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Managing lupus patients during pregnancy
Best Practice & Research Clinical Rheumatology 23 (2009) 575–582
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Managing lupus patients during pregnancy Guillermo Ruiz-Irastorza, MD, PhD, Doctor a, Munther A. Khamashta, MD, FRCP, PhD, Doctor b, * a b
Service and Department of Internal Medicine, Hospital De Cruces, University of the Basque Country, Bizkaia, Spain Lupus Research Unit, The Rayne Institute, St. Thomas’ Hospital, King’s College, London SE1 7EH, UK
Keywords: systemic lupus erythematosus anti-cardiolipin lupus anticoagulant miscarriage foetal death pre-eclampsia
Pregnancy still constitutes a major challenge for women with systemic lupus erythematosus. Coordinated medical/obstetric care is essential to maximise the chance of success. Pregnancy should be planned in advance, following a pre-conceptional visit in which the specific risk for complications can be assessed. Previous complicated pregnancies, renal disease, irreversible damage, antiphospholipid antibodies and treatment with high-dose steroids are adverse features. Pregnancy should be discouraged in women with symptomatic pulmonary hypertension, heart failure, severe restrictive pulmonary disease, severe chronic renal failure and recent serious lupus activity. Treatment is based on hydroxychloroquine, low-dose steroids, azathioprine and in patients with anti-phospholipid antibodies, low-dose aspirin low molecular weight heparin. Close surveillance, with monitoring of blood pressure, proteinuria and placental blood flow by Doppler studies helps the early diagnosis and treatment of complications such as pre-eclampsia and foetal distress. Post-partum follow-up is also essential. Ó 2009 Published by Elsevier Ltd.
Just 20 years ago, women with systemic lupus erythematosus (SLE) were advised against pregnancy due to fear of irreversible consequences for the mother. Today the scenario has changed dramatically with the advent of combined teams of obstetricians and ‘lupus doctors’ offering coordinated care for both, the mother and the baby. Pregnancy should be considered a high-risk period during the course of lupus, with a large number of potential complications that can influence the course of the disease as well as the final result of pregnancy itself.
* Corresponding author. Tel.: þ44 20 7620 2567; Fax: þ44 20 7620 26 58. E-mail address: [email protected] (M.A. Khamashta). 1521-6942/$ – see front matter Ó 2009 Published by Elsevier Ltd. doi:10.1016/j.berh.2009.04.004
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Recently, a national study in the US identified, between 2000 and 2003, 13 555 deliveries among women with a diagnosis of SLE at discharge [1]. Compared with women without SLE, those with lupus were more likely to suffer from pre-gestational diabetes mellitus, hypertension, pulmonary hypertension, renal failure and thrombophilia (mainly anti-phospholipid syndrome, or APS). During pregnancy, pre-eclampsia occurred in 22.5% of women with lupus as against 7.6% in the general population. Intrauterine growth restriction, pre-term delivery and caesarean section were all more frequent in women with SLE. Medical complications such as stroke, pulmonary embolus, deep vein thrombosis, major infections, bleeding and thrombocytopaenia were also seen with a much higher frequency in SLE patients. Indeed, adverse pregnancy outcomes have been seen in as many as 76% of women from the LUpus in MInority populations: NAture vs. nurture (LUMINA) cohort in a recent publication [2]. Moreover, these authors identified a substantial degree of post-partum damage accrual in women with SLE, which was especially determined by disease activity and the presence of damage before conception. Severe activity and corticosteroid use have also been associated with prematurity and embryo/foetal death [3,4]. In this setting, it is clear that pregnancy in women with SLE is usually possible, but not free from serious potential complications. Specific care should be offered to women with lupus during, but also before and after pregnancy, in order to assure correct planning, surveillance and management of medical and obstetric problems that can present during this period. Pre-pregnancy counselling One of the most important points in managing pregnancy in women with SLE is pre-pregnancy counselling [5]. This includes pertinent information about the risks of adverse outcomes, both for the baby and herself, and the planning of antenatal care. Pre-pregnancy counselling is also essential in order to estimate the chance of both foetal and maternal problems (Table 1). At this point, a complete set of auto-antibodies should be available, especially anti-phospholipid antibodies (aPL), both anti-cardiolipin antibodies (aCL) and lupus anticoagulant (LA) and anti-Ro and anti-La antibodies, given their close link with specific pregnancy complications (thrombosis, embryo/foetal loss, pre-eclampsia and congenital heart block). Also, the degree of lupus activity and irreversible organ damage should be determined. Women with active lupus should delay pregnancy until a quiescent phase of the disease, especially in the event of serious organ involvement (renal, neurological, etc.). Likewise, women with a high degree of irreversible damage are more likely to suffer complications and even further damage during and after pregnancy [2], particularly those with chronic renal disease [6]. This is also the time to evaluate the safety of the treatment received by the patient, since many drugs are contraindicated during pregnancy (see ahead). Most forbidden medications can (and should) be stopped at this point and be substituted by alternative immunosuppressant and anti-hypertensive drugs. Women with mild disease, who are considered to be at low risk for complications, could be managed by their local obstetricians with just some additional visits to monitor the course of SLE. In contrast, high-risk patients should be identified at this point, so that a closer surveillance can be planned in advance. Several clinical and immunological features identify a high-risk lupus pregnancy (Table 2). Table 1 Pre-conceptional visit checklist. Age Any previous pregnancy? Previous pregnancy complications? SLE organ involvement Degree of irreversible damage Recent or current SLE activity? Presence of anti-phospholipid antibodies/syndrome? Positivity of anti-Ro/anti-La? Current treatment: any ‘forbidden’ drugs? SLE: systemic lupus erythematosus.
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Table 2 High-risk lupus pregnancy. Previous poor obstetric history Lupus nephritis Renal failure Heart failure Pulmonary hypertension Interstitial lung disease Active disease High degree of irreversible organ damage High-dose steroid therapy Presence of anti-phospholipid antibodies/syndrome Presence of anti-Ro/La antibodies Multiple pregnancy Age over 40 years
A previous complicated pregnancy is, by itself, an important adverse prognostic variable [7]. The presence of aPL is a predictor of maternal thrombosis, embryo/foetal loss and pre-eclampsia [8–10]. Among the different aPLs available in clinical practice, LA is the most strongly associated with APSrelated clinical manifestations [11,12]. Thus, patients with aPL need special management based on treatment with low-dose aspirin heparin and placental Doppler studies (see ahead). Maternal antiRo and anti-La antibodies may cause congenital heart block in 2% of babies [13]. This is a rare, but very serious condition, with a high mortality rate and a high chance of the baby requiring a permanent pacemaker [14]. Chronic renal failure is also associated with other obstetric complications such as hypertensive disorders and miscarriage, the risk of which increases sharply in women with serum creatinine levels over 3 mg dl1 [6,15]. Restrictive pulmonary disease may also worsen during pregnancy due to thoracic compression by the growing uterus. Likewise, women with cardiac disease may be at risk of heart failure due to volume overload caused by the normal increase in circulating volume [16]. In some situations, the physicians should advise against pregnancy (Table 3). Women with current or recent lupus activity, particularly if affecting internal organs, should avoid pregnancy. The same recommendation applies to women with APS and recent thrombosis, particularly in the arterial bed [17]. Women with severe kidney, lung or heart disease should also be discouraged from getting pregnant, due to the high risk of maternal complications [5]. Likewise, pregnancy should be considered absolutely contraindicated in women with symptomatic pulmonary hypertension, which carries a higher than 30% maternal mortality during late pregnancy and the puerperium [18]. Pregnancy management plan Women considered to be at high risk are best managed in a combined medical–obstetric clinic throughout the whole pregnancy. The general schedule includes more frequent visits as pregnancy progresses, with weekly visits during the last 8 weeks of pregnancy. Close monitoring of blood pressure
Table 3 Contraindications to pregnancy in women with SLE. Severe pulmonary hypertension (estimated systolic PAP > 50 mm Hg or symptomatic) Severe restrictive lung disease (FVC < 1 litre) Heart failure Chronic renal failure (Cr > 2.8 mg dl1) Previous severe pre-eclampsia or HELLP despite therapy with aspirin and heparin Stroke within the previous six months Severe lupus flare within the previous six months PAP: pulmonary arterial pressure. FVC: forced vital capacity. HELLP: Hemolysis, Elevated Liver enzymes, Low Platelets.
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is very important in order to ensure the early detection of pregnancy-induced hypertension or preeclampsia. It should be measured on each visit, but women with hypertension, previous pre-eclampsia or past or present lupus nephritis should also provide additional home measurements. Likewise, regular urine analysis is essential to detect proteinuria, which could be the first sign of impending preeclampsia or renal lupus flare. Blood tests are necessary in order to monitor haemoglobin levels and platelet count, both of which decrease during a normal pregnancy, but can also be affected by lupus-related immune haemolytic anaemia, thrombocytopaenia and pre-eclampsia with hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. In women treated with iodine, monitoring thyroid hormones is also warranted. Anti-DNA and complement levels may help in monitoring SLE activity; however, the sensitivity of the latter is lower during pregnancy as increased values are normal in this period. Doppler studies of the placental vessels are very useful to estimate placental function and predict the occurrence of complications such as pre-eclampsia and foetal distress. Uterine Doppler studies are recommended around the 20th week and repeated 4 weeks later if abnormal. The finding of persistently high resistance and early diastolic notch is associated with an increased risk of pre-eclampsia. Umbilical Doppler ultrasound after the 24th week may show absent or even reverse diastolic flow, a sign of impending placental insufficiency and foetal distress. The finding of abnormal Doppler studies is considered an adverse prognostic sign that increases the risk of adverse outcomes, although not all women with an abnormal Doppler will suffer complications. However, the negative predictive value of this test is higher as repeated normal results are associated with very low frequency of obstetric complications [19,20]. Repeated ultrasound examination of baby’s heart is needed between the 18th and 28th weeks when the mother is anti-Ro and/or anti-La positive in order to detect congenital heart block [14]. Pharmacological therapy during pregnancy One of the critical issues in managing women with SLE during pregnancy is choosing the right medication to treat the mother without harming the baby. Unfortunately, most information regarding drug safety in pregnant women comes from case series or case reports. A recent consensus document has established, after an extensive literature review, the safety of a number of drugs commonly used in pregnant women with rheumatic diseases [21]. Non-steroidal anti-inflammatory drugs are generally safe; however, they should be avoided in the last weeks of pregnancy due to the risk of premature closure of the ductus arteriosus. These drugs may also cause fluid retention and worsen hypertension. With the exception of fluorinated compounds (dexamethasone and betamethasone), corticosteroids are mostly inactivated by placental hydroxylases. Despite this lack of direct effect on the baby, they can, especially in high doses (>20 mgm day1), cause important medical and obstetric problems, including diabetes, hypertension, pre-eclampsia and premature rupture of membranes [3,5]. We strongly oppose the prolonged use of more than 7.5 mg day1 of prednisone/prednisolone. In cases of severe activity, intravenous pulses of 250 or 500 mg of methylprednisolone can be used safely [22]. Most immunosuppressive drugs (cyclophosphamide, methotrexate, mycophenolate, leflunomide) are contraindicated during pregnancy. The exceptions are azathioprine, cyclosporine and tacrolimus, all with an extensive experience in pregnant women, particularly in transplant recipients [21]. Among antiaggregant drugs, low-dose aspirin and dipyridamole are safe, whilst the use of ticlopidine and clopidogrel is not recommended. Likewise, heparin in all forms does not cross the placenta and can be safely used in pregnant women. On the contrary, warfarin and coumadin must be avoided during the organogenesis (weeks 6 to 10) due to the well-defined warfarin embryopathy. Women receiving heparin during pregnancy, as well as those treated with corticosteroids or at risk for osteoporosis, should receive calcium plus vitamin D until the end of lactation [23]. A specific problem of drugs affecting haemostasis is the possibility of receiving spinal anaesthesia. Consensus guidelines on this issue recommend that in women receiving prophylactic doses of lowmolecular weight heparin (enoxaparin 40 mg day1 or dalteparin 5000 IU day1), the time after the last dose of heparin should be at least 12 h before performing a safe procedure [24]. This period should
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be extended to 24 h after the last dose in case of higher doses of heparin, whether given once or twice daily. However, evidence is scarce and the final decision mainly depends on the opinion of the anaesthetist in charge of the patient [25]. The biological drugs (e.g. anti-tumor necrosis factor (TNF) agents and rituximab) are currently not recommended during pregnancy, due to the potential trans-placental transfer [21]. Anti-hypertensive drugs are frequently needed in pregnant women with SLE. Many of the most common drugs in this group are contraindicated during pregnancy (angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, diuretics), given their toxicity on the foetal kidneys, causing renal failure and oligoamnios. Thus, treatment of hypertension during pregnancy relies on old drugs such as methyldopa, nifedipine and labetalol [26]. Among the different drugs used to treat SLE, anti-malarials merit a special comment. These drugs have shown a wide range of beneficial effects in patients with lupus, including protection against flares, thrombosis and damage accrual, lowering cholesterol and a consequent increase in the long-term survival of anti-malarial users [27–30]. Moreover, hydroxychloroquine and chloroquine are absolutely safe during pregnancy, with more than 300 treated pregnancies in women with SLE reported (plus many more with malaria) without any unexpected malformation or cases of ocular, auditory or neurological toxicity [31]. In addition, discontinuation of hydroxychloroquine during pregnancy can result in a flare of SLE [32,33]. Thus, anti-malarials should not be withdrawn during or in prevision of pregnancy. If possible, hydroxychloroquine could be used instead of chloroquine, given its more favourable safety profile for the mother. Specific clinical problems during pregnancy Lupus flare Lupus activity is likely to increase during pregnancy [34,35] although most flares are not severe, and it is well documented that women on longstanding remission have a low probability of lupus reactivation during or shortly after pregnancy [36,37]. As noted earlier, hydroxychloroquine discontinuation can result in a significantly higher risk of SLE flares [32,33]. SLE activity has important implications for pregnancy. On the one hand, it is an obvious threat for the mother, especially if affecting deep organs such as the kidney or the central nervous systems. Moreover, flares during pregnancy have been associated with accrual of irreversible damage afterwards [2]. On the other hand, the baby may be affected as well. Firstly, the foetus could be exposed to a higher number and amount of potentially dangerous medications. Secondly, it has been shown that activity itself is a predictor of adverse obstetric outcomes [38]. Clinical and immunological features of lupus activity may be different during pregnancy. Fatigue and mild arthralgia are common among normal pregnant women and can be confused with SLE flares. Likewise, oedema normally appears during the last phases of pregnancy and, in the absence of hypertension and/or proteinuria, is not a warning sign. On the laboratory side, mild anaemia and thrombocytopaenia are also common features in pregnant women. On the contrary, complement levels tend to rise during pregnancy, thus reducing their ability to act as useful markers of disease activity. The variation of C3 and C4 levels, rather than their absolute values, should be taken into account [10]. Lupus activity scales that are specific for pregnancy have been established [39]. One of them, the Lupus Activity Index in Pregnancy has been also validated [40]. However, the use of these tools is mainly for research purposes; the clinical recognition of SLE flares still relies on the skill of the physician. Lupus nephritis and pre-eclampsia A common challenge in lupus pregnancies is differentiating pre-eclampsia from a nephritic SLE flare. Women with past kidney disease are at a higher risk for developing pregnancy-induced hypertension [10] and are also more likely to suffer a renal flare [41]. Proteinuria and hypertension are common to both conditions. However, some clinical features may help with the differential: rising uric acid levels point to toxaemia whilst the presence of haematuria and/or cellular casts, extrarenal
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activity, rising anti-DNA antibody levels and falling complement levels (even within normal limits for non-pregnant patients) point to lupus nephritis [10]. The correct diagnosis may be extremely difficult and empirical therapy, sometimes including the indication of pregnancy termination, is commonly adopted. Apart from renal disease, a recent systematic review has identified a previous history of preeclampsia (odds ratio 7.19) and the presence of APS (odds ratio 9.72) as important predictors of the condition in the general population [42]. The usefulness of antiaggregant drugs to prevent preeclampsia has been a subject of debate; however, a recent meta-analysis of data of individual patients has shown a consistent and statistically significant reduction in the risk of pre-eclampsia, pre-term delivery before 34 weeks and serious adverse outcomes among women taking low-dose aspirin (and/or dipyridamole in a few of them) [43]. Pre-eclampsia, pre-term delivery <34 weeks, perinatal death, small babies at birth and any serious adverse outcome were all significantly reduced by around 10%. In high-risk populations, the resulting number needing treatment was estimated to be between 40 and 60 patients. Extrapolating these data to SLE patients, treatment with low-dose aspirin during pregnancy would be indicated in women with aPL, history of pre-eclampsia, hypertension and/or renal disease.
Anti-phospholipid syndrome The presence of aPL increases the risk for both maternal (thrombosis, pre-eclampsia) and foetal complications (early and late miscarriage, prematurity). Thus, specific measures should be taken in women with aPL, particularly those with APS (i.e., with previous thrombosis and/or obstetric complications), LA or persistently high-levels of aCL. Low-dose aspirin should be taken by all women with aPL, if possible before conception [44], in order to decrease the risk of miscarriage [45] and, as shown earlier, pre-eclampsia [43]. Heparin at full anti-thrombotic doses is given to women with previous thrombosis, since warfarin is contraindicated during organogenesis and is complicated to manage later, with an increased risk of foetal bleeding [46]. In patients with previous poor obstetric history, there is agreement in treating those with foetal (late) deaths with aspirin plus low-dose heparin. On the other hand, some women suffering only early miscarriages do well with low-dose aspirin alone [45]. Thus, although recent guidelines recommend the universal combination of aspirin and heparin [47,48], we believe that drug therapy should be individualised and the different options discussed with the patient, with a place for monotherapy with aspirin in young women with recurrent early miscarriages. In any case, adequate thrombo-prophylaxis is essential in all women with aPL during 4–6 weeks postpartum [46]. Post-natal care Optimal management is not over with the birth of a healthy baby. In fact, the post-partum period should be considered high risk for women with SLE, with several possible complications ahead. First, the mother can suffer a lupus flare, since several studies have found the puerperium a period of particularly high risk for lupus activity [49]. A close surveillance in the first 4 weeks after delivery is thus warranted, especially in women with recent activity or previous severe disease. However, no specific prophylactic therapy (such as increasing the dose of steroids) is recommended. The puerperium is also a high-risk period for thrombo-embolic complications. This is especially true in women with aPL, in whom adequate thrombo-prophylaxis with low molecular weight heparin should be extended for 4 to 6 weeks after delivery (as mentioned earlier). Those with a previous history of thrombosis can be back on their usual full anticoagulant therapy within 2 to 3 days post-partum. It should be remembered that both, warfarin and heparin, are perfectly safe during lactation. Women on long-term heparin should receive therapy with calcium plus vitamin D until the end of nursing [23]. Lastly, as in the general population, ferritin and thyroid hormones should be monitored during the post-partum period in order to detect and treat iron deficiency (almost universal) and pregnancy and/ or iodine-induced thyroid dysfunction.
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Practice points
Pregnancy is frequently possible in women with SLE, but complications are common. A careful planning of pregnancy before conception is essential. A risk profile of each woman should be established. Women with severe organ damage or severe activity should best avoid pregnancy. SLE disease activity during pregnancy must be actively managed. Low-dose and/or pulse corticosteroids are the drugs of choice. Hydroxychloroquine is perfectly safe during pregnancy and should not be stopped, since withdrawal increases the likelihood of flare. Aspirin and heparin are the recommended drugs for the prevention of miscarriage in women with APS. Close monitoring of blood pressure, proteinuria and placental blood flow by Doppler helps the early detection of complications. Congenital heart block has a strong relationship with the presence of anti-Ro/Anti La antibodies in the mother. Post-partum follow-up should be followed in all women with SLE.
Research agenda
Accurate assessment of SLE disease activity during pregnancy Predictors of flare in SLE pregnancy Clinical trials to assess treatment effects on late-pregnancy complications in APS Regular updated information regarding risks and benefits of medication taken during pregnancy and breastfeeding.
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Managing lupus patients during pregnancy Guillermo Ruiz-Irastorza, MD, PhD, Doctor a, Munther A. Khamashta, MD, FRCP, PhD, Doctor b, * a b
Service and Department of Internal Medicine, Hospital De Cruces, University of the Basque Country, Bizkaia, Spain Lupus Research Unit, The Rayne Institute, St. Thomas’ Hospital, King’s College, London SE1 7EH, UK
Keywords: systemic lupus erythematosus anti-cardiolipin lupus anticoagulant miscarriage foetal death pre-eclampsia
Pregnancy still constitutes a major challenge for women with systemic lupus erythematosus. Coordinated medical/obstetric care is essential to maximise the chance of success. Pregnancy should be planned in advance, following a pre-conceptional visit in which the specific risk for complications can be assessed. Previous complicated pregnancies, renal disease, irreversible damage, antiphospholipid antibodies and treatment with high-dose steroids are adverse features. Pregnancy should be discouraged in women with symptomatic pulmonary hypertension, heart failure, severe restrictive pulmonary disease, severe chronic renal failure and recent serious lupus activity. Treatment is based on hydroxychloroquine, low-dose steroids, azathioprine and in patients with anti-phospholipid antibodies, low-dose aspirin low molecular weight heparin. Close surveillance, with monitoring of blood pressure, proteinuria and placental blood flow by Doppler studies helps the early diagnosis and treatment of complications such as pre-eclampsia and foetal distress. Post-partum follow-up is also essential. Ó 2009 Published by Elsevier Ltd.
Just 20 years ago, women with systemic lupus erythematosus (SLE) were advised against pregnancy due to fear of irreversible consequences for the mother. Today the scenario has changed dramatically with the advent of combined teams of obstetricians and ‘lupus doctors’ offering coordinated care for both, the mother and the baby. Pregnancy should be considered a high-risk period during the course of lupus, with a large number of potential complications that can influence the course of the disease as well as the final result of pregnancy itself.
* Corresponding author. Tel.: þ44 20 7620 2567; Fax: þ44 20 7620 26 58. E-mail address: [email protected] (M.A. Khamashta). 1521-6942/$ – see front matter Ó 2009 Published by Elsevier Ltd. doi:10.1016/j.berh.2009.04.004
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Recently, a national study in the US identified, between 2000 and 2003, 13 555 deliveries among women with a diagnosis of SLE at discharge [1]. Compared with women without SLE, those with lupus were more likely to suffer from pre-gestational diabetes mellitus, hypertension, pulmonary hypertension, renal failure and thrombophilia (mainly anti-phospholipid syndrome, or APS). During pregnancy, pre-eclampsia occurred in 22.5% of women with lupus as against 7.6% in the general population. Intrauterine growth restriction, pre-term delivery and caesarean section were all more frequent in women with SLE. Medical complications such as stroke, pulmonary embolus, deep vein thrombosis, major infections, bleeding and thrombocytopaenia were also seen with a much higher frequency in SLE patients. Indeed, adverse pregnancy outcomes have been seen in as many as 76% of women from the LUpus in MInority populations: NAture vs. nurture (LUMINA) cohort in a recent publication [2]. Moreover, these authors identified a substantial degree of post-partum damage accrual in women with SLE, which was especially determined by disease activity and the presence of damage before conception. Severe activity and corticosteroid use have also been associated with prematurity and embryo/foetal death [3,4]. In this setting, it is clear that pregnancy in women with SLE is usually possible, but not free from serious potential complications. Specific care should be offered to women with lupus during, but also before and after pregnancy, in order to assure correct planning, surveillance and management of medical and obstetric problems that can present during this period. Pre-pregnancy counselling One of the most important points in managing pregnancy in women with SLE is pre-pregnancy counselling [5]. This includes pertinent information about the risks of adverse outcomes, both for the baby and herself, and the planning of antenatal care. Pre-pregnancy counselling is also essential in order to estimate the chance of both foetal and maternal problems (Table 1). At this point, a complete set of auto-antibodies should be available, especially anti-phospholipid antibodies (aPL), both anti-cardiolipin antibodies (aCL) and lupus anticoagulant (LA) and anti-Ro and anti-La antibodies, given their close link with specific pregnancy complications (thrombosis, embryo/foetal loss, pre-eclampsia and congenital heart block). Also, the degree of lupus activity and irreversible organ damage should be determined. Women with active lupus should delay pregnancy until a quiescent phase of the disease, especially in the event of serious organ involvement (renal, neurological, etc.). Likewise, women with a high degree of irreversible damage are more likely to suffer complications and even further damage during and after pregnancy [2], particularly those with chronic renal disease [6]. This is also the time to evaluate the safety of the treatment received by the patient, since many drugs are contraindicated during pregnancy (see ahead). Most forbidden medications can (and should) be stopped at this point and be substituted by alternative immunosuppressant and anti-hypertensive drugs. Women with mild disease, who are considered to be at low risk for complications, could be managed by their local obstetricians with just some additional visits to monitor the course of SLE. In contrast, high-risk patients should be identified at this point, so that a closer surveillance can be planned in advance. Several clinical and immunological features identify a high-risk lupus pregnancy (Table 2). Table 1 Pre-conceptional visit checklist. Age Any previous pregnancy? Previous pregnancy complications? SLE organ involvement Degree of irreversible damage Recent or current SLE activity? Presence of anti-phospholipid antibodies/syndrome? Positivity of anti-Ro/anti-La? Current treatment: any ‘forbidden’ drugs? SLE: systemic lupus erythematosus.
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Table 2 High-risk lupus pregnancy. Previous poor obstetric history Lupus nephritis Renal failure Heart failure Pulmonary hypertension Interstitial lung disease Active disease High degree of irreversible organ damage High-dose steroid therapy Presence of anti-phospholipid antibodies/syndrome Presence of anti-Ro/La antibodies Multiple pregnancy Age over 40 years
A previous complicated pregnancy is, by itself, an important adverse prognostic variable [7]. The presence of aPL is a predictor of maternal thrombosis, embryo/foetal loss and pre-eclampsia [8–10]. Among the different aPLs available in clinical practice, LA is the most strongly associated with APSrelated clinical manifestations [11,12]. Thus, patients with aPL need special management based on treatment with low-dose aspirin heparin and placental Doppler studies (see ahead). Maternal antiRo and anti-La antibodies may cause congenital heart block in 2% of babies [13]. This is a rare, but very serious condition, with a high mortality rate and a high chance of the baby requiring a permanent pacemaker [14]. Chronic renal failure is also associated with other obstetric complications such as hypertensive disorders and miscarriage, the risk of which increases sharply in women with serum creatinine levels over 3 mg dl1 [6,15]. Restrictive pulmonary disease may also worsen during pregnancy due to thoracic compression by the growing uterus. Likewise, women with cardiac disease may be at risk of heart failure due to volume overload caused by the normal increase in circulating volume [16]. In some situations, the physicians should advise against pregnancy (Table 3). Women with current or recent lupus activity, particularly if affecting internal organs, should avoid pregnancy. The same recommendation applies to women with APS and recent thrombosis, particularly in the arterial bed [17]. Women with severe kidney, lung or heart disease should also be discouraged from getting pregnant, due to the high risk of maternal complications [5]. Likewise, pregnancy should be considered absolutely contraindicated in women with symptomatic pulmonary hypertension, which carries a higher than 30% maternal mortality during late pregnancy and the puerperium [18]. Pregnancy management plan Women considered to be at high risk are best managed in a combined medical–obstetric clinic throughout the whole pregnancy. The general schedule includes more frequent visits as pregnancy progresses, with weekly visits during the last 8 weeks of pregnancy. Close monitoring of blood pressure
Table 3 Contraindications to pregnancy in women with SLE. Severe pulmonary hypertension (estimated systolic PAP > 50 mm Hg or symptomatic) Severe restrictive lung disease (FVC < 1 litre) Heart failure Chronic renal failure (Cr > 2.8 mg dl1) Previous severe pre-eclampsia or HELLP despite therapy with aspirin and heparin Stroke within the previous six months Severe lupus flare within the previous six months PAP: pulmonary arterial pressure. FVC: forced vital capacity. HELLP: Hemolysis, Elevated Liver enzymes, Low Platelets.
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is very important in order to ensure the early detection of pregnancy-induced hypertension or preeclampsia. It should be measured on each visit, but women with hypertension, previous pre-eclampsia or past or present lupus nephritis should also provide additional home measurements. Likewise, regular urine analysis is essential to detect proteinuria, which could be the first sign of impending preeclampsia or renal lupus flare. Blood tests are necessary in order to monitor haemoglobin levels and platelet count, both of which decrease during a normal pregnancy, but can also be affected by lupus-related immune haemolytic anaemia, thrombocytopaenia and pre-eclampsia with hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. In women treated with iodine, monitoring thyroid hormones is also warranted. Anti-DNA and complement levels may help in monitoring SLE activity; however, the sensitivity of the latter is lower during pregnancy as increased values are normal in this period. Doppler studies of the placental vessels are very useful to estimate placental function and predict the occurrence of complications such as pre-eclampsia and foetal distress. Uterine Doppler studies are recommended around the 20th week and repeated 4 weeks later if abnormal. The finding of persistently high resistance and early diastolic notch is associated with an increased risk of pre-eclampsia. Umbilical Doppler ultrasound after the 24th week may show absent or even reverse diastolic flow, a sign of impending placental insufficiency and foetal distress. The finding of abnormal Doppler studies is considered an adverse prognostic sign that increases the risk of adverse outcomes, although not all women with an abnormal Doppler will suffer complications. However, the negative predictive value of this test is higher as repeated normal results are associated with very low frequency of obstetric complications [19,20]. Repeated ultrasound examination of baby’s heart is needed between the 18th and 28th weeks when the mother is anti-Ro and/or anti-La positive in order to detect congenital heart block [14]. Pharmacological therapy during pregnancy One of the critical issues in managing women with SLE during pregnancy is choosing the right medication to treat the mother without harming the baby. Unfortunately, most information regarding drug safety in pregnant women comes from case series or case reports. A recent consensus document has established, after an extensive literature review, the safety of a number of drugs commonly used in pregnant women with rheumatic diseases [21]. Non-steroidal anti-inflammatory drugs are generally safe; however, they should be avoided in the last weeks of pregnancy due to the risk of premature closure of the ductus arteriosus. These drugs may also cause fluid retention and worsen hypertension. With the exception of fluorinated compounds (dexamethasone and betamethasone), corticosteroids are mostly inactivated by placental hydroxylases. Despite this lack of direct effect on the baby, they can, especially in high doses (>20 mgm day1), cause important medical and obstetric problems, including diabetes, hypertension, pre-eclampsia and premature rupture of membranes [3,5]. We strongly oppose the prolonged use of more than 7.5 mg day1 of prednisone/prednisolone. In cases of severe activity, intravenous pulses of 250 or 500 mg of methylprednisolone can be used safely [22]. Most immunosuppressive drugs (cyclophosphamide, methotrexate, mycophenolate, leflunomide) are contraindicated during pregnancy. The exceptions are azathioprine, cyclosporine and tacrolimus, all with an extensive experience in pregnant women, particularly in transplant recipients [21]. Among antiaggregant drugs, low-dose aspirin and dipyridamole are safe, whilst the use of ticlopidine and clopidogrel is not recommended. Likewise, heparin in all forms does not cross the placenta and can be safely used in pregnant women. On the contrary, warfarin and coumadin must be avoided during the organogenesis (weeks 6 to 10) due to the well-defined warfarin embryopathy. Women receiving heparin during pregnancy, as well as those treated with corticosteroids or at risk for osteoporosis, should receive calcium plus vitamin D until the end of lactation [23]. A specific problem of drugs affecting haemostasis is the possibility of receiving spinal anaesthesia. Consensus guidelines on this issue recommend that in women receiving prophylactic doses of lowmolecular weight heparin (enoxaparin 40 mg day1 or dalteparin 5000 IU day1), the time after the last dose of heparin should be at least 12 h before performing a safe procedure [24]. This period should
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be extended to 24 h after the last dose in case of higher doses of heparin, whether given once or twice daily. However, evidence is scarce and the final decision mainly depends on the opinion of the anaesthetist in charge of the patient [25]. The biological drugs (e.g. anti-tumor necrosis factor (TNF) agents and rituximab) are currently not recommended during pregnancy, due to the potential trans-placental transfer [21]. Anti-hypertensive drugs are frequently needed in pregnant women with SLE. Many of the most common drugs in this group are contraindicated during pregnancy (angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, diuretics), given their toxicity on the foetal kidneys, causing renal failure and oligoamnios. Thus, treatment of hypertension during pregnancy relies on old drugs such as methyldopa, nifedipine and labetalol [26]. Among the different drugs used to treat SLE, anti-malarials merit a special comment. These drugs have shown a wide range of beneficial effects in patients with lupus, including protection against flares, thrombosis and damage accrual, lowering cholesterol and a consequent increase in the long-term survival of anti-malarial users [27–30]. Moreover, hydroxychloroquine and chloroquine are absolutely safe during pregnancy, with more than 300 treated pregnancies in women with SLE reported (plus many more with malaria) without any unexpected malformation or cases of ocular, auditory or neurological toxicity [31]. In addition, discontinuation of hydroxychloroquine during pregnancy can result in a flare of SLE [32,33]. Thus, anti-malarials should not be withdrawn during or in prevision of pregnancy. If possible, hydroxychloroquine could be used instead of chloroquine, given its more favourable safety profile for the mother. Specific clinical problems during pregnancy Lupus flare Lupus activity is likely to increase during pregnancy [34,35] although most flares are not severe, and it is well documented that women on longstanding remission have a low probability of lupus reactivation during or shortly after pregnancy [36,37]. As noted earlier, hydroxychloroquine discontinuation can result in a significantly higher risk of SLE flares [32,33]. SLE activity has important implications for pregnancy. On the one hand, it is an obvious threat for the mother, especially if affecting deep organs such as the kidney or the central nervous systems. Moreover, flares during pregnancy have been associated with accrual of irreversible damage afterwards [2]. On the other hand, the baby may be affected as well. Firstly, the foetus could be exposed to a higher number and amount of potentially dangerous medications. Secondly, it has been shown that activity itself is a predictor of adverse obstetric outcomes [38]. Clinical and immunological features of lupus activity may be different during pregnancy. Fatigue and mild arthralgia are common among normal pregnant women and can be confused with SLE flares. Likewise, oedema normally appears during the last phases of pregnancy and, in the absence of hypertension and/or proteinuria, is not a warning sign. On the laboratory side, mild anaemia and thrombocytopaenia are also common features in pregnant women. On the contrary, complement levels tend to rise during pregnancy, thus reducing their ability to act as useful markers of disease activity. The variation of C3 and C4 levels, rather than their absolute values, should be taken into account [10]. Lupus activity scales that are specific for pregnancy have been established [39]. One of them, the Lupus Activity Index in Pregnancy has been also validated [40]. However, the use of these tools is mainly for research purposes; the clinical recognition of SLE flares still relies on the skill of the physician. Lupus nephritis and pre-eclampsia A common challenge in lupus pregnancies is differentiating pre-eclampsia from a nephritic SLE flare. Women with past kidney disease are at a higher risk for developing pregnancy-induced hypertension [10] and are also more likely to suffer a renal flare [41]. Proteinuria and hypertension are common to both conditions. However, some clinical features may help with the differential: rising uric acid levels point to toxaemia whilst the presence of haematuria and/or cellular casts, extrarenal
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activity, rising anti-DNA antibody levels and falling complement levels (even within normal limits for non-pregnant patients) point to lupus nephritis [10]. The correct diagnosis may be extremely difficult and empirical therapy, sometimes including the indication of pregnancy termination, is commonly adopted. Apart from renal disease, a recent systematic review has identified a previous history of preeclampsia (odds ratio 7.19) and the presence of APS (odds ratio 9.72) as important predictors of the condition in the general population [42]. The usefulness of antiaggregant drugs to prevent preeclampsia has been a subject of debate; however, a recent meta-analysis of data of individual patients has shown a consistent and statistically significant reduction in the risk of pre-eclampsia, pre-term delivery before 34 weeks and serious adverse outcomes among women taking low-dose aspirin (and/or dipyridamole in a few of them) [43]. Pre-eclampsia, pre-term delivery <34 weeks, perinatal death, small babies at birth and any serious adverse outcome were all significantly reduced by around 10%. In high-risk populations, the resulting number needing treatment was estimated to be between 40 and 60 patients. Extrapolating these data to SLE patients, treatment with low-dose aspirin during pregnancy would be indicated in women with aPL, history of pre-eclampsia, hypertension and/or renal disease.
Anti-phospholipid syndrome The presence of aPL increases the risk for both maternal (thrombosis, pre-eclampsia) and foetal complications (early and late miscarriage, prematurity). Thus, specific measures should be taken in women with aPL, particularly those with APS (i.e., with previous thrombosis and/or obstetric complications), LA or persistently high-levels of aCL. Low-dose aspirin should be taken by all women with aPL, if possible before conception [44], in order to decrease the risk of miscarriage [45] and, as shown earlier, pre-eclampsia [43]. Heparin at full anti-thrombotic doses is given to women with previous thrombosis, since warfarin is contraindicated during organogenesis and is complicated to manage later, with an increased risk of foetal bleeding [46]. In patients with previous poor obstetric history, there is agreement in treating those with foetal (late) deaths with aspirin plus low-dose heparin. On the other hand, some women suffering only early miscarriages do well with low-dose aspirin alone [45]. Thus, although recent guidelines recommend the universal combination of aspirin and heparin [47,48], we believe that drug therapy should be individualised and the different options discussed with the patient, with a place for monotherapy with aspirin in young women with recurrent early miscarriages. In any case, adequate thrombo-prophylaxis is essential in all women with aPL during 4–6 weeks postpartum [46]. Post-natal care Optimal management is not over with the birth of a healthy baby. In fact, the post-partum period should be considered high risk for women with SLE, with several possible complications ahead. First, the mother can suffer a lupus flare, since several studies have found the puerperium a period of particularly high risk for lupus activity [49]. A close surveillance in the first 4 weeks after delivery is thus warranted, especially in women with recent activity or previous severe disease. However, no specific prophylactic therapy (such as increasing the dose of steroids) is recommended. The puerperium is also a high-risk period for thrombo-embolic complications. This is especially true in women with aPL, in whom adequate thrombo-prophylaxis with low molecular weight heparin should be extended for 4 to 6 weeks after delivery (as mentioned earlier). Those with a previous history of thrombosis can be back on their usual full anticoagulant therapy within 2 to 3 days post-partum. It should be remembered that both, warfarin and heparin, are perfectly safe during lactation. Women on long-term heparin should receive therapy with calcium plus vitamin D until the end of nursing [23]. Lastly, as in the general population, ferritin and thyroid hormones should be monitored during the post-partum period in order to detect and treat iron deficiency (almost universal) and pregnancy and/ or iodine-induced thyroid dysfunction.
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Practice points
Pregnancy is frequently possible in women with SLE, but complications are common. A careful planning of pregnancy before conception is essential. A risk profile of each woman should be established. Women with severe organ damage or severe activity should best avoid pregnancy. SLE disease activity during pregnancy must be actively managed. Low-dose and/or pulse corticosteroids are the drugs of choice. Hydroxychloroquine is perfectly safe during pregnancy and should not be stopped, since withdrawal increases the likelihood of flare. Aspirin and heparin are the recommended drugs for the prevention of miscarriage in women with APS. Close monitoring of blood pressure, proteinuria and placental blood flow by Doppler helps the early detection of complications. Congenital heart block has a strong relationship with the presence of anti-Ro/Anti La antibodies in the mother. Post-partum follow-up should be followed in all women with SLE.
Research agenda
Accurate assessment of SLE disease activity during pregnancy Predictors of flare in SLE pregnancy Clinical trials to assess treatment effects on late-pregnancy complications in APS Regular updated information regarding risks and benefits of medication taken during pregnancy and breastfeeding.
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