Management of Rheumatologic Diseases in Pregnancy

Oier Ateka-Barrutia; Catherine Nelson-Piercy

Disclosures

Int J Clin Rheumatol. 2012;7(5):541-558. 

In This Article

Connective Tissue Diseases

SLE

Effect of Pregnancy on SLE Pregnancy is considered a high-risk time in lupus patients, as flares during pregnancy have been related to irreversible organ damage.[7] However, whether pregnancy increases the risk of lupus flare is still an unsolved question.[8–14] Some authors have suggested the puerperium as a period of particular high risk for lupus flare.[15] Based on these studies, lupus flare seems unpredictable. However, the risk of flare appears to be dependent on the disease activity 6–12 months prior to conception. Women with quiescent lupus over this period have less risk of flare during pregnancy,[12,16] whereas women with active SLE during this time have a high risk of flare.[9,17] Therefore, pregnancy should be planned when the disease has been in remission for at least 6 months.

Active lupus nephritis (LN) at conception confers a higher risk of flare during pregnancy,[18] and even those with LN in remission have an increased risk of flare.[14] In women with previous LN, pregnancy does not seem to endanger long-term renal function, although generally the higher the baseline creatinine, the greater the risk of deterioration.[14,18,19]

Lupus flares during pregnancy and postpartum are normally nonsevere, characterized by articular, dermatological and mild hematological involvement,[9,10,13] and are usually well controlled with short-term introduction or increase of oral steroids. Nonetheless, severe flares with major organ involvement may occur.[9]

A recent systematic review established the protective effects of hydroxychloroquine (HCQ) in terms of organ damage, flares, thrombosis, bone mass loss and long-term survival in the general lupus population, as well as the potential to prevent disease activity in pregnant women.[20] Two recent prospective studies corroborated these findings, suggesting that women who had taken HCQ throughout pregnancy presented lower activity scores and had lower prednisone doses at the end of pregnancy,[21] whereas those who discontinued HCQ or did not take it at all had higher activity scores, more flares and required higher doses of steroids.[22]

Distinguishing pregnancy-related signs and symptoms from certain lupus features may sometimes be difficult. Assessment by experienced physicians is important. Fatigue, arthralgia, hair loss, dyspnea, headaches, malar and palmar erythema, edema, anemia and thrombocytopenia represent some of the most common ambiguous manifestations. In pregnancy, erythrocyte sedimentation rate is usually raised due to higher fibrinogen production in the liver, hence it is not considered a valid marker of disease activity in pregnancy. Serum C3 and C4 levels also rise in pregnancy due to increased liver production, so even in women with active lupus they may remain within normal range. Relative variation rather than absolute levels of C3 and C4 should be assessed. A drop of 25% or more in serum complement levels in pregnancy may suggest lupus flare.[23] In patients with permanent significant protein loss due to previous LN, proteinuria may increase throughout pregnancy due to increased renal blood flow, without indicating active nephritis.[19] This may be more pronounced in patients who withdraw from angiotensin converting enzyme inhibitors (ACEI) and/or angiotensin receptor blockers (ARB) shortly before or early in pregnancy. Up to a doubling of proteinuria from the baseline level in early pregnancy is to be expected.[19]

Pregnancy may have a detrimental effect on other major organs/systems, such as the heart, CNS, lungs and pulmonary arterial system, with associated high morbidity and mortality.[24] Women with moderate–severe lupus flare or stroke within the previous 6 months, CKD 4–5 (Cr >2.5–2.8 mg/dl, >220–250 µmol/l; or eGFR<35 ml/min), pulmonary hypertension, moderate–severe cardiomyopathy (ejection fraction <30–40%), or severe restrictive lung disease (forced vital capacity <50% of predicted) are at highest risk for medical and obstetric complications and should be appropriately counseled, generally against conception or continuation of pregnancy.

Effect of SLE on Pregnancy SLE patients are at risk of multiple medical and obstetric complications during pregnancy. A recent study from the USA showed that lupus patients have a 20-fold increased risk of maternal mortality and a higher rate of hypertension, pregestational diabetes, renal impairment, pulmonary hypertension, major infections, thrombotic events and other hematologic complications, compared with the general population.[25] Furthermore, the risk of preeclampsia, cesarean section, preterm labor and intrauterine growth restriction (IUGR) was two- to four-fold higher in women with SLE, particularly in patients with chronic hypertension, renal impairment and women on high-dose oral steroids.[25] Conversely, those with SLE in remission without major organ involvement are likely to have a normal pregnancy outcome.

Approximately 25% of all lupus pregnancies end in preterm (<37 weeks) delivery.[26] Disease activity,[17] hypertension[27] and hypothyroidism[28] have been identified as risk factors for preterm delivery. Fetal growth restriction secondary to placental insufficiency is frequent in lupus pregnancies,[29] even in those with mild disease,[30] with an incidence of 6–35% of small for gestational age babies.[31]

Pregnancy loss occurs in up to one in five pregnancies of lupus patients (compared with ~one in ten in controls), with a high percentage of stillbirths (up to four- to six-fold seen in controls).[26] Hypertension, proteinuria >500 mg/day, thrombocytopenia and secondary APS have been recognized as risk factors for pregnancy loss.[31]

Patients with nonreversible organ damage are more prone to developing complications and further damage both during and after gestation,[7] this is especially true in women with CKD, which has been related to higher rates of fetal loss.[17] Women with active SLE during the 6 months prior to conception or high clinical activity in pregnancy, often associated with corticosteroid use, have worse pregnancy outcomes compared with those with low or no activity.[17,32,33] Likewise, patients with hypocomplementemia or positive anti-dsDNA antibodies have been shown to have the highest risk of pregnancy loss and preterm birth.[27] Patients with active LN are at particularly high risk for poorer pregnancy outcome,[34] therefore they should be advised to postpone pregnancy until at least 6 months (ideally 12–18 months) after the last LN flare. There is no evidence to suggest that different subclasses of LN affect this risk.[34] Women with creatinine >2.5–2.8 mg/dl (>220–250 µmol/l; eGFR<35 ml/min), on dialysis or with renal transplant present the highest complication rates.[19] A history of LN, as with any cause of CKD, is associated with an increased risk of hypertensive disorders in pregnancy.[34]

Overall, women with SLE have a three- to four-fold increased chance of developing preeclampsia,[33,35] compared with the general population.[36] Risk factors for developing preeclampsia in the general population have been extensively described elsewhere.[19,20] Differentiating preeclampsia from LN may not be straight forward, as both may involve hypertension, worsening proteinuria, edema, renal impairment and thrombocytopenia, and sometimes both may overlap. Findings indicative of preeclampsia are severe headache, visual problems (including flashing lights), epigastric or right upper quadrant tenderness, nausea or vomiting, clonus (>2 beats), deranged liver function tests, rising uric acid level and signs of hemolysis.[201] Features indicative of LN are onset before 20 weeks of gestation, active urinary sediment, low or falling complement levels, high or increasing anti-dsDNA, and evidence of lupus flare involving other organs. If renal biopsy is indicated (because the result would inform management by confirming or refuting a diagnosis of LN and the class), special care should be taken owing to the higher bleeding risk after biopsy in pregnancy.[37] New biomarkers of preeclampsia and further studies regarding their behavior in SLE populations may be of value in the future.

Scleroderma/Systemic Sclerosis

As the average age of onset of scleroderma is the early 40s, until the end of last century, most women would have completed their pregnancies before the onset of the disease. At present, that is changing as women frequently delay pregnancy.

Pregnancy does not seem to affect disease activity in the majority (63–72%) of women with scleroderma/systemic sclerosis (SSc). A third will either improve or worsen in pregnancy.[38,39] Importantly, SSc may be associated with an increased risk of developing hypertensive disorders in pregnancy, including preeclampsia, possibly related to associated hypertension. Women should be closely monitored for signs of renal crisis and preeclampsia throughout pregnancy.[40]

Clinically, Raynaud's phenomenon generally improves, whereas gastro-esophageal reflux disease worsens, which may be complicated by Mallory–Weiss tears and severe bleeding. Skin involvement usually remains stable or improves, but may worsen postpartum. Other features such as edema, shortness of breath and arthralgias may be difficult to differentiate from pregnancy itself and must be carefully assessed.

Importantly, recent onset of scleroderma symptoms (<4 years), diffuse cutaneous involvement or anti-Scl-70 (anti-topoisomerase-I) or anti-RNA-polymerase-III antibodies are associated with increased risk of suffering more active and aggressive disease than longstanding SSc and the presence of anticentromere antibodies.[41] Patients with marked malabsorption, CKD (Cr>2.5–2.8 mg/dl, >220–250 µmol/l; or eGFR<35 ml/min), pulmonary hypertension, moderate–severe cardiomyopathy (ejection fraction <30–40%) or severe restrictive lung disease (forced vital capacity <50% of predicted) are at highest risk for medical and obstetric complications and should be appropriately counseled, generally against conception or continuation of pregnancy.[42] Thorough assessment of scleroderma organ involvement and full autoantibody screen are important prior to conception in order to allow accurate counseling.

Renal crisis does not occur more frequently in pregnancy. However, if it does happen, management must be with ACEI despite the risks to the baby, as it is lifesaving for the mother.[43] Preeclampsia can present with similar features as renal crisis, and ACEI should be considered if there is doubt about the diagnosis. SSc renal crisis, however, does not derange liver function tests, is often characterized by rapidly rising serum creatinine and rarely presents major proteinuria or pathologic urinary sediment.

A previous renal crisis does not contraindicate future pregnancies, but women are generally persuaded to delay pregnancy for several years until their disease stabilizes. The best treatment approach for hypertension control in pregnancy after a previous renal crisis remains unknown. A trial without ACEI before attempting conception may be of help to assess blood pressure (BP) control with other medications, as well as renal function and proteinuria response.[42] If, after having withdrawn ACEI, BP is not well controlled on other drugs, an ACEI should be restarted owing to the severe deleterious effects of uncontrolled BP on the mother's renal function and the baby. A compromise may be to keep a low dose of ACEI plus other hypertensives, after proper counseling.

Women with scleroderma have higher rates of adverse pregnancy outcome in most case–control studies.[44,45] However, these risks should not discourage women from pregnancy provided they receive appropriate antenatal care. SSc is associated with increased risk of preterm delivery (14–29%), IUGR, longer hospitalization and, in women with longstanding diffuse scleroderma, miscarriage.[38–40] Women with limited scleroderma generally have better pregnancy outcomes than those with diffuse disease. In many cases, the unfavorable pregnancy outcomes may precede the diagnosis of the disease, but there is a trend towards worse outcomes after diagnosis of the disease. In cases of likely preterm delivery, corticosteroids for fetal lung maturation should not be given as they may precipitate a renal crisis. Epidural anesthesia and venous access are recommended during labor. Episiotomy or cesarean section may be performed with caution, as wound healing is not usually impaired and there is no contraindication for such procedures.[42]

Undifferentiated Connective Tissue Disease

Three prospective studies identified more than 125 pregnancies in women with undifferentiated connective tissue disease (UCTD). Flare of symptoms occurred in approximately a third,[46–48] and there was a small tendency for UCTD to evolve into well-defined disease. Women with UCTD suffered worse pregnancy outcomes, with more frequent preeclampsia, IUGR and preterm deliveries compared with background.

Sjögren's Syndrome

Although Sjögren's syndrome (SS) is generally diagnosed beyond the age of 40 years, there are considerable numbers of women who plan pregnancy after diagnosis. Despite the lack of published data regarding pregnancy in SS patients, we would recommend planning pregnancy when the disease is inactive and well controlled with safe medications (see below). There are no data concerning the use of drugs such as pilocarpine (US FDA class C) and cevimeline (FDA class C) in pregnancy. Most patients with SS are anti-Ro positive and women require appropriate pre-pregnancy counseling (see below).

Polymyositis/Dermatomyositis

Polymyositis and dermatomyositis in women are usually diagnosed after the child-bearing age. Two small series suggest that approximately half will flare during pregnancy, while disease activity seems to be the main predictor of obstetric complications.[49,50] Women with quiescent disease are more likely to have uncomplicated pregnancies, whereas those with active polymyositis/dermatomyositis have higher risk of preterm delivery and pregnancy loss.

Mixed Connective Tissue Disease

The available evidence for mixed connective tissue disease comes from a few small retrospective studies and case reports. Overall, flare rates and pregnancy outcomes in these women seem to resemble those seen in SLE rather than those in RA or in SSc, thus their pregnancy counseling and management should probably be similar to that described in SLE.[51]

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