Managing lupus patients during pregnancy




Abstract


Systemic lupus erythematosus (SLE) is an auto-immune disease, primarily affecting young females. Pregnancy in a woman with SLE remains a high-risk situation with higher maternal and foetal mortality and morbidity. Although live births are achieved in majority of the pregnancies, active disease and major organ involvement can negatively affect the outcomes. A higher risk of foetal loss, pre-term birth, intra-uterine growth restriction (IUGR) and neonatal lupus syndromes (NLSs) are major foetal issues. Mothers are faced with disease flares, pre-eclampsia and other complications. Disease flares during SLE pregnancy pose the unique issue of recognition and differentiation between physiologic changes and disease state. Similarly, pre-eclampsia and lupus nephritis may lead to diagnostic confusion. Treatment choices during pregnancy are limited to a few safe drugs, further restricting the options. Refractory pregnancy loss associated with anti-phospholipid antibodies (aPLs) and complete heart block associated with anti-Ro antibodies remain unresolved issues. A multidisciplinary approach, with close monitoring, is essential for optimal outcomes.


Introduction


Systemic lupus erythematosus (SLE) is an auto-immune disease with significant female predominance. The onset during reproductive years, coupled with improved survival, has led to increased numbers of pregnancies in women with SLE. The pregnancy outcomes have also significantly improved. The rate of pregnancy loss has decreased from 43% to 17% in recent years . However, SLE patients have fewer children than their normal counterparts, and SLE pregnancy still carries a high risk of complications . A multidisciplinary approach, with close medical, obstetric and neonatal monitoring, is essential for optimal outcomes. This chapter highlights major issues in SLE pregnancy and discusses the management strategies to minimise maternal and foetal risks.




Pregnancy planning in SLE


Active SLE at the time of conception is known to be the strongest predictor of adverse pregnancy outcomes . Hence, ideally, all pregnancies in women with SLE should be planned during periods of disease control. Unplanned pregnancies during periods of disease activity highlight the often neglected need of effective contraceptive counselling of all young women with SLE . Natural and barrier methods of contraception have a high failure rate and may not be sufficient for a patient with active disease. Safety of oral contraceptives has been documented in two large randomised controlled trials . However, patients with a severely active disease were excluded from the studies. Patients with anti-phospholipid antibodies (aPLs) are at a high risk of thrombosis and should avoid oestrogen-containing contraceptives . Certain drugs interfere with the oral contraceptive efficacy. This fact has recently been added to the Food and Drug Administration (FDA) labelling of mycophenolate mofetil. Although effective, progesterone-only contraceptives have to be used judiciously. Long-term use, especially of depot preparations, leads to negative effects on bone mineral density . The intra-uterine contraceptive device remains a viable and safe option for many patients with SLE .




Pregnancy planning in SLE


Active SLE at the time of conception is known to be the strongest predictor of adverse pregnancy outcomes . Hence, ideally, all pregnancies in women with SLE should be planned during periods of disease control. Unplanned pregnancies during periods of disease activity highlight the often neglected need of effective contraceptive counselling of all young women with SLE . Natural and barrier methods of contraception have a high failure rate and may not be sufficient for a patient with active disease. Safety of oral contraceptives has been documented in two large randomised controlled trials . However, patients with a severely active disease were excluded from the studies. Patients with anti-phospholipid antibodies (aPLs) are at a high risk of thrombosis and should avoid oestrogen-containing contraceptives . Certain drugs interfere with the oral contraceptive efficacy. This fact has recently been added to the Food and Drug Administration (FDA) labelling of mycophenolate mofetil. Although effective, progesterone-only contraceptives have to be used judiciously. Long-term use, especially of depot preparations, leads to negative effects on bone mineral density . The intra-uterine contraceptive device remains a viable and safe option for many patients with SLE .




Pre-conception evaluation


Pre-conception assessment is an essential component of pregnancy planning in women with SLE. In a limited number of patients, pregnancy may pose an unacceptably high maternal risk, justifying an advice to defer or avoid pregnancy ( Table 1 ). If there are no contraindications, the patient should undergo pre-conception counselling, maternal and foetal risk assessment and medication review, before conception ( Fig. 1 ). A complete set of autoantibodies should be obtained as certain specific maternal antibodies (aPLs and anti-Ro antibodies) in the mother pose unique foetal risks. Every effort should be made to ensure optimal disease control for at least 6 months prior to conception. Medications should be reviewed and adjusted to achieve good disease control on permitted medication. Thyroid function should be assessed as hypothyroidism in SLE is associated with poorer outcomes .



Table 1

Situations where pregnancy is not advisable in patient with SLE.























Contra-indications to pregnancy:
Severe pulmonary hypertension (systolic pulmonary artery pressure >50 mm Hg)
Severe restrictive lung disease (Forced vital capacity <1 L)
Advanced renal insufficiency (creatinine >2.8 mg/dL)
Advance heart failure
Previous severe preeclampsia or HELLP despite therapy
Pregnancy should be deferred:
Severe disease flare within last 6 months
Active lupus nephritis
Stroke within the previous 6 months



Fig. 1


Planning a pregnancy in the setting of SLE.




Pre-pregnancy counselling


SLE pregnancies are considered to be of high risk. All patients should be counselled about the possible issues, including the risk of disease flares, higher rates of pregnancy complications, sub-optimal obstetric outcomes and the risk of neonatal lupus syndromes (NLSs). The need for optimal disease control with safe medications during pregnancy should be explained.


Disease activity during pregnancy


One of the major issues in SLE pregnancy is the risk of disease exacerbation. Although it is generally agreed that pregnancy may lead to higher rates of disease flares, widely variable flare rates of between 25% and 65% have been reported . Different organ systems may have variable response to pregnancy; musculoskeletal flares are less common, while renal and haematological flares are more common . Majority of the flares in pregnancy are mild to moderate, with only a small percentage of patients developing severe flares . Active disease during the 6 months prior to conception, history of lupus nephritis and discontinuation of anti-malarial significantly increase the risk of flares during pregnancy .


Pregnancy complications


Pregnancy in the setting of SLE is associated with a higher risk of complications, compared to normal women. A large national database study of 16.7 million deliveries reported manyfold increased risk of maternal death, pre-eclampsia, pre-term labour, thrombosis, infection and haematological complications during SLE pregnancy . However, these results have to be interpreted with caution. Non-pregnant SLE patients also have a higher risk of medical complications and mortality rate. In addition, women with SLE in this study were older and had significantly higher rates of co-morbidities.


The biggest issue is the 3–5 times higher risk of pre-eclampsia, complicating 16–30% of SLE pregnancies . The predisposing factors for pre-eclampsia include advanced maternal age, previous personal or family history of pre-eclampsia, pre-existing hypertension or diabetes mellitus and obesity . In SLE, additional specific risk factors include active or history of lupus nephritis, presence of aPLs, declining complement levels and thrombocytopaenia . A genetic predisposition with heterozygous mutations in complement regulatory proteins was reported in the PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus study) cohort but needs further evaluation .


Obstetric outcomes


The main obstetric issues in the SLE pregnancy are higher rates of foetal loss, pre-term birth, intra-uterine growth restriction (IUGR) and NLSs. However, the rate of foetal loss has declined and live birth rates of 80–90% have recently been reported . Active disease and lupus nephritis increase the risk of foetal loss and other adverse outcomes . Proteinuria, hypertension, thrombocytopaenia and the presence of aPLs are other negative predictors for foetal survival .


Pre-term births, and the morbidity associated with them, are the most frequent problems of SLE pregnancy. Variable rates have been reported, but in the presence of the mentioned adverse prognostic factors, up to half of the pregnancies may end in premature delivery. Thyroid disease is also associated with a higher risk of pre-term birth in SLE pregnancy . About 10–30% of SLE pregnancies are complicated with foetal growth restriction and small for gestational age babies .


Neonatal lupus syndromes


NLSs are a form of passively acquired foetal auto-immunity from maternal antibodies, anti-Ro and anti-La antibodies. Majority of the manifestations, such as rash, and haematological and hepatic abnormalities, parallel the presence of maternal antibodies in the neonatal circulation. They tend to resolve with the clearance of the antibodies by 6–8 months of life. By contrast, cardiac complications are a result of permanent damage to the foetal cardiac conduction system by maternal antibodies.


The cardiac manifestations of NLSs include conduction defects, structural abnormalities, cardiomyopathy and congestive cardiac failure . However, the most common issue is the congenital heart block (CHB). CHB leads to a high foetal mortality; rates of 15–30% have been reported. The majority of survivors require pacemakers, adding to the significant morbidity . CHB affects about 2% of children born to primigravid women with anti-Ro antibodies . However, the risk rises to about 16–20% in subsequent pregnancies, after the birth of an affected child . Other suggested risk factors include higher levels of maternal antibodies, maternal hypothyroidism and foetal genetic polymorphisms .


Medication use during pregnancy


An essential component of pre-pregnancy counselling is the discussion about the use of appropriate medications during pregnancy. Unfortunately, concerns over presumed toxicity often lead to discontinuation of necessary therapy with a resultant increase in disease activity, worsening the outcomes. The United States FDA categories are often not helpful as they are mostly derived from animal data or are outdated. Although majority of SLE therapeutics are potentially harmful and contraindicated, safe options exist and should be continued during pregnancy ( Table 2 ).



Table 2

Medications safe for use during SLE pregnancy.




































Drugs Comments Recommendations
Non-steroidal anti-inflammatory drugs (NSAIDS) First trimester use may be associated with higher risk of congenital malformations, foetal renal impairment and premature closure of ductus arteriosus with use in last trimester Use with caution during the first and second trimester
Discontinue during last trimester
Corticosteroids



  • Prednisolone/Pulse methylprednisolone



  • Flourinated compounds (Betamethasone/dexamethasone)

High doses can lead to higher maternal complications
Some association with impaired neuro-psychological development of the child
Use lowest possible dose
Pulse therapy can be used for acute flares
Limit to one course, for foetal lung maturation
Antimalarials



  • Hydroxychloroquine

Reduced risk of disease flares, CHB and NLS Should be continued in all SLE pregnancies
Immunosuppressants



  • Azathioprine



  • Calcineurin inhibitors (cyclosporine/tacrolimus)

Used in large number of transplant recipients. Recent report of late developmental delays in off springs with azathioprine Limit azathioprine dose to 2 mg/kg/day
Explain the probability of late effects in the child to mother
Anti-hypertensives



  • Methyldopa



  • Labetalol



  • Nifedipine



  • Hydralazine

Concerns about growth retardation with labetalol and impaired utero-placental blood flow with hydralazine Generally safe and preferred drugs for hypertension during pregnancy


Non-steroidal anti-inflammatory drugs (NSAIDs) were considered safe during the first and second trimesters . However, moderate associations between NSAID use in the first trimester and specific birth defects were recently reported . There is also an increased risk of impaired foetal renal function with use of NSAIDs after 20 weeks of gestation. Hence, caution needs to be exercised when using NSAIDs during early pregnancy. Continued use after 32 weeks of gestation can increase the risk of premature closure of the ductus arteriosus by almost 15-fold and should be avoided . The data on the cyclo-oxygenase 2 inhibitors in pregnancy are very limited, and they are best avoided during pregnancy.


Steroid exposure should be limited to a minimum during pregnancy. High doses during pregnancy are associated with an increased risk of diabetes, hypertension, pre-eclampsia and premature rupture of membranes . However, in the case of disease flares, short courses of high doses and/or intravenous pulse methylprednisolone can be used. Patients on a long-term steroid therapy should also receive stress doses at the time of delivery. The use of fluorinated compounds, such as dexamethasone and betamethasone, should be limited to a single course for foetal lung maturity, in cases of premature delivery. Repeated use has been associated with impaired neuro-psychological development of the child in later life and should be avoided .


Hydroxychloroquine should be continued in all pregnant women with SLE. Multiple studies have proven the beneficial effects of hydroxychloroquine in SLE, including during pregnancy. A reduction in the disease activity was noted with no harmful effects on the baby with use of hydroxychloroquine during pregnancy, while discontinuation led to an increase in disease flares . The risk of CHB and NLSs was also significantly reduced in at-risk pregnancies with sustained use of hydroxychloroquine .


Azathioprine is one of the only few immunosuppressive agents that has documented safety during pregnancy . The dose should be limited to a maximum of 2 mg/kg/day, to avoid the risk of foetal cytopenias and immune suppression . An association between the maternal azathioprine therapy during pregnancy and late developmental delays in offspring was suggested by a recent study . However, the confidence intervals were very wide and the study had serious limitations (small sample size, retrospective nature and lack of validated measures). Azathioprine can still be considered safe during pregnancy, but it is prudent to counsel the women about the possible association. Other immunosuppressive drugs with no reported increase in foetal risk are the calcineurin inhibitors, tacrolimus and cyclosporine . Leflunomide was considered to be teratogenic and traditional advice has been to discontinue it for 2 years or perform a wash-out procedure before conception. Recently, two cohort studies reported no increase in the risk of malformations after inadvertent exposure during pregnancy . However, caution needs to be exercised and routine use of leflunomide during pregnancy is not recommended. Most other agents, such as cyclophosphamide, methotrexate and mycophenolate, are contraindicated during pregnancy and should be discontinued at least 3 months before conception. Data on the biologics, such as rituximab or belimumab, during pregnancy are very limited, and they should be discontinued before conception.


Most of the commonly used anti-hypertensive drugs have to be either avoided or used with extreme caution during pregnancy . Angiotensin-converting-enzyme (ACE) inhibitors and angiotensin II receptor blockers can cause specific malformations, the ACE-inhibitor foetopathy. In addition, neonatal arterial hypotension, renal failure and death have been reported. Beta-adrenergic blockers have been associated with IUGR and foetal bradycardia. Diuretics can lead to maternal volume depletion and reduced uteroplacental perfusion. Hence, the safe armamentarium against hypertension during pregnancy is quite limited, including drugs such as hydralazine, methyl-dopa, nifedipine and labetalol .


Low-dose aspirin as an anti-platelet agent is safe during pregnancy, but data on other anti-platelet agents are limited . Heparin does not cross the placenta and is the anticoagulant of choice during pregnancy. Low-molecular-weight heparin (LMWH) has a similar efficacy and safety to unfractionated heparin (UFH). The ease of administration, higher anti-thrombotic to anticoagulant ratio and predictable bioavailability have led to the widespread use of LMWH instead of UFH . Warfarin should be avoided during pregnancy, especially during the first trimester, due to the risk of warfarin embryopathy syndrome . The data on direct factor Xa inhibitor, fondaparinux, are limited but reassuring. It does not cross placenta and may be a possible choice in women intolerant to heparin .


Calcium supplementation should be routinely provided to all pregnant women with SLE, especially those receiving corticosteroids and heparin. Insufficient vitamin D levels during pregnancy are associated with a higher pregnancy morbidity, including gestational diabetes, pre-eclampsia and small for gestational age infants . However, supplemental vitamin D during pregnancy did not consistently or significantly reduce the risk . Although guidelines differ, currently the safest approach is to supplement vitamin D during pregnancy in women at a higher risk . Bisphosphonates should be discontinued 6–12 months prior to pregnancy. Animal data showed a higher maternal and foetal mortality and morbidity, albeit at levels many times higher than clinical doses. Limited human data did not show any serious adverse maternal or foetal effects, but some reports of foetal hypocalcaemia and growth retardation have been noted .




Ante-natal management in SLE patients


Ante-natal management of pregnant patients with SLE requires a close collaboration between rheumatologist and obstetrician. The monitoring should be more frequent and detailed than the usual standard of care. Each visit should include a thorough physical examination, routine laboratory tests and specific investigations, tailored to the risk profile of the particular pregnancy ( Table 3 ). Certain situations, such as disease flare or the presence of specific antibodies, require specific strategies, as discussed below.



Pregnancy in the presence of anti-phospholipid antibodies


The presence of aPLs during pregnancy is associated with a significant risk of pregnancy morbidity and loss. Although aPLs are present in about a quarter to half of patients with SLE, only a fraction of these patients develop antiphospholipid syndrome (APS), defined by the persistence of medium-to-high titre aPLs (anticardiolipin, anti–β2 glycoprotein and/or the lupus anticoagulant) on at least two laboratory tests, 12 weeks apart, in the presence of at least one clinical criterion of thrombosis and/or pregnancy morbidity . However, even asymptomatic women with aPLs, not fulfilling the criteria, have higher rates of pregnancy loss. In addition, aPLs increase the risk of pre-eclampsia, placental insufficiency, IUGR and pre-term delivery. Lupus anticoagulant is more specific in predicting the risk of adverse pregnancy outcomes, compared with other aPLs .


The outcomes of pregnancies exposed to aPLs have significantly improved, and live birth rates of over 80% have been recently reported . The management strategies differ based on the risk profile of each pregnancy. Low-dose aspirin alone is generally recommended for asymptomatic women with only persistently positive aPLs and no prior event, despite limited evidence . The group with recurrent early losses or one or more late foetal losses, but no history of systemic thrombosis, is termed obstetric APS. Aspirin, in combination with prophylactic doses of heparin, significantly reduces the risk of pregnancy loss in this group . LMWH has a similar efficacy to UFH, but requires twice-daily administration at all doses during pregnancy . LMWH must be transitioned to UFH prior to delivery. Heparin treatment needs to be continued for 6 weeks post-partum . The patients with prior systemic thrombosis should receive full therapeutic doses of heparin throughout pregnancy.


Some patients are refractory to the aspirin and heparin treatment and continue to have recurrent losses. The management of these patients requires an individualised approach; all decisions have to be made in discussion with the woman and her partner. An addition of steroids has been reported to improve outcomes . IVIg and plasmapheresis have been tried with benefit in case reports, but data are limited .


Pregnancy in the presence of anti-Ro antibodies


The biggest issue with exposure to the anti-Ro antibodies during pregnancy is the high risk of CHB. Most often CHB develops between 18 and 24 weeks of gestation. It is usually preceded by lesser degrees of conduction delays which may be reversed with early treatment . However, conduction abnormalities can progress very rapidly and many times the first-rhythm abnormality detected is CHB. Many tools have been developed for early detection of lesser degrees of heart block, including foetal Doppler echocardiography, foetal kinetocardiogram and transabdominal foetal electrocardiogram .


Foetal Doppler echocardiography remains the most commonly used modality. All exposed foetuses should be monitored weekly between 16 and 26 weeks of gestation and bi-weekly thereafter . The detection of an early conduction defect, such as prolonged PR interval, should be considered a danger signal. Although some early blocks are transient, the progression to CHB remains unpredictable. Prophylactic treatment should be discussed if the PR interval remains persistently prolonged. Maternal administration of fluorinated corticosteroids has shown foetal survival benefit in some studies. However, the results have not been consistent and the benefits have to be weighed against the higher risk of IUGR and pre-term birth . The treatment of established CHB remains even more unsatisfactory. Improved foetal outcomes were reported after trans-placental treatment with dexamethasone and beta-adrenergic stimulants in one study, but these findings were not replicated . Hydroxychloroquine during pregnancy reduces the risk of cardiac NLSs in at-risk foetuses .


The recurrence risk of CHB in subsequent pregnancies, after an affected pregnancy, is manyfold higher. Hydroxychloroquine reduced this risk by 65% in one study . Open-label data showed beneficial effects of intravenous immunoglobulin (IVIG), but two large randomised controlled trials showed negative results . The study design, dose of IVIG used and different compositions of IVIG may have contributed to the negative outcomes . In summary, currently there is no satisfactory treatment for established CHB.


Disease flare during pregnancy


An important management issue is the difficultly of recognising disease flare in pregnant SLE patients. Many physiological changes of pregnancy may overlap with features of active disease, making differentiation difficult ( Table 4 ). Some common laboratory tests also become less reliable: mild anaemia and thrombocytopaenia are common, erythrocyte sedimentation rate is raised and up to 300 mg/day proteinuria can occur during normal pregnancy. Complement levels rise by 10–50% during normal pregnancy and may appear to remain in the ‘normal’ range, despite disease activity. Thus, the trend of complement levels becomes more important than absolute values. Low and declining levels of complement during pregnancy have been associated with poor pregnancy outcomes . Anti-double-stranded DNA (anti-dsDNA) antibodies may be helpful in the evaluation of disease activity .


Nov 11, 2017 | Posted by in RHEUMATOLOGY | Comments Off on Managing lupus patients during pregnancy
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