2/6/2020 Pregnancy in women with systemic lupus erythematosus - UpToDate

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Pregnancy in women with systemic lupus erythematosus

Authors: Bonnie L Bermas, MD, Nicole A Smith, MD, MPH
Section Editors: David S Pisetsky, MD, PhD, Charles J Lockwood, MD, MHCM
Deputy Editor: Monica Ramirez Curtis, MD, MPH

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jan 2020. | This topic last updated: Jan 23, 2020.

INTRODUCTION

Systemic lupus erythematosus (SLE) predominantly affects women of childbearing age. Fertility in
SLE patients does not appear to be altered by disease itself; however, a decrease in ovarian reserve
can occur in women exposed to cyclophosphamide.

Pregnancy in women with SLE carries a higher maternal and fetal risk compared with pregnancy in
healthy women. The prognosis for both mother and child is best when SLE has been quiescent for at
least six months prior to the pregnancy. Disease flares during SLE pregnancy pose challenges with
respect to distinguishing physiologic changes related to pregnancy from disease-related
manifestations. Thus, a multidisciplinary approach with close medical, obstetric, and neonatal
monitoring is necessary to optimize both maternal and fetal outcomes.

This topic review will discuss the major risks associated with pregnancy in SLE patients, as well as
management recommendations. Issues related to menstrual function, menopause, estrogen
replacement therapy, and the use of oral contraceptives in women with systemic lupus erythematosus
are presented separately (see "Menstrual function, menopause, and hormone replacement therapy in
women with systemic lupus erythematosus" and "Approach to contraception in women with systemic
lupus erythematosus"). Issues related to pregnancy in patients with impaired renal function or with
antiphospholipid syndrome (APS) are also presented elsewhere. (See "Pregnancy in women with
nondialysis chronic kidney disease" and "Antiphospholipid syndrome: Pregnancy implications and
management in pregnant women" and "Neonatal lupus: Epidemiology, pathogenesis, clinical
manifestations, and diagnosis".)

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PREGNANCY PLANNING

Ideally, disease should be quiescent for six months prior to systemic lupus erythematosus (SLE)
patients attempting conception. Active SLE at the time of conception is a strong predictor of adverse
maternal and obstetrical outcomes [1-3]. In spite of this risk, the majority of such pregnancies still
result in live births. The following studies are illustrative:

● The largest observational study, including 385 pregnant lupus patients with inactive or mild or
moderate disease at conception, found 81 percent of subjects had uncomplicated pregnancies
[4]. After controlling for baseline risk factors such as lupus anticoagulant, treatment for
hypertension, thrombocytopenia, disease flare, or moderate disease activity at baseline, non-
Hispanic white patients had an 8 percent rate of adverse pregnancy outcomes. However, the
study population was limited as it excluded women with high disease activity, active lupus
nephritis, uncontrolled hypertension, and diabetes.

● A study of 267 pregnancies in a cohort of lupus patients found that women with high disease
activity compared with low disease activity in the first and second trimesters showed a threefold
increase in pregnancy loss (miscarriages and perinatal mortality) [1]. However, overall there was
no statistically significant difference in the number of live births between the women with high
disease activity compared with low disease activity (77 percent versus 88 percent, respectively).

Our approach to pregnancy planning and management in SLE is generally consistent with
recommendations developed by the European League Against Rheumatism (EULAR) [5].

Preconception evaluation — A preconception assessment is essential in women with SLE to

determine whether pregnancy may pose an unacceptably high maternal or fetal risk, to initiate
interventions to optimize disease activity, and to adjust medications to those that are least harmful to
the fetus.

Women should be advised that discontinuation of medications used to control disease activity
increases the risk of lupus flare and pregnancy complications. Ideally, women considering conception
should be maintained on medications that are compatible with pregnancy and should continue these
medications in pregnancy. Clinical features specific to pregnancy in the setting of SLE are discussed
below. A more general discussion on preconception care and risk assessment in all women is
presented separately. (See "The preconception office visit".)

Risk assessment — The preconception evaluation in women with SLE should include an
assessment of disease activity and major organ involvement, as well as hypercoagulability or
concurrent medical disorders that may impact pregnancy. Previous obstetric outcomes should be

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reviewed, with particular attention paid to history of small for gestational age fetus, preeclampsia,
stillbirth, miscarriage, and preterm birth. An approach to the assessment of disease activity and
severity of SLE is discussed separately. (See "Overview of the management and prognosis of
systemic lupus erythematosus in adults", section on 'Assessment of disease activity and severity'.)

Patients with evidence of active SLE, especially lupus nephritis, should be advised to defer
pregnancy until the disease is well controlled for at least six months. For those with renal
insufficiency, counseling should include an assessment of the risk of temporary or permanent decline
in renal function. (See "Pregnancy in women with nondialysis chronic kidney disease".)

Increased severity of maternal disease generally correlates with higher maternal and fetal risk in
pregnancy. Thus, recent stroke, cardiac involvement, pulmonary hypertension, severe interstitial lung
disease, and advanced renal insufficiency can be dangerous to both mother and fetus. Women with
these or other worrisome medical conditions should be counseled carefully by a Maternal Fetal
Medicine specialist as to their individual risk profile, with clear discussion of the morbidity and
mortality risks to both mother and fetus associated with pregnancy. Alternatives such as gestational
carriers and adoption should be presented. Should they elect to pursue pregnancy, they should be
followed in a multidisciplinary fashion in a high-risk center [6,7].

Specific maternal antibody status such as antiphospholipid antibodies (aPLs) and antibodies to Ro/La
should be assessed. aPLs may increase obstetric risks such as recurrent pregnancy loss, stillbirths,
and preeclampsia while antibodies to Ro/La predispose to neonatal lupus (NL) [6]. (See "Neonatal
lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis" and "Antiphospholipid
syndrome: Pregnancy implications and management in pregnant women".)

Specific laboratory testing — In addition to routine preconception labs (see "The preconception
office visit", section on 'Laboratory assessment'), the following should be reviewed during the
preconception evaluation (see "Overview of the management and prognosis of systemic lupus
erythematosus in adults", section on 'Laboratory evaluation'):

● aPLs: lupus anticoagulant (LA), immunoglobulin G (IgG) and IgM anticardiolipin (aCL) antibodies,
and IgG and IgM anti-beta2-glycoprotein (GP) I antibodies
● Anti-Ro/SSA and anti-La/SSB antibodies
● Renal function (creatinine, urinalysis with urine sediment, spot urine protein/creatinine ratio)
● Complete blood count (CBC)
● Liver function tests
● Anti-double-stranded deoxyribonucleic acid (dsDNA) antibodies
● Complement (CH50, or C3 and C4)

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Medications — Medications must be reviewed and adjusted prior to conception with the goal of
maintaining disease control with medications with the best safety profile during pregnancy. Although
some medications used to treat SLE are potentially harmful or contraindicated during pregnancy,
there are safe options. Information regarding the use of immunosuppressive agents in pregnant
patients with SLE can be found below, and in a separate topic (see "Safety of rheumatic disease
medication use during pregnancy and lactation"). The most commonly used medications used to treat
patients with SLE are reviewed briefly below.

Recommended during pregnancy

● Hydroxychloroquine – We continue use of hydroxychloroquine (HCQ) during pregnancy in all

patients with SLE, unless otherwise contraindicated. Several studies have demonstrated fewer
disease flares and better outcomes in patients continuing HCQ during pregnancy, with no
increase in adverse events or congenital malformations [8-16]. A randomized trial including 20
consecutive pregnant patients with SLE found no differences between disease flare rates, but
patients in the HCQ group were able to reduce the prednisone dosage [13]. In addition, the HCQ
group had significantly lower disease activity scores after delivery compared with the placebo
group. Findings from a larger prospective study with 257 pregnancies in 197 women also found
that discontinuation of HCQ during pregnancy was associated with a higher rate of flare
compared with women who either continued HCQ during pregnancy or never took it [8]. In
addition, high disease activity occurred in twice as many pregnancies in which HCQ was stopped
compared with those who continued taking HCQ. The relative safety of HCQ during pregnancy is
discussed in detail separately. (See "Safety of rheumatic disease medication use during
pregnancy and lactation", section on 'Hydroxychloroquine'.)

Additionally, some data suggest a decrease in occurrence of congenital heart block in at-risk
fetuses of mothers with anti-Ro/SSA and anti-LA/SSB antibodies exposed to HCQ [17]. (See
"Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on
'Heart block'.)

● Low-dose aspirin – We initiate low-dose aspirin in all women with SLE, starting from
approximately 12 weeks gestation, to reduce the risk of preeclampsia and its sequelae (eg, fetal
growth restriction), regardless of the presence of antiphospholipid antibodies (aPLs). This
approach is consistent with the recommendation by the United States Preventive Services Task
Force to use low-dose aspirin in women at high-risk of developing preeclampsia, which includes
women with SLE [18]. Recommendations for prophylactic use of low-dose aspirin during
pregnancy for prevention of preeclampsia are discussed in detail separately. (See "Safety of
rheumatic disease medication use during pregnancy and lactation", section on 'NSAIDs' and
"Preeclampsia: Prevention".)

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Selective use allowed during pregnancy — The following drugs have a reasonable safety
profile during pregnancy, but certain limitations apply to their use. Nonsteroidal antiinflammatory
drugs (NSAIDs), glucocorticoids, azathioprine, and some antihypertensive medications are included
in this category. They each have a small risk of causing fetal harm, but their use may be acceptable if
needed to control manifestations of SLE during pregnancy.

● Nonsteroidal antiinflammatory drugs – NSAID use is not associated with congenital anomalies.
There is conflicting evidence as to whether exposure to NSAIDs during the first trimester
increases the risk of spontaneous abortion; in women having difficulty conceiving, one can
consider avoiding these medications during the first trimester. After the first trimester, NSAIDs
may be used until 30 weeks of gestation. As transient oligohydramnios has been reported with
daily use of diclofenac, these medications should be used judiciously. Use of NSAIDs after 30
weeks of gestation may cause premature closure of the ductus arteriosus as well as other
complications, and should be avoided during that time.

● Glucocorticoids – Glucocorticoids are used for a wide range of maternal diseases in pregnancy.
We suggest control of disease with the lowest possible dose of prednisone, ideally less than 10
mg/day. While there were some reports of glucocorticoid use during the first trimester being
associated with cleft lip, with and without cleft palate, subsequent studies have failed to
consistently demonstrate an increased risk of this malformation. Maternal and fetal adverse
effects of glucocorticoids are discussed in detail separately. (See "Safety of rheumatic disease
medication use during pregnancy and lactation", section on 'Glucocorticoids'.)

● Azathioprine – Azathioprine is compatible with pregnancy, but doses should not exceed 2
mg/kg/day. (See "Safety of rheumatic disease medication use during pregnancy and lactation",
section on 'Azathioprine and 6-mercaptopurine'.)

● Cyclosporine – Limited observations suggest that children exposed in utero to cyclosporine have
normal renal function and blood pressure. The manufacturer suggests that use in pregnancy
should be limited to when maternal benefit outweighs fetal risk. (See "Safety of rheumatic
disease medication use during pregnancy and lactation", section on 'Cyclosporine'.)

● Tacrolimus – A causal relationship between tacrolimus use and birth defects has not been found,
though the number of fetuses exposed in utero has been small. An small case series of nine
pregnant lupus patients reported successful disease maintenance or control of lupus nephritis
flares with tacrolimus [19] (See "Safety of rheumatic disease medication use during pregnancy
and lactation", section on 'Tacrolimus'.)

● Antihypertensive medications – Methyldopa, labetalol, nifedipine, and hydralazine are the most
commonly used antihypertensives in pregnancy. By comparison, angiotensin-converting enzyme

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(ACE) inhibitors and angiotensin II receptor blockers are contraindicated during pregnancy.
Diuretics should be used with caution. Nitroprusside is the agent of last resort for urgent control
of refractory severe hypertension; its use should be limited to a short period of time in an
emergency situation. (See "Management of hypertension in pregnant and postpartum women"
and "Adverse effects of angiotensin converting enzyme inhibitors and receptor blockers in
pregnancy".)

Selective use with caution in pregnancy

● Biologic medications – Data regarding the use of biologic medications such as the B-cell
depleting antibody, rituximab, or the BAFF inhibitor, belimumab, during pregnancy are limited.
Given that IgG does not cross the placenta in significant amounts until week 12 of gestation, we
continue these medications through conception. In our practice, while we do not encourage
rituximab use if there is another option, we will continue to support its use throughout pregnancy
as preferable to a flare of SLE. (See "Safety of rheumatic disease medication use during
pregnancy and lactation", section on 'Rituximab'.)

Contraindicated in pregnancy

● Cyclophosphamide – Cyclophosphamide is associated with congenital (or fetal) malformations

and should be avoided during the first 10 weeks of gestation, when the fetus is most susceptible
to teratogens (figure 1). However, in life-threatening clinical situations, this medication has been
used in late pregnancy. (See "Safety of rheumatic disease medication use during pregnancy and
lactation", section on 'Cyclophosphamide'.)

● Mycophenolate mofetil – Congenital anomalies have been reported in infants exposed to

mycophenolate mofetil during pregnancy. This medication should be avoided during pregnancy.
(See "Safety of rheumatic disease medication use during pregnancy and lactation", section on
'Mycophenolate mofetil'.)

Azathioprine or tacrolimus can be substituted for mycophenolate prior to and during pregnancy,
or, alternatively, glucocorticoids may be used at the lowest dose that controls disease activity.
Ideally, this transition in medication should take place six months prior to conception. (See
"Safety of rheumatic disease medication use during pregnancy and lactation", section on
'Azathioprine and 6-mercaptopurine'.)

● Methotrexate – Methotrexate is teratogenic and should not be used during pregnancy. (See
"Safety of rheumatic disease medication use during pregnancy and lactation", section on
'Methotrexate'.)

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● Leflunomide – While not a definitive teratogen, this medication should be avoided during
pregnancy. Patients taking this medication who would like to conceive should do a
cholestyramine washout until blood levels are undetectable. (See "Safety of rheumatic disease
medication use during pregnancy and lactation".)

Ideally conception should only be attempted in a state of disease remission or stable disease on
medications compatible with pregnancy. However, if pregnancy occurs during a period of disease
activity, medications will need to be adjusted for fetal and maternal safety.

SPECIFIC CONSIDERATIONS DURING PREGNANCY

Exacerbation of SLE — Although it is generally accepted that pregnancy and the postpartum period
are associated with a higher rate of systemic lupus erythematosus (SLE) disease flares, widely
variable rates have been reported ranging from 25 to 60 percent [3,7,20,21]. Some of this variation
may be attributed to the heterogeneous study designs, diverse patient and control groups, and
different definitions of flares used in the studies. For comparison, the background rate of flare of SLE
is approximately 30 percent per year.

The following factors are associated with an increased risk of SLE flare during pregnancy [1,8,22-24]:

● Active disease during the six months prior to conception

● A history of lupus nephritis
● Discontinuation of hydroxychloroquine (HCQ)
● Primigravidas

Impact of lupus on pregnancy — Pregnancy in the setting of SLE is associated with a higher risk of
complications compared with healthy women. The largest study to evaluate maternal and pregnancy
complications associated with SLE included 13,555 pregnancies [25]. Women with SLE also had a
two- to fourfold increased rate of obstetric complications including preterm labor, unplanned cesarean
delivery, fetal growth restriction, preeclampsia, and eclampsia. Patients with SLE also had a
significantly higher risk of thrombosis, infection, thrombocytopenia, and transfusion. This study also
reported that maternal mortality was 20-fold higher among women with SLE; however, mortality
amongst similar-aged SLE patients who were not pregnant was even higher. Another study found that
increased rates of hypertension during pregnancy, preterm delivery, unplanned cesarean delivery,
postpartum hemorrhage, and maternal venous thromboembolism were all more frequent in women
with SLE compared with pregnancies of women without SLE [26]. Encouragingly, a large population-
based study suggested that pregnancy complications including mortality rates are decreasing in SLE,
although still higher compared with those without SLE [27].

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Several predictors of adverse pregnancy outcomes among women with SLE have been identified and
include active disease, use of antihypertensives, prior lupus nephritis, the presence of
antiphospholipid antibodies (aPLs), and thrombocytopenia [4,28]. Moreover, primigravidas are at
higher risk for pregnancy complications [24].

Preeclampsia — Preeclampsia is one of the most frequent complications of pregnancy in SLE,

occurring in 16 to 30 percent of women with SLE, compared with 4.6 percent of pregnancies in the
general obstetric population [3,29-31]. Risk factors for preeclampsia in women with SLE are the same
as those in healthy women and are discussed separately (see "Preeclampsia: Clinical features and
diagnosis", section on 'Risk factors'). Additional risk factors for preeclampsia that are specific to SLE
patients include an active or prior history of lupus nephritis, declining complement levels, and
thrombocytopenia. The data on whether aPLs predispose to preeclampsia is unclear, although some
studies suggest an association [29,32].

Preterm birth — Preterm birth is the most common obstetric complication in women with SLE. Rates
of preterm birth from 15 to 50 percent are reported, with increased incidence in women with lupus
nephritis or high disease activity. This compares with 12 percent of pregnancies in the general United
States obstetric population [1,23,29]. In women with SLE, the majority of preterm births are medically
indicated due to preeclampsia or maternal SLE activity [33]. The presence of lupus nephritis and
active disease are the strongest predictors for early delivery [20,30,34]. The rates of preterm birth are
likely better among women without such risk factors [4].

Fetal complications — Fetal complications during pregnancy in patients with SLE include
miscarriage, stillbirth, growth restriction, neonatal lupus (NL) syndromes, and complications of
prematurity.

● Fetal loss – Historically, significantly elevated rates of both early and late pregnancy loss have
been seen in women with SLE. Many contemporary studies group all losses from the embryonic
stage (up to 9 to 10 weeks gestation) to stillbirth (fetal death at 20 or more weeks) under the term
“fetal loss,” making it challenging to interpret the risk of early miscarriage versus later fetal death.

The effect of SLE on embryonic losses is controversial, with a possible slight increase in risk.
Women with SLE are at increased risk of fetal death beyond 10 weeks, particularly in the
presence of active SLE, lupus nephritis, and antiphospholipid syndrome (APS). Overall, fetal loss
rates amongst SLE patients have been declining over the last decades, with increased rates of
livebirths [1,34,35]. A large observational cohort of patients with inactive lupus or mild to
moderate disease activity at conception found that 5 percent of pregnancies ended in fetal or
neonatal death [4]. For comparison, the population risk of miscarriage at less than 20 weeks
gestation ranges from 8 to 20 percent [36,37].

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● Fetal growth restriction – About 10 to 30 percent of pregnancies in women with SLE are
complicated by fetal growth restriction and small-for-gestational-age babies compared with about
10 percent of pregnancies in the general obstetric population [20,23,38]. As with the other
complications, the risk is higher in the presence of active disease, hypertension, and lupus
nephritis. Lower birth weight at every gestational age is also more prevalent in women with SLE
[26].

● Neonatal lupus – NL is a passively transferred autoimmune disease that occurs in some babies
born to mothers with anti-Ro/SSA or anti-LA/SSB antibodies, who may or may not carry the
diagnosis of SLE or Sjögren’s. The major manifestations of NL are either cutaneous or cardiac,
but other manifestations of NL include hematologic and hepatic abnormalities.

The most serious complication in the neonate is congenital complete heart block, which occurs in
approximately 2 percent of children born to primigravid women with anti-Ro/SSA antibodies [39].
In women who have had a child with congenital complete heart block, the risk of complete heart
block increases to approximately 16 to 18 percent for subsequent pregnancies, or 10 to 15
percent when a previous infant had cutaneous NL [40-42]. Data suggest that congenital heart
block may occur more frequently in the setting of anti-Ro52, as opposed to anti-Ro60 or anti-La
antibodies; however, at this time, neonatal surveillance should not be altered by antibody type,
and Ro antibody differentiation is not routinely performed to guide obstetric care [43,44]. The
pathogenesis, clinical manifestations, screening, prevention, and treatment of NL are discussed
separately. (See "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and
diagnosis" and "Congenital third degree (complete) atrioventricular block".)

SLE does not appear to confer risks for other identifiable congenital abnormalities [45,46]. Some
studies have found that learning disabilities may be more frequent in children, particularly sons, of
SLE mothers, while others support similar neurodevelopmental outcomes in children of women with
and without SLE [47-50].

Special considerations

Lupus nephritis — Women with active lupus nephritis should be encouraged to delay pregnancy
until the disease is inactive for at least six months to optimize maternal outcomes. As discussed
above, a previous history of lupus nephritis or active lupus nephritis during pregnancy is associated
with higher rates of maternal and fetal complications. The following examples are illustrative:

● An observational study with 193 pregnancies of 104 women with SLE, among which 81 occurred
in the presence of active renal disease, found that low birth weight was observed more frequently
in pregnancies with renal disease [22]. The presence of active renal disease during pregnancy

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was also associated with an increased frequency of pregnancy-induced hypertension and lupus
flares.

● Another retrospective study of 95 pregnancies among women with SLE found that a previous
history of lupus nephritis was a predictor for adverse maternal outcomes [23]. Pregnancies of
women with previous nephritis were associated with a higher risk of maternal complications (88
percent versus 43 percent, respectively) and a higher rate of flares (54 percent versus 25
percent, respectively), most of which were renal flares. However, most renal flares in this cohort
were not severe, responded to high doses of prednisone, and did not lead to pregnancy loss.

● A retrospective study of 90 pregnancies among 58 lupus patients found significantly lower rates
of preeclampsia, preterm birth, and pregnancy loss among women with lupus nephritis in
remission compared with women with active lupus nephritis (35, 30, and 25 percent versus 57,
52, and 35 percent, respectively) [34].

Thus, these women require careful monitoring during pregnancy, and may require medication to
control their disease. A detailed discussion of pregnancy in women with underlying renal disease is
presented separately (see "Pregnancy in women with nondialysis chronic kidney disease"), and the
approach to therapy of a flare of lupus during pregnancy is discussed below. (See 'Management
during pregnancy' below.)

Women with SLE who have received renal transplants have pregnancy outcomes that are similar to
those of other transplant recipients [51]. Management of pregnancy following renal transplantation is
discussed separately. (See "Sexual and reproductive health after kidney transplantation", section on
'Pregnancy'.)

Presence of antiphospholipid antibodies — aPLs are present in about a quarter to a half of

patients with SLE; however, few patients develop thrombotic or obstetric complications related to
APS.

Pregnant women with SLE who have an obstetric history suggestive of APS (fetal death after 10
weeks or three or more consecutive miscarriages, or premature birth <34 weeks due to preeclampsia
or placental insufficiency) or unexplained venous or arterial thrombotic event, should be tested for the
presence of aPLs (ie, lupus anticoagulant [LA], immunoglobulin G [IgG] and IgM anticardiolipin [aCL]
antibodies; and IgG and IgM anti-beta2-glycoprotein [GP] I). The clinical manifestations, diagnosis,
and management of women with aPL who are contemplating pregnancy or who are pregnant are
discussed in more detail separately. (See "Antiphospholipid syndrome: Pregnancy implications and
management in pregnant women" and "Diagnosis of antiphospholipid syndrome".)

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It is unclear whether women with aPLs without an APS diagnosis are at increased risk of pregnancy
loss [52]. Issues associated with the presence of these autoantibodies in pregnant women and the
management of such patients is discussed separately. (See "Antiphospholipid syndrome: Pregnancy
implications and management in pregnant women", section on 'Management'.)

Presence of anti-Ro and anti-La antibodies — As mentioned above, a fetus exposed to anti-
Ro/SSA and/or anti-La/SSB antibodies is at an increased risk of developing congenital complete
heart block or NL (see 'Fetal complications' above). In most cases, congenital heart block develops
between 18 and 24 weeks of gestation. Thus, in some centers, women who have antibodies to
Ro/SSA and/or La/SSB undergo increased fetal surveillance for heart block, with differing surveillance
protocols at different sites. While there is no therapeutic intervention proven to prevent progression,
early detection allows for increased monitoring. The monitoring and management of congenital heart
block associated with neonatal lupus is discussed in detail separately. (See "Neonatal lupus:
Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Heart block' and
"Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on
'Fetal surveillance for heart block' and "Neonatal lupus: Management and outcomes", section on 'In
utero management'.)

HCQ use during pregnancy has been associated with reduced rates of congenital heart block
[17,53,54]. (See "Neonatal lupus: Management and outcomes", section on 'Prevention of NL in
subsequent pregnancies'.)

Women with anti-Ro/SSA and anti-La/SSB may have detectable amounts of these antibodies in
breast milk, but there is no evidence that NL results from breast feeding [55].

MANAGEMENT DURING PREGNANCY

Management of pregnant women with systemic lupus erythematosus (SLE) should involve close
collaboration between a rheumatologist and an obstetrician experienced in caring for high-risk
mothers. An approach to monitoring pregnant women with SLE as well as treating active SLE during
pregnancy is presented below.

Monitoring SLE activity — Women should be assessed by a rheumatologist for disease activity at
least once each trimester, and more frequently if they have active SLE. The schedule for monitoring
includes:

Initial evaluation — At the first visit after (or at which) pregnancy is confirmed, the following
investigations are recommended [56]:

● Physical examination, including blood pressure

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● Renal function (creatinine, urinalysis, spot urine protein/creatinine ratio)

● Complete blood count (CBC)
● Liver function tests
● Anti-Ro/SSA and anti-La/SSB antibodies
● Lupus anticoagulant (LA) and anticardiolipin antibody (aCL) assays
● Anti-double stranded DNA (dsDNA) antibodies
● Complement (CH50, or C3 and C4)
● Serum uric acid

Some physiological changes of pregnancy may overlap with features of active SLE, making
differentiation difficult. As an example, laboratory findings that may be observed during a normal
pregnancy include mild anemia, mild thrombocytopenia, elevated erythrocyte sedimentation rate
(ESR), and proteinuria. Protein excretion increases in the course of normal pregnancy, but should
remain below 300 mg/24 hours. A baseline 24-hour urine collection can be helpful in distinguishing
lupus flare from preeclampsia and normal changes later in pregnancy (see 'Preeclampsia versus
lupus nephritis' below). Also, during normal pregnancy, complement levels may rise by 10 to 50
percent, and may appear to remain normal despite active SLE. Thus, the trend of complement levels
is generally more informative than the actual value.

Thus, laboratory testing must be interpreted in the clinical context and women who show evidence of
increased serologic activity but who remain asymptomatic should be monitored more closely. We do
not initiate therapy for serologic findings alone.

Laboratory testing — In addition to a physical examination with blood pressure testing, the
following laboratory tests are recommended at regular intervals during pregnancy:

● CBC
● Creatinine
● Urinalysis with examination of urinary sediment
● Spot urine protein/creatinine ratio or 24-hour urine collection

The following laboratory tests should be performed in patients with active disease or who have
previously manifested changes in these levels with a flare:

● Anti-dsDNA antibodies
● Complement (CH50, or C3 and C4)

Ordering additional laboratory tests such as liver function tests and serum uric acid should be guided
by the clinical presentation. The frequency of laboratory testing is individualized and varies with

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disease activity. Patients with stable disease should ideally undergo laboratory testing each trimester,
but those with active lupus will require more frequent testing.

Postpartum laboratory testing — Some women will experience exacerbations of SLE in the
postpartum period. Those who have had active disease at conception and those with significant end-
organ damage are at greater risk of disease flares in the postpartum period compared with women
with inactive disease [57]. Thus, periodic assessment of disease activity is warranted postpartum.
The following laboratory tests are recommended at one month following an uncomplicated delivery
[56]:

● Urinalysis, urine protein/urine creatinine ratio

● Renal function if the urinalysis is abnormal
● CBC

We also check the following laboratory tests in patients with severe disease or in those in whom the
anti-dsDNA and complement levels correlate well with disease activity:

● Anti-dsDNA
● Complement (CH50, or C3 and C4)

Treatment of postpartum women with active SLE is the same as that of nonpregnant women. Some
medications used for the management of active SLE are not compatible with breastfeeding; thus,
breastfeeding women will require thoughtful discussions with their clinicians as to the risks and
benefits of various treatment approaches. Medication safety in pregnancy differs in many instances
from medication safety in lactation. (See 'Breastfeeding' below.)

Maternal-fetal monitoring — The optimal monitoring schedule to ensure maternal and fetal health
during pregnancy is not known. Women with risk factors or poor prognostic indicators will require
more frequent monitoring. In addition to routine prenatal care, fetal monitoring for women with SLE
includes:

● First-trimester ultrasound evaluation to establish the estimated date of delivery. A fetal anatomic
survey is performed at approximately 18 weeks of gestation.

● Ultrasound evaluation for fetal growth and placental insufficiency in the third trimester. Frequency
of surveillance for fetal growth will depend upon maternal and fetal wellbeing, but typically will be
performed approximately every four weeks. More frequent monitoring, including Doppler
velocimetry, is also recommended if growth restriction or placental insufficiency is suspected.
(See "Fetal growth restriction: Evaluation and management", section on 'Pregnancy
management'.)

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● Fetal testing with nonstress tests and/or biophysical profile during the final four to six weeks of
pregnancy is indicated in most women with lupus, with individual surveillance plans based on
fetal and maternal assessment. (See "Overview of antepartum fetal surveillance".)

● In patients with positive anti-Ro/SSA and/or anti-La/SSB antibodies, increased surveillance for
congenital heart block is recommended. (See "Neonatal lupus: Epidemiology, pathogenesis,
clinical manifestations, and diagnosis", section on 'Fetal surveillance for heart block' and
'Presence of anti-Ro and anti-La antibodies' above.)

Preeclampsia — Women with SLE are at higher risk of preeclampsia than the general population.
These patients require additional vigilance, as the presentation of hypertension, proteinuria, or end-
organ dysfunction after 20 weeks of gestation is concerning for development of preeclampsia.
Severe, early-onset growth restriction is similarly concerning for developing preeclampsia. While
preeclampsia presenting later in pregnancy can often be managed expectantly, in pre-and peri-viable
gestations, delivery is indicated to prevent catastrophic maternal complications. For this reason, early
diagnosis is essential.

In women at elevated risk of preeclampsia, including all women with SLE, low-dose aspirin has been
shown to reduce the absolute risk of disease by approximately 2 to 5 percent when initiated between
12 to 16 weeks gestation [18,58]. The use of low-dose aspirin for preeclampsia prophylaxis is
discussed in detail separately (see "Preeclampsia: Prevention", section on 'Candidates' and
'Recommended during pregnancy' above). Preeclampsia in women with antiphospholipid syndrome
(APS) is also discussed separately. (See "Antiphospholipid syndrome: Pregnancy implications and
management in pregnant women".)

Preeclampsia versus lupus nephritis — Differentiating preeclampsia from lupus nephritis or a

lupus flare can be challenging. Lupus nephritis flares during pregnancy can mimic preeclampsia,
presenting with increasing proteinuria, hypertension, thrombocytopenia, and a deterioration in renal
function. Active lupus nephritis and preeclampsia can also occur at the same time. Evidence of lupus
activity in other organs can sometimes help distinguish SLE from preeclampsia.

Laboratory testing may be, but is not always, useful in distinguishing preeclampsia from nephritis or a
lupus flare:

● Lupus nephritis is often associated with proteinuria and/or an active urine sediment (red and
white cells and cellular casts), whereas only proteinuria is seen in preeclampsia.

● Flares of SLE are likely to be associated with low or decreasing complement levels and
increased titers of anti-dsDNA antibodies; by comparison, complement levels are usually, but not
always, normal or increased in preeclampsia [59-61].

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● Thrombocytopenia, elevated serum levels of liver enzymes and an elevated or rising level of uric
acid are more prominent in preeclampsia than lupus nephritis. However, thrombocytopenia may
also be seen in association with antiphospholipid antibodies (aPLs), thrombotic
thrombocytopenic purpura, and immune thrombocytopenia, each of which may complicate
pregnancy in women with SLE.

The onset of these overlapping symptoms before 20 weeks of gestation is more consistent with lupus
nephritis. Renal biopsy can help differentiate the two conditions, but the higher risk of complications
during pregnancy limits the use in pregnancy. (See "Acute kidney injury in pregnancy".)

Treating active SLE — The treatment of active SLE during pregnancy is guided by the severity and
degree of organ involvement, similar to patients in the non-pregnant state. Treatment should not be
withheld due to pregnancy; however, some medications used to treat SLE may cross the placenta
and cause fetal harm. Thus, the risks and benefits of treatment during pregnancy must be weighed
against the risk of SLE activity having a deleterious effect on the mother and the fetus. The most
commonly used medications used to treat patients with SLE are reviewed above (see 'Medications'
above). The use of immunosuppressive drugs during pregnancy is discussed in detail separately.
(See "Safety of rheumatic disease medication use during pregnancy and lactation".)

A detailed discussion regarding the treatment of active lupus is presented separately. (See "Overview
of the management and prognosis of systemic lupus erythematosus in adults", section on
'Pharmacologic therapies'.)

Lupus nephritis in pregnancy requires special consideration because of its potential morbidity and
possible confusion with preeclampsia. (See 'Lupus nephritis' above and 'Preeclampsia versus lupus
nephritis' above.)

BREASTFEEDING

Breastfeeding is encouraged for most women with systemic lupus erythematosus (SLE). The safety
of medications in lactation sometimes differs, and their use should be discussed on an individual level
and specific risks reviewed. Premature or ill infants may be at increased risk of some medication
exposures.

Hydroxychloroquine (HCQ), prednisone, cyclosporine, azathioprine, and tacrolimus are considered

compatible with breastfeeding. Methotrexate, mycophenolate mofetil, cyclophosphamide, leflunomide,
and small molecules such as tofacitinib are not compatible with breastfeeding. Biologics, given their
large size, are unlikely to be transferred into breast milk in significant concentration and are
compatible with breastfeeding. Detailed information regarding compatibility of medications with

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lactation is provided by the United States National Library of Medicine (LactMed drug and lactation
database) [62]. A more detailed discussion on the use of immunosuppressive drugs during lactation
can be found elsewhere. (See "Safety of rheumatic disease medication use during pregnancy and
lactation".)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions around
the world are provided separately. (See "Society guideline links: Systemic lupus erythematosus".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The
Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and
they answer the four or five key questions a patient might have about a given condition. These
articles are best for patients who want a general overview and who prefer short, easy-to-read
materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10th to 12th grade reading level and are best for patients
who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-
mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topics (see "Patient education: Lupus and pregnancy (The Basics)" and "Patient
education: Lupus and kidney disease (The Basics)")

● Beyond the Basics topic (see "Patient education: Systemic lupus erythematosus and pregnancy
(Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

● Ideally, all pregnancies in women with systemic lupus erythematosus (SLE) should be planned
during periods of disease quiescence for at least six months prior to conception. Active SLE at
the time of conception is a strong predictor of adverse maternal and obstetrical outcomes. In
spite of this risk, the majority of such pregnancies still result in live births. (See 'Introduction'
above and 'Pregnancy planning' above.)

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● A preconception assessment is essential in women with SLE to determine whether pregnancy

may pose an unacceptably high maternal or fetal risk, to initiate interventions to optimize disease
activity, and to adjust medications to those with the best safety profile during pregnancy. (See
'Preconception evaluation' above and 'Specific laboratory testing' above and 'Medications'
above.)

● Women who are primigravidas and women with a history of lupus nephritis or active nephritis are
at highest risk of flare. Higher rates of complications such as preeclampsia, preterm birth, fetal
loss, growth restriction, neonatal lupus (NL) syndromes, and prematurity are seen in lupus
pregnancy. (See 'Exacerbation of SLE' above and 'Impact of lupus on pregnancy' above and
'Fetal complications' above and 'Special considerations' above.)

● Management of pregnant women with SLE should involve close collaboration between a
rheumatologist and an obstetrician experienced in caring for high risk mothers. Periodic
assessment for disease activity should occur throughout pregnancy and the postpartum period.
(See 'Management during pregnancy' above and 'Monitoring SLE activity' above.)

● For all pregnant women with SLE, we suggest continuation of hydroxychloroquine to reduce the
risk of SLE flares (Grade 2C). (See 'Recommended during pregnancy' above.)

● Women with SLE are at higher risk of preeclampsia than the general population.
Recommendations for prophylactic use of low-dose aspirin for preeclampsia is discussed in
detail separately (see "Preeclampsia: Prevention", section on 'Candidates'). Lupus nephritis
flares during pregnancy can mimic preeclampsia, and differentiating one from the other can be
challenging. (See 'Preeclampsia' above and 'Recommended during pregnancy' above.)

● Women with risk factors or poor prognostic indicators may require more frequent maternal-fetal
monitoring. In patients with positive anti-Ro/SSA and/or anti-La/SSB antibodies, increased
surveillance for congenital heart block is appropriate. (See 'Maternal-fetal monitoring' above.)

● The treatment of active SLE during pregnancy is guided by the severity and degree of organ
involvement, similar to patients in the non-pregnant state. Treatment should not be withheld due
to pregnancy; however, some medications used to treat SLE may cross the placenta and cause
fetal harm. Thus, the risks and benefits of treatment during pregnancy must be weighed against
the risk of SLE activity having a deleterious effect on the mother and the fetus. (See 'Treating
active SLE' above.)

ACKNOWLEDGMENT

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The editorial staff at UpToDate would like to acknowledge Peter Schur, MD, who contributed to an
earlier version of this topic review.

Use of UpToDate is subject to the Subscription and License Agreement.

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GRAPHICS

The developing fetus

The black bars represent the critical period during which development may be disrupted by a teratogen resulting in a
major structural malformation. Cell differentiation occurs over a longer period (white bars); exposure during this
period can result in minor structural malformations, growth restriction, or functional deficiency. Note, embryonic age
is counted from fertilization, whereas menstrual age (ie, gestational age) is counted from the first day of the last
menstrual period. Thus, an embryonic age of six weeks corresponds to a menstrual age (gestational age) of eight
weeks. Embryonic weeks 1 to 8 are considered the embryonic period of development and are followed by the fetal
period of development.

CNS: central nervous system.

Reproduced with permission from: Moore K. The developing human: Clinically oriented embryology, WB Saunders,
Philadelphia 1982. Copyright ©1982 Elsevier.

Graphic 56642 Version 4.0

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Contributor Disclosures
Bonnie L Bermas, MD Nothing to disclose Nicole A Smith, MD, MPH Nothing to disclose David S Pisetsky,
MD, PhD Consultant/Advisory Boards: Celgene [Lupus (Phase 2 study of cereblon-modulating agent)]; Lilly
[Rheumatoid arthritis (Baricitinib)]; DILIsym [Drug-induced liver injury]; EMD Serono [SLE (Evobrutinib)]. Charles
J Lockwood, MD, MHCM Nothing to disclose Monica Ramirez Curtis, MD, MPH Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform to
UpToDate standards of evidence.

Conflict of interest policy

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