Pregnancy and autoimmune connective tissue diseases




Abstract


Autoimmune connective tissue diseases predominantly affect women and often occur during the reproductive years. Thus, specialized issues in pregnancy planning and management are commonly encountered in this patient population. This chapter provides a current overview of pregnancy as a risk factor for onset of autoimmune disease, considerations related to the course of pregnancy in several autoimmune connective tissue diseases, and disease management and medication issues before pregnancy, during pregnancy, and in the postpartum period. A major theme that has emerged across these inflammatory diseases is that active maternal disease during pregnancy is associated with adverse pregnancy outcomes, and that maternal and fetal health can be optimized when conception is planned during times of inactive disease and through maintaining treatment regimens compatible with pregnancy.


Autoimmune connective tissue diseases (CTDs) are associated with strong female preponderance, and often present before or during the reproductive years . As such, specialized issues in pregnancy planning and management are commonly encountered in this patient population, which includes rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), antiphospholipid antibody syndrome (APS), systemic sclerosis (SSc), primary Sjogren’s syndrome (PSS), and inflammatory myositis. For decades, women particularly with SLE were advised against pregnancy given the high rates of observed poor outcomes, concern for disease flare, and lack of evidence for safe treatment options. Indeed, women with SLE/APS especially have higher rates of preeclampsia, intrauterine growth restriction (IUGR), and prematurity . However, with advances in disease management, pregnancy outcomes in these populations have improved, and increasingly more women with CTDs are choosing to attempt pregnancies . Furthermore, interesting research in the field is leading to identification of predictors for high-risk pregnancies, which will increasingly allow for a personalized approach to pregnancy management. An emphasis on preconception counseling and tight disease control in the months leading up to conception are essential components of this new era of pregnancy and CTDs. Equally important is the recognition that untreated disease in pregnancy is associated with risks to both the mother and child , and the preponderance of evidence demonstrates the importance of continuing medications that prevent active disease and that do not harm the baby throughout pregnancy. A thorough understanding of the range of therapeutic options available for treatment during pregnancy is therefore essential, and has expanded in recent years to include monoclonal antibody therapy. In this context, and with increasing accrual of follow-up data for children born to mothers with CTDs, the best practices for management of these pregnancies are evolving rapidly.


Pregnancy and subsequent risk of autoimmune CTDs


Whether pregnancy is a risk factor for the development of new-onset autoimmune CTD remains an open question. Among the rheumatic diseases, RA has perhaps received the most attention on this topic. As reviewed elsewhere, a significantly decreased risk of RA has been described in several retrospective studies in women who have ever been pregnant compared to nulliparous women , whereas a number of other studies, including population-based cohort studies, have not detected an association between parity and subsequent risk of RA . Conflicting results have been reported in other diseases such as SLE and SSc, also reviewed elsewhere .


Notably, a large population-based Danish study examining the autoimmune diseases as a group found that risk of developing maternal autoimmune disease significantly increased during the first year post partum, but it subsequently trended in the opposite direction . Onset of RA has particularly been described to occur with increasing frequency during the postpartum period. In fact, a 1953 study concluded that “The onset of rheumatoid arthritis during pregnancy or immediately after it is so common that in certain circumstances pregnancy can be regarded as an aetiological factor” . A 1992 British case–control study found a reduced incidence of onset of RA during pregnancy, but the highest postpartum increase was also observed during the first 3 months post partum (OR 5.6) and remained elevated during the subsequent 9 months . A 1993 case–control study from the Netherlands reported similar trends . Together, these studies underscore the importance of delineating time windows in relation to pregnancy, and they suggest that the postpartum period warrants special consideration in terms of risk of autoimmune diseases among women.




Pregnancy considerations in autoimmune CTDs


Systemic lupus erythematosus


SLE (or “lupus”) affects females in a 9:1 ratio to males , with a 2.5-fold increase in prevalence among African-Americans . The adverse pregnancy outcomes observed with lupus are well known, and include increased rates of IUGR, preterm birth, and fetal loss, as well as the syndrome of neonatal lupus (NL), associated with the transplacental passage of autoantibodies, discussed below. A 2006 study using the Nationwide Inpatient Sample in 2002 comparing CTD pregnancies to control pregnancies revealed significantly higher rates of hypertensive disorders (odds ratio (OR) 3.3 (95% confidence interval (CI) 2.8–4.0)), IUGR (OR 3.5 (95% CI 2.5–4.9)) and cesarean delivery (OR 1.6 (95% CI 1.4–1.9)) among patients with lupus, who had an increased length of hospital stay even after adjustment for cesarean delivery . A subsequent study focusing on lupus pregnancy within this database for the years 2000–2003 revealed that maternal mortality was 20-fold higher among women with SLE, as was preterm labor, preeclampsia, and other comorbidities associated with adverse pregnancy outcomes such as diabetes, hypertension, and thrombophilia . Observations that high disease activity at the time of conception, or in the months preceding conception, is an independent predictor for increased risk of adverse pregnancy outcomes including prematurity, IUGR, and fetal demise have led to the current recommendations that patients with lupus achieve 6 months of disease quiescence before attempting conception . Furthermore, the benefit of treating lupus to maintain good disease control throughout pregnancy, particularly with hydroxychloroquine (HCQ), has been demonstrated in studies where improved birth outcomes among lupus mothers who continued HCQ were observed when compared with lupus mothers who did not take HCQ in pregnancy .


In the context of these practice patterns, and with emphasis on a multidisciplinary approach to management from preconception through the postpartum period, improved outcomes have been increasingly observed in lupus pregnancies . Furthermore, recent work has focused on identifying predictors of poor pregnancy outcomes in this patient population, which will no doubt continue to improve care, as it may help identify a subset of patients for whom closer follow-up is indicated. Prospective data on predictors of adverse pregnancy outcomes in SLE pregnancies have recently been reported from the PROMISSE study (Predictors of Pregnancy Outcome: Biomarkers In Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus), an ongoing multicenter, prospective observational study of pregnancies in women with antiphospholipid antibodies (aPLs), SLE, or both . Three hundred and eighty-five pregnant women with stable lupus, with or without APS, were enrolled and compared with pregnant control women. In this population, predictors of adverse pregnancy outcomes in lupus pregnancies included African and Hispanic descent, use of antihypertensives at baseline, the presence of lupus anticoagulant (LAC), mild or moderate flare of lupus, moderate clinical disease activity at baseline, and thrombocytopenia. Of note, the patients with lupus enrolled in the PROMISSE cohort had very low disease activity: the rate of flare in the second and third trimesters was 2.5% and 3%, respectively, which is much lower than flare rates reported in previous pregnancy studies . The enrollment criteria for this study included optimized lupus disease activity (exclusion of patients with urine protein/creatinine ratio of >1000 mg/g, creatinine level >1.2 mg/dL, and prednisone use >20 mg/d), confirming that effective preconception planning results in favorable outcomes in this population.


Lupus nephritis


In a large meta-analysis of pregnancy outcomes in SLE and lupus nephritis (LN), in which 37 studies with 1842 patients with lupus and 2751 pregnancies were included, significant associations were observed between LN and both premature birth and preeclampsia . It can also be difficult to distinguish active LN in pregnancy from preeclampsia. Both are associated with proteinuria and rising creatinine levels, but examination of urinary sediment will reveal activity in LN as opposed to a bland urinary sediment in preeclampsia. Serum uric acid may be elevated in preeclampsia and could provide another marker to help distinguish between the two processes, but usually the clinical picture is nebulous, highlighting a large knowledge gap that can lead to inappropriate treatment decisions, as gram doses of intravenous (IV) corticosteroid and IV cyclophosphamide (CYC) would be indicated for severe LN, whereas prompt delivery of the baby would be indicated for preeclampsia.


Antiphospholipid antibody syndrome


Obstetric antiphospholipid antibody syndrome (OB–APS) was defined according to the updated Sydney classification criteria developed by expert consensus agreement in 2006 . aPLs include the LAC, anticardiolipin (aCL) IgG and IgM, and anti-β2-glycoprotein I antibody. In addition to the detection of aPLs on at least two occasions >12 weeks apart, OB–APS is defined by any one of the following adverse pregnancy outcomes: 1) otherwise unexplained recurrent pregnancy loss before the 10th week of gestation, 2) otherwise unexplained fetal death ≥10 weeks of gestation, and 3) preterm birth before 24 weeks of gestation due to preeclampsia or placental insufficiency . Other OB–APS complications include catastrophic APS, thrombosis, HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count), IUGR, fetal distress, premature rupture of membranes, and thrombocytopenia .


Poor pregnancy outcomes, including second-trimester pregnancy loss, fetal growth restriction, and preeclampsia have been observed in association with APS for years , but only recently has it been recognized that the LAC, among the three aPLs, is the primary predictor of poor pregnancy outcomes in women both with or without SLE and with or without other aPLs . Of the 144 women enrolled in the PROMISSE study between 2003 and 2011, 28 had adverse pregnancy outcomes defined as otherwise unexplained fetal demise after 12 weeks of gestation, neonatal death before discharge associated with complications of prematurity, preterm delivery before 34 weeks because of gestational hypertension, preeclampsia or placental insufficiency, or small for gestational age (birth weight < fifth percentile). Thirty-nine percent of women with LAC had adverse pregnancy outcomes compared with 3% of those without LAC ( p < 0.0001). Of the remaining aPLs, only IgG aCL at ≥40 units/ml appeared to also be associated with adverse pregnancy outcomes (8% vs. 43% who were also positive for LAC; p = 0.002). In multivariate analysis, the other contributors to obstetric risk included SLE (relative risk (RR) = 2.16; 95% CI 1.27–3.68; p = 0.005), a history of thrombosis (RR = 1.90; 95% CI 1.14–3.17; p = 0.01), age (RR = 1.56 for every 5-year decrease in age; 95% CI 1.18–2.08; p = 0.002), and race (RR = 3.24 for white vs. non-white; 95% CI 1.16–9.07; p = 0.03).


Regarding treatment of patients with anticoagulation in the PROMISSE study, the patients’ physicians made all treatment decisions. Upon study entry, out of 75 women who were treated with heparin, 56 were receiving low-molecular-weight heparin (LMWH) and 19 were receiving unfractionated heparin (36 at therapeutic doses and 39 at prophylactic doses). Out of 97 women who regularly took aspirin, all but one took 81 mg per day and the other took 325 mg a day. No benefit of heparin was found, and a protective effect of aspirin was not significant after adjustment for the predictors mentioned above. However, the study was not designed or powered as a treatment trial.


Low-dose aspirin to mitigate the risk of fetal loss in women with APS has been used for years . More recent systematic reviews and meta-analyses comparing the use of low-dose aspirin versus low-dose aspirin and heparin in pregnant women with aPLs and recurrent miscarriage have shown that combination treatment with aspirin and heparin is superior to aspirin alone in conferring a significant benefit in live births . LMWH has been accepted as the standard of care when treating pregnant women with APS . Heparin does not cross the placenta and is considered safe for the embryo/fetus. LMWH may offer some advantages over unfractionated heparin. The most notable is that LMWH is less likely to cause heparin-induced thrombocytopenia and osteoporosis, and it is more bioavailable than unfractionated heparin.


Despite this treatment, and even with comprehensive medical and obstetric management, about 30% of APS pregnancies will still result in pregnancy loss . Other proposed therapies to prevent adverse pregnancy outcomes in OB–APS are being investigated, including the use of HCQ, for which prospective trial data are lacking, but for which encouraging results from in vitro and animal models exist . Mechanistically, the anti-inflammatory, antithrombotic, and proendothelial effects of HCQ, in addition to its safety profile in pregnancy, suggest a potential protective effect in OB–APS . Due to the lack of substantial clinical data on the ability of HCQ to affect adverse pregnancy outcomes in OB–APS, an expert panel was recently convened to formulate an opinion about its use for prevention of OB–APS based on the available literature and expert judgment of clinical OB–APS scenarios . They concluded that adding HCQ could be considered in selected cases or after standard treatment failure with aspirin and a heparin agent. Specific scenarios where the majority opinion was to add HCQ included women with previous thrombosis or previous ischemic placenta-mediated complications.


Rheumatoid arthritis


A widely held perception based on retrospective data is that the majority of RA patients experience spontaneous remission during pregnancy, and a tendency toward postpartum flare within 3–4 months. Newer prospective data from RA patients followed during and after pregnancy; with objective assessments of disease activity, these data have provided a more complete picture related to disease activity during and after pregnancy. Of importance, because physiologic changes of pregnancy influence standard disease assessment parameters, such as the Global Health scale of the Disease Activity Score (DAS) and erythrocyte sedimentation rate (ESR) levels, modified assessment tools for use in studies of RA pregnancies have been suggested . The DAS28-CRP without the Global Health scale (and excluding ESR as an inflammatory marker) has been shown to perform well in pregnancy . A major study of 84 RA patients in the Netherlands recruited between 2002 and 2006 indeed found that mean DASs (by modified DAS28-CRP) declined during pregnancy despite reduced rates of medication use compared with before conception . Approximately 25% of women experienced RA remission during the third trimester, a substantial yet smaller proportion than previously expected. Based on the European League Against Rheumatism (EULAR) response criteria among the 52 women with moderate baseline disease activity in the first trimester (DAS28 > 3.2), 30.8% had a “moderate” response and 17.3% had a “good” response between the first and third trimesters. In the postpartum period, disease activity increased with more than one-third of the women having a moderate or severe flare (defined by revised EULAR response criteria), even in the context of increased medication use after delivery.


In terms of pregnancy outcomes, a national study of approximately 1400 RA pregnancies in the US in 2002 documented IUGR in 6.4% and premature rupture of membranes in 3.9% of women — rates that were 1.5–2 times higher than in the general obstetric population even when controlling for factors such as maternal age . Significant progress has also been made in recent prospective studies with respect to understanding the contribution of disease severity to pregnancy outcomes in RA. Data now indicate that for women with well-controlled RA, pregnancy outcomes are comparable with the general obstetric population , whereas higher levels of RA disease activity are associated with an increased risk of less favorable pregnancy outcomes . de Man et al. found that among 152 Dutch RA patients with singleton pregnancies, higher levels of disease activity in the third trimester were independently associated with lower birth weight, controlling for several covariates including smoking, maternal age, and prednisone use . Furthermore, prednisone use during pregnancy was linked to lower gestational age at birth (no effect of prednisone dose observed), with deliveries on average 1 week earlier and more often occurring at <37 weeks compared with RA patients not taking prednisone during pregnancy . The earlier gestational age underlies an association between prednisone use and lower birth weight. In a North American study, which enrolled 440 pregnant women with RA between 2005 and 2015, Bharti et al. found that RA disease severity, measured in early pregnancy, was predictive of preterm delivery and small for gestational age . Consistent with the Dutch study, prednisone use (≥10 mg) during pregnancy was also associated with preterm birth, and not thought to simply serve as a marker of disease severity, as the relationship between disease severity and preterm delivery also held up.


Systemic sclerosis (or scleroderma)


As with SLE, pregnancy in women with SSc was previously considered problematic and was discouraged due to concern for poor outcomes . Recent research has revealed a more favorable picture of SSc pregnancies; however, certain patterns of increased risk do exist. In a US study based on the 2002–2004 Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project, SSc was associated with an increased risk of hypertensive disease in pregnancy, including preeclampsia, IUGR, and increased length of hospital stay . Retrospective data on 214 women with SSc, 167 women with RA, and 2015 healthy controls in the US have also identified an increase in premature births and low birth weight for babies born to SSc mothers . These findings were later confirmed in a study of pregnancy outcomes in an Italian multicenter study of 109 pregnancies among 99 women with SSc from 2000 to 2010, in which the data are obtained prospectively starting a year before conception . The mean age at conception was 31.9 years in this population; 54 had limited cutaneous SSc, 48 diffuse cutaneous SSc, six fulfilled LeRoy and Medsger criteria for early SSc, and one scleroderma sine sclerosis . When compared with a control population, preterm deliveries were found to be significantly increased among women with SSc (25% vs. 12%), including severe preterm deliveries defined as <34 weeks of gestation (10% vs. 5%). IUGR and low birth weight were also increased, and in multivariate analysis, the use of corticosteroids was associated with preterm deliveries (OR 3.63; 95% CI 1.12–11/78). No significant differences in pregnancy outcomes were found in diffuse versus limited cutaneous subsets. Although none of the women in the study had pulmonary hypertension or severe cardiac or renal disease at baseline, two women had severe gastrointestinal (GI) disease associated with intestinal malabsorption, one with IUGR and one delivering preterm, and three women had severe lung fibrosis associated with forced vital capacity (FVC) <50%, but none with obstetrical complications. The use of folic acid and the presence of antitopoisomerase were protective, and in general Raynaud’s phenomenon and digital ulcers improved temporarily starting in the second trimester; however, the effect did not persist after pregnancy. In general, the disease stayed stable during pregnancies. These authors concluded that women with SSc can have successful pregnancies, but are at a higher risk than the general population of preterm deliveries, low-birth-weight babies, and IUGR; these women should be cautioned against pregnancy if severe target organ damage is present.


Myositis


Data on inflammatory myositis and pregnancy are sparse, reflecting the rarity of the disease and onset that typically occurs after the reproductive years. A 2014 review of 36 publications comprised only 78 pregnancies from 59 women . Approximately 60% of the pregnancies occurred among women with preexisting myositis, and an overall trend was that disease activity, especially during early pregnancy, appeared to be associated with adverse pregnancy outcomes, whereas treatment of disease during pregnancy (with corticosteroids or intravenous immunoglobulin (IVIG)) appeared to be beneficial . Based on the available data, neonatal outcome was described as generally good, with preterm delivery and small for gestational age reported as the main complications . The most extensive individual study, also published in 2014 and thus not included in the above review, included a total of 102 pregnancies from a retrospective Spanish cohort of 51 women with idiopathic inflammatory myopathies diagnosed between 1983 and 2013 ; 80% of women were classified as having dermatomyositis, and 20% as having polymyositis according to the Bohan and Peter criteria for definite or probable myositis . The authors concluded that pregnancy did not appear to be associated with adverse maternal or fetal outcomes, and that clinical improvement tended to occur during pregnancy, while postpartum relapse was common . They also found no evidence for pregnancy as a trigger of myositis .


Sjogren’s syndrome


The incidence of PSS is highest during postmenopausal years. However, it can occur at any age, and indeed a pregnancy resulting in NL (discussed below) may be the earliest indication of PSS associated with anti-Ro/La antibodies . Pregnancy outcomes beyond cardiac NL have not been studied as extensively as in SLE or APS, but from small case–control studies, it appears that PSS may be associated with lower mean birth weights in offspring, older maternal age, and more common delivery by cesarean section or vacuum extraction than in the background population . A study of >100 pregnancies in women with primary and secondary SS revealed that only the presence of concomitant SLE and likely aPLs were associated with higher rates of spontaneous abortion and premature deliveries than controls . As discussed below, however, appropriate screening for the presence of NL is essential in the management of pregnancy in patients with primary or secondary SS and anti-Ro/La antibodies.


Neonatal lupus syndrome


NL syndrome represents passively acquired autoimmunity resulting from transplacental transfer of maternal anti-Ro/SSA (52 or 60 kD) or La/SSB (48 kD) antibodies. Although transient features of the syndrome (characteristic rash of NL, hepatic, and hematologic abnormalities) may be observed, the major morbidity and mortality associated with NL involve the developing fetal cardiac tissue, leading to autoimmune congenital heart block (ACHB) due to inflammatory and fibrotic changes of the AV node, in addition to more severe complications including endocardial fibroelastosis (EFE) and dilated cardiomyopathy, which may develop even in the absence of conduction abnormalities .


Although the overwhelming majority of ACHB cases involve anti-Ro-positive mothers, isolated anti-La-associated cases have also been reported, representing <1% of total cases . Therefore, recommendations for screening and therapy apply to mothers positive for either autoantibody. Among mothers positive for anti-Ro/SSA, an incidence of ACHB of 2% is widely accepted, as reported in a large prospective study of pregnancy outcomes in 100 anti-Ro-positive women . The estimated recurrence of heart block in subsequent pregnancies for a mother with a previous child born with ACHB is about 18% . Among children born with ACHB, a 20% overall mortality rate, with a 79% 3-year survival, has been observed with pacemaker requirement in 64% .


Recommendations for early, noninvasive diagnosis of ACHB involve fetal echocardiography with Doppler mechanical PR interval measurement beginning between weeks 16 and 18, and continuing weekly through week 26 . Although there is support for the use of fluorinated steroids (FSs) aimed at reversing incomplete heart block presumably due to ongoing inflammation, treatment recommendations have been less clear for advanced heart block until recent evidence against their use was published . A retrospective study in 2015 from the Research Registry for Neonatal Lupus (RRNL) of babies from anti-Ro+ pregnancies born with isolated advanced ACHB revealed similar outcomes for those who received FSs ( n = 71) within 1 week of detection than those who received no treatment ( n = 85) . The risk of developing extranodal disease in this study was similar, revealing that 14 (19.7%) of 71 fetuses exposed to FSs developed extranodal disease compared with 17 (20%) of 85 unexposed fetuses, with an unadjusted hazard ratio (HR) of 1.02 (95% CI 0.51–2.06; p = 0.96). Furthermore, FSs failed to improve survival, with deaths in 7/71 (9.9%) of FS-exposed compared with 7/80 (8.8%) of untreated (HR = 1.19 (95% CI 0.42–3.40; p = 0.74)). Likewise, FS treatment did not prevent future pacemaker implantation, with 42/64 (66%) of FS-exposed live births paced compared with 60/78 (75%) of untreated (HR = 0.94 (95% CI 0.64–1.40; p = 0.77)). These data therefore do not support the use of FSs for fetuses with isolated advanced heart block, which, in addition to extranodal cardiac disease, remains a marker of poor outcome .


Support for the use of HCQ for prevention of cardiac NL comes from an analysis of 257 anti-SSA/Ro-positive SLE pregnancies at high risk for cardiac NL in the RRNL database . The authors compared outcomes of 40 mothers who had taken HCQ throughout their pregnancies, having started within 10 weeks of gestation, to 217 mothers unexposed to HCQ, subsequent to the birth of a child with cardiac NL. The recurrence rate of cardiac NL in HCQ-exposed fetuses was 7.5% (three of 40) compared with 21.2% (46 of 217) in the unexposed group ( p = 0.05), a significant association that persisted after the multivariate analysis adjusting for maternal race/ethnicity, anti-SSB/La status, and confounding by indication. The authors therefore concluded that HCQ therapy may be protective in subsequent pregnancies among mothers with a history of having a child with cardiac NL. An open-label prospective trial, the Preventive Approach to Congenital Heart Block with Hydroxychloroquine (PATCH) study ( NCT01379573 ), is currently recruiting, which will assess the effect of HCQ in preventing recurrence of cardiac NL in high-risk women with a previously affected child.


There is no convincing evidence in support of β-agonists, IVIG therapy, or plasmapheresis for prevention of cardiac-NL lupus, and no agreement on appropriate dose or schedule .


Contraindications to pregnancy


Contraindications to pregnancy for women with lupus in particular, and rheumatic CTDs in general, include pulmonary hypertension defined by a mean pulmonary artery pressure of ≥25 mm Hg at rest, measured during right-heart catheterization , advanced heart failure, severe restrictive lung disease (FVC <1 L), chronic renal failure (Cr > 2.8 mg/dL), and previous severe preeclampsia or HELLP syndrome despite therapy with aspirin and heparin, stroke, or severe lupus flare within the previous 6 months .




Pregnancy considerations in autoimmune CTDs


Systemic lupus erythematosus


SLE (or “lupus”) affects females in a 9:1 ratio to males , with a 2.5-fold increase in prevalence among African-Americans . The adverse pregnancy outcomes observed with lupus are well known, and include increased rates of IUGR, preterm birth, and fetal loss, as well as the syndrome of neonatal lupus (NL), associated with the transplacental passage of autoantibodies, discussed below. A 2006 study using the Nationwide Inpatient Sample in 2002 comparing CTD pregnancies to control pregnancies revealed significantly higher rates of hypertensive disorders (odds ratio (OR) 3.3 (95% confidence interval (CI) 2.8–4.0)), IUGR (OR 3.5 (95% CI 2.5–4.9)) and cesarean delivery (OR 1.6 (95% CI 1.4–1.9)) among patients with lupus, who had an increased length of hospital stay even after adjustment for cesarean delivery . A subsequent study focusing on lupus pregnancy within this database for the years 2000–2003 revealed that maternal mortality was 20-fold higher among women with SLE, as was preterm labor, preeclampsia, and other comorbidities associated with adverse pregnancy outcomes such as diabetes, hypertension, and thrombophilia . Observations that high disease activity at the time of conception, or in the months preceding conception, is an independent predictor for increased risk of adverse pregnancy outcomes including prematurity, IUGR, and fetal demise have led to the current recommendations that patients with lupus achieve 6 months of disease quiescence before attempting conception . Furthermore, the benefit of treating lupus to maintain good disease control throughout pregnancy, particularly with hydroxychloroquine (HCQ), has been demonstrated in studies where improved birth outcomes among lupus mothers who continued HCQ were observed when compared with lupus mothers who did not take HCQ in pregnancy .


In the context of these practice patterns, and with emphasis on a multidisciplinary approach to management from preconception through the postpartum period, improved outcomes have been increasingly observed in lupus pregnancies . Furthermore, recent work has focused on identifying predictors of poor pregnancy outcomes in this patient population, which will no doubt continue to improve care, as it may help identify a subset of patients for whom closer follow-up is indicated. Prospective data on predictors of adverse pregnancy outcomes in SLE pregnancies have recently been reported from the PROMISSE study (Predictors of Pregnancy Outcome: Biomarkers In Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus), an ongoing multicenter, prospective observational study of pregnancies in women with antiphospholipid antibodies (aPLs), SLE, or both . Three hundred and eighty-five pregnant women with stable lupus, with or without APS, were enrolled and compared with pregnant control women. In this population, predictors of adverse pregnancy outcomes in lupus pregnancies included African and Hispanic descent, use of antihypertensives at baseline, the presence of lupus anticoagulant (LAC), mild or moderate flare of lupus, moderate clinical disease activity at baseline, and thrombocytopenia. Of note, the patients with lupus enrolled in the PROMISSE cohort had very low disease activity: the rate of flare in the second and third trimesters was 2.5% and 3%, respectively, which is much lower than flare rates reported in previous pregnancy studies . The enrollment criteria for this study included optimized lupus disease activity (exclusion of patients with urine protein/creatinine ratio of >1000 mg/g, creatinine level >1.2 mg/dL, and prednisone use >20 mg/d), confirming that effective preconception planning results in favorable outcomes in this population.


Lupus nephritis


In a large meta-analysis of pregnancy outcomes in SLE and lupus nephritis (LN), in which 37 studies with 1842 patients with lupus and 2751 pregnancies were included, significant associations were observed between LN and both premature birth and preeclampsia . It can also be difficult to distinguish active LN in pregnancy from preeclampsia. Both are associated with proteinuria and rising creatinine levels, but examination of urinary sediment will reveal activity in LN as opposed to a bland urinary sediment in preeclampsia. Serum uric acid may be elevated in preeclampsia and could provide another marker to help distinguish between the two processes, but usually the clinical picture is nebulous, highlighting a large knowledge gap that can lead to inappropriate treatment decisions, as gram doses of intravenous (IV) corticosteroid and IV cyclophosphamide (CYC) would be indicated for severe LN, whereas prompt delivery of the baby would be indicated for preeclampsia.


Antiphospholipid antibody syndrome


Obstetric antiphospholipid antibody syndrome (OB–APS) was defined according to the updated Sydney classification criteria developed by expert consensus agreement in 2006 . aPLs include the LAC, anticardiolipin (aCL) IgG and IgM, and anti-β2-glycoprotein I antibody. In addition to the detection of aPLs on at least two occasions >12 weeks apart, OB–APS is defined by any one of the following adverse pregnancy outcomes: 1) otherwise unexplained recurrent pregnancy loss before the 10th week of gestation, 2) otherwise unexplained fetal death ≥10 weeks of gestation, and 3) preterm birth before 24 weeks of gestation due to preeclampsia or placental insufficiency . Other OB–APS complications include catastrophic APS, thrombosis, HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count), IUGR, fetal distress, premature rupture of membranes, and thrombocytopenia .


Poor pregnancy outcomes, including second-trimester pregnancy loss, fetal growth restriction, and preeclampsia have been observed in association with APS for years , but only recently has it been recognized that the LAC, among the three aPLs, is the primary predictor of poor pregnancy outcomes in women both with or without SLE and with or without other aPLs . Of the 144 women enrolled in the PROMISSE study between 2003 and 2011, 28 had adverse pregnancy outcomes defined as otherwise unexplained fetal demise after 12 weeks of gestation, neonatal death before discharge associated with complications of prematurity, preterm delivery before 34 weeks because of gestational hypertension, preeclampsia or placental insufficiency, or small for gestational age (birth weight < fifth percentile). Thirty-nine percent of women with LAC had adverse pregnancy outcomes compared with 3% of those without LAC ( p < 0.0001). Of the remaining aPLs, only IgG aCL at ≥40 units/ml appeared to also be associated with adverse pregnancy outcomes (8% vs. 43% who were also positive for LAC; p = 0.002). In multivariate analysis, the other contributors to obstetric risk included SLE (relative risk (RR) = 2.16; 95% CI 1.27–3.68; p = 0.005), a history of thrombosis (RR = 1.90; 95% CI 1.14–3.17; p = 0.01), age (RR = 1.56 for every 5-year decrease in age; 95% CI 1.18–2.08; p = 0.002), and race (RR = 3.24 for white vs. non-white; 95% CI 1.16–9.07; p = 0.03).


Regarding treatment of patients with anticoagulation in the PROMISSE study, the patients’ physicians made all treatment decisions. Upon study entry, out of 75 women who were treated with heparin, 56 were receiving low-molecular-weight heparin (LMWH) and 19 were receiving unfractionated heparin (36 at therapeutic doses and 39 at prophylactic doses). Out of 97 women who regularly took aspirin, all but one took 81 mg per day and the other took 325 mg a day. No benefit of heparin was found, and a protective effect of aspirin was not significant after adjustment for the predictors mentioned above. However, the study was not designed or powered as a treatment trial.


Low-dose aspirin to mitigate the risk of fetal loss in women with APS has been used for years . More recent systematic reviews and meta-analyses comparing the use of low-dose aspirin versus low-dose aspirin and heparin in pregnant women with aPLs and recurrent miscarriage have shown that combination treatment with aspirin and heparin is superior to aspirin alone in conferring a significant benefit in live births . LMWH has been accepted as the standard of care when treating pregnant women with APS . Heparin does not cross the placenta and is considered safe for the embryo/fetus. LMWH may offer some advantages over unfractionated heparin. The most notable is that LMWH is less likely to cause heparin-induced thrombocytopenia and osteoporosis, and it is more bioavailable than unfractionated heparin.


Despite this treatment, and even with comprehensive medical and obstetric management, about 30% of APS pregnancies will still result in pregnancy loss . Other proposed therapies to prevent adverse pregnancy outcomes in OB–APS are being investigated, including the use of HCQ, for which prospective trial data are lacking, but for which encouraging results from in vitro and animal models exist . Mechanistically, the anti-inflammatory, antithrombotic, and proendothelial effects of HCQ, in addition to its safety profile in pregnancy, suggest a potential protective effect in OB–APS . Due to the lack of substantial clinical data on the ability of HCQ to affect adverse pregnancy outcomes in OB–APS, an expert panel was recently convened to formulate an opinion about its use for prevention of OB–APS based on the available literature and expert judgment of clinical OB–APS scenarios . They concluded that adding HCQ could be considered in selected cases or after standard treatment failure with aspirin and a heparin agent. Specific scenarios where the majority opinion was to add HCQ included women with previous thrombosis or previous ischemic placenta-mediated complications.


Rheumatoid arthritis


A widely held perception based on retrospective data is that the majority of RA patients experience spontaneous remission during pregnancy, and a tendency toward postpartum flare within 3–4 months. Newer prospective data from RA patients followed during and after pregnancy; with objective assessments of disease activity, these data have provided a more complete picture related to disease activity during and after pregnancy. Of importance, because physiologic changes of pregnancy influence standard disease assessment parameters, such as the Global Health scale of the Disease Activity Score (DAS) and erythrocyte sedimentation rate (ESR) levels, modified assessment tools for use in studies of RA pregnancies have been suggested . The DAS28-CRP without the Global Health scale (and excluding ESR as an inflammatory marker) has been shown to perform well in pregnancy . A major study of 84 RA patients in the Netherlands recruited between 2002 and 2006 indeed found that mean DASs (by modified DAS28-CRP) declined during pregnancy despite reduced rates of medication use compared with before conception . Approximately 25% of women experienced RA remission during the third trimester, a substantial yet smaller proportion than previously expected. Based on the European League Against Rheumatism (EULAR) response criteria among the 52 women with moderate baseline disease activity in the first trimester (DAS28 > 3.2), 30.8% had a “moderate” response and 17.3% had a “good” response between the first and third trimesters. In the postpartum period, disease activity increased with more than one-third of the women having a moderate or severe flare (defined by revised EULAR response criteria), even in the context of increased medication use after delivery.


In terms of pregnancy outcomes, a national study of approximately 1400 RA pregnancies in the US in 2002 documented IUGR in 6.4% and premature rupture of membranes in 3.9% of women — rates that were 1.5–2 times higher than in the general obstetric population even when controlling for factors such as maternal age . Significant progress has also been made in recent prospective studies with respect to understanding the contribution of disease severity to pregnancy outcomes in RA. Data now indicate that for women with well-controlled RA, pregnancy outcomes are comparable with the general obstetric population , whereas higher levels of RA disease activity are associated with an increased risk of less favorable pregnancy outcomes . de Man et al. found that among 152 Dutch RA patients with singleton pregnancies, higher levels of disease activity in the third trimester were independently associated with lower birth weight, controlling for several covariates including smoking, maternal age, and prednisone use . Furthermore, prednisone use during pregnancy was linked to lower gestational age at birth (no effect of prednisone dose observed), with deliveries on average 1 week earlier and more often occurring at <37 weeks compared with RA patients not taking prednisone during pregnancy . The earlier gestational age underlies an association between prednisone use and lower birth weight. In a North American study, which enrolled 440 pregnant women with RA between 2005 and 2015, Bharti et al. found that RA disease severity, measured in early pregnancy, was predictive of preterm delivery and small for gestational age . Consistent with the Dutch study, prednisone use (≥10 mg) during pregnancy was also associated with preterm birth, and not thought to simply serve as a marker of disease severity, as the relationship between disease severity and preterm delivery also held up.


Systemic sclerosis (or scleroderma)


As with SLE, pregnancy in women with SSc was previously considered problematic and was discouraged due to concern for poor outcomes . Recent research has revealed a more favorable picture of SSc pregnancies; however, certain patterns of increased risk do exist. In a US study based on the 2002–2004 Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project, SSc was associated with an increased risk of hypertensive disease in pregnancy, including preeclampsia, IUGR, and increased length of hospital stay . Retrospective data on 214 women with SSc, 167 women with RA, and 2015 healthy controls in the US have also identified an increase in premature births and low birth weight for babies born to SSc mothers . These findings were later confirmed in a study of pregnancy outcomes in an Italian multicenter study of 109 pregnancies among 99 women with SSc from 2000 to 2010, in which the data are obtained prospectively starting a year before conception . The mean age at conception was 31.9 years in this population; 54 had limited cutaneous SSc, 48 diffuse cutaneous SSc, six fulfilled LeRoy and Medsger criteria for early SSc, and one scleroderma sine sclerosis . When compared with a control population, preterm deliveries were found to be significantly increased among women with SSc (25% vs. 12%), including severe preterm deliveries defined as <34 weeks of gestation (10% vs. 5%). IUGR and low birth weight were also increased, and in multivariate analysis, the use of corticosteroids was associated with preterm deliveries (OR 3.63; 95% CI 1.12–11/78). No significant differences in pregnancy outcomes were found in diffuse versus limited cutaneous subsets. Although none of the women in the study had pulmonary hypertension or severe cardiac or renal disease at baseline, two women had severe gastrointestinal (GI) disease associated with intestinal malabsorption, one with IUGR and one delivering preterm, and three women had severe lung fibrosis associated with forced vital capacity (FVC) <50%, but none with obstetrical complications. The use of folic acid and the presence of antitopoisomerase were protective, and in general Raynaud’s phenomenon and digital ulcers improved temporarily starting in the second trimester; however, the effect did not persist after pregnancy. In general, the disease stayed stable during pregnancies. These authors concluded that women with SSc can have successful pregnancies, but are at a higher risk than the general population of preterm deliveries, low-birth-weight babies, and IUGR; these women should be cautioned against pregnancy if severe target organ damage is present.


Myositis


Data on inflammatory myositis and pregnancy are sparse, reflecting the rarity of the disease and onset that typically occurs after the reproductive years. A 2014 review of 36 publications comprised only 78 pregnancies from 59 women . Approximately 60% of the pregnancies occurred among women with preexisting myositis, and an overall trend was that disease activity, especially during early pregnancy, appeared to be associated with adverse pregnancy outcomes, whereas treatment of disease during pregnancy (with corticosteroids or intravenous immunoglobulin (IVIG)) appeared to be beneficial . Based on the available data, neonatal outcome was described as generally good, with preterm delivery and small for gestational age reported as the main complications . The most extensive individual study, also published in 2014 and thus not included in the above review, included a total of 102 pregnancies from a retrospective Spanish cohort of 51 women with idiopathic inflammatory myopathies diagnosed between 1983 and 2013 ; 80% of women were classified as having dermatomyositis, and 20% as having polymyositis according to the Bohan and Peter criteria for definite or probable myositis . The authors concluded that pregnancy did not appear to be associated with adverse maternal or fetal outcomes, and that clinical improvement tended to occur during pregnancy, while postpartum relapse was common . They also found no evidence for pregnancy as a trigger of myositis .


Sjogren’s syndrome


The incidence of PSS is highest during postmenopausal years. However, it can occur at any age, and indeed a pregnancy resulting in NL (discussed below) may be the earliest indication of PSS associated with anti-Ro/La antibodies . Pregnancy outcomes beyond cardiac NL have not been studied as extensively as in SLE or APS, but from small case–control studies, it appears that PSS may be associated with lower mean birth weights in offspring, older maternal age, and more common delivery by cesarean section or vacuum extraction than in the background population . A study of >100 pregnancies in women with primary and secondary SS revealed that only the presence of concomitant SLE and likely aPLs were associated with higher rates of spontaneous abortion and premature deliveries than controls . As discussed below, however, appropriate screening for the presence of NL is essential in the management of pregnancy in patients with primary or secondary SS and anti-Ro/La antibodies.


Neonatal lupus syndrome


NL syndrome represents passively acquired autoimmunity resulting from transplacental transfer of maternal anti-Ro/SSA (52 or 60 kD) or La/SSB (48 kD) antibodies. Although transient features of the syndrome (characteristic rash of NL, hepatic, and hematologic abnormalities) may be observed, the major morbidity and mortality associated with NL involve the developing fetal cardiac tissue, leading to autoimmune congenital heart block (ACHB) due to inflammatory and fibrotic changes of the AV node, in addition to more severe complications including endocardial fibroelastosis (EFE) and dilated cardiomyopathy, which may develop even in the absence of conduction abnormalities .


Although the overwhelming majority of ACHB cases involve anti-Ro-positive mothers, isolated anti-La-associated cases have also been reported, representing <1% of total cases . Therefore, recommendations for screening and therapy apply to mothers positive for either autoantibody. Among mothers positive for anti-Ro/SSA, an incidence of ACHB of 2% is widely accepted, as reported in a large prospective study of pregnancy outcomes in 100 anti-Ro-positive women . The estimated recurrence of heart block in subsequent pregnancies for a mother with a previous child born with ACHB is about 18% . Among children born with ACHB, a 20% overall mortality rate, with a 79% 3-year survival, has been observed with pacemaker requirement in 64% .


Recommendations for early, noninvasive diagnosis of ACHB involve fetal echocardiography with Doppler mechanical PR interval measurement beginning between weeks 16 and 18, and continuing weekly through week 26 . Although there is support for the use of fluorinated steroids (FSs) aimed at reversing incomplete heart block presumably due to ongoing inflammation, treatment recommendations have been less clear for advanced heart block until recent evidence against their use was published . A retrospective study in 2015 from the Research Registry for Neonatal Lupus (RRNL) of babies from anti-Ro+ pregnancies born with isolated advanced ACHB revealed similar outcomes for those who received FSs ( n = 71) within 1 week of detection than those who received no treatment ( n = 85) . The risk of developing extranodal disease in this study was similar, revealing that 14 (19.7%) of 71 fetuses exposed to FSs developed extranodal disease compared with 17 (20%) of 85 unexposed fetuses, with an unadjusted hazard ratio (HR) of 1.02 (95% CI 0.51–2.06; p = 0.96). Furthermore, FSs failed to improve survival, with deaths in 7/71 (9.9%) of FS-exposed compared with 7/80 (8.8%) of untreated (HR = 1.19 (95% CI 0.42–3.40; p = 0.74)). Likewise, FS treatment did not prevent future pacemaker implantation, with 42/64 (66%) of FS-exposed live births paced compared with 60/78 (75%) of untreated (HR = 0.94 (95% CI 0.64–1.40; p = 0.77)). These data therefore do not support the use of FSs for fetuses with isolated advanced heart block, which, in addition to extranodal cardiac disease, remains a marker of poor outcome .


Support for the use of HCQ for prevention of cardiac NL comes from an analysis of 257 anti-SSA/Ro-positive SLE pregnancies at high risk for cardiac NL in the RRNL database . The authors compared outcomes of 40 mothers who had taken HCQ throughout their pregnancies, having started within 10 weeks of gestation, to 217 mothers unexposed to HCQ, subsequent to the birth of a child with cardiac NL. The recurrence rate of cardiac NL in HCQ-exposed fetuses was 7.5% (three of 40) compared with 21.2% (46 of 217) in the unexposed group ( p = 0.05), a significant association that persisted after the multivariate analysis adjusting for maternal race/ethnicity, anti-SSB/La status, and confounding by indication. The authors therefore concluded that HCQ therapy may be protective in subsequent pregnancies among mothers with a history of having a child with cardiac NL. An open-label prospective trial, the Preventive Approach to Congenital Heart Block with Hydroxychloroquine (PATCH) study ( NCT01379573 ), is currently recruiting, which will assess the effect of HCQ in preventing recurrence of cardiac NL in high-risk women with a previously affected child.


There is no convincing evidence in support of β-agonists, IVIG therapy, or plasmapheresis for prevention of cardiac-NL lupus, and no agreement on appropriate dose or schedule .


Contraindications to pregnancy


Contraindications to pregnancy for women with lupus in particular, and rheumatic CTDs in general, include pulmonary hypertension defined by a mean pulmonary artery pressure of ≥25 mm Hg at rest, measured during right-heart catheterization , advanced heart failure, severe restrictive lung disease (FVC <1 L), chronic renal failure (Cr > 2.8 mg/dL), and previous severe preeclampsia or HELLP syndrome despite therapy with aspirin and heparin, stroke, or severe lupus flare within the previous 6 months .

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Nov 10, 2017 | Posted by in RHEUMATOLOGY | Comments Off on Pregnancy and autoimmune connective tissue diseases

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