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Pregnancy in women with systemic lupus erythematosus

Last literature review version 17.3: September 2009  |  This topic last updated: October 16, 2008   (More)

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 the patient's underlying renal function is stable and normal or near normal. 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, 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 > 50mm Hg)
  • Restrictive lung disease (forced vital capacity <1 liter)
  • Heart failure
  • Chronic renal failure (creatinine >2.8 mg/dL)
  • History of severe preeclampsia or HELLP syndrome despite therapy
  • 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 oral 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, increased use of elective pregnancy termination (in those who did flare), or may reflect different patient populations.

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, of preterm delivery, unplanned cesarean delivery, postpartum hemorrhage, 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 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 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 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 [21]. Furthermore, preeclampsia is more likely to occur in patients with antiphospholipid antibodies (aPL), diabetes mellitus, or 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 "Clinical features, diagnosis, and long-term prognosis of preeclampsia".)

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

  • 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 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], lupus nephritis [3,8,30] and those with hypocomplementemia, elevated levels of anti-DNA antibodies, aPL, 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 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 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 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 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 is discussed in detail separately. (See "Neonatal lupus syndrome".)

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 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 corticosteroid dose, renal complications, hypertension, aPL, 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 APS, 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]. Currently available information 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 anti-rheumatic drugs (eg, etanercept, infliximab, adalimumab, rituximab, abatacept) during lactation, but 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 immunosuppressive drugs in 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
  • LA and aCL assay
  • Anti-double stranded DNA antibodies
  • Complement (CH50, or C3 and C4)

In the absence of any historical features of the 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. Others have suggested the use of low dose heparin and aspirin for such patients even in the absence of prior pregnancy complications. 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 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 when therapeutic interventions may prevent progression. Issues related to the timing of this type of monitoring are presented separately. (See "Neonatal lupus syndrome", section on 'Detecting and 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
  • aCL
  • Complement (CH50 or C3 and C4)
  • Anti-dsDNA antibodies

During the last trimester of pregnancy

Women who show evidence of increased serologic activity but remain asymptomatic should be monitored more closely. We do not initiate therapy for serologic findings alone, with the possible exception of the development of aPL. (See "Management of pregnant women with antiphospholipid antibodies or the antiphospholipid syndrome".)

If fetal growth restriction is noted, then umbilical artery Doppler ultrasonography is recommended, if available, to monitor fetal well-being. Information from umbilical artery Doppler ultrasonography helps guide decision making regarding timing of delivery and has been proven to reduce perinatal mortality in this setting. (See "Doppler ultrasound of the umbilical artery for fetal surveillance".)

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 in nonpregnant women. However, women who are breast feeding may have 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:

  • Medications used to treat SLE may cross the placenta and cause fetal harm. Thus, the risks and benefits of treatment during pregnancy must be repeatedly weighed against the risk of activity of SLE having a deleterious effect on the mother and the fetus [42,43]. As noted earlier, the use of immunosuppressive drugs during pregnancy is discussed in detail separately. (See "Use of immunosuppressive drugs in pregnancy and lactation".)

  • Nephritis in pregnancy requires special consideration because of its potential morbidity, and possible confusion with preeclampsia. (See 'Renal disease' above.)

Medication use — Medications that are typically used to treat patients with SLE may be divided into three categories: those that should be avoided in pregnancy, those that may have a small risk of fetal harm when used in pregnant patients; and those that are probably safe. (See "Use of immunosuppressive drugs in pregnancy and lactation".)

Drugs to avoid — Medications with a high risk of causing birth defects should be avoided. (See "Use of immunosuppressive drugs in pregnancy and lactation".)

  • Mycophenolate mofetil — Mycophenolate should not be used during pregnancy. It 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.
  • Biologic agents — Use of biologic anti-rheumatic drugs such as anti-tumor necrosis factor agents, 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 immunosuppressive drugs in pregnancy and lactation", section on 'Drugs with insufficient data'.)
  • 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.

Drugs with a small risk of harm — NSAIDs, glucocorticoids, and azathioprine 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 immunosuppressive drugs in 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, to control 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].

Azathioprine — Azathioprine may be used very cautiously. (See "Use of immunosuppressive drugs in pregnancy and lactation", section on Azathioprine.)

Drugs that are probably safe during pregnancy — NSAID use during early and late pregnancy and antimalarial drug use throughout pregnancy is 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 physicians experienced in treating patients with SLE (median of 75 patients per year) and participating in the management of pregnancy in such patients (4 to 5 per year per physician), 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.

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, 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 aPL [42,43]. Treatment includes high dose prednisone and intravenous immune globulin [42].

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Systemic lupus erythematosus and pregnancy".) We encourage you to print or e-mail this topic, or to refer patients to our public web site www.uptodate.com/patients, which includes this and other topics.

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UpToDate performs a continuous review of over 430 journals and other resources. Updates are added as important new information is published. The literature review for version 17.3 is current through September 2009; this topic was last changed on October 16, 2008. The next version of UpToDate (18.1) will be released in March 2010.

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