and osteoporotic fractures.
He offered a hypothetical case. A 32-year-old woman with prior severe preeclampsia who delivered at 32 weeks asks you, “Should I be treated with LMWH in my next pregnancy?” What should you tell her? To answer this question, Dr. Rodger and his associates conducted a study-level meta-analysis of six randomized controlled trials that included 848 pregnant women with prior placenta-mediated pregnancy complications (Blood. 2014;123[6]:822-8). The primary objective was to determine the effect of LMWH in preventing placenta-mediated pregnancy complications in women with prior late placenta-mediated pregnancy complications. This included patients with or without thrombophilia who were treated with or without LMWH. The primary outcome was a composite of preeclampsia, birth of an SGA newborn, placental abruption, or pregnancy loss greater than 20 weeks. Overall, 67 (18.7%) of 358 of women being given prophylactic LMWH had recurrent severe placenta-mediated pregnancy complications, compared with 127 (42.9%) of 296 women with no LMWH (relative risk reduction, 0.52; P = .01, indicating moderate heterogeneity). They identified similar relative risk reductions with LMWH for individual outcomes, including any preeclampsia, severe preeclampsia, SGA below the 10th percentile, SGA below the 5th percentile, preterm delivery less than 37 weeks, and preterm delivery less than 34 weeks with minimal heterogeneity. They concluded that LMWH “may be a promising therapy for recurrent, especially severe, placenta-mediated pregnancy complications, but further research is required.”
At the meeting, Dr. Rodger noted that the positive studies in the analysis were single-center trials, “which are generally acknowledged to be of a lesser methodologic quality, and the majority of patients in these single-center trials are from a small area in the south of France. Multicenter trials don’t show an effect, so is it single-centeredness or is it something else? The other feature that’s distinct is that the positive trials recruited patients with prior severe complications only, while the negative trials included patients with nonsevere complications. So maybe LMWH works in patients who have a very strong phenotype that have had very bad prior complications. We can’t tease that out with a study-level meta-analysis because we’re getting average effects over heterogeneous groups of patients.”
To expand on the study-level meta-analysis, Dr. Rodger and his associates conducted a systematic review and individual patient data meta-analysis of eight randomized trials of 963 patients conducted between 2000 and 2013 of LMWH to prevent recurrent placenta-mediated pregnancy complications (Lancet. 2016;388:2629-41). “In this approach you get individual patient data from the trials, and you create a new randomized, controlled data set,” he explained. “That way we could tease out the patients who have had the prior severe complications and whether their mild or severe outcomes are being prevented or not.”
The study’s composite primary outcome was one or more of the following: early-onset or severe preeclampsia, SGA newborn below the 5th percentile, late pregnancy loss (over 20 weeks), or placental abruption. Dr. Rodger and his associates found that LMWH did not significantly reduce the risk of recurrent placenta-mediated pregnancy complications, compared with patients who did not receive LMWH (14% vs. 22%, respectively; P = .09). In subgroup analyses, however, LMWH in multicenter trials reduced the primary outcome in women with previous abruption (P = .006) but not in any of the other subgroups of previous complications. “There were small numbers of patients in this subgroup, though, so I would use caution,” Dr. Rodger said. Two recent randomized, controlled trials from separate investigators further support the overall null findings of the individual patient data meta-analysis (Obstet Gynecol. 2016;128[5]:1053-63 and Am J Obstet Gynecol. 2017 Mar;216[3]:296.e1-296.e14).
Revisiting the hypothetical case of a 32-year-old woman with prior severe preeclampsia who delivered at 32 weeks, Dr. Rodger said that he would “definitely not” recommend LMWH during her next pregnancy.
He acknowledged limitations of the systematic review, including the limited numbers of patients in subgroups and the large differences between single-center and multicenter trials. “We still can’t explain this, and it remains an open question that bugs me,” he said. “This has been seen in many disease areas. Empirically, single-centeredness leans toward positivity.”
He called for more research in women with recurrent pregnancy loss. Dr. Rodger reported having no financial disclosures.
SAN DIEGO – Low molecular weight heparin does not appear to reduce the risk of recurrent placenta-mediated pregnancy complications in women with prior such complications, according to Marc Rodger, MD.
“It’s time to put the needles away for pregnant patients,” he said at the biennial summit of the Thrombosis & Hemostasis Societies of North America.
The pathophysiology of placenta-mediated pregnancy complications includes placental thrombosis. Thrombophilias predispose to the development of thrombosis in slow-flow circulation of the placenta. “It’s possible that the etiology mix of placental-mediated pregnancy complications includes thrombophilias, and by extension, that anticoagulants would prevent these complications,” said Dr. Rodger, a senior scientist at the hospital and professor at the University of Ottawa.
In a study from 1999, researchers demonstrated that patients with pregnancy-mediated placental complications were 8.2 times more likely to develop thrombophilia, compared with controls (N Engl J Med. 1999;340:9-13). “But as with positive initial case-control studies, subsequent work downplayed this association,” Dr. Rodger said. “Now, we’re at a point where we recognize that thrombophilias are weakly associated with recurrent early loss, late pregnancy loss, and severe preeclampsia ([odds ratio] of about 1.5-2.0 for all associations), while thrombophilias are not associated with nonsevere preeclampsia and small for gestational age.”
Currently, low-molecular-weight heparin (LMWH) is the preferred pharmacoprophylaxis in pregnancy. Unfractionated heparin, meanwhile, requires b.i.d. or t.i.d. injections, and has a 10-fold higher risk of heparin-induced thrombocytopenia and a greater than 10-fold higher risk of osteoporotic fracture. Warfarin is teratogenic antepartum and inconvenient postpartum, while direct oral anticoagulants cross the placenta and enter breast milk.
Downsides of LMWH include the burden of self-injections and costs of over $10,000 per antepartum period, Dr. Rodger said. Common side effects include minor bleeding and elevated liver function tests, and it complicates regional anesthetic options at term. Uncommon side effects include major bleeding, skin reactions, and postpartum wound complications, while rare but serious complications include heparin-induced thrombocytopenia and osteoporotic fractures.
He offered a hypothetical case. A 32-year-old woman with prior severe preeclampsia who delivered at 32 weeks asks you, “Should I be treated with LMWH in my next pregnancy?” What should you tell her? To answer this question, Dr. Rodger and his associates conducted a study-level meta-analysis of six randomized controlled trials that included 848 pregnant women with prior placenta-mediated pregnancy complications (Blood. 2014;123[6]:822-8). The primary objective was to determine the effect of LMWH in preventing placenta-mediated pregnancy complications in women with prior late placenta-mediated pregnancy complications. This included patients with or without thrombophilia who were treated with or without LMWH. The primary outcome was a composite of preeclampsia, birth of an SGA newborn, placental abruption, or pregnancy loss greater than 20 weeks. Overall, 67 (18.7%) of 358 of women being given prophylactic LMWH had recurrent severe placenta-mediated pregnancy complications, compared with 127 (42.9%) of 296 women with no LMWH (relative risk reduction, 0.52; P = .01, indicating moderate heterogeneity). They identified similar relative risk reductions with LMWH for individual outcomes, including any preeclampsia, severe preeclampsia, SGA below the 10th percentile, SGA below the 5th percentile, preterm delivery less than 37 weeks, and preterm delivery less than 34 weeks with minimal heterogeneity. They concluded that LMWH “may be a promising therapy for recurrent, especially severe, placenta-mediated pregnancy complications, but further research is required.”
At the meeting, Dr. Rodger noted that the positive studies in the analysis were single-center trials, “which are generally acknowledged to be of a lesser methodologic quality, and the majority of patients in these single-center trials are from a small area in the south of France. Multicenter trials don’t show an effect, so is it single-centeredness or is it something else? The other feature that’s distinct is that the positive trials recruited patients with prior severe complications only, while the negative trials included patients with nonsevere complications. So maybe LMWH works in patients who have a very strong phenotype that have had very bad prior complications. We can’t tease that out with a study-level meta-analysis because we’re getting average effects over heterogeneous groups of patients.”
To expand on the study-level meta-analysis, Dr. Rodger and his associates conducted a systematic review and individual patient data meta-analysis of eight randomized trials of 963 patients conducted between 2000 and 2013 of LMWH to prevent recurrent placenta-mediated pregnancy complications (Lancet. 2016;388:2629-41). “In this approach you get individual patient data from the trials, and you create a new randomized, controlled data set,” he explained. “That way we could tease out the patients who have had the prior severe complications and whether their mild or severe outcomes are being prevented or not.”
The study’s composite primary outcome was one or more of the following: early-onset or severe preeclampsia, SGA newborn below the 5th percentile, late pregnancy loss (over 20 weeks), or placental abruption. Dr. Rodger and his associates found that LMWH did not significantly reduce the risk of recurrent placenta-mediated pregnancy complications, compared with patients who did not receive LMWH (14% vs. 22%, respectively; P = .09). In subgroup analyses, however, LMWH in multicenter trials reduced the primary outcome in women with previous abruption (P = .006) but not in any of the other subgroups of previous complications. “There were small numbers of patients in this subgroup, though, so I would use caution,” Dr. Rodger said. Two recent randomized, controlled trials from separate investigators further support the overall null findings of the individual patient data meta-analysis (Obstet Gynecol. 2016;128[5]:1053-63 and Am J Obstet Gynecol. 2017 Mar;216[3]:296.e1-296.e14).
Revisiting the hypothetical case of a 32-year-old woman with prior severe preeclampsia who delivered at 32 weeks, Dr. Rodger said that he would “definitely not” recommend LMWH during her next pregnancy.
He acknowledged limitations of the systematic review, including the limited numbers of patients in subgroups and the large differences between single-center and multicenter trials. “We still can’t explain this, and it remains an open question that bugs me,” he said. “This has been seen in many disease areas. Empirically, single-centeredness leans toward positivity.”
He called for more research in women with recurrent pregnancy loss. Dr. Rodger reported having no financial disclosures.
REPORTING FROM THSNA 2018