What to Expect: Prepregnancy Planning in Patients With Systemic Lupus Erythematosus
Kimberly DeQuattro, MD
Clinical Instructor, Department of Medicine
University of California, San Francisco
Citation: DeQuattro K. What to expect: prepregnancy planning in patients with systemic lupus erythematosus [published online August 20, 2019]. Rheumatology Consultant.
Women with systemic lupus erythematosus (SLE), their physicians, and their care teams have entered an era where pregnancy outcomes are commonly successful with management expertise, treatment options, and a multidisciplinary approach. Often, normal pregnancy outcomes occur in SLE patients with stable mild to moderate disease and in those with stable lupus nephritis. Patients with initial pregnancy losses can have subsequent live births. Rheumatologist-led prepregnancy planning for patients who desire children is vital to maximizing positive outcomes in pregnancy. This article addresses key considerations in prepregnancy planning, bearing in mind that each patient is unique and requires a personalized approach. As reproductive guidelines evolve, these recommendations may change in the context of additional evidence-based data.
When is the best time for a patient with SLE to become pregnant?
In general, at least 6 months of controlled SLE prior to conception lowers the risk of flares, maternal hypertension, preeclampsia, and intrauterine growth restriction.
How long before conception should pregnancies be planned?
Planning may take 2 to 3 years prior to conception. Important SLE-specific considerations include current disease activity and manifestations, prior organ damage, active medications/medication history, antibody status (specifically anti-Ro/SSA, anti-La/SSB, and antiphospholipid antibodies [APLa]), as well as prior pregnancy outcomes. Factors common to the general population include time to conceive, establishment of social support, and emotional, mental, and financial readiness. Sharing a timeline and anticipated barriers helps patients to set realistic expectations.
Which specialists are on the multidisciplinary team?
It is appropriate to involve maternal-fetal medicine (MFM) specialists at the preconception counseling phase. Consider MFM referrals for active or recent severe manifestations such as stroke, cardiac involvement, pulmonary hypertension, severe interstitial lung disease, and lupus nephritis, as well as positive antibody status (anti-Ro/SSA, anti-La/SSB, APLa). In select scenarios—severe pulmonary hypertension, interstitial lung disease, for example—the risk of pregnancy may be too great for maternal survival. For these patients, surrogacy or adoption may be safest options. In addition to MFM specialists, nephrologists, hematologists, cardiologists, and/or pulmonologists are important to include in the team depending on relevant organ manifestations. Patients can expect increased frequency of blood draws and office visits, and if there is anti-Ro/SSA or anti-La/SSB positivity, fetal echocardiography.
What are common complications during pregnancy in SLE?
Flares: The overall risk of SLE flare during pregnancy is relatively low, and when flares do occur, most are mild to moderate. Flares conferring the highest obstetric risk are severe flares of nephritis, cytopenias, serositis, and central nervous system lupus.
Maternal Outcomes: Rates of maternal hypertension, preeclampsia, and eclampsia are significantly increased among patients with SLE, particularly in those with a history of nephritis, chronic kidney disease, and/or APLa positivity. Risk of renal damage is high in those with history of nephritis.
Fetal Outcomes: The most common fetal complication is preterm delivery (<37 weeks).1 Others include premature rupture of membranes, preterm premature rupture of membranes, small for gestational age, intrauterine growth restriction, and fetal loss. The acronym, PATH (Proteinuria, Antiphospholipid syndrome [APS], Thrombocytopenia, and Hypertension) indicates factors in the first trimester that increase risk of fetal loss in patients with SLE.
Who is at highest risk of flares during pregnancy?
Patients at highest risk of flares during pregnancy are those with active disease less than 6 months prior to conception, particularly those with active lupus nephritis, and those who stop taking hydroxychloroquine. Active lupus nephritis at conception increases the risk of SLE flares during pregnancy.
How do I guide patients who desire pregnancy yet have active disease?
Occasionally, patients who suspect that their SLE is well-controlled learn from their rheumatologist that it is not. For example, a woman with lupus nephritis appropriately sought prepregnancy planning. After review of her history and new laboratory test results, her rheumatologists recommended a repeated renal biopsy. The biopsy showed active proliferative lupus nephritis, and she was treated with cyclophosphamide. The process to ensure renal response, disease quiescence, and an appropriate nonteratogenic maintenance treatment option delayed her conception by more than a year and a half. Her rheumatologists allayed her concerns about the prolonged prepregnancy course by validating her frustration and providing reassurance. Prepregnancy discussions using clear, direct language at the patient’s level of understanding helps patients weigh risks and make decisions with their partners. This approach can also bolster patient-physician trust towards the goal for a safe pregnancy in the setting of a SLE diagnosis.
Which medications are safe during pregnancy and lactation?
Most teratogenic medications should be stopped and switched to nonteratogenic options 3 months prior to trying to conceive (some exceptions include angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers and warfarin). This allows for a clinical response to the medication change and time for additional adjustments. Review medications that are safe to continue throughout pregnancy with patients to ensure that therapies are not accidentally discontinued. The Table below details teratogenic and nonteratogenic medications. Some considerations include the following:
- Hydroxychloroquine is associated with decreased SLE activity, fewer flares, and improved outcomes in pregnancy. All women with SLE planning to conceive and who are pregnant should take hydroxychloroquine unless there is a contraindication (history of allergy/retinopathy).
- Start low-dose aspirin (81 mg) for all SLE patients beyond 12 weeks of gestation to reduce the risk of preeclampsia. The benefits of higher-dose (162 mg) aspirin nightly is under investigation.
- If possible, taper glucocorticoid therapy to below 20 mg/d and in favor of glucocorticoid-sparing agents.
- Studies on the safety of belimumab during pregnancy are ongoing, although the current recommendation is to stop belimumab at least 4 months prior to conception.
- Nonsteroidal anti-inflammatory drugs are not recommended in the third trimester due to risk of premature closure of the ductus arteriosus.
- Rarely, organ-threatening disease may require the use of certain therapies (cyclophosphamide, rituximab) in the second or third trimesters.
Table. Teratogenic vs Nonteratogenic Medications
LMWH, unfractionated heparind
Labetalol, nifedipine, hydralazinec
aRequires washout prior to conception/during pregnancy
bStop prior to conception
cLikely safe in lactation
dSafe in lactation
Abbreviations: ACEIs, angiotensin-converting enzyme inhibitors; ARBs, angiotensin II receptor blockers; IVIG, intravenous immunoglobulin; LMWH, low-molecular-weight heparin; TNFi, tumor necrosis factor inhibitor.
Source: Drugs and Lactation Database (LactMed). US National Library of Medicine. https://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm. Accessed August 20, 2019.
Which laboratory values should be rechecked prior to each pregnancy, and what should be done if they are positive?
Anti-Ro/SSA antibodies, anti-La/SSB antibodies, and APLa.
- Anti-Ro/SSA and anti-La/SSB antibodies cross the placenta and affect the skin and/or cardiac conduction system of the fetus (see https://www.consultant360.com/exclusive/rheumatology/lupus/erythematous-papules-and-plaques-newborn-case-neonatal-lupus for additional discussion on neonatal lupus). There is a 1% to 2% risk of congenital heart block with anti-Ro/SSA anti-La/SSB antibody positivity due to the impact on the cardiac conduction system.2 This risk increases in a woman with a previous pregnancy affected by neonatal lupus, with or without congenital heart block. Serial fetal echocardiography is considered in the second trimester, from week 16 to 28 of pregnancy.
- SLE patients with positive APLa who have secondary APS have a greater risk of fetal or neonatal death, preterm delivery from placental insufficiency, hypertension, preeclampsia, and small for gestational age than those without APS.3 The risk of thromboses and miscarriage/fetal loss is increased, as well.
Do all patients with APS receive the same anticoagulation just prior to conception and during pregnancy?
No. Treatment recommendations differ if there is a history of obstetric APS or thrombotic APS:
- For positive APLa only, no additional therapy is needed.
- For positive APLa with obstetric* APS, use prophylactic doses of unfractionated or low-molecular-weight heparin and low-dose aspirin.
- For positive APLa with thrombotic APS, use therapeutic doses of unfractionated or low-molecular-weight heparin and low-dose aspirin.
*Obstetric APS: >1 fetal death with normal morphology at >10 weeks of gestation; >1 normal neonate with birth <34 weeks due to preeclampsia, eclampsia, or placental insufficiency; and >3 consecutive spontaneous abortions at <10 weeks of gestation not due to chromosomal, maternal, or hormonal abnormalities.
Overall, what is a general timeline prior to conception?
Recall 3:3:3 to help SLE patients plan before trying to conceive: 3 trimesters in pregnancy; 3 key preconception time points; and by 3s (3 years, 3 × 2 months, and 3 months). Consider the following:
- 3 years prior to conception, start prepregnancy planning. Assess using the mnemonic DiAMOnD MAP: Disease Activity and Manifestations; Organ Damage; Medications; Antibody status (anti-Ro/SSA, anti-La/SSB, APLa); and Prior pregnancy outcomes—and begin to assemble the multidisciplinary team.
- 3 × 2 months (6 months) prior, achieve disease quiescence to minimize flares, preeclampsia, and other adverse pregnancy outcomes.
- 3 months prior, switch to a nonteratogenic medication regimen and recheck anti-Ro/SSA, anti-La/SSB, and APLa.
- Clowse ME, Magder LS, Witter F, Petri M. The impact of increased lupus activity on obstetric outcomes. Arthritis Rheum. 2005;52(2):514-52
- Cimaz R, Spence DL, Homberger L, Silverman ED. Incidence and spectrum of neonatal lupus erythematosus: a prospective study of infants born to mothers with anti-Ro autoantibodies. J Pediatr. 2003;142(6):678-683.
- Buyon JP, Kim MY, Guerra MM, et al. Predictors of pregnancy outcomes in patients with lupus: a cohort study. Ann Intern Med. 2015;163(3):153-16
Acknowledgement: Sarah Goglin, MD, for content input.
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