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Written by: Cristina Popa, MD, Anoushka Krishnan FRACP
AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.
Systemic lupus erythematosus (SLE) affects young women of childbearing age and has significant implications for pregnancy- for both the mother and the fetus. Given that most nephrologists will come across a scenario wherein a young lupus patient wishes to conceive a child, it is essential to have some basic concepts on the outcomes of lupus on pregnancy and vice versa, preconception counseling, and medication regimens that are safe in pregnancy. While some of these topics have been touched upon in the blog on Pregnancy and Transplantation, we will deep dive into lupus and pregnancy in this section.
Let us start by discussing maternal and fetal outcomes in patients with lupus. Perhaps the greatest risk for the mother is lupus flares, which can result in declining (or loss of) kidney function and a significant risk of pre-eclampsia. A systematic review looking at 37 studies, including 1,842 women with active (defined as presence of proteinuria 500 mg/24 hours and/or active urine sediment with or without an elevation in serum creatinine, at time of conception; lupus nephritis flare during pregnancy or a new diagnosis of lupus nephritis during pregnancy) and quiescent lupus nephritis, demonstrated that a systemic lupus flare was not uncommon and occurred in up to 26% of pregnancies. Active lupus nephritis occurred in 16.1% of pregnancies, hypertension was seen in 16.1%, pre-eclampsia in 7.6%, and eclampsia or stroke in 1%. Women with active LN had a higher risk of adverse outcomes. These are all major issues that should be discussed with the mother, emphasizing the need for preconception counseling. Additionally, maternal mortality is nearly 20-fold higher in women with lupus, with a 3-7 fold higher risk of thrombosis and infections. Notably, patients with class 3 or 4 SLE tend to be at higher risk of lupus nephritis (LN) flare and hypertensive complications.
There are several risks to the fetus as well, particularly in patients with active lupus nephritis. Risks include a higher need for cesarean section, spontaneous abortion (16%), higher risk of premature delivery (35%), stillbirth (3.6%), neonatal death (2.5%), and intra-uterine growth restriction (12%). There is also a small risk of neonatal lupus erythematosus (NLE), wherein maternal auto-antibodies cross the placenta and cause symptoms. The incidence rate is estimated at 5-10%, mostly in pregnancies exposed to anti-Ro and anti-La antibodies. The most severe manifestation is congenital heart block (1-2%), requiring early diagnosis and intervention, otherwise resulting in up to 20% perinatal mortality. Congenital heart block typically manifests between 18-24 weeks of pregnancy (when immunoglobulins can cross the placenta), and most surviving children will usually require a pacemaker at an early age. Other manifestations of NLE usually resolve within 3-6 months of birth (coinciding with the half-life of auto-antibodies).
How might women with quiescent disease fare? A large prospective study including patients in the United States and Canada evaluating 385 women at low risk of complications (quiescent disease, no lupus nephritis or active systemic disease {uPCR <1000 mg/g, serum creatinine <1.2 mg/dl, prednisolone use <20 mg}, follow-up in specialist centers, on hydroxychloroquine) demonstrated that severe flares mostly occurred in the second (2.5%) and third trimesters (3%). Nearly 81% had uncomplicated pregnancies. Of those who did have complications, risk factors included ethnicity (non-white or Hispanic), lupus anti-coagulant positive, and those on anti-hypertensive agents. Adverse outcomes, including fetal or neonatal death, preeclampsia or hypertension, in this group were high at 58%.
These data may suggest that women with well-managed lupus do not necessarily have a bad outcome. If pregnancy is planned, the disease is quiescent, the patient is on appropriate pharmacological therapy, and the risk of adverse outcomes can be reduced under close specialist surveillance. Nevertheless, the high-risk nature of this population warrants close supervision and the involvement of a multidisciplinary team.
The conundrum of symptoms: is this a flare or just typical pregnancy symptoms?
Clinicians face a real challenge distinguishing symptoms of an SLE flare in pregnancy because the many physiological signs and symptoms of pregnancy overlap with the clinical features of a lupus flare (Figure 1). Fortunately, most of the time, flares of SLE activity in pregnancy are not severe. In most studies, skin, joint, and constitutional symptoms are the most commonly reported. SLE activity scores were adapted to differentiate between SLE activity and pregnancy.
Figure 1. Common manifestations in lupus and pregnancy (created with BioRender.com)
SLE is associated with a higher risk of flares during pregnancy and a higher risk of preeclampsia. Preeclampsia and lupus activity may have common clinical features, often challenging the differentiation between said entities (Table 1). A kidney biopsy may be advised, but know it is associated with a higher complication rate and a higher bleeding risk, particularly at 23-26 weeks of gestation. The 2019 UK guideline recommends biopsy in the first and early second pregnancy trimesters only if the histological diagnosis is likely to change management (class 1C).
Table 1. Differential diagnostics in SLE flare vs Preeclampsia: laboratory findings (Clowse WE, 2007, Zeisler H, et al, 2016, Dijkstra DJ et al, 2022)
Anti-phospholipid antibody syndrome and pregnancy: a dreaded combination
Up to 40% of patients with lupus have antiphospholipid syndrome (APS). Pregnancy complications in obstetric APS (OAPS) include unexplained, recurrent, early pregnancy loss (before ten weeks gestation), fetal death, or premature birth due to severe preeclampsia, eclampsia, and intrauterine growth restriction. Anti-b2-glycoprotein antibodies, lupus anticoagulant (LAC), and anti-cardiolipin antibodies should be tested. The presence of LAC conveys the greatest risk of adverse outcomes in pregnant women with or without SLE. Other risk factors include younger age and a history of prior thrombotic events. Treating OAPS early improved pregnancy outcomes; in a European registry study of 1000 women with OAPS, 45% received recommended OAPS treatment, and subsequently, nearly 85% had a good live-birth rate.
Preconception planning:
Pre-conception counseling is a pivotal parts of ensuring safe pregnancy for both mother and baby. Clinicians should aim to work with their patients to optimize disease control and work towards the shared goal of a safe pregnancy and healthy baby.
SLE's systemic activity must be evaluated clinically and biochemically, as a recent lupus nephritis flare is a risk factor for recurrence. Ideally, kidney function should be stable, on a safe medical regimen, and without evidence of a flare for at least six months before conception.
Antepartum care must be provided in a multi-disciplinary setting involving obstetricians and nephrologists/ rheumatologists. Expectant mothers should be monitored on a monthly basis (and more frequently if at higher risk). Serial fetal ultrasounds should be performed to evaluate growth.
Pharmacotherapy in pregnancy:
Appropriate pharamco-therapy is also crucial to avoid the associated risks of fetal malformations and miscarriages.
Immunosuppressants: Immunosuppressive drugs safe to use in pregnancy include corticosteroids and azathioprine.
Tacrolimus has been used on occasion, although we lack well-controlled studies on safety in pregnant women. Tacrolimus is considered safe to be used in pregnancy, with a small risk of neonatal hyperkalemia and renal dysfunction, and these parameters should be monitored in the newborn. Any of these three agents may also be used to treat a flare in pregnancy.
Hydroxychloroquine should be continued throughout pregnancy or initiated if there are no contraindications.
Immunosuppressive agents that are unsafe in pregnancy include mycophenolate (risk of miscarriage, first-trimester pregnancy loss, malformations like cleft lip and cleft palate), cyclophosphamide (severe birth defects) and methotrexate (risk of miscarriage and possible birth defects).
Rituximab lacks adequate safety data. EULAR guidelines suggest that while sound data is unavailable for rituximab, registry data have not shown an increased risk of congenital malformations. While it may be considered for use in early pregnancy, its use in late pregnancy can result in severe B-cell depletion in the neonate. The American College of Rheumatology conditionally recommends its use in life/ organ threatening disease. The use of belimumab is also not recommended in pregnancy.
Intravenous immunoglobulins (IVIG) may be used in a flare of LN refractory to other therapies but can be associated with a risk of kidney insufficiency.
In the relatively rare but important scenario of a severe life-threatening flare whereby treatment typically involves teratogenic therapy, shared decision-making should be undertaken with the clinical team and the patient and the patient’s family to discuss the option of termination of pregnancy.
Figure 2. Lupus flare - treatment (created with BioRender.com)
Anti-hypertensive agents: This has already been discussed in detail in our ‘Hypertension in Pregnancy’ segment, but labetalol, nifedipine, and methyldopa are generally safe bets. ACE inhibitors (ACEi) and angiotensin receptor blockers (ARBs) are avoided in the second and third trimesters of pregnancy as they are associated with severe birth defects (oligohydramnios, renal failure, and pulmonary hypoplasia, amongst others). Some evidence suggests that using an ACEi in the first trimester may not be associated with significant anomalies or adverse outcomes. So if your patient is dependable and has reliable menstrual cycles, it may be an idea to continue the ACEi or ARB until she falls pregnant and then cease it (to achieve the maximal anti-proteinuric effect).
ACEi, such as enalapril or captopril, are considered safe during lactation, more on a common practice ground. In a little study, both drugs have been shown to be relatively safe when breastfeeding, with minimal amounts secreted into breast milk. It may be associated with a small risk of neonatal hypotension, and monitoring is recommended.
Anticoagulation: If deep vein thrombosis prophylaxis is required, either unfractionated heparin or low molecular weight heparin may be used. Warfarin is contraindicated in pregnancy due to the risk of fetal birth malformations, spontaneous abortion, perinatal bleeding, and risk of fatal hemorrhage to the fetus in utero (it can cross the placental barrier). Data is limited on direct-acting oral anticoagulants in pregnancy and should therefore be avoided until robust evidence is available. As pregnancy is a pro-coagulant state, low-dose aspirin and therapeutic anticoagulation are advised for all patients with a history of anti-phospholipid (APS) antibody syndrome and a history of the thrombotic events (characterized by venous, arterial, and/or small vessel thrombosis with persistently positive anti-phospholipid antibodies). Treatment is advised throughout pregnancy and 6-12 weeks post-partum. Low-dose aspirin and prophylactically dosed anti-coagulation are recommended for women with known obstetric APS. Close surveillance may be considered in those with APS antibodies who do not meet the criteria for APS, or either low-dose aspirin or anti-coagulation may be used. Prophylactic anticoagulation should also be considered in pregnant women with nephrotic syndrome in the absence of APS antibodies (figure 2). Low-dose aspirin is recommended for all pregnant women with SLE at the beginning of the first trimester.
Lupus remains a tricky condition to manage, and given the population it affects, a working knowledge of how to manage fertility and pregnancy around this challenging condition is important. A shared decision-making process with the treating team and the patient incorporating the patient’s core values and preferences is the key to ensuring optimal maternal and fetal outcomes.
AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.