INTRODUCTION — Systemic lupus erythematosus (SLE) occurs frequently in women of childbearing age. Although patients with SLE are as fertile as women in the general population, their pregnancies may be associated with complications. The prognosis for both mother and child is best when SLE has been quiescent for at least six months prior to the pregnancy and, if the patient has renal disease, when it has been in remission for at least six months. Thus, contraception and family planning are important. Maternal health and fetal development should be monitored frequently during pregnancy. If possible, delivery should occur in a controlled setting. In addition, many women with SLE should be followed by an obstetrician knowledgeable in high-risk pregnancies [1].
An obstetrician experienced in management of high risk pregnancies is particularly desirable for women with one or more of the following clinical features [2]:
- Prior history of poor obstetric outcomes
- Renal involvement
- Cardiac involvement
- Pulmonary hypertension
- Interstitial lung disease
- Evidence of active lupus
- High-dose glucocorticoid therapy
- Antiphospholipid antibodies/syndrome
- Antibodies to Ro/La (predisposing to neonatal lupus)
- Multiple gestation
The following characteristics are associated with high maternal and fetal risk [2]:
- Severe pulmonary hypertension (mean pressure >50 mmHg)
- Restrictive lung disease (forced vital capacity <1 liter)
- Heart failure
- Chronic renal failure (creatinine >2.8 mg/dL)
- Active renal disease
- History of severe preeclampsia or HELLP syndrome
- Stroke within the previous six months
- Severe lupus flare within the previous six months
If any of the listed high risk factors for poor maternal/fetal outcomes are present, a decision to pursue pregnancy should be carefully considered and made with an awareness of the potentially serious consequences.
Four major issues unique to pregnant patients with SLE and their children are discussed in this review of pregnancy in women with SLE:
- Exacerbation of the disease
- Fetal loss, intrauterine growth retardation, and preterm delivery (often in the setting of antiphospholipid antibodies)
- Neonatal lupus
- Breast feeding
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 hormonal contraceptives in women with systemic lupus erythematosus".) Issues related to pregnancy in patients with impaired renal function are also presented in more detail elsewhere. (See "Pregnancy in women with underlying renal disease".)
EXACERBATION OF SLE — Exacerbation of SLE in the past occurred in over 50 percent of patients during pregnancy. Flares occurred during all three trimesters with approximately equal frequency and often in the immediate postpartum period. However, the incidence of exacerbation during pregnancy and the postpartum period, especially in those in remission at the beginning of pregnancy, has been progressively diminishing in the last 30 years.
The reduction in rates of SLE flares could be a result of reporting bias, better disease control, or a better understanding of how one defines a flare during pregnancy. Some investigators believe that the rate of flares during pregnancy may be similar to the frequency of exacerbation while not pregnant, while other researchers maintain that pregnancy is a time of vulnerability to increased disease activity [3-7]:
- One study prospectively evaluated 40 pregnancies in 37 women with SLE [4]. Flare occurred in 24 (60 percent) of the pregnancies. Comparison of the rates of flare in the same patients after delivery and in nonpregnant patients with SLE showed a significant increase in the rate of flare during pregnancy. Flares presented most commonly as constitutional symptoms, renal disease, or involvement of the skin and joints. Similar findings were found in another prospective study of 68 patients with SLE [8].
- In contrast, a second case-control study found that lupus flares occurred in similar percentages of pregnant and control patients [5]. In this report, active SLE at study entry was not predictive of flare in either control or pregnant patients, but patients with inactive lupus at presentation were less likely to experience a flare [5].
Other investigators have been in agreement with the findings in the latter study, showing no overall increase in SLE exacerbation associated with pregnancy [3,6,7]. This improved outlook may reflect better management, judicious use of glucocorticoids, or increased use of elective pregnancy termination (in those who did flare), or it may reflect different patient populations. It could also represent, in part, changes in practice to follow newer treatment guidelines, recommended only in the last 10 to 20 years, to initiate pregnancy only after the disease has been quiet for at least six months.
The frequency of exacerbation (or persistently active disease) varies with the state of disease activity at conception, ranging from 7 to 33 percent in women who have been in remission for at least six months and from 61 to 67 percent in women who have active disease at the time of conception [9,10]. As noted above, however, it is not clear if these disease flares are due to pregnancy or to spontaneous fluctuations in the course of the disease.
While there is uncertainty about the effect of pregnancy on the course of SLE, there is some evidence that the hormonal manipulation required for in vitro fertilization may result in increased disease activity [11,12].
On the other hand, pregnancy outcomes are generally more likely to be complicated. In one prospective study, 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 than others [13]; fetal growth restriction and neonatal deaths were also more often seen in association with SLE [14].
RENAL DISEASE — Patients with organ damage at the time of pregnancy may have difficulty since pregnancy imposes an added burden on malfunctioning organs. This phenomenon is particularly important in patients with renal disease.
Lupus nephritis — Pregnancy in women with lupus nephritis is associated with an increased risk of fetal loss (up to 75 percent) and with worsening of the renal and extrarenal manifestations in most [9,10,15] but not all [16] studies.
Although the incidence is not high, severe renal exacerbations can occur [10,17]. As a result, during preconception counseling women with lupus nephritis should be encouraged to delay pregnancy until the disease can be rendered inactive for at least six months [9,10]. While the risk of adverse effects upon the fetus are minimized if conception and pregnancy occur in the absence of glucocorticoids or other immunosuppressive drugs, it may be preferable in some patients to continue glucocorticoids at the lowest effective dose and/or to cautiously use azathioprine.
Patients with preexisting hypertension, proteinuria, and azotemia are at increased risk [18]. The approach to therapy of a flare of lupus nephritis is discussed below. (See 'Treatment recommendations' below.)
Pregnancy following renal transplantation — Women with SLE who have received renal transplants have pregnancy outcomes that are remarkably similar to those of other transplant recipients. This was the conclusion of a study of 36 women with SLE and 274 women who had received renal transplants and who did not have lupus [19]. The course of 60 pregnancies in women with SLE and of 374 pregnancies that occurred in other renal transplant recipients included the following:
- Live births in 77 versus 76 percent of the pregnancies
- Miscarriages and/or still births in 17 versus 16 percent
- Therapeutic terminations of pregnancy in 10 versus 8 percent
The incidence of hypertension, gestational diabetes, and rates of Cesarean delivery were all lower in the patients with SLE than in the other transplant recipients. Prematurity and low birth weight affected many infants of both groups.
Management of pregnancy following renal transplantation is discussed separately. (See "Pregnancy in women with underlying renal disease", section on 'Pregnancy in the renal transplant recipient'.)
Preeclampsia — Preeclampsia is a frequent complication of pregnancy in SLE, occurring in approximately 13 percent of patients [3]. Among women with renal disease, the incidence may be much higher (66 percent in one study) [20]. It is often difficult to distinguish preeclampsia from lupus nephritis or a lupus flare [21]. Furthermore, preeclampsia is more likely to occur in patients with antiphospholipid antibodies (aPL), diabetes mellitus, or a prior episode of preeclampsia [2]. Preexisting thrombocytopenia may also be a risk factor [22]. Preexisting hypertension, though a risk factor for preeclampsia in the general population, was not confirmed as a risk factor in women with SLE in a small retrospective study [23]. (See "Preeclampsia: Clinical features and diagnosis".)
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 hypocomplementemia and increased titers of anti-DNA antibodies; in comparison, complement levels are usually but not always normal or increased in preeclampsia [3,15,24-26].
- Thrombocytopenia, elevated serum levels of liver enzymes and uric acid, and decreased urinary excretion of calcium are more prominent in preeclampsia than lupus nephritis. However, thrombocytopenia may also be seen in association with aPL, thrombotic thrombocytopenic purpura, and immune thrombocytopenia, each of which may complicate pregnancy in women with SLE.
FETAL LOSS — Although fetal losses approaching 50 percent have been noted in pregnant patients with SLE [3,27,28], subsequent studies suggest that pregnancy losses may be decreasing. This was illustrated in a study of published pregnancy outcomes from different time periods [29].
- 1960 to 1965 - The mean rate of fetal loss was 43 percent.
- 2000 to 2003 - In one center, the rate was 17 percent.
However, in a multiethnic population in North America, the rate of fetal losses and still births was reported in 2008 to be 45 percent [30]. The risk of fetal loss is increased in women with hypertension, active lupus [31], or lupus nephritis [3,8,30] and in those with hypocomplementemia, elevated levels of anti-DNA antibodies, antiphospholipid antibodies, or thrombocytopenia [24,32]. Anti-DNA antibodies may potentiate pregnancy loss by cross reacting with laminin, a molecule critical for placenta implantation [33].
Role of antiphospholipid antibodies — The principal antiphospholipid antibodies (aPL) measured for clinical purposes are anticardiolipin antibodies (aCL) and lupus anticoagulants (LA). Although the presence of aPL does not necessarily predict fetal loss [34], patients with SLE and aPL appear to be at increased risk for spontaneous miscarriage. A review of 10 studies of 554 women with SLE found that fetal demise was more common in those with aPL (38 to 59 percent versus 16 to 20 percent in those without such antibodies), LAs (36 versus 13 percent), or aCL (39 versus 18 percent) [35]. Fetal loss typically occurs after 10 weeks gestation [35]. (See "Obstetrical manifestations of the antiphospholipid syndrome".)
It is possible to decrease the risk of fetal loss during subsequent pregnancies in these patients. Thus, all pregnant women with SLE should be tested for the presence of aPL (eg, lupus anticoagulants and aCL). Management of women with aPL who are contemplating pregnancy or are pregnant is discussed in more detail separately. (See "Management of pregnant women with antiphospholipid antibodies or the antiphospholipid syndrome".)
NEONATAL LUPUS — Neonatal lupus is a passively transferred autoimmune disease that occurs in some babies born to mothers with anti-Ro/SSA and/or anti-La/SSB antibodies; many of these women do not have lupus or other autoimmune disease, although they frequently develop such a disease during follow-up. The most serious complication in the neonate is complete heart block, which occurs in approximately 2 percent of such pregnancies. Isolated skin rash occurs in a similar percentage. Neonatal lupus accounts for 90 to 95 percent of cases of heart block occurring in utero or in the neonatal period and for 60 to 90 percent of congenital complete heart block. Once a woman has given birth to an infant with congenital heart block, the recurrence rate of congenital heart block is about 15 percent; another 6 percent have an isolated rash consistent with neonatal lupus. Neonatal lupus, including approaches to prevention, screening, and treatment, is discussed in detail separately. (See "Neonatal lupus".)
OTHER CONSEQUENCES OF SLE — SLE does not confer risks for other identifiable congenital abnormalities. Learning disabilities, however, may be more frequent in offspring of SLE mothers, especially in male children [36].
Patients with SLE have a greater incidence of premature delivery (three times that of patients without SLE). Prematurity and intrauterine growth restriction are associated with glucocorticoid dose, renal complications, hypertension, antiphospholipid antibodies, preeclampsia, or premature rupture of membranes [37]. Severe disease flares were associated with an increased risk of prematurity in one study [22].
The risk of preterm delivery may be decreasing. A slight decrease in preterm delivery from 1980 to 2002 was noted in a review of published pregnancy outcomes [29], decreasing from 37.3 to 32 percent. This improvement may be due to the increased recognition and improved treatment of the antiphospholipid syndrome, which can affect many women with SLE.
BREAST FEEDING — Breast feeding is feasible for most women with SLE. However, some medications may enter breast milk. A database of information regarding the use of individual drugs during lactation is provided by the United States Library of Medicine (LactMed drug and lactation data base) [38]. Information available in the database suggests that short-acting NSAIDs, antimalarials, low-dose prednisone (less than 15 to 20 mg/day), warfarin, and heparin are safe for the nursing infant, as little or no active drug is secreted in breast milk.
Limited data are available regarding the safety of biological disease modifying antirheumatic drugs (eg, etanercept, infliximab, adalimumab, rituximab, abatacept) during lactation. However, these agents have high molecular weights, and limited absorption would be expected when these agents are ingested by an infant or child. Published information on these agents is summarized in the LactMed database and is also discussed elsewhere. (See "Use of antiinflammatory and immunosuppressive drugs in rheumatic diseases during pregnancy and lactation".)
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 neonatal lupus results from breast feeding [39].
TREATMENT RECOMMENDATIONS — There are two issues related to therapy of women with lupus who become pregnant: monitoring of disease activity in both asymptomatic and symptomatic patients and treatment of active disease.
Monitoring — Mothers should be assessed for disease activity at least once each trimester and more often if they have active lupus. The schedule for monitoring includes:
First visit — At the first visit after (or at which) pregnancy is confirmed, the following investigations are recommended [40]:
- Physical examination, including blood pressure
- Renal function (glomerular filtration rate, urinalysis, urine protein/urine creatinine ratio)
- Complete blood count
- Anti-Ro/SSA and anti-La/SSB antibodies
- Lupus anticoagulant (LA) and anticardiolipin antibody (aCL) assays
- Anti-double stranded DNA antibodies
- Complement (CH50, or C3 and C4)
- Uric acid level
In the absence of any historical features of the antiphospholipid syndrome (APS) (eg, recurrent pregnancy loss, venous or arterial thromboembolism), we recommend that patients with high levels of aCL or the presence of an LA receive low-dose aspirin therapy, although the data regarding the management of these patients are equivocal. Women with lupus and the APS require more frequent monitoring than those with SLE alone. (See "Management of pregnant women with antiphospholipid antibodies or the antiphospholipid syndrome".)
Women who have antibodies to Ro/SSA and/or La/SSB and who are, therefore, at increased risk of having pregnancies complicated by fetal heart block may benefit from serial fetal echocardiographic monitoring starting at week 18 [2]. The goal is to detect fetal heart block at an early stage. To date, there has been no proven therapeutic intervention to prevent progression. Issues related to the timing of this type of monitoring are presented separately. (See "Neonatal lupus", section on 'Treating fetal heart block'.)
Monthly during the first two trimesters — A platelet count (or CBC) is recommended on a monthly basis [40].
End of each trimester — The following are recommended at the end of each trimester of pregnancy [40]:
- Glomerular filtration rate, urine protein/urine creatinine ratio
- Anticardiolipin antibodies (aCL)
- Complement (CH50 or C3 and C4)
- Anti-dsDNA antibodies
During the last trimester of pregnancy
Postpartum — 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, and they have a poorer prognosis than those who have inactive disease prior to pregnancy [41]. Thus, periodic assessment of disease activity is warranted postpartum. The following laboratory tests are recommended following an uncomplicated delivery [40]:
- Urinalysis, urine protein/urine creatinine ratio
- Renal function if the urinalysis is abnormal
- Complete blood count
- Anti-double stranded DNA (anti-dsDNA)
- Complement (CH50, or C3 and C4)
Treatment of postpartum women with active SLE is the same as that of nonpregnant women. However, women who are breast feeding may have to stop doing so, depending upon which medications are needed. (See 'Breast feeding' above.)
Treating active lupus — Treatment of SLE during pregnancy is associated with some unique problems. Consideration must be given to the following issues:
Medication use — Medications that are typically used to treat patients with SLE may be divided into four categories:
- Drugs with a moderate to high risk of fetal harm
- Drugs that may be used selectively during pregnancy
- Drugs with minimal fetal and maternal risk
- Drugs with an unknown level of risk
The most commonly used medications are reviewed briefly below. Other medications and a detailed discussion of the use of specific antiinflammatory and immunosuppressive medications in pregnancy are presented elsewhere. (See "Use of antiinflammatory and immunosuppressive drugs in rheumatic diseases during pregnancy and lactation".)
Moderate to high risk of fetal harm — Medications with a high risk of causing birth defects should be avoided during conception and pregnancy. These include:
- Mycophenolate mofetil — Mycophenolate should not be used during pregnancy. It is listed as a category D drug (positive evidence of risk) for use in pregnancy by the FDA due to increases in both first trimester pregnancy loss and congenital malformations (table 1).
Azathioprine can be substituted for mycophenolate prior to and during pregnancy, or, alternatively, glucocorticoids may be used at the lowest dose that controls disease activity. - Cyclophosphamide — Cyclophosphamide should not be used during pregnancy, unless there is no alternative available for life-threatening disease affecting the mother. Fetal loss is a likely outcome of cyclophosphamide administration during pregnancy, either as a result of cyclophosphamide toxicity, severe disease, or a combination these factors. In one retrospective review of four such pregnancies, there were no live births [44].
- Methotrexate — Methotrexate is teratogenic and should not be used during pregnancy.
- Warfarin — Warfarin or related anticoagulants are teratogenic when used in early pregnancy. Cautious use after the first trimester has been suggested by some authors [2]. However, these drugs cross the placenta and result in fetal anticoagulation; thus, there is a risk of fetal hemorrhage.
Heparin is generally safe but must be discontinued prior to delivery to reduce the risk of postpartum hemorrhage or intra- or postoperative bleeding should Cesarean delivery be required.
Selective use allowed during pregnancy — The following drugs are potentially safe during pregnancy, but certain limitations apply to their use. NSAIDs, glucocorticoids, and azathioprine 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. (See "Use of antiinflammatory and immunosuppressive drugs in rheumatic diseases during pregnancy and lactation".)
Summarized briefly, they include:
- An increased risk of cleft palate in children
- Premature rupture of membranes
- Maternal hypertension
- Gestational diabetes
- Intrauterine growth retardation
We recommend, if at all possible, control of the disease with low doses (less than 10 mg/day) of prednisone [45].
Steroid side effects in the mother may be reduced by recommending a low salt diet (to prevent weight increase and hypertension), an exercise program (to prevent bone loss and depression), and calcium and vitamin D supplementation (to prevent osteoporosis) [24].
Minimal fetal and maternal risk — NSAID use during early and late pregnancy and antimalarial drug use throughout pregnancy are probably safe.
- NSAIDs in late first and in second trimester — NSAIDs are generally safe during the latter part of the first and during the second trimester but should be discontinued in the last trimester of pregnancy. Use of NSAIDs in the third trimester may cause premature closure of the ductus arteriosus and inhibition of labor. Indeed, use of indomethacin is one of several approaches to inhibiting preterm labor, but use of indomethacin or any other NSAID for more than 48 hours should be accompanied by fetal sonographic monitoring for signs of tricuspid regurgitation that could indicate unwanted constriction of the ductus. (See "Inhibition of acute preterm labor".)
- Antimalarial drugs — The safety of use of antimalarial drugs is uncertain. Though there is considerable experience with these drugs for malarial prophylaxis, there has been one report of ocular and ototoxicity in three children in a single family in which the mother had SLE and was taking chloroquine during the pregnancies [46]. However, data from observational studies of the infants of patients with SLE and other rheumatic disorders who received antimalarials during pregnancy suggest that these agents are safe [47-50]. Patients who discontinue hydroxychloroquine prior to, or during, pregnancy are more likely to have exacerbations of SLE [51].
Among a group of 52 clinicians experienced in treating patients with SLE (median of 75 patients per year) and in participating in the management of pregnancy in such patients (four to five per year per clinician), 69 percent of respondents to a survey reported that they continued antimalarial drugs in at least some patients during pregnancy [47]. A slightly smaller proportion reported advising breast feeding during continued use of these agents postpartum.
Unknown level of risk — Use of biologic antirheumatic drugs such as B cell targeted antibodies (eg, rituximab) and T-B cell costimulation blockers (eg, abatacept) is discouraged in part because of a lack of data on safety of their use during pregnancy. (See "Use of antiinflammatory and immunosuppressive drugs in rheumatic diseases during pregnancy and lactation", section on 'Unknown risk'.)
Renal disease — Signs of a renal flare include renewed activity of the urine sediment and an increase in the plasma creatinine concentration. In comparison, an isolated elevation in protein excretion is a common, probably hemodynamically mediated finding in all glomerulopathies during pregnancy and should not necessarily be considered a finding of increased lupus activity. (See "Pregnancy in women with underlying renal disease".)
Patients with a significant flare of lupus nephritis should be treated with high-dose prednisone and antihypertensive medication (eg, hydralazine, methyldopa, and calcium channel blockers, but not angiotensin converting enzyme inhibitors or some beta blockers). There is little if any experience with pulse methylprednisolone in pregnancy, and its effects on the fetus are unknown. Cyclophosphamide is contraindicated during pregnancy, but azathioprine can be used cautiously. In addition, the fetus should be delivered as soon as possible [10,42].
Thrombocytopenia — Thrombocytopenia during lupus pregnancies may have multiple causes, including antiplatelet antibodies, toxemia, and antiphospholipid antibodies [42,43]. Treatment includes high-dose prednisone and intravenous immune globulin [42].
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