Pregnancy and Lupus: Risks and Best Practices

Many women with lupus can have safe, successful pregnancies if they plan in advance with their healthcare teams. This article discusses the different pregnancy risk factors every woman who has lupus should understand, as well as the appropriate steps for modifying her disease management when she wants to have a baby.

• If I have lupus, is it safe for me to get pregnant?
• What are my risks if I have lupus and get pregnant?
• How is pregnancy managed in women with lupus?
• Which lupus medications are safe during pregnancy?
• Which lupus medications are safe for breastfeeding?
• Key points to remember

If I have lupus, is it safe for me to get pregnant?

In years past, women with systemic lupus erythematosus (SLE or “lupus”) were often advised by their rheumatologists and obstetricians to avoid pregnancy due to concern that pregnancy would trigger life-threatening lupus flares. Today, we know that most women with lupus can have successful pregnancies with far less risk. Ideally, pregnancies in patients with lupus are planned in advance and are managed by both an obstetrician (often a high-risk specialist) and a rheumatologist to optimize outcomes.

What are my risks if I have lupus and get pregnant?

Even with improvements in management over the years, the risks of pregnancy-related complications are still increased for lupus pregnancies when compared to the general population. However, recent clinical research has helped rheumatologists to identify patients who may have the highest risk of complications. Complications affecting pregnancies in women with lupus can include:

• Pregnancy loss (early or late)
• Premature babies (premature delivery)
• Small-for-gestational age (SGA) infants (low-birth weight babies)
• Lupus disease flares that may damage the mother’s organs or (very rarely) be life-threatening
• Higher-than-average risks of other pregnancy associated conditions, such as:
  • Gestational hypertension (high blood pressure during pregnancy)
  • Preeclampsia – A condition that affects some women during pregnancy, this can involve gestational hypertension and other blood disorders, high protein in the urine and, in some cases, kidney and liver damage or dysfunction
  • Eclampsia – Seizures caused by the damage to the body described in preeclampsia above, this condition can lead to organ failure and other life-threatening complications

What lupus-related factors affect the risk of pregnancy complications?

The likelihood of problems for both mother and infant depends in part on the degree of the woman’s lupus activity before and during her pregnancy. Pregnancy should be avoided if a woman:

• Experiences severe organ damage, such as kidney failure or insufficiency
• Has very active lupus
• Has certain autoantibodies
• Requires medications to control her lupus which can increase risk of birth defects

For this reason, rheumatologists encourage lupus patients to think ahead and discuss family planning with their physicians, so that these known risk factors can be addressed and modified whenever possible.

Risk factor: Prior organ damage related to SLE

Although severe disease-related organ damage is very rare, when it occurs, becoming pregnant may be dangerous or harmful to either the mother, the child or both. Pregnancy is a very high risk for any woman who has a severe case of kidney or other organ damage due to lupus.

However, patients who undergo successful kidney transplantation after kidney failure can proceed with pregnancy (usually about one year after the transplant). In some circumstances, a patient with serious organ damage may still be able to safely undergo in vitro fertilization and have a surrogate mother carry the pregnancy, in order to have her own biological child. Others may choose to adopt.

Patients with a history of kidney inflammation due to lupus (lupus nephritis) – even if they currently have normal kidney function – are at a higher risk for pregnancy complications than those lupus patients who have not ever had lupus nephritis. The risk of the pregnancy-associated complications preeclampsia and eclampsia may be as high as 25% for lupus patients, versus 5% in the general population. Follow up visits during the pregnancy will include frequent monitoring of blood pressure and urine protein.

Formerly called toxemia, preeclampsia is a condition that develops after 20 weeks of pregnancy and reflects placental insufficiency. (Sometimes also called “uteroplacental vascular insufficiency,” this is when the placenta cannot provide enough nutrients and oxygen to the fetus to support growth.) Symptoms of preeclampsia usually include:

• New onset hypertension (sudden high blood pressure with no previous history of the same)
• High levels of protein in the urine
• Swelling in legs and feet
• Eclampsia, the most severe form of preeclampsia, is much rarer and can lead to seizures or stroke

Distinguishing preeclampsia from a recurrence of active lupus nephritis is challenging, because both affect the kidneys and can cause similar symptoms. Since preeclampsia occurs only after 20 weeks gestation, kidney problems that occur prior to 20 weeks are likely due to SLE. A flare of lupus nephritis is more likely if other clinical symptoms of lupus are also present, such as rash or arthritis, as well as if changes in certain lupus-specific laboratory tests develop, such as rising DNA antibody or dropping complement levels. It is important to differentiate between preeclampsia and lupus nephritis whenever possible, because preeclampsia resolves only after delivery of the baby ends the pregnancy term, whereas active lupus must be managed with medical therapy.

Risk factor: Very active lupus disease activity

Although pregnancy is possible at some point for most lupus patients, optimal pregnancy timing depends in part on the level of lupus disease activity in the months prior to pregnancy. Pregnancy almost always has a better outcome for both mother and child when lupus has been quiet or stable for about six months prior to conception. When a patient’s lupus is very active, it is better to wait and get the disease under control before considering pregnancy. Patients with active disease during the six months prior to conception are at the highest risk for a lupus flare during pregnancy, with rates estimated as high as 60%.

Lupus pregnancy outcomes may also vary with race and ethnicity. Black and Hispanic women with lupus have poorer pregnancy outcomes, even when adjusting for other known risk factors, such as high blood pressure, kidney disease, etc. In addition, first births may be associated with a slight increased risk of flare when compared with subsequent pregnancies.

In a recent report from the PROMISSE study (Predictors of pRegnancy Outcome: bioMarkers In antiphospholipid Syndrome and Systemic Lupus Erythematosus), the risk factors present at the start of pregnancy that were associated with pregnancy complications included:

• High level of lupus disease activity
• Presence of lupus anticoagulant (LAC), a type of antiphospholipid antibody
• The patient’s preexisting need to take medication for high blood pressure before pregnancy
• Non-Caucasian ethnicity

Doctors still do not all agree on the precise risk of the development of a lupus flare as a direct result of becoming pregnant. The PROMISSE study findings suggest that the rate of flare during pregnancy in women with stable lupus and normal kidney function at the time of conception is low. The rate of a severe lupus flare (one that requires hospitalization or a major change in medication) was 3% in the second trimester and 3% in the third trimester. The rate of a mild or moderate flare was less than 15%.

Risk factor: Presence of certain autoantibodies

The presence of certain autoantibodies can be important in predicting risk and in guiding monitoring and therapy.

The presence of antiphospholipid antibodies is associated with an increased risk for early and late pregnancy loss (miscarriage), premature delivery, and SGA infants. These antibodies also appear to increase the risk of developing preeclampsia/eclampsia, including a severe variant called HELLP syndrome (Hemolysis, Elevated Liver function tests and Low Platelets). Antiphospholipid antibodies (aPL) are found in about one-third of patients with lupus, and include three types of aPL:

• Anticardiolipin antibody (aCL)
• anti-Beta-2-glycoprotein-I (aβ2GPI) antibody
• Lupus anticoagulant (LAC)

For patients with a history of typical aPL complications, prophylactic (preventative) therapy is used in subsequent pregnancies.

Obstetric antiphospholipid syndrome (OB APS) is the term used to describe situations where aPL antibodies are moderate to high positive and certain obstetric complications are noted. These include:

• Early pregnancy losses (three or more consecutive losses at less than 10 weeks gestation)
• Late pregnancy losses (one or more losses at 10 or greater weeks gestation)
• Early delivery (at or prior to 34 weeks gestation) due to development of preeclampsia, intrauterine growth delay, or fetal distress

While moderate or high titers of any of the three aPL antibodies may increase risk, LAC is most strongly associated with risk of pregnancy complications. The degree of risk associated with lower level aPL is uncertain but appears to be lower than the risk with moderate to high titer antibodies.

Infants of mothers with anti-Ro/SS-A and anti-La/SS-B antibodies are at risk for a condition called “neonatal lupus erythematosus” (NLE). Approximately one-third of SLE patients and a majority of Sjogren’s syndrome patients have anti-Ro/SS-A and/or anti-La/SS-B antibodies. NLE is not true lupus, but rather the result of inflammation in the developing fetus due to the passage of these antibodies through the placenta. The risk of inflammation in the infant is about 15% to 20%, and usually this inflammation is reversible. When it is present it can cause temporary low platelet count, an irritated liver or rash. The presence of these antibodies generates a 2% risk that the baby will develop complete congenital heart block. This is an irreversible damage to the heart that usually requires placement of a pacemaker in the infant. Very rarely, generalized inflammation of the heart may occur and lead to stillbirth or death of the infant soon after birth.

Risk factor: Medications to control lupus or other rheumatic disease, which can increase the risk of birth defects

When planning pregnancy, it is important to be aware of which lupus medications should not be taken several months before or during the pregnancy, due to their known risk of causing birth defects. These include:

• Mycophenolate mofetil (CellCept)
• Methotrexate
• Cyclophosphamide (Cytoxan)

Patients on these medications are usually tapered off (if possible) or switched to medications that are considered compatible with pregnancy. They are then monitored by their doctor for some months to assure that the new medications are tolerated and effective before a pregnancy is attempted.

How is pregnancy managed in women with lupus?

Plan ahead

One of the most effective ways to optimize the outcome of a pregnancy in lupus patients is to plan ahead and assure that disease is well-controlled using medications that are safe for pregnancy.

Schedule regular rheumatology appointments for monitoring

In general, lupus patients should be seen by a rheumatologist a minimum of once a trimester, with labs checked during those visits. More frequent visits are warranted if there are any complicating issues, and the obstetrician will have separately scheduled follow-up appointments.

Review medications

As noted above, patients should have their medications reviewed and altered prior to pregnancy if necessary.

Check autoantibodies

Patients should have aPL and anti-SSA/Ro and anti-SSB/La antibodies checked prior to or early in a pregnancy. These test results help to define monitoring and possible therapy.

Treat patients with positive aPL

Patients with positive aPL without a history of related obstetric complications are generally treated with low-dose aspirin during pregnancy for potential preeclampsia prevention. The combination of low-dose aspirin (81 mg daily) and injections of a low dose of heparin (most commonly a daily, 40 mg subcutaneous injection of the low-molecular-weight heparin enoxaparin) is the standard prophylactic therapy for aPL-positive patients with typical obstetric complications (OB APS) and has been shown to reduce risk of subsequent pregnancy complications or loss.

For patients with a history of blood clots who are on warfarin, warfarin should be discontinued and replaced with a therapeutic dosage of enoxaparin before or at the onset of pregnancy. During the third trimester, patients are generally monitored with a weekly series of ultrasound tests, as well as nonstress testing (or other fetal monitoring). Aspirin or anticoagulation medication is generally continued for 6 to 12 weeks postpartum to minimize risk of postpartum blood clots.

Monitor the fetus in patients with positive anti-Ro/SS-A and/or La/SS-B antibodies

Because anti-Ro/SS-A and anti-La/SS-B antibodies are associated with risk of complete congenital heart block in the fetus or newborn, monitoring with fetal echocardiograms during part of the pregnancy is recommended.

Antibody-positive women are generally advised to have a series of screenings using fetal echocardiograms between weeks 16 and 26 to monitor the development of the fetal heart conduction system (although the best timing interval for these tests is not known). Because the risk of heart block is 15% to 20% in children of a mother with a previously affected child, many experts recommend that women with such a history have weekly fetal echocardiograms during that period.

Most experts treat incomplete heart block (defined as first- or second-degree heart block) with the steroid dexamethasone (4 mg daily) with the hope of preventing progression. Dexamethasone is a fluorinated steroid, and unlike prednisone, it passes through the placenta largely intact so that it may suppress the autoantibody-induced inflammation in the fetus. Complete heart block in utero has not been shown to be reversible with any therapy, however, and is generally not treated medicinally unless associated with other inflammatory changes in the heart tissue. Instead, a complete heart block in the newborn usually requires a permanent pacemaker.

Preliminary research suggests that being on hydroxychloroquine throughout pregnancy may protect somewhat against the development of heart block. Although it is not yet clear what benefit may be expected, patients with a history of neonatal lupus erythematosus in prior children are generally treated with hydroxychloroquine if they are not already taking the drug and there is no contraindication. While it is not known whether antibody-positive patients without a history of NLE will benefit, many patients with positive serologies are also treated because of the low risk associated with this medication.

Which lupus medications are safe during pregnancy?

Medications unsafe for pregnancy

As discussed in the risk factors section above, mycophenolate mofetil, methotrexate and cyclophosphamide should not be taken several months before or during the pregnancy.*

Medications safe for pregnancy

Common medications for lupus that are safe for pregnant women include:

• Nonsteroidal anti-inflammatory drugs (NSAIDs)
• Nonfluorinated steroids
• Hydroxychloroquine
• Immunosuppressive agents
• Rituximab and belimumab

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Several studies suggest that taking NSAIDs while trying to conceive can negatively affect ovulation and implantation, but the clinical significance of these possible effects is not clear. NSAIDs must be discontinued in the third trimester, however, due to the risk of premature closure of the ductus arteriosus (a primary blood vessel of the heart) in the fetus, which can lead to progressive fetal heart failure). Most experts also suggest low-dose aspirin during pregnancy for all patients with lupus, as this may decrease the risk of developing preeclampsia.

Steroids

The commonly used (nonfluorinated) steroids prednisone and prednisolone are routinely utilized to manage active lupus during pregnancy. In contrast to fluorinated glucocorticoids, these medications cross the placenta in low concentrations due to inactivation by placental enzymes. While early reports suggested an increased risk of cleft lip/palate formation with steroid use during pregnancy, more recent studies have not shown this.

However, the use of steroids throughout pregnancy may increase the risk of:

• Pregnancy-induced hypertension (high blood pressure)
• Gestational diabetes
• Osteoporosis

For these reasons, the goal of treatment is to use the lowest dose for the shortest amount of time.

Hydroxychloroquine

Hydroxychloroquine is an essential component of the management of SLE. Patients with SLE have been shown to have better pregnancy outcomes if they remain on this drug, which does not increase risk of congenital anomalies. Retinal exams of infants exposed to hydroxychloroquine in utero do not show evidence of toxicity.

Immunosuppressive agents

Disease flares are generally managed with prednisone or prednisolone, but if necessary, stronger, immunosuppressive agents safe for pregnancy, such as azathioprine, are used. Azathioprine is commonly used in the management of transplant patients, inflammatory bowel disease patients, and patients with lupus and other rheumatic diseases throughout pregnancy. Published data do not show any increased risk of birth defects in infants exposed to these medications in utero. Similarly, cyclosporine and tacrolimus, studied primarily in pregnant transplant patients, do not appear to increase the risk of birth defects and are alternatives for patients who are unable to tolerate or do not respond to azathioprine.

Rituximab and belimumab

There are limited data regarding use of these relatively new biologic medications during pregnancy. However, because they are modeled on the structure of immunoglobulin G (IgG) proteins, it is expected that very little of either medication is transferred to the fetus until after 12 weeks of gestation, when placental transfer of IgG begins. Because of this delay in transfer to the fetus, it is reasonable to consider continuation of these agents, if necessary, right up until a pregnancy is confirmed. Routine use of these medications throughout pregnancy is discouraged based on the limited number of reports, but rituximab may be considered for use during pregnancy for severe organ or life-threatening disease.

Which lupus medications are safe for breastfeeding?

Several of the above-mentioned therapies are safe for women who are breastfeeding, with some exceptions and variations.

The American Academy of Pediatrics recommends exclusive breastfeeding during the first six months of life and continued breastfeeding for another six months. The short-term benefits of breast-feeding include better nutrition and improved immunity in the infant. Below are helpful guidelines for lupus medication use by women who are breastfeeding:

NSAIDs

NSAIDs cross into breast milk in low concentrations and are compatible with nursing. Ibuprofen is generally recommended, since this has the most information.

Steroids

Nonfluorinated forms such as prednisone and prednisolone are compatible with nursing, since they enter breast milk in low concentrations. With prednisone, at doses greater than 20 mg daily, women are encouraged to either refrain from breastfeeding or pump and discard breast milk for the first four hours after taking the medication to minimize the amount transferred to the infant.

Hydroxychloroquine

Very little hydroxychloroquine is transferred into breast milk, and it is considered compatible with breastfeeding. Breastfed infants whose mothers were taking hydroxychloroquine have not shown retinal or other abnormalities.

Immunosuppressive agents

• Azathioprine is rapidly metabolized (during which it converts to 6-mercaptopurine) and appears in breast milk in very low concentrations; it is considered compatible with nursing.
• Cyclosporine appears to have more variable transfer although it too is considered compatible, as is tacrolimus.
• Mycophenolate mofetil, methotrexate and cyclophosphamide are not recommended for use in lactating women.

Rituximab and belimumab

There are limited data on these biologic drugs during lactation, however very little IgG is transferred into breast milk and so these are likely safe for breastfeeding.

Summary

Successful pregnancies have become the rule, rather than the exception, for women with lupus. In years past, the fear of serious illness or death prevented many women with lupus from pursuing pregnancy. Things have changed: in a recently published analysis of a large national pregnancy database, Bella Mehta, MD, and her coauthors found that rates of pregnancy-related maternal death in patients with lupus decreased dramatically over the last 10 to 15 years. While the overall numbers are very low, the relative risk of women with lupus dying in the setting of pregnancy has dropped from 100 times to 2.5 times the current risk expected in the general population. Other pregnancy complications, though still increased in women with lupus, have improved as well.

Pregnancy outcome is optimized if pregnancy is planned for times of stable or quiet disease and while on pregnancy compatible medications. Open communication between patients and their physicians is critical. Both the rheumatologist and the obstetrician should follow the patient, working together with the patient as a team. Continued research and education should lead to even better outcomes in the years to come.

Key points to remember

• Most patients with lupus can have successful pregnancies.
• Planning for pregnancy can reduce the risk of pregnancy complications.
• Important risk factors for pregnancy complications include active lupus, history of nephritis, and presence of antiphospholipid antibodies.
• Patients with a history of aPL pregnancy complications should be treated with low-dose aspirin and enoxaparin (or other heparin) during pregnancy.
• Patients with positive anti-Ro/SS-A and anti-La/SS-B antibodies are at risk to have a child with neonatal lupus erythematosus, including a 2% risk of complete heart block, and should be monitored with serial fetal echocardiograms from week 16 to week 26.
• Lupus medications considered compatible with pregnancy include hydroxychloroquine, prednisone and prednisolone, azathioprine, cyclosporine and tacrolimus.
• Medications that should not be used during pregnancy include mycophenolate mofetil, methotrexate, and cyclophosphamide. Other medications have inadequate data for use in pregnancy.

Additional online resources

MotherToBaby

• Organization of Teratology Information Specialists (OTIS)
• Includes printable patient fact sheets for common meds
• MotherToBaby.org

Treating for Two Initiative

• Centers for Disease Control and Prevention (CDC)
• cdc.gov/pregnancy/meds/treatingfortwo

End Note

*For many years, physicians relied on the US Food and Drug Administration (FDA) system of assigning a category of risk (A-B-C-D or X) to guide use of any medication during pregnancy. While the categories were developed to reflect the quality and type of information available (animal vs. human clinical research), the letter grade was often incorrectly assumed to imply only risk of birth defects. The FDA is in the process of changing medication labeling to include more clinically relevant data.

Selected references

Sammaritano LR. Management of systemic lupus erythematous during pregnancy. Annual Review of Medicine 2017;68:271-285.

Chakravarty EF, Sammaritano LR. “Pregnancy and Autoimmune Disease, Reproductive and Hormonal Issues”. In: Wallace DJ and Hahn BH (eds). Dubois’ Lupus Erythematosus and Related Syndromes, Ninth Edition. Elsevier; 2019 pp. 499-519.

Buyon JP, Kim MY, Guerra MM, et al. Predictors of pregnancy outcomes in patients with lupus: a cohort study. Ann Int Med. 2015;163(3):153-63.

Flint J, Panchal S, Hurrell A, et. al. BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding-Part 1: standard and biologic disease modifying anti-rheumatic drugs and corticosteroids. Rheumatol. 2016;55:1693-7.

Mehta B, Luo Y, Xu J, et al. "Trends in Maternal and Fetal Outcomes Among Pregnant Women with Systemic Lupus Erythematosus in the United States: A Cross-sectional Analysis". Annals of Internal Medicine. Online July 9, 2019.

Posted: 8/6/2019

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