Pregnancy in Rheumatic Disease Patients
Pregnancy in Rheumatic Disease Patients
Antiphospholipid antibody syndrome (APS) is based on the concurrent presence of 1 laboratory criterion (anticardiolipin, anti–β2 glycoprotein I [aβ2GPI], or lupus anticoagulant [LAC] antibody) and 1 clinical criterion (obstetric or thrombotic). Formal laboratory criteria for APS include anticardiolipin, LAC, and anti-β2 glycoprotein I antibodies. Specifically, the criteria mandate the presence of immunoglobulin G (IgG) and IgM, but not IgA, anticardiolipin antibody (aCL) with a minimal level of 40 IgG antiphospholipid units or IgM antiphospholipid units. Lupus anticoagulant confirmation depends on presence of a prolonged clotting assay followed by a mixing test (with normal plasma) that does not correct, with ultimate correction of the clotting time through addition of excess phospholipid. As with aCL, criteria for aβ2GPI antibody include IgG and IgM isotypes only, with a titer greater than 99th percentile. Importantly, any antiphospholipid antibody (aPL) test should be positive on 2 occasions 12 weeks apart, because transient elevations can occur in the setting of infection. The clinical obstetric APS criteria include pregnancy loss greater than or equal to 3 consecutive losses at less than 10 weeks' gestation, 1 or more losses after 10 weeks' gestation, or early delivery at less than 34 weeks' gestation due to preeclampsia, intrauterine growth restriction (IUGR), or fetal distress. These formal criteria help identify those patients who will require treatment in a subsequent pregnancy. We are all familiar with pregnancy loss as an obstetric APS complication, but preeclampsia and eclampsia are also surprisingly common and are more frequent in patients who have both aPL and SLE. When HELLP syndrome occurs in the setting of aPL, it occurs more frequently and is more severe, often occurring in the second trimester rather than the third. Up to one third of aPL patients with HELLP develop hepatic infarction as compared with 1% in the general HELLP population. In addition, APS patients often develop other thrombotic complications that need to be treated aggressively, in contrast to patients with traditional HELLP syndrome that resolves promptly after delivery. Maternal thrombosis is also a consideration because these patients, at risk for thrombosis baseline, now have the additional risk of the hypercoagulable state of pregnancy. The rare multisystemic and fulminant catastrophic APS can present during pregnancy: there have been about 15 cases reported, almost half of them as an initial presentation of APS. Patients may have other antiphospholipid-related complications as well: severe thrombocytopenia is not uncommon toward the end of the pregnancy.
The most common adverse events related to neonatal outcome are prematurity and IUGR. Prematurity is most common in patients who have both APS and SLE, and incidence ranges from 10% to 40%. One study that looked specifically at poor neonatal outcomes in primary APS patients (defined as early gestational age, IUGR, and poor Apgar scores) identified risk factors to be presence of the LAC, presence of all 3 aPL antibodies, and a history of vascular thrombosis before pregnancy. Patients with a history of previous pregnancy morbidity alone had a more favorable neonatal outcome.
The rare occurrence of fetal and neonatal thromboses, termed neonatal APS, has been reported in less than 20 infants in various collected case reports. Transplacental passage of aCL has been documented in some cases, and complications include the usual spectrum of vascular thrombosis. Evaluation of long-term complications in the offspring suggests an increased risk of learning disability. There is an ongoing European registry with early data reported: of 130 children followed out to age 3 years, 4 had behavioral abnormalities. Eventually we will have important information from this registry regarding whether these children are at an increased risk for learning disability or other neuropsychological issues.
Lupus anticoagulant appears to be the most important risk factor for adverse pregnancy outcome including pregnancy loss. A variety of LAC assays may be used, unlike the more standardized enzyme-linked immunosorbent assay–based aCL and aβ2GPI tests. The PROMISSE study is an ongoing multicenter prospective observational study of aPL-positive and SLE patients during pregnancy. A recent interim analysis showed LAC (performed in a core laboratory with 3 LAC assays) to be the only aPL independently associated with adverse pregnancy outcomes that included fetal loss, IUGR, and early gestational age. Other studies have identified triple antiphospholipid positivity, that is, the presence of LAC, anticardiolipin, and aβ2GPI antibodies within the same patient, as a strong risk factor for poor outcome. This is somewhat reassuring for those patients who have low to moderate titer anticardiolipin or aβ2GPI antibody only and can help when trying to estimate risk for patients. The persistence of the aPL antibody is important, and the presence of other risk factors may also increase risk. History of thrombosis preceding the pregnancy has been identified as being a risk factor for poor pregnancy outcome, as has concurrent diagnosis of SLE in patients with APS. Elevated homocysteine may also contribute to poor outcome, but while heritable thrombophilias in general have been shown to be important in risk of thrombosis in APS, there are few supporting data to date to suggest they play a major role in pregnancy outcome. Additional and obvious risk factors include abnormal measurements of vascular flow and fetal well-being. Serum complement levels during pregnancy may be relevant, although interpretation of complement in pregnancy is difficult because levels are often elevated because of increased synthesis and, in addition, preeclampsia may cause lower levels. Complement appears to be an important mediator of pregnancy morbidity and mortality in a murine model of APS, and it seems likely that complement activation is associated with outcome in human aPL pregnancy.
The PROMISSE study, mentioned above, should answer this important question. Patient groups include aPL antibody alone, lupus alone, aPL antibody and lupus, and a normal cohort. The goal is to identify markers that predict poor pregnancy outcomes, specifically looking at complement and complement activation products as well as antiangiogenic factors that have also been identified as being important in the pathogenesis of preeclampsia. Patients have standard follow-up and treatment with their private doctors in this purely observational study. Patients are generally enrolled by 10 to 12 weeks, so events occurring during the first trimester are not included. Because early losses are not included as part of this study, this may be why, in part, the numbers for pregnancy success are very good compared with some other reports. The LAC was the strongest predictor of adverse outcome, which included pregnancy loss, IUGR, and premature delivery. Relative risk for adverse outcome was 12.33. Other factors that were also important included lower age, history of thrombosis, and the diagnosis of lupus. Interestingly, anticardiolipin and aβ2GPI antibodies, even at high titer, were not independently associated with poor outcome.
Early treatment of obstetric APS dates back to the 1980s when patients with aPL and history of pregnancy loss were treated with prednisone and low-dose aspirin; in fact, prednisone was often increased until the LAC effect disappeared. In the 1990s, studies suggested that low-dose heparin with low-dose aspirin was as effective with far fewer adverse effects, and this remains the current standard, whether with low-molecular-weight or unfractionated heparin. Dosing of low-molecular-weight heparin is usually 40 mg of enoxaparin daily; some physicians use 30 mg twice a day. The dose for unfractionated heparin is usually 5000 U twice a day.
Studies show that low-dose heparin and low-dose aspirin are more effective than aspirin alone, with success rates of about 75% versus 40%. Low-dose heparin seems to be as effective as a higher, therapeutic, dose. There is ongoing controversy about this standard treatment, however: certain meta-analyses suggest it is more useful for early losses than for late losses, and there is controversy about whether unfractionated heparin and low-molecular-weight heparin are really equal in terms of their efficacy. Another meta-analysis that analyzed studies of treatment for aPL-positive patients with prior fetal loss included 5 studies with a total of 334 patients with primary APS: a small sample size for a meta-analysis. The trials were all considered low-quality trials for various reasons including lack of appropriate controls, differing study designs, and differing criteria for antiphospholipid antibodies; however, standard therapy was confirmed as being effective.
Second-line therapy for treatment failure is usually the addition of intravenous immunoglobulin (IVIG); some experts will increase to a therapeutic dose of heparin. In the single controlled study utilizing IVIG, it did not make a difference in outcome, but it is often used because case reports suggest benefit for some patients. Plasmapheresis has also been suggested and supported in a couple of case reports. In the future, complement inhibition may be studied because it is effective in the murine model, as are certain cytokine therapies.
Treatment of obstetric patients with asymptomatic aPL antibodies is uncertain: there are no data. Low-dose aspirin is often used even in the absence of supporting data for patients who have high-titer aPL with 1 or 2 early losses because of the very low risk of low-dose aspirin. We may consider low-dose aspirin in lupus patients without a prior history of pregnancy morbidity, often for preeclampsia prophylaxis in patients with previous renal disease who are at increased risk. There may be unusual circumstances where the standard therapy of low-dose aspirin and heparin is used as individualized therapy, for example, in a woman who is older than 40 years with positive LAC pregnant for the first time through in vitro fertilization: this is a patient I would treat aggressively, because this may be her only chance to have a successful pregnancy. Finally, for patients with a history of previous thrombosis, one needs to treat with therapeutic levels of heparin throughout the pregnancy, usually changing to heparin from warfarin before conception. Fetal monitoring is important, usually with nonstress tests from week 30 onward. The heparin dose is sometimes adjusted later in the pregnancy because of increased clearance, and many obstetricians prefer to change from low molecular weight to unfractionated heparin at the end of pregnancy because of the shorter half-life. Postpartum anticoagulation should be continued for 6 to 8 weeks even in patients without a history of thrombosis.
Antiphospholipid Antibody
Antiphospholipid antibody syndrome (APS) is based on the concurrent presence of 1 laboratory criterion (anticardiolipin, anti–β2 glycoprotein I [aβ2GPI], or lupus anticoagulant [LAC] antibody) and 1 clinical criterion (obstetric or thrombotic). Formal laboratory criteria for APS include anticardiolipin, LAC, and anti-β2 glycoprotein I antibodies. Specifically, the criteria mandate the presence of immunoglobulin G (IgG) and IgM, but not IgA, anticardiolipin antibody (aCL) with a minimal level of 40 IgG antiphospholipid units or IgM antiphospholipid units. Lupus anticoagulant confirmation depends on presence of a prolonged clotting assay followed by a mixing test (with normal plasma) that does not correct, with ultimate correction of the clotting time through addition of excess phospholipid. As with aCL, criteria for aβ2GPI antibody include IgG and IgM isotypes only, with a titer greater than 99th percentile. Importantly, any antiphospholipid antibody (aPL) test should be positive on 2 occasions 12 weeks apart, because transient elevations can occur in the setting of infection. The clinical obstetric APS criteria include pregnancy loss greater than or equal to 3 consecutive losses at less than 10 weeks' gestation, 1 or more losses after 10 weeks' gestation, or early delivery at less than 34 weeks' gestation due to preeclampsia, intrauterine growth restriction (IUGR), or fetal distress. These formal criteria help identify those patients who will require treatment in a subsequent pregnancy. We are all familiar with pregnancy loss as an obstetric APS complication, but preeclampsia and eclampsia are also surprisingly common and are more frequent in patients who have both aPL and SLE. When HELLP syndrome occurs in the setting of aPL, it occurs more frequently and is more severe, often occurring in the second trimester rather than the third. Up to one third of aPL patients with HELLP develop hepatic infarction as compared with 1% in the general HELLP population. In addition, APS patients often develop other thrombotic complications that need to be treated aggressively, in contrast to patients with traditional HELLP syndrome that resolves promptly after delivery. Maternal thrombosis is also a consideration because these patients, at risk for thrombosis baseline, now have the additional risk of the hypercoagulable state of pregnancy. The rare multisystemic and fulminant catastrophic APS can present during pregnancy: there have been about 15 cases reported, almost half of them as an initial presentation of APS. Patients may have other antiphospholipid-related complications as well: severe thrombocytopenia is not uncommon toward the end of the pregnancy.
The most common adverse events related to neonatal outcome are prematurity and IUGR. Prematurity is most common in patients who have both APS and SLE, and incidence ranges from 10% to 40%. One study that looked specifically at poor neonatal outcomes in primary APS patients (defined as early gestational age, IUGR, and poor Apgar scores) identified risk factors to be presence of the LAC, presence of all 3 aPL antibodies, and a history of vascular thrombosis before pregnancy. Patients with a history of previous pregnancy morbidity alone had a more favorable neonatal outcome.
The rare occurrence of fetal and neonatal thromboses, termed neonatal APS, has been reported in less than 20 infants in various collected case reports. Transplacental passage of aCL has been documented in some cases, and complications include the usual spectrum of vascular thrombosis. Evaluation of long-term complications in the offspring suggests an increased risk of learning disability. There is an ongoing European registry with early data reported: of 130 children followed out to age 3 years, 4 had behavioral abnormalities. Eventually we will have important information from this registry regarding whether these children are at an increased risk for learning disability or other neuropsychological issues.
Lupus anticoagulant appears to be the most important risk factor for adverse pregnancy outcome including pregnancy loss. A variety of LAC assays may be used, unlike the more standardized enzyme-linked immunosorbent assay–based aCL and aβ2GPI tests. The PROMISSE study is an ongoing multicenter prospective observational study of aPL-positive and SLE patients during pregnancy. A recent interim analysis showed LAC (performed in a core laboratory with 3 LAC assays) to be the only aPL independently associated with adverse pregnancy outcomes that included fetal loss, IUGR, and early gestational age. Other studies have identified triple antiphospholipid positivity, that is, the presence of LAC, anticardiolipin, and aβ2GPI antibodies within the same patient, as a strong risk factor for poor outcome. This is somewhat reassuring for those patients who have low to moderate titer anticardiolipin or aβ2GPI antibody only and can help when trying to estimate risk for patients. The persistence of the aPL antibody is important, and the presence of other risk factors may also increase risk. History of thrombosis preceding the pregnancy has been identified as being a risk factor for poor pregnancy outcome, as has concurrent diagnosis of SLE in patients with APS. Elevated homocysteine may also contribute to poor outcome, but while heritable thrombophilias in general have been shown to be important in risk of thrombosis in APS, there are few supporting data to date to suggest they play a major role in pregnancy outcome. Additional and obvious risk factors include abnormal measurements of vascular flow and fetal well-being. Serum complement levels during pregnancy may be relevant, although interpretation of complement in pregnancy is difficult because levels are often elevated because of increased synthesis and, in addition, preeclampsia may cause lower levels. Complement appears to be an important mediator of pregnancy morbidity and mortality in a murine model of APS, and it seems likely that complement activation is associated with outcome in human aPL pregnancy.
The PROMISSE study, mentioned above, should answer this important question. Patient groups include aPL antibody alone, lupus alone, aPL antibody and lupus, and a normal cohort. The goal is to identify markers that predict poor pregnancy outcomes, specifically looking at complement and complement activation products as well as antiangiogenic factors that have also been identified as being important in the pathogenesis of preeclampsia. Patients have standard follow-up and treatment with their private doctors in this purely observational study. Patients are generally enrolled by 10 to 12 weeks, so events occurring during the first trimester are not included. Because early losses are not included as part of this study, this may be why, in part, the numbers for pregnancy success are very good compared with some other reports. The LAC was the strongest predictor of adverse outcome, which included pregnancy loss, IUGR, and premature delivery. Relative risk for adverse outcome was 12.33. Other factors that were also important included lower age, history of thrombosis, and the diagnosis of lupus. Interestingly, anticardiolipin and aβ2GPI antibodies, even at high titer, were not independently associated with poor outcome.
Early treatment of obstetric APS dates back to the 1980s when patients with aPL and history of pregnancy loss were treated with prednisone and low-dose aspirin; in fact, prednisone was often increased until the LAC effect disappeared. In the 1990s, studies suggested that low-dose heparin with low-dose aspirin was as effective with far fewer adverse effects, and this remains the current standard, whether with low-molecular-weight or unfractionated heparin. Dosing of low-molecular-weight heparin is usually 40 mg of enoxaparin daily; some physicians use 30 mg twice a day. The dose for unfractionated heparin is usually 5000 U twice a day.
Studies show that low-dose heparin and low-dose aspirin are more effective than aspirin alone, with success rates of about 75% versus 40%. Low-dose heparin seems to be as effective as a higher, therapeutic, dose. There is ongoing controversy about this standard treatment, however: certain meta-analyses suggest it is more useful for early losses than for late losses, and there is controversy about whether unfractionated heparin and low-molecular-weight heparin are really equal in terms of their efficacy. Another meta-analysis that analyzed studies of treatment for aPL-positive patients with prior fetal loss included 5 studies with a total of 334 patients with primary APS: a small sample size for a meta-analysis. The trials were all considered low-quality trials for various reasons including lack of appropriate controls, differing study designs, and differing criteria for antiphospholipid antibodies; however, standard therapy was confirmed as being effective.
Second-line therapy for treatment failure is usually the addition of intravenous immunoglobulin (IVIG); some experts will increase to a therapeutic dose of heparin. In the single controlled study utilizing IVIG, it did not make a difference in outcome, but it is often used because case reports suggest benefit for some patients. Plasmapheresis has also been suggested and supported in a couple of case reports. In the future, complement inhibition may be studied because it is effective in the murine model, as are certain cytokine therapies.
Treatment of obstetric patients with asymptomatic aPL antibodies is uncertain: there are no data. Low-dose aspirin is often used even in the absence of supporting data for patients who have high-titer aPL with 1 or 2 early losses because of the very low risk of low-dose aspirin. We may consider low-dose aspirin in lupus patients without a prior history of pregnancy morbidity, often for preeclampsia prophylaxis in patients with previous renal disease who are at increased risk. There may be unusual circumstances where the standard therapy of low-dose aspirin and heparin is used as individualized therapy, for example, in a woman who is older than 40 years with positive LAC pregnant for the first time through in vitro fertilization: this is a patient I would treat aggressively, because this may be her only chance to have a successful pregnancy. Finally, for patients with a history of previous thrombosis, one needs to treat with therapeutic levels of heparin throughout the pregnancy, usually changing to heparin from warfarin before conception. Fetal monitoring is important, usually with nonstress tests from week 30 onward. The heparin dose is sometimes adjusted later in the pregnancy because of increased clearance, and many obstetricians prefer to change from low molecular weight to unfractionated heparin at the end of pregnancy because of the shorter half-life. Postpartum anticoagulation should be continued for 6 to 8 weeks even in patients without a history of thrombosis.
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