Collagen Vascular Diseases CALLA HOLMGREN AND D. WARE BRANCH CHAPTER 42Systemic Lupus Erythematosus 1080 Epidemiology 1088 Clinical Manifestations and Introduction 1080 Pathophysiology 1088 Laboratory Findings 1093 Epidemiology 1080 Diagnosis 1089 Pregnancy and Rheumatoid Clinical Manifestations 1081 Pregnancy in Women Arthritis 1094 Systemic Lupus Erythematosus and with Antiphospholipid Systemic Sclerosis 1096 Pregnancy 1082 Syndrome 1090 Introduction 1096 Treatment of Systemic Lupus Management 1090 Pathogenesis 1096 Erythematosus in Pregnancy 1087 Rheumatoid Arthritis 1092 Clinical Manifestations andAntiphospholipid Syndrome 1088 Introduction 1092 Diagnosis 1096 Introduction 1088 Pathophysiology 1092 Pregnancy 1097 KEY ABBREVIATIONS SYSTEMIC LUPUS ERYTHEMATOSUS Anti-double-stranded DNA Anti-ds DNA Introduction Antinuclear antibodies ANA Antiphospholipid antibodies aPL Systemic lupus erythematosus (SLE) is the most Antiphospholipid syndrome APS common serious autoimmune disease affecting women Congenital complete heart block CCHB of reproductive age. It is an idiopathic chronic inﬂam- Diffuse proliferative DPGN matory disease that affects skin, joints, kidneys, lungs, glumerulonephritis serous membranes, nervous system, liver, and other Food and Drug Administration FDA organs of the body. Like other autoimmune diseases, Gestational hypertension GH its course is characterized by periods of remission Human leukocyte antigen HLA and relapse. Frequent presenting symptoms include Interleukin-1 IL-1 extreme fatigue, weight loss, myalgia, arthralgia, and Intrauterine growth restriction IUGR fever (Table 42-1). Intravenous immune globulin IVIG Juvenile rheumatoid arthritis JRA Lupus anticoagulant LA Epidemiology Lupus nephritis LN Mycophenolate mofentil MMF The annual incidence of SLE is 5 to 10 per 100,000 Neonatal lupus erythematosus NLE individuals, depending on the population studied. The Non-steroidal anti-inﬂammatory NSAIDs overall prevalence is 1 in 2,500 to 1 in 6,500. The inci- drugs dence and prevalence vary among populations; SLE is Nuclear ribonucleoprotein nRNP approximately two to four times more frequent in blacks Preterm birth PTB and Hispanics.1 The disease is at least ﬁve to 10 times Preterm premature rupture of PPROM more common among adult women than adult men,2 the membranes and the prevalence in women is 1 in 245 (black women) Recurrent pregnancy loss RPL to 1 in 2,400. The lifetime risk of developing SLE for a Rheumatoid arthritis RA white woman is one in 700.1 The peak age of onset is Rheumatoid factor RF between 15 and 25 years, and the mean age of time of Single-stranded DNA ssDNA diagnosis is 30 years. Although pediatric SLE occurs, Systemic lupus erythematosus SLE most cases of SLE are associated with adolescence or Systemic sclerosis SSc young adulthood. Transforming growth factor-β TGF-β Approximately 10 percent of patients with SLE also Tumor necrosis factor-α TNF-α have an affected relative.3 In addition to this, concordance between twins is reportedly greater than 50 percent.41080
Chapter 42 Collagen Vascular Diseases 1081Several alterations in the human leukocyte antigen (HLA) Clinical Manifestationssystem have been linked to the development of SLE,and homozygous carriers of mutations responsible for DIAGNOSTIC CRITERIAcomplement deﬁciency disorders also appear to be pre-disposed to development of the disease. In 1971, the American Rheumatism Association devised criteria for SLE, primarily to facilitate clinical studies. These criteria were revised in 19825 and in 19976 (Table 42-2). An individual must have at least four of 11 clini- Table 42-1. Approximate Frequency of Clinical Symptoms cal and laboratory criteria at one time or serially to be in SLE classiﬁed as having SLE. These criteria are very sensitive and speciﬁc for SLE, but were never intended to be the SYMPTOMS PATIENTS (%) only basis for the diagnosis of SLE. Frequently, individual Fatigue 80–100 patients will present with less than four clinical or labora- Fever 80–100 tory features of SLE, thus not meeting strict diagnostic Arthralgia, arthritis 95 criteria. Some experts use the terms such as probable Myalgia 70 lupus or lupus-like disease in reference to these cases. Indi- Weight loss >60 viduals with lupus-like disease may beneﬁt from therapies Skin butterﬂy rash 50 for SLE and require special care during pregnancy. photosensitivity 60 mucous membrane lesions 35 Renal involvement 50 CLINICAL FEATURES Pulmonary Pleurisy 50 The most common presenting complaints in women Effusion 25 diagnosed with SLE include fatigue, weight loss, arthral- Pneumonitis 5–10 gias, arthritis, and myalgias. Pleurisy and pericarditis are Cardiac (pericarditis) 10–50 also seen. The joints most commonly involved are the Lymphadenopathy 50 CNS proximal interphalangeal, knee, wrist, and metacarpo- Seizures 15–20 phalangeal. Morning stiffness that improves as the day Psychosis <25 evolves is typical. The migratory nature of the joints involved can be striking. Deforming, erosive arthritis isCNS, central nervous system; SLE, systemic lupus erythematosus. uncommon. Table 42-2. Revised ARA Classiﬁcation Criteria for SLE (1982 and 1997) CRITERION DEFINITION Malar rash Fixed erythema, ﬂat or raised, over the malar eminences, tending to spare the nasolabial folds Discoid rash Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions Photosensitivity Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation Oral ulcers Oral or nasopharyngeal ulceration, usually painless Arthritis Nonerosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling, or effusion Serositis a. Pleuritis—convincing history of pleuritic pain or rubbing heard by a physician or evidence of pleural effusion b. Pericarditis documented by ECG or rub or evidence of effusion Renal a. Persistent proteinuria greater than 0.5 g/day or greater than 3+ if quantitation not performed b. Cellular casts—red cell, hemoglobin, granular, tubular, or mixed Neurologic a. Seizures—in the absence of offending drugs or known metabolic derangements; e.g., uremia, ketoacidosis, or electrolyte imbalance b. Psychosis—in the absence of drugs or metabolic derangements Hematologic a. Hemolytic anemia–with reticulocytosis b. Leukopenia—less than 4,000/mm on two or more occasions c. Lymphopenia—less than 1,500/mm on two or more occasions d. Thrombocytopenia—less than 100,000/mm in absence of drugs Immunologic a. Anti-DNA: antibody to native DNA in abnormal titer b. Anti-Sm: presence of antibody to Sm nuclear antigen c. Positive ﬁnding of antiphospholipid antibodies based on (1) an abnormal serum level of IgG or IgM anticardiolipin antibodies, (2) a positive test result for lupus anticoagulant using a standard method, or (3) a false-positive serologic test for syphilis for 6 months Antinuclear An abnormal titer of antinuclear antibody by immunoﬂuorescence or an equivalent assay at any point in antibody time and in the absence of drugs known to be associated with drug-induced lupus syndromeARA, American Rheumatism Association; ECG, electrocardiogram.
1082 Section VI Pregnancy and Coexisting Disease The sun-sensitive, erythematous butterﬂy rash along immunotherapy. Particularly useful are anti–double-the malar eminences and across the upper nose occurs stranded DNA (anti-dsDNA) antibodies, present in 80 toin about 50 percent of patients. Patients also may have 90 percent of patients with newly diagnosed SLE. Whena pruritic, maculopapular eruption, particularly in sun- elevated, these antibodies have been associated with aexposed areas. Two distinct forms of cutaneous lupus are symptomatic ﬂare in 80 percent of SLE patients followeddiscoid and subacute. The lesions of discoid lupus mature prospectively.7,8 In pregnancy, anti-dsDNA antibodiesto clearly outlined papules and plaques, with a central correlate with ﬂare and preterm delivery.8,9 Antibodiesarea eventually becoming atrophied and depressed. Scar- to single-stranded DNA (ssDNA) are also found in a largering is the result. In contrast, subacute lesions appear proportion of untreated SLE patients but are less speciﬁcas distinctly deﬁned erythematous plaques that do not for SLE than anti-dsDNA. Patients with SLE may haveundergo central atrophy and scarring. Subacute lesions antibodies to RNA-protein conjugates, often referred toare usually more widespread than discoid lesions, with as soluble or extractable antigens, because they can bethe latter tending to be conﬁned to the face, neck, scalp, separated from tissue extracts. These antigens include theand upper arms or shoulders. Sm antigen, nuclear ribonucleoprotein, and the Ro/SSA Clinically obvious renal disease eventually occurs in and La/SSB antigens. The Sm and nuclear ribonucleo-about 50 percent of patients with SLE. Lupus nephritis protein antigens are nuclear in origin, and the presence(LN) is likely a result of immune complex deposition of anti-Sm, found in about 30 to 40 percent of patientsleading to complement activation and inﬂammatory tissue with SLE, is highly speciﬁc for the disease. Anti-Ro/SS-damage in the kidney. The most common presenting sign A and La/SS-B, found in the sera of both SLE patientsof renal involvement is proteinuria; about 40 percent of and patients with Sjögren’s syndrome, are of particularpatients with SLE renal disease have hematuria or pyuria, importance to obstetricians because they are associatedand about a third have urinary casts. with neonatal lupus. Conﬁrming the diagnosis of LN requires a renal biopsy.This veriﬁcation is an important factor in determiningprognosis and providing appropriate treatment. Renal Systemic Lupus Erythematosusbiopsy ﬁndings are used to group LN into four basic his- and Pregnancytologic and clinical categories. Of the four, diffuse prolif-erative glomerulonephritis (DPGN) is the most common Preexisting SLE or onset during pregnancy carries(40 percent) and most severe. DPGN has a 10-year sur- important implications for the mother and the fetus. Forvival rate of approximately 60 percent. Patients with the mother, the primary concerns are SLE exacerbation,DPGN typically present with hypertension, moderate- nephritis and preeclampsia, possible need for pretermto-heavy proteinuria and nephrotic syndrome, hematu- delivery, and an increased rate of cesarean delivery. Fetal-ria, pyuria, casts, hypocomplementemia and circulating neonatal concerns include miscarriage and fetal death,immune complexes. Another category is focal prolifera- preeclampsia, placental insufﬁciency and intrauterinetive glomerulonephritis, which is usually associated with growth restriction (IUGR), preterm birth (PTB) and com-mild hypertension and proteinuria. Serious renal insuf- plications thereof, and neonatal lupus.ﬁciency with focal proliferative glomerulonephritis isuncommon. Membranous glomerulonephritis typicallypresents with moderate to heavy proteinuria but lacks THE RISK OF SYSTEMIC LUPUS ERYTHEMATOSUSthe active urinary sediment and does not cause renal EXACERBATION (FLARE)insufﬁciency. Mesangial glomerulonephritis appears tobe the least clinically severe lesion and carries the best Whether or not pregnancy is associated with a higherlong-term prognosis. rate of SLE exacerbation is a matter of considerable debate. Early studies were hampered by poor study design and difﬁculties differentiating between SLE andLABORATORY TESTS obstetric disorders, for example, severe hypertension due to preeclampsia. The small, retrospective series published The diagnosis of SLE, suspected based upon the clinical during the 1960s and 1970s suggested that pregnancy inpresentation, is conﬁrmed by demonstrating the presence women with SLE was associated with substantial risk forof pertinent circulating autoantibodies. Most clinicians severe maternal morbidity and mortality and that thisinitially test for autoantibodies directed against nuclear risk was related to SLE activity.10 Given this concern,antigens, most commonly using immunoﬂuorescent assays many practitioners held the opinion that patients withfor antinuclear antibodies (ANA). Positive test results are SLE should not become pregnant.typically reported in terms of the antibody titer and the Studies since 1980 have done much to clarify thepattern of antibody binding. A homogeneous pattern is relationship of pregnancy to the rate and nature of SLEfound most commonly in patients with SLE (65 percent), exacerbations. Overall, 15 to 60 percent of women withalthough its speciﬁcity is low. A peripheral pattern is SLE have a ﬂare during pregnancy or the postpartumthe most speciﬁc for SLE, but is not very sensitive. The period.3,11–23 Several prospective studies deserve specialspeckled and nucleolar patterns are more speciﬁc for consideration. Using a previously published scoring systemother autoimmune diseases. to deﬁne SLE exacerbations, Lockshin et al.11 matched Immunoﬂourescent assays that identify speciﬁc nuclear non-pregnant SLE patients with 28 SLE patients under-antigen-antibody reactions are better for conﬁrming the taking 33 pregnancies. There was no difference in thediagnosis of SLE, monitoring disease activity, and guiding ﬂare score between the cases and controls, and a similar
Chapter 42 Collagen Vascular Diseases 1083number in either group required a change in their medica- Thus, from the available literature one can surmise thattion. When only signs or symptoms speciﬁc for SLE were if pregnancy predisposes to a lupus ﬂare, it does so onlyincluded, exacerbations occurred in only 13 percent of modestly. A majority of studies of pregnant women withcases. Mintz et al.13 prospectively studied 92 pregnancies SLE indicate that most ﬂares are mild to moderate inin women with SLE and used a similar group of nonpreg- nature and easily treated with glucocorticoids.11,13,15,16,20–22nant SLE patients on oral contraceptives derived from a The routine or prophylactic use of glucocorticoids inprevious study as controls. Exacerbations were deﬁned by all pregnant SLE patients, as suggested by some investi-criteria different from those used by Lockshin et al.11 As gators, seems unnecessary in view of the excellent resultsa matter of policy, all pregnant women were started on achieved by others without the routine prophylactic10 mg prednisone daily, even if there was no evidence of immunosuppression.SLE activity. The rate of SLE ﬂares per month at risk was To ensure timely and accurate detection of an SLEsimilar in both groups. Most of the exacerbations tended exacerbation, thorough and frequent clinical assessmentto be easily controlled with low to moderate doses of remains essential. The criteria for measuring an SLE ﬂareglucocorticoids, but seven patients (8 percent) had severe during pregnancy have been recently tested and foundexacerbations requiring more aggressive therapies. Inter- valid.24 Commonly presenting symptoms of ﬂare duringestingly, the majority (54 percent) of the exacerbations pregnancy are extreme fatigue, skin lesions (>90 percent),occurred in the ﬁrst trimester. Urowitz et al.15 reported and arthritis/arthralgias (>80 percent).22,25their experience comparing 79 pregnancies in patients Serologic evaluation of SLE disease activity may bewith active SLE with a matched control group of 59 non- beneﬁcial in conﬁrming a ﬂare in confusing cases. Aspregnant active SLE women. They also compared these mentioned earlier, elevations in anti-dsDNA titers thatwomen with 216 women with inactive disease. Using a precede or accompany a lupus ﬂare in more than 80previously deﬁned SLE exacerbation score, they found percent of patients are a speciﬁc indicator.7,8 In addition,no signiﬁcant difference in disease activity between the some reports suggest that the serial serologic evaluationthree groups. Georgiou et al.22 prospectively evaluated of complement components and activation products isthe frequency of SLE exacerbation during 59 pregnan- beneﬁcial in predicting an SLE ﬂare during pregnancy.cies in 47 women with SLE and 59 nonpregnant women In two studies, Devoe and colleagues found that an SLEmatched for parameters other than disease activity and exacerbation was signaled by a decline of C3 and C4duration. Using accepted clinical criteria, they reported into the subnormal range.26,27 Buyon et al.28 found thatan SLE exacerbation in 8 (13.5 percent) of the preg- an SLE exacerbation was associated with an absence ofnant patients compared with 13 (22 percent) of the non- the usual increase in C3 and C4 levels during normalpregnant group. More than half of the exacerbations in pregnancies. However, the practical utility of serial deter-the pregnant women occurred during the ﬁrst trimes- minations of complement components or their activationter; all exacerbations were mild and easily treated with products during pregnancy remains unproven. Lockshinglucocorticoids. et al.29 reported that low-grade activation of the classic In contrast to the negative ﬁndings discussed above, pathway may be attributed to pregnancy alone. Wongtwo prospective series suggest that pregnant women et al.30 prospectively studied 19 continuing pregnancieswith SLE have higher rates of exacerbation. Petri et al.3 complicated by SLE and found that neither ANA norfound SLE ﬂares (ﬂares per person years) to be more C3 or C4 levels predicted which patients were going tocommon among pregnant women than among controls. have a ﬂare, whereas Nossent and Swaak31 observed thatFortunately, more than three quarters of the ﬂares were fewer than half of the pregnancies with decreased serummild to moderate in nature. Only inactive patients at C3 levels were associated with a clinical SLE ﬂare. Last,the onset of pregnancy showed a signiﬁcant reduction in although some have found that hypocomplementemiaSLE activity (41 percent). Ruiz-Irastorza et al.16 analyzed correlates with poor pregnancy outcomes,32–34 hypocom-the course of SLE in 78 pregnancies in 68 patients and plementemia may occur in pregnant patients without SLEa matched control group of 50 nonpregnant women. or adverse pregnancy outcomes.35Sixty-ﬁve percent of the patients experienced an exacer-bation of SLE during pregnancy, for a ﬂare rate of 0.082per patient-month. In the control group, 42 percent of LUPUS NEPHRITIS EXACERBATIONthe patients ﬂared, with a ﬂare rate of 0.039 per patient-month, representing a statistically signiﬁcant difference. Women with LN face several challenges during preg- Without a doubt, preexisting disease activity, plays a nancy. Pregnancy may worsen renal function. Moreover,large role in the risk of SLE ﬂare during pregnancy. underlying renal disease is associated with increased risksDerksen et al.19 reported that SLE exacerbation occurred of maternal and fetal complications. Those with chronicin fewer than 20 percent of women with sustained renal disease are likely to experience worsening protein-remission prior to pregnancy. More recently, Cortez- uria during gestation as renal perfusion increases. In turn,Hernandez and colleagues23 studied 60 women with 103 this inevitably poses the diagnostic dilemma as to whetherpregnancies and found that SLE exacerbations during the increased proteinuria represents an exacerbation ofpregnancy were more likely in women who discontinued underlying renal disease, preeclampsia, or both.maintenance therapy before pregnancy or had a history As with an SLE exacerbation in general, whether or notof more than three severe ﬂares before pregnancy. The renal ﬂares are more common in pregnant women withﬁndings of several other studies support the notion that SLE remains controversial. Two studies have reportedwomen with active disease should postpone pregnancy high frequencies of renal ﬂares (43 to 46 percent) duringuntil sustained remission can be achieved.20–22 pregnancy,25,30 but others have reported lower ﬁgures (9
1084 Section VI Pregnancy and Coexisting Diseaseto 28 percent).13,16,31,36 Three studies assessed the patients’ Table 42-3. Distinguishing Between Preeclampsia andstatus during pregnancy in regard to whether the SLE was SLE/LN Flareactive or in remission prior to conception.37–39 In all three,the rate of SLE exacerbation was lower in pregnancies in TEST PREECLAMPSIA SLEwhich the patient was in remission before conception. Serologic Studies of pregnancy outcome in women with past Decreased complement ++ +++or current LN are limited. This may be explained, in Elevated Ba or Bb fragments ± ++part, by (1) the reduced fertility associated with long- with low CH50term cyclophosphamide or impaired renal function, or Elevated anti-dsDNA − +++both, and (2) the traditional assumption that pregnancy Antithrombin III deﬁciency ++ ±should be discouraged in women with a history of LN. HematologicThe earliest reports suggest that LN was a major con- Microangiopathic hemolytic ++ −tributor to serious maternal morbidity or death.40–42 More anemia Coombs’ positive hemolytic − ++recent series suggest that the outlook of pregnancy for anemiawomen with LN is usually favorable if the disease is Thrombocytopenia ++ ++well controlled and renal function preserved.43 Oviasu Leukopenia − ++et al.44 reviewed eight studies (151 pregnancies) pub- Renallished between 1973 and 1991 to determine the effect Hematuria + +++of completed pregnancy on maternal renal function in Cellular casts − +++established LN and reported transient deterioration of Elevated serum creatinine ± ++renal function in 17 percent and permanent deterioration Elevated ratio of serum blood urea ++ ±in 8 percent of the pregnancies.44 nitrogen/creatinine Better outcomes were reported in three studies pub- Hypocalciuria ++ ± Liver Transaminases ++ ±lished in the 1990s.43–45 Out of 143 patients with LN,only one developed irreversible loss of renal function +++, present; ++, occasionally present; ±, may or may not beafter pregnancy. It is important to note that the majority present; −, not present; LN, lupus nephritis; SLE, systemic lupusof women in these studies had normal renal function, erythematosus.mild proteinuria, and well-controlled hypertension beforeconception. Petri and colleagues at the Hopkins LupusPregnancy Center reported that only women who began risk of preeclampsia and early delivery. Moderate renalpregnancy with nephrotic syndrome went on to renal insufﬁciency (creatinine 1.5 to 2.0 mg/dl) is a relativefailure after delivery.25 Hayslett and Lynn37 and Bobrie contraindication to pregnancy and advanced renal insuf-et al.39 found that the rate of renal deterioration was ﬁciency (creatinine greater than 2.0 mg/dl) should be con-somewhat lower among pregnancies in which the patient sidered an absolute contraindication to pregnancy.was in remission before conception. In a recent study,Moroni and colleagues46 reported that renal ﬂare occurredin 5 percent (1/20) of pregnancies in women with inac- PREGNANCY LOSStive LN before conception compared with 39 percent(12/31) in women with active LN before conception. The In most retrospective studies, the rate of pregnancysole predictors for renal ﬂare were a plasma creatinine loss appears to be higher in women with SLE than ingreater than 1.2 mg/dL or proteinuria equal to 500 mg the general obstetric population, ranging between 8 andin 24-hour collection. Permanent deterioration occurred 41 percent, with a median of 22 percent.10,12,37,38,50–55 Ain two women with active LN before conception, one of large case-controlled study compared obstetric outcomeswhom eventually died. in 481 pregnancies in 203 lupus patients with those of A troublesome clinical situation is differentiating 566 pregnancies in 177 healthy relatives and 356 preg-between renal exacerbation and preeclampsia, because nancies in 166 healthy unrelated women.55a The investi-both may present with proteinuria, hypertension, and gators found that pregnancy loss occurred signiﬁcantlyevidence of multiorgan dysfunction. Some of the features more often in women with SLE (21 percent) than in eitherthat may prove helpful in the distinction between the their healthy relatives (8 percent) or unrelated healthytwo conditions are listed in Table 42-3. Preeclampsia is controls (14 percent). However, the pregnancy loss ratesmore likely in women with decreased levels of antithrom- observed in most prospective trials of lupus pregnanciesbin III.47,48 Complement concentrations are not always have been better than those of their retrospective coun-helpful because activation may also occur in women with terparts, possibly because of careful monitoring of SLEpreeclampsia.49 In the most severe and confusing cases, activity and routine antenatal surveillance. In the mostthe correct diagnosis is possible only by renal biopsy. In recent, well-detailed, prospective trials, fetal deaths in thereality, situations involving either the more severe cases second or third trimester accounted for between 10 to 40of SLE ﬂare or preeclampsia inevitably raise concerns percent of the total losses.22,23about maternal and fetal well-being and often prompt Control of disease activity appears to have a helpfuldelivery, thus rendering the distinction between the two effect on the rate of pregnancy loss,56 with one early studyclinically moot. reporting live births in 64 percent of women with active Women with active LN (especially DPGN), nephritic disease within 6 months of conception, compared withsyndrome, and severe hypertension are at considerable 88 percent in women with quiescent disease.37 In a more
Chapter 42 Collagen Vascular Diseases 1085recent, prospective study, pregnancy loss occurred in 75 FETAL GROWTH RESTRICTIONpercent of women with active disease compared with 14percent of women with inactive disease.22 Not surpris- Uteroplacental insufﬁciency resulting in IUGR andingly, pregnancy loss is more likely if SLE is diagnosed small-for-gestational-age neonates has been reported induring the index pregnancy.38,52,57 between 12 and 40 percent of pregnancies complicated Preexisting renal disease appears to increase the rate of by SLE.16,21,23,45,56,64 It would seem likely that factors suchpregnancy loss in women with SLE, but loss rates vary as underlying renal insufﬁciency and chronic hypertensionwidely among studies, likely because of variations in the play a role.23,62,65 Medications, such as glucocorticoids,degree of renal impairment of patients included. Also, might also be related to IUGR. In a recent prospectivethe degree of renal impairment is a factor in the rate of trial Georgiou and colleagues reported no signiﬁcant dif-pregnancy loss in women with LN. In a recent study of ferences in the rate of IUGR between SLE pregnanciesLN in pregnancy that included only women with inactive and healthy controls.22 In this study, glucocorticoids weredisease and normal renal function (serum creatinine less given only for symptomatic SLE ﬂare.than 0.8 mg/dl), the overall fetal survival rate was greater90 percent, after exclusion of embryonic losses (lossesless than 10 weeks’ gestation).20 These results contrast PRETERM BIRTHmarkedly to those of another study in which the rate offetal loss was 50 percent in pregnant women with LN PTB has been reported in as few as 3 percent andand moderate-to-severe renal insufﬁciency (serum creati- as many as 73 percent of pregnancies complicated bynine = 1.5 mg/dl).37 In another study comparing obstetric SLE.13,30,37,38,50,52,57,58,60,66,67 aPLs, chronic hypertension,outcomes according to the degree of renal impairment in and disease activity have all been reported to increasewomen with LN, spontaneous abortion occurred in 26 the likelihood of PTB in women with SLE.22,23 Onlypercent of women with minimally impaired renal func- a few studies have included controls for comparison.tion (serum creatinine less than 1 mg/dl, clearance greater PTB was more common in a group of women with SLEthan 80 ml/min, and proteinuria less than 1 g/day) and 36 than in a group of matched controls (12 percent vs 4percent in women with “mild” impairment (clearance 50 percent) in one retrospective case-control study.55a In ato 80 ml/min, proteinuria 1 to 3 g/day).50 recent prospective trial, PTB in women with SLE and Fetal death (greater than 10 weeks’ gestation) among healthy controls was statistically similar (8 percent versusSLE pregnancies is tied to the presence of antiphos- 15 percent),22 although PTB was more common amongpholipid antibodies (aPL) (see the section on Antiphos- women with active SLE compared with those with inac-pholipid Syndrome). In several studies, the existence of tive disease (12.5 percent versus 4 percent).aPL has been the single most sensitive predictor of fetal A substantial proportion of PTB associated with SLE isdeath,58 with a positive predictive value of more than 50 without a doubt the result of iatrogenic delivery for obstet-percent.59 For women with SLE and a prior fetal death, ric and medical indications. Data from the few studiesthe predictive value is more than 85 percent.60 In the most that provide sufﬁcient detail suggest that between 28 torecent prospective trial, the presence of any aPL was the 66 percent of preterm deliveries are indicated because ofsingle strongest predictor of subsequent pregnancy loss, preeclampsia and another 12 to 33 percent because ofeven in women with active disease and underlying renal suspected or conﬁrmed fetal compromise.23,52,55a,60,66 Animpairment.23 association between SLE and preterm premature rupture of membranes (PPROM) has also been reported, occur- ring in 39 percent of pregnancies delivered at 24 to 36 weeks’ gestation.68PREECLAMPSIA It is difﬁcult to estimate the exact incidence of preg- NEONATAL LUPUS ERYTHEMATOSUSnancy-related hypertension associated with SLE. This isin large part due to inconsistencies in the deﬁnition and Neonatal lupus erythematosus (NLE) is an infrequentclassiﬁcation of these disorders, as well as the inclusion condition of the fetus and neonate, occurring in 1 ofof patients with LN in the various studies. Neverthe- 15,000 of all live births and in a relatively small per-less, it appears that between 20 to 30 percent of women centage of lupus pregnancies. It is a result of passivelywith SLE develop either gestational hypertension (GH) acquired immunity in pregnant women with circulatingor preeclampsia (GH with proteinuria) sometime during antibodies directed against Ro/SSA and La/SSB ribo-pregnancy.37,58,61–63 Women with LN are most suscep- nucleoprotein antigens.69–73 These antibodies can crosstible, probably owing to the known association between the placenta as early as 11 weeks’ gestation, and theypreeclampsia and underlying renal disease of any origin. are associated with congenital complete atrioventricularIn one prospective series, preeclampsia occurred in 7 heart block (CCHB), a neonatal lupus rash, and hepaticof 19 (37 percent) women with LN, compared with 15 and blood cell abnormalities.of 106 (14 percent) without. Other factors that likely Anti-Ro/SSA antibodies are found in 75 to 95 percentpredispose SLE patients to GH or preeclampsia include mothers who deliver babies with NLE.70,72,73 A smallerchronic hypertension, secondary antiphospholipid syn- percentage has only anti-La/SSB. Dermatologic NLE hasdrome (APS), and chronic steroid use17,37,45,50,62,63a (see also been associated with anti-U1RNP without anti-Ro/Table 42-3). SSA or anti-La/SSB.70,74 Fortunately, of mothers with SLE
1086 Section VI Pregnancy and Coexisting Diseasewho are serologically positive for anti-Ro/SSA antibod- preventing further or ongoing damage using glucocorti-ies, no more than 15 percent to 20 percent deliver an coids or intravenous immune globulin (IVIG). Again, thisinfant affected with evidence of NLE. The most common approach is of unproven efﬁcacy.manifestation is dermatologic NLE. Of all women with The apparent success of IVIG in the treatment ofanti-Ro/SSA or anti-La/SSB, 1 to 5 percent deliver an fetal-neonatal alloimmune thrombocytopenia has led toinfant with CCHB. It is important to note, however, speculation that IVIG might be effective in preventing orthat once a woman with SLE and anti-Ro/SSA antibod- treating autoantibody-mediated CCHB. An international,ies delivers one infant with CCHB, the risk for recur- multicenter trial has been suggested.rence is at least two- to threefold higher than in womenwith anti-Ro/SSA-La/SSB antibodies who has never hadan affected child.73 Recurrence of dermatologic NLE is OBSTETRIC MANAGEMENTapproximately 25 percent.72,76 The skin lesions of NLE are erythematous, scaling Women with SLE who are contemplating pregnancyannular, or elliptical plaques occurring on the face or should be counseled before conception about potentialscalp. They are analogous to the subacute cutaneous obstetric problems including pregnancy loss, gestationallesions in adults. They typically appear in the ﬁrst weeks hypertensive disorders, IUGR, and PTB. They should alsoof life, probably induced by exposure of the skin to be informed of the risk of SLE ﬂare and special concernsultraviolet light, and may last for up to 6 months.77 related to APS and NLE. Laboratory evaluation beforeHypopigmentation may persist for up to 2 years. Hema- pregnancy should include an assessment for anemia andtologic NLE is rare and may be manifest as autoimmune thrombocytopenia, underlying renal disease (urinalysis,hemolytic anemia, leukopenia, thrombocytopenia and serum creatinine and 24-hour urine for creatinine clear-hepatosplenomegaly. ance and total protein), and aPL (lupus anticoagulant, Cardiac NLE lesions include CCHB and the less fre- anticardiolipin and anti-β2-glycoprotein I antibodies).quently reported endocardial ﬁbroelastosis. CCHB is due Many experts routinely obtain anti-Ro/SSA and anti-La/to disruption of the cardiac conduction system, especially SSB antibodies in patients with SLE; however, the cost-in the area of the atrioventricular node. The diagnosis of effectiveness of these tests is not proven.CCHB is typically made around 23 weeks’ gestation73 Women with active SLE should be discouraged fromwhen a ﬁxed bradycardia of 60 to 80 beats per minute becoming pregnant until they are in remission. Cyto-is detected during a routine prenatal visit. Fetal echocar- toxic drugs should be stopped before conception, anddiography reveals complete atrioventricular dissociation every effort should be made to reduce or eliminate long-with a structurally normal heart. CCHB is irreversible, term treatment with nonsteroidal anti-inﬂammatory drugand greater than 65 percent of surviving infants will (NSAID). However, maintenance therapy with hydroxy-require a pacemaker, 50 percent of them at birth. In chloroquine or low doses of glucocorticoids need not bethe more severely affected fetus, more widespread endo- discontinued.myocardial damage leads to ﬁbroelastosis and markedly The prenatal care of the patient with SLE should bediminished cardiac pump function, hydrops fetalis, and guided by the potential risks to the mother and fetus.fetal death. In the largest series of prenatally diagnosed Prenatal visits should occur every 1 to 2 weeks in theCCHB, the 3-year survival was 79 percent; the majority ﬁrst and second trimesters and every week thereafter.of deaths occurred before 90 days of life.73 A primary goal of the antenatal visits after 20 weeks’ Suspected cases of CCHB in utero should be evaluated gestation is the detection of hypertension, proteinuria, orby fetal echocardiography and maternal tests for anti- suspicion of IUGR. Because of the risk of uteroplacentalRo/SSA and anti-La/SSB antibodies. If the diagnosis of insufﬁciency, fetal ultrasonography should be performedCCHB due to NLE is made, some experts currently rec- every 4 to 6 weeks starting at 18 to 20 weeks’ gestation.ommend administration of a glucocorticoid that crosses In the usual case, fetal surveillance (daily fetal move-the placenta to limit further damage to the fetal heart. ment counts and periodic nonstress tests and amnioticMaternal plasmapheresis, to reduce the antibody load, or ﬂuid volume measurements) should be instituted at 30 toinvasive fetal pacing to increase the fetal ventricular rate 32 weeks’ gestation. More frequent ultrasonography andalso have been used. None of these treatments have been fetal testing may be indicated in patients with SLE ﬂare,shown to be effective.78 In addition, all of the aforemen- hypertension, proteinuria, clinical evidence of IUGR, ortioned maternal treatments have known potential and APS. Fetal surveillance as early as 24 to 25 weeks mayreal side effects. The efﬁcacy of prenatal treatments is be necessary in patients with APS.80being examined in a registry of cases collected by Dr. J.P. Management of SLE during labor and delivery is aBuyon, Hospital for Joint Disease, New York University, continuation of antenatal care. Exacerbations of SLE canNew York City (email@example.com). occur during labor and may require the acute adminis- Although of unproven efﬁcacy, many experts recom- tration of steroids. Regardless, stress doses of glucocor-mend screening fetuses of antibody-positive mothers ticoids should be given during labor or at the time ofwho have previously delivered an infant with CCHB cesarean delivery to all patients who have been treatedusing echocardiographic-Doppler techniques to measure with chronic steroids within the year. Intravenous hydro-the mechanical PR interval79 from 16 weeks’ forward. cortisone, given in doses of 100 mg every 9 hours forBecause of the grave nature of CCHB, the ﬁnding of three doses, is an acceptable regimen. Obstetric com-any conduction disturbance would prompt attempts at plications, such as preeclampsia and IUGR, should be
Chapter 42 Collagen Vascular Diseases 1087managed in the usual fashion, and not speciﬁcally altered otic90 and ocular damage.91 Considerable clinical experi-because of the SLE. Neonatology support may be needed ence, in cases with malaria prophylaxis, failed to conﬁrmat delivery for problems associated with CCHB and other rare reports of these adverse fetal effects. And recent casemanifestations of NLE. series suggest hydroxychloroquine is relatively safe during It is uncertain which patients, if any, are at risk for pregnancy.92–95 The ﬁndings of a recent case-controlledSLE ﬂare following delivery, and it probably best to trial, which compared the effects of in utero exposure tomaintain frequent contact with SLE patients in the post- hydroxychloroquine, were conﬁrmatory.96 No differencespartum period. Maintenance medications discontinued were noted between the 122 infants with in utero expo-during labor and delivery should be restarted immedi- sure to hydroxychloroquine and the 70 control infantsately following delivery, at similar doses as during the regarding the number and type of defects identiﬁed atpregnancy. Dose adjustments can be handled in the out- birth. There was also no difference in the percentages ofpatient setting. infants affected with visual, hearing, growth, or devel- opmental abnormalities at follow-up (median follow-up, 24 months).Treatment of Systemic Lupus Just as importantly, hydroxychloroquine may beErythematosus in Pregnancy emerging as the best overall agent for maintenance SLE therapy during pregnancy. In a recent randomized con-GLUCOCORTICOIDS trolled trial, women who continued hydroxychloroquine during pregnancy experienced a signiﬁcant reduction in Glucocorticoids are often used to treat SLE during SLE disease activity compared with women who changedpregnancy. These medications can be given as mainte- to glucocorticoid therapy.97 Many experts now recom-nance therapy or in “bursts” to treat SLE ﬂares. The mend continuing hydroxychloroquine during pregnancydoses used in pregnancy are the same as those in non- in patients being treated with this agent.pregnant patients. Tapering to the lowest dose requiredto manage the disease is prudent because glucocorticoidsare associated with preeclampsia, gestational diabetes CYTOTOXIC AGENTSmellitus, and PPROM. Some experts have recommended the use of prophylac- Cytotoxic agents, including azathioprine, methotrex-tic glucocorticoids during pregnancy.13,36,81 However, this ate, and cyclophosphamide, are used to treat only thepractice is not evidence based, and comparable maternal most severely affected patients with SLE. Limited dataand fetal outcomes have been documented in patients suggest that azathioprine, a derivative of 6-mercaptopu-without prophylactic treatment in the presence of stable rine, is not teratogenic in humans but is associated withdisease.82 IUGR98,99 and impaired neonatal immunity.100 Thus, in Despite the fact that glucocorticoids have a low poten- women requiring chronic azathioprine, consideration oftial for teratogenesis,83 they are not without risk during pregnancy demands that the patient and physician havepregnancy. Patients requiring long-term therapy are best carefully weighed potential fetal risks against the beneﬁtstreated with prednisolone or methylprednisolone because of the medication.of their conversion to relatively inactive forms by the Cyclophosphamide has been reported to be teratogenicabundant 11-β-ol dehydrogenase found in the human in both animal101 and human studies102,103; it should beplacenta. Glucocorticoids such as dexamethasone and avoided during the ﬁrst trimester. Thereafter, cyclophos-betamethasone, with ﬂuorine at the 9-a position, are phamide should be used only in special circumstances,poorly metabolized by the placenta, and long-term use such as in women with severe, progressive proliferativeduring pregnancy should be avoided. Recent analyses glomerulonephritis.104suggest a very slight increased risk of cleft lip and palate Methotrexate is toxic to actively dividing trophoblastassociated with glucocorticoid exposure in the early ﬁrst and causes miscarriage and early fetal death. Moreover,trimester.84–86 Maternal side effects may be signiﬁcant and methotrexate is documented to cause malformations ininclude weight gain, striae, acne, hirsutism, immunosup- up to 30 percent of surviving pregnancies when usingpression, osteonecrosis and gastrointestinal ulceration. doses greater than 10 mg per week in the ﬁrst trimes-Long-term glucocorticoid therapy during pregnancy has ter. These malformations include cranial dysostosis withbeen associated with an increased risk of preeclamp- delayed ossiﬁcation, hypertelorism, wide nasal bridge,sia,58,87,88 PPROM, uteroplacental insufﬁciency, and micrognathia, and ear anomalies.105 Case reports haveIUGR.89 Because of the increased risk of glucose intoler- also described cleft palate and deformities of the toes andance,87,88 women treated over the long term with glu- ﬁngers when methotrexate is used in early pregnancy.106cocorticoids should be screened for gestational diabetes Principles underlying teratogenicity of a drug are dis-mellitus somewhat earlier and more than once, probably cussed in Chapter 8.at 22 to 24, 28 to 30, and 32 to 34 weeks’ of gestation.ANTIMALARIAL MEDICATIONS NONSTEROIDAL ANTI-INFLAMMATORY DRUGS In the past, many patients and their physicians havediscontinued antimalarials before or during pregnancy NSAIDs are the most common type of analgesics usedbecause of concerns about teratogenicity, speciﬁcally in the treatment of SLE outside of pregnancy. Although
1088 Section VI Pregnancy and Coexisting Diseaseeffective, they readily cross the placenta and can block ANTIPHOSPHOLIPID SYNDROMEprostaglandin synthesis in a wide variety of fetal tissues.Maternal ingestion of normal adult doses of aspirin in Introductionthe week before delivery has been associated with intra-cranial hemorrhage in preterm neonates.107,108 Although aPL are a family of autoantibodies that bind to epi-short-term (less than 72 hours) tocolytic therapy with topes associated with negatively charged phospholipidsindomethacin appears to be safe,109,110 long-term use has or proteins that bind to negatively charged phospholip-been associated with a number of untoward fetal effects. ids. Clinicians ﬁrst recognized that aPL were associatedAfter 32 weeks’ gestation, indomethacin can cause con- with hypercoagulability 50 years ago, and an associationstriction or closure of the fetal ductus arteriosus.111 with pregnancy loss was established in the mid-1970s.Long-term use of any NSAID has been associated with The term APS was introduced in 1986 to formalize thedecreased fetal urinary output, oligohydramnios, and association of aPL with these clinical features. Over aneonatal renal insufﬁciency.112 Given these risks, long- decade of subsequent international laboratory and clini-term use of adult dosages of aspirin and other NSAIDs cal experience led to the development of an internationalshould be avoided during pregnancy, especially after the consensus statement on preliminary criteria for deﬁniteﬁrst trimester. Acetaminophen and narcotic-containing APS, published in 1999 and revised in 2005 (Table 42-preparations are reasonable alternatives if analgesia is 4).113,114 Clinicians should recognize that the diagnosisneeded during pregnancy. of APS rests ﬁrst and foremost on clinical features and is conﬁrmed by demonstrating repeatedly positive tests for aPL.OTHER IMMUNOSUPPRESSIVE AGENTS Several other treatments, including cyclosporin, high- Epidemiologydose IVIG, mycophenolate mofetil (MMF), and tha-lidomide, are sometimes used in SLE patients.104 Only The actual prevalence and incidence of APS is unknown.IVIG has been used during pregnancy without reports APS may exist as an isolated immunologic derangementof adverse fetal effects. MMF is a reversible inhibitor (primary APS) or in combination with other autoimmuneof inosine monophosphate dehydrogenase. It works by diseases (secondary APS), most commonly SLE. aPL areblocking de novo purine synthesis. MMF is an Food and found in up to 5 percent of apparently healthy controlsDrug Administration (FDA) Category C drug, but terato- and in up to 35 percent of patients with SLE.115 Thegenic risks are a concern because experiments in animals prospective risks associated with a positive test for aPLrevealed developmental toxicity, malformations, and antibodies in otherwise healthy subjects are unknownintrauterine death at dosages that coincide with recom- (Table 42-5).mended clinical dosages.98 Given this information, thereis a possibility of increased risk in humans, and therefore, PathophysiologyMMF is contraindicated in pregnancy. Thalidomide isstrictly contraindicated during pregnancy because of its Whether aPL per se are the cause of adverse obstet-known potent teratogenicity. ric outcomes associated with the antibodies remains a Table 42-4. Preliminary Classiﬁcation Criteria for APS* Clinical criteria Vascular thrombosis a. One or more clinical episodes of arterial, venous, or small-vessel thrombosis in any tissue or organ, AND b. Thrombosis conﬁrmed by imaging or Doppler studies or histopathology, with the exception of superﬁcial venous thrombosis, AND c. For histopathologic conﬁrmation, thrombosis should be present without signiﬁcant evidence of inﬂammation in the vessel wall. Pregnancy morbidity a. One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, with normal fetal morphology documented by ultrasound or by direct examination of the fetus, OR b. One or more premature births of a morphologically normal neonate at or before the 34th week of gestation because of severe preeclampsia or severe placental insufﬁciency, OR c. Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded. Laboratory criteria a. Anticardiolipin antibody of IgG and/or IgM isotype in blood, present in medium or high titer, on at least 2 occasions at least 6 weeks apart, measured by standard enzyme-linked immunosorbent assay for β2-glycoprotein I-dependent anticardiolipin antibodies, OR b. Lupus anticoagulant present in plasma, on 2 or more occasions at least 6 weeks apart, detected according to the guidelines of the International Society on Thrombosis and Hemostasis.*Deﬁnite antiphospholipid syndrome (APS) is considered to be present if at least 1 of the clinical and 1 of the laboratory criteria are met.
Chapter 42 Collagen Vascular Diseases 1089 Table 42-5. Nonautoimmune Causes for Positive Antiphospholipid Antibody Tests ASSAY TYPE ANTIBODY TYPE CAUSES ELISA β2-glycoprotein independent Infection: syphilis, Lyme disease, leptospirosis, pinta, HIV β2-glycoprotein dependent Advanced age Drugs Either Lymphoproliferative disease Hyperimmunoglobulin M Lupus anticoagulant — Infection; HIV, drugsELISA, enzyme-linked immunosorbent assay; HIV, human immunodeﬁciency virus.subject of debate, although mounting evidence supports Diagnosisa direct antibody-mediated effect. Working with mice,some investigators found administration of human aPL CLINICAL MANIFESTATIONresults in clinical manifestations of APS, including fetalloss.116,117 Rodent venous thrombosis models have also The International Consensus Statement provides sim-been developed.118 pliﬁed criteria for the diagnosis of APS.113,124 Patients with A variety of mechanisms by which aPL may cause bona ﬁde APS must manifest at least one of two clinicalpregnancy loss (and thrombosis) have been suggested. criteria (vascular thrombosis or pregnancy morbidity).Considerable work has focused on aPL interfering with Thrombosis may be either arterial or venous and mustthe normal in vivo function of phospholipids or phospho- be conﬁrmed by an imaging or Doppler study or by his-lipid-binding proteins crucial to the regulation of coag- topathology. Pregnancy morbidity is divided into threeulation. Candidate molecules or pathways that might categories: (1) otherwise unexplained fetal death (10be adversely affected include β2-glycoprotein I (which weeks’ gestation or older), (2) PTB (less than 34 weeks’has anticoagulant properties), prostacyclin, prothrombin, gestation) for severe preeclampsia or placental insufﬁ-protein C, annexin V, and tissue factor. aPL may activate ciency, or (3) otherwise unexplained recurrent preembry-endothelial cells, as indicated by increased expression onic or embryonic pregnancy loss. Other clinical features,of adhesion molecules, secretion of cytokines, and pro- such as autoimmune thrombocytopenia, are associatedduction of arachidonic acid metabolites. Other evidence with aPL but are not considered speciﬁc enough to besuggests that aPL cross-react with oxidized low-density diagnostic criteria.lipoprotein and bind only to oxidized cardiolipin,119 Obstetric features of APS, which include events ofimplying that aPL may participate in oxidant-mediated both the preembryonic-embryonic and the fetal-neonatalinjury of the vascular endothelium. These abnormalities periods, are divided into three categories—one encom-may result in thrombosis during the development of the passing early pregnancy loss, and the other two relat-normal maternoplacental circulation, perhaps through ing primarily to complications in the second or thirdinterference with trophoblastic annexin V,120 which is trimester (see Table 42-5). In the original descriptionabundant in the human placenta, or by impairing tropho- of APS, the single obstetric criterion for diagnosis wasblastic hormone production or invasion.121 fetal loss.125,126 Recently, APS-related pregnancy loss has The in vivo targets of aPL remain uncertain. Normal been extended to include women with early recurrentliving cells do not express phospholipids bound by aPL pregnancy loss [RPL] including those occurring in theon their surface. The antibodies do, however, bind to preembryonic (less than 6 menstrual weeks of gestation)phospholipids expressed by perturbed cells, such as acti- and embryonic periods (6 through 9 menstrual weeks ofvated platelets or apoptotic cells. Recent work points gestation).114 In serologic evaluation of women with RPL,to the complement system as having a primary role in 10 to 20 percent have detectable aPL.127–132APS-related pregnancy loss, showing that C3 activation Complications occurring in the fetal-neonatal periodis required for fetal loss in a mouse model.122 Moreover, of pregnancies affected by APS can be serious. At leastthe beneﬁcial effect of heparin seen in this model appears 40 percent of pregnancy losses reported by womento be linked to heparin’s anticomplement, not anticoagu- with lupus anticoagulant (LA) or medium-to-high posi-lant activity. Anticoagulants other than heparin do not tive IgG aCL occur in the fetal period.133–137 For thoseprevent fetal loss in this murine system,123 suggesting that pregnancies complicated by APS with fetal survivalthrombosis may not be the immediate cause of pregnancy past 20 weeks’ gestation, the median rate of gestationalmorbidity and mortality in this syndrome. hypertension-preeclampsia is 32 percent, ranging up to Regardless of the primary mechanism, the negative 50 percent.134–140 Indeed, preeclampsia may develop aseffect of APS on human pregnancy appears to be tied to early as 15 to 17 weeks’ gestation,134 and two groupsabnormal maternal-fetal circulation. Some investigators of investigators have reported that women with early-have found narrowing of the spiral arterioles, intimal onset, severe preeclampsia are more likely to test positivethickening, acute atherosis, and ﬁbrinoid necrosis in cases for aPL antibodies compared to healthy controls.141,142of fetal loss associated with APS. Others have found Several investigators have relatively high rates of IUGRextensive placental necrosis, infarction, and thrombosis. in association with aPL antibodies.134,138,141,143,144 Even
1090 Section VI Pregnancy and Coexisting Diseasewith currently used treatment protocols, the rate of used to make the diagnosis of APS. When they occurIUGR approaches 30 percent.134,138 Pregnancies compli- alone, IgM results are widely considered to have reducedcated by APS are also more likely to exhibit nonreas- speciﬁcity for APS. In spite of well-intentioned efforts atsuring fetal heart rate patterns during antenatal tests of standardization and the availability of positive standardfetal well being and intrapartum monitoring.59,134,135 Not sera, substantial interlaboratory variation when testingsurprisingly, the rate of PTB in these series ranges from the same sera remains a serious problem for both anti-32 to 65 percent.134,138,140 cardiolipin and anti–β2-glycoprotein I antibodies. This is due in part to the large number of commercial kits and homemade assays used worldwide.LABORATORY FEATURES Clinicians should recognize that the international con- sensus criteria were developed primarily for research pur- Laboratory testing for aPL is necessary to conﬁrm or poses to ensure more uniform characterization, as well asrefute the diagnosis of APS. As indicated in Table 42-5, subcategorization, of patients included in studies. Thisa patient with APS should manifest at least one of three objective is crucial for credible investigative efforts andlaboratory criteria: (1) presence of LA, or (2) medium- for appreciation of subtleties of treatment. The consen-to-high titers of β2-glycoprotein I-dependent IgG or IgM sus criteria also serve to emphasize standardization ofisotype anticardiolipin antibodies, or (3) medium to high laboratory testing, an area of proven concern in aPL. Astiters of IgG or IgM isotype anti-β2-glycoprotein I anti- with other autoimmune conditions, such as SLE, therebodies. Very importantly, positive tests must be conﬁrmed are individuals who present with one or more clinical oron two separate occasions, at least 12 weeks apart. laboratory features suggestive of APS but in whom the LA is identiﬁed by in vitro coagulation assays and diagnosis cannot be made by the relatively strict inter-named as such because the antibodies present prolong national consensus criteria. In such cases, experiencedclotting times. It is important that published labora- clinical judgment is required for best care.tory criteria for the diagnosis of LA be followed. Anti-cardiolipin antibodies are detected by a standardizedenzyme-linked immunosorbent assay that measures β2- Pregnancy in Women withglycoprotein I-dependent IgG and IgM anticardiolipin Antiphospholipid Syndromeantibodies. The standard anticardiolipin antibody assaydetects β2-glycoprotein I-dependent anticardiolipin anti- Even with treatment, the potential complications ofbodies because β2-glycoprotein I is present in the diluted pregnancy in women with APS include RPL (includingpatient serum and in the bovine serum typically used in fetal death), preeclampsia, placental insufﬁciency, mater-the assay buffer-diluent. There is the possibility that the nal thrombosis (including stroke), and complications dueuse of bovine serum biases the standard anticardiolipin to treatment. In women with SLE, the potential complica-antibody assay to detect antibodies that react with both tions also include lupus exacerbation.bovine and human β2-glycoprotein I and explains differ- It is perhaps obvious that pregnancy-related risks varyences in reactivity between anticardiolipin antibodies and depending on the population in which the diagnosis ofanti-β2-glycoprotein I assays. APS is made. Women diagnosed because of recurrent Recent work in the ﬁeld of aPL has emphasized assays preembryonic or embryonic loss, who appear to be typi-that speciﬁcally detect the antibody that binds to β2- cally healthy, are not at high risk for maternal thrombo-glycoprotein I itself. Most experts now believe that posi- sis, fetal death, preeclampsia, or placenta insufﬁciencytive tests for this antibody or group of antibodies, referred requiring PTB.14,145–149to as anti-β2-glycoprotein I, are relatively speciﬁc for APS. These low-risk patients contrast with those patientsThus, anti–β2-glycoprotein I antibodies are now included that have a history of medical problems (see discussionas one of three antibodies diagnostic of the condition. under Clinical Manifestations earlier). In a case series Whereas LA is reported as being positive or negative, of APS pregnancies that included women with SLE andanticardiolipin and anti–β2-glycoprotein I antibodies are prior thrombosis, the median rate of gestational hyper-reported in terms of international units (designated GPL tension–preeclampsia was 32 percent, ranging up to 50for IgG binding and MPL for IgM binding). In most percent.134,139–141,143,150 Placental insufﬁciency requiringlaboratories, there is substantial concordance between delivery is also relatively frequent in some of these caseLA activity and anticardiolipin and anti–β2-glycoprotein series.134,139,143 In contrast to the high rate of preeclamp-I antibodies, with approximately 70 percent of patients sia observed in some case series of women previouslywith deﬁnite APS having both LA and anticardiolipin or diagnosed with APS, aPL are not found in a statisticallyanti–β2-glycoprotein I antibodies. However, the antibod- signiﬁcant proportion of a general obstetric populationies detected in three assays are likely not to be identical. presenting with preeclampsia151 or in women at moderateAs a general rule, LA and IgG anti–β2-glycoprotein I risk to develop preeclampsia because of conditions suchantibodies are more speciﬁc for APS, and anticardio- as underlying chronic hypertension or preeclampsia in alipin antibody detected in the standard enzyme-linked prior pregnancy.152immunosorbent assay is the more sensitive test for APS.For both anticardiolipin and anti-β2-glycoprotein I anti-bodies, speciﬁcity is highest for the IgG isotype and for Managementmedium-to-high titers. Low positive results should beviewed with suspicion because they may be found in up Given the array of potential complications in APSto 5 percent of normal individuals and should not be pregnancy, appropriate obstetric care calls for frequent
Chapter 42 Collagen Vascular Diseases 1091prenatal visits, at least every 2 weeks before midgesta- regimen. A paradigm for the management of APS intion and every week thereafter. The objectives are close pregnancy is shown in Figure 42-1.observation for maternal thrombosis, hypertension, and It is important that clinicians be aware that the heparinother features of preeclampsia, periodic patient evalua- doses recommended for APS patients with prior throm-tion and obstetric ultrasound to assess fetal growth and bosis are considerably higher than the 5000 U twice dailyamniotic ﬂuid volume, and appropriate fetal surveillance used by Rai and colleagues.148 Indeed, full anticoagula-testing. The latter should begin at 32 weeks’ gestation, or tion is urged by some experts.154 The optimal dose ofearlier if the clinical situation is suspicious for placental heparin for women with APS diagnosed because of priorinsufﬁciency, and continue at least weekly until delivery. fetal loss or neonatal death after delivery at less than 34Frequent rheumatologic consultation every 2 to 4 weeks weeks’ gestation, for severe preeclampsia or placentalduring pregnancy is recommended, especially in women insufﬁciency, but who do not have a history of throm-with SLE. boembolism, is controversial. These women are at risk The ideal treatment for APS during pregnancy for thromboembolic disease,155 and it seems reasonablewould (1) improve maternal and fetal-neonatal outcome that these cases receive sufﬁcient thromboprophylaxisby preventing pregnancy loss, preeclampsia, placental (see Table 42-6).insufﬁciency, and PTB; and (2) reduce or eliminate the Low-molecular-weight heparins are an acceptablematernal thrombotic risk of APS during pregnancy. option for the treatment of APS pregnancy. Cost consid-Treatment of APS in pregnancy to improve fetal outcome erations limit the use of low-molecular-weight heparins inhas evolved considerably. Enthusiasm for glucocorticoids the United States, and there is little reason to suspect thatwaned when a small, randomized trial found maternally one preparation would be better than the other if usedadministered heparin to be as effective as prednisone.153 in regimens that provide equivalent anticoagulant effectsMaternally administered heparin is widely considered the over 24 hours. A direct comparison of standard heparintreatment of choice at present (Table 42-6), usually initi- versus low molecular-weight-heparin in pregnancy isated in the early ﬁrst trimester after ultrasonographic dem- lacking. The potential complications of heparin treatmentonstration of a live embryo. The dose of heparin required during pregnancy include hemorrhage, osteoporosis withfor safe and effective treatment is debated, however. In fracture, and heparin-induced thrombocytopenia. Fortu-one trial of nearly 100 women, two thirds of whom had nately, the reported rate of osteoporosis and associatedrecurrent preembryonic and embryonic pregnancy loss fracture is low, although cases have occurred, even withand none of whom had a history of thromboembolic low-molecular-weight heparin.139 However, it is likely thatdisease, a heparin dose of 5000 U twice daily was associ- the risk is higher in women with underlying autoimmuneated with a 71-percent live-birth rate.148 Another study of disease who have required glucocorticosteroid treatment.women with aPL and predominantly preembryonic and Heparin-induced thrombocytopenia, which may be lethal,embryonic pregnancy loss, none of whom had a history is also fortunately infrequent in pregnant women.156of thromboembolic disease, with heparin administered Women with particularly serious thrombotic histories,in a twice daily regimen and adjusted to keep the mid- such as recurrent thrombotic events or cerebral throm-interval activated partial thromboplastin time approxi- botic events, are understandably viewed as being at verymately 1.5 times the control mean, was associated with high risk for thrombosis during pregnancy. In selectedan 80-percent live-birth rate.146 In most case series and such cases, we recommend the judicious use of warfarintrials, daily low-dose aspirin is included in the treatment anticoagulation rather than heparin. Table 42-6. Subcutaneous Heparin Regimens Used in the Treatment of Antiphospholipid Syndrome During Pregnancy Prophylactic Regimens Recurrent Preembryonic and Embryonic Loss; No History of Thrombotic Events Standard heparin 1. 5,000–7,500 U every 12 hours in the ﬁrst trimester, 5,000–10,000 U every 12 hours in the second and third trimesters Low-molecular-weight heparin 1. Enoxaparin 40 mg once daily or dalteparin 5,000 U once daily, OR 2. Enoxaparin 30 mg every 12 hours or dalteparin 5,000 U every 12 hours Prior Fetal Death or Early Delivery Because of Severe Preeclampsia or Severe Placental Insufﬁciency; No History of Thrombotic Events Standard heparin 1. 7,500–10,000 U every 12 hours in the ﬁrst trimester, 10,000 U every 12 hours in the second and third trimesters Low-molecular-weight heparin 1. Enoxaparin 40 mg once daily or dalteparin 5,000 U once daily, OR 2. Enoxaparin 30 mg every 12 hours or dalteparin 5,000 U every 12 hours Anticoagulation Regimens—Recommended in Women with A History of Thrombotic Events Standard heparin 1. 7,500 U every 8–12 hours adjusted to maintain the mid-interval heparin levels in the therapeutic range Low-molecular-weight heparin 1. Weight-adjusted (e.g., enoxaparin 1 mg/kg every 12 hours or dalteparin 200 U/kg every 12 hours)
1092 Section VI Pregnancy and Coexisting Disease Woman diagnosed with antiphospholipid syndrome desires pregnancy Preconception consultations with obstetrician and rheumatologist Initiate low-dose aspirin Transvaginal ultrasound to confirm live embryo at 5.5–6.5 weeks of gestation Figure 42-1. Suggested algorithm for the management of antiphospholipid syndrome in pregnancy. See Table 42- Initiate heparin treatment* 6 for dosing. In the United Kingdom, Doppler assessment of the uterine arteries is commonly used at 20–24 weeks’ gestation for the prediction Clinical care Diagnostic tests of preeclampsia and placental insuf- ﬁciency risks. This is not commonly done in the United States. Prenatal visits every 2–4 weeks until 20–24 Obstetric ultrasound every 3–4 weeks weeks of gestation then every 1–2 weeks beginning at 17–20 weeks of gestation Monitor for fetal death, preeclampsia, and Assess fetal growth and amniotic fluid intrauterine growth restriction volume† Rheumatologic visits every 2–4 weeks Fetal surveillance testing at least weekly beginning at 30–32 weeks of gestation, or earlier if placental insufficiency is suspected IVIG has also been used during pregnancy, usually in RHEUMATOID ARTHRITISconjunction with heparin and low-dose aspirin, especiallyin women with particularly poor histories or RPL during Introductionheparin treatment.157 However, a randomized, controlled,pilot study of IVIG treatment during pregnancy in Rheumatoid arthritis (RA) is a debilitating diseaseunselected APS cases found no beneﬁt to this expensive involving chronic symmetric inﬂammatory arthritis oftherapy relative to heparin and low-dose aspirin.158 the synovial joints with an incidence of 2.5 to 7 per Clinicians should realize that otherwise healthy women 10,000 per year and a prevalence of approximately 1with RPL and low titers of aPL do not require treatment. percent in the adult U.S. population. RA is usually diag-The controlled trial of Pattison and colleagues159 included nosed between ages 40 and 50 years, but can appear ata majority of such women and found no difference in live- any age of life and the prevalence increases with age intobirth rates using either low-dose aspirin or a placebo. the 60s or 70s in both women and men. Although found Anticoagulant coverage of the postpartum period in in virtually all populations, it is more common in somewomen with APS and prior thrombosis is critical.160 We (Native American) and less common in others (Nativeprefer switching the patient to warfarin thromboprophy- African). As with most autoimmune conditions, RA islaxis as soon as she is clinically stable after delivery. In more common in women than in men, with a ratio of 2most cases, an international normalized ratio of 2.0 to 3.0 to 3 female cases to one male.161is desirable. There is no international consensus regarding Juvenile rheumatoid arthritis (JRA) is diagnosed inthe postpartum management of those women without children before age 16 years and can be clinically indis-prior thrombosis in whom APS is diagnosed because of tinguishable from RA at time of presentation. However,a prior fetal loss, or neonatal death after delivery at or JRA tends to have a milder clinical course and typicallybefore 34 weeks’ gestation, or for severe preeclampsia resolves without serious disability in 70 to 90 percent ofor placental insufﬁciency, although all agree there is an children diagnosed.increased risk of thrombosis. The recommendation inthe United States is anticoagulant therapy for 6 weeksfollowing delivery. The need for postpartum anticoagula- Pathophysiologytion in women with APS diagnosed solely on the basis ofrecurrent preembryonic or embryonic losses is uncertain The histologic features of RA include symmetric inﬂam-but may be unnecessary. Both heparin and warfarin are matory synovitis marked by cellular hyperplasia, accu-safe to use in patients who are breast-feeding. mulation of inﬂammatory leukocytes, and angiogenesis
Chapter 42 Collagen Vascular Diseases 1093with membrane thickening, edema, and ﬁbrin deposition Clinical Manifestations andas common early ﬁndings. Inﬂammatory damage at the Laboratory Findingssynovium eventually leads to typical joint erosion involv-ing a locally invasive synovial tissue called pannus. RA typically has an insidious onset over several The inﬂammatory damage in RA appears to be primar- months; less commonly, the disease onset is acute andily mediated by CD4+ T cells. The CD4+ T cells recognize somewhat rapid. Twice as many patients present duringunknown endogenous or exogenous antigens, are acti- winter months compared with the summer months, andvated by these antigens, and stimulate monocytes, mac- trauma (including surgery) may be a precursor. The mostrophages, and synovial ﬁbroblasts to produce cytokines common initial features of RA are morning stiffness,interleukin-1 (IL-1), IL-6, and tumor necrosis factor-α pain, and swelling of peripheral joints. Fatigue, weak-(TNF-α), which, in turn, are key contributors to inﬂam- ness, weight loss, and malaise can also be common ﬁnd-mation in RA. CD4+ T cells also express osteoprotegerin ings. The disease tends to involve primarily the joints ofligands that stimulate osteoclastogenesis, as conﬁrmed the wrists, knees, shoulders, and metacarpophalangealin animal models of RA.162 Activated CD4+ T cells also joints in an erosive arthritis that usually follows a slowlystimulate B cells to produce immunoglobulins, one of progressive course marked by exacerbations and remis-which is rheumatoid factor (RF), the characteristic auto- sions. Eventually, joint deformities may occur; these areantibody in patients with RA. RF is present in the periph- especially obvious at the metacarpophalangeal joint anderal circulation and synovium of RA patients. Whether or proximal and distal interphalangeal joints of the hands.not RF autoantibodies are substantially involved in tissue Rheumatoid nodules, composed of a local prolifera-damage remains controversial. There is some evidence tion of small vessels, histiocytes, ﬁbroblasts, and otherthat RF autoantibodies form aggregates in synovial ﬂuid, cells, present in 20 to 30 percent of affected patientsresulting in complement activation and local inﬂamma- and are usually located in the subcutaneous tissues oftion, and eventual joint erosion. the extensor surfaces of the forearm. Although uncom- Concordance for RA is found in approximately 15 mon, extra-articular tissues may also be affected. Thesepercent of monozygotic twins and 5 percent of dizygotic extra-articular tissues include the lung (pleuritis, pleuraltwins. It is estimated that heritable factors account for effusions, interstitial ﬁbrosis, pulmonary nodules, pneu-approximately 60 percent of the predisposition to RA.163 monitis, and airway disease) and heart (pericarditis, effu-The HLA region (HLA class II gene locus DRB1, encoding sion, myocarditis, endocardial inﬂammation, conductionHLA-DR), is of primary importance in RA susceptibility. defects, and arteritis leading to myocardial infarction).Variant forms of DRB1 have been identiﬁed in association The classiﬁcation criteria published by the Americanwith RA including DRB1*0401, *0404, *0405, *0101, College of Rheumatology are shown in Table 42-7. Physi-*1402, and *1001. These alleles encode for similar amino cal examination should reveal evidence of joint inﬂamma-acid sequences (so-called shared epitopes) that are sus- tion including joint tenderness, synovial thickening, jointpected of bestowing susceptibility to RA. Other suspect effusion, erythema, and decreased range of motion. Sym-HLA complex genes are located on chromosomes 1p and metric involvement should be noted. Radiographic evi-1q, 9, 12 p, 16 cen, and 18q.164,165 dence of RA includes joint space narrowing and erosion Table 42-7. Classiﬁcation Criteria for the Diagnosis of Rheumatoid Arthritis (1987, ACR) CRITERIA* DEFINITION Morning stiffness Morning stiffness in and around the joints, lasting at least 1 hour before maximal improvement Arthritis of three joint At least 3 joint areas simultaneously have had soft tissue swelling or ﬂuid (not bony areas overgrowth alone) observed by a physician. The 14 possible areas are right or left PIP, MCP, wrist, elbow, knee, ankle, and MTP joints Arthritis of hand joints At least 1 area swollen (as deﬁned above) in a wrist, MCP, or PIP joint Symmetric arthritis Simultaneous involvement of the same joint areas (as deﬁned in 2) on both sides of the body (bilateral involvement of PIPs, MCPs, or MTPs is acceptable without absolute symmetry) Rheumatoid nodules Subcutaneous nodules, over bony prominences, or extensor surfaces, or in juxtaarticular regions, observed by a physician Serum rheumatoid Demonstration of abnormal amounts of serum rheumatoid factor by any method for which the result has been positive in less than 5% of normal control subjects Radiographic changes Radiographic changes typical of rheumatoid arthritis on posteroanterior hand and wrist radiographs, which must include erosions or unequivocal bony decalciﬁcation localized in or most marked adjacent to the involved joints (osteoarthritis changes alone do not qualify)*For classiﬁcation purposes, a patient shall be said to have rheumatoid arthritis if he/she has satisﬁed at least four of these seven criteria. Criteriaone through four must have been present for at least 6 weeks. Patients with two clinical diagnoses are not excluded. Designation as classic,deﬁnite, or probable rheumatoid arthritis is not to be made. MCP, metacarpophalangeal joint; MTP, metatarsophalangeal joint; PIP, proximal interphalangeal joint. Arnett FC, Edworthy SM, Bloch DA, et al: The American Rheumatism Association 1987 revised criteria for the classiﬁcation of rheumatoidarthritis. Arthritis Rheum 31:315, 1988.
1094 Section VI Pregnancy and Coexisting Diseaseand, though too expensive for routine use, magnetic reso- There are no data to suggest that RA in remission isnance imaging may detect synovial hypertrophy, edema, likely to have a better course during pregnancy than activeand early erosive changes. RA. The long-term prognosis for RA patients undertak- Of those patients with clinical features of RA, 70 percent ing pregnancy appears to be similar to those that avoidare also seropositive for RF. In addition, some of those pregnancy. Oka and Vainio173 compared 100 consecu-who are initially seronegative eventually convert, leaving tive pregnant RA patients with age- and disease-matchedonly 10 percent of patients with RA without a positive controls, and found no signiﬁcant differences between theRF. Approximately 5 percent of people in the general groups in terms of the severity of their disease.population test positive for RF, as do many patients The mechanisms by which pregnancy favorably affectswith viral infections, parasitic infections, chronic bac- RA is unknown. Plasma cortisol, which rises during preg-terial infections, irradiation or chemotherapy, or other nancy to peak at term, was initially thought to be impor-autoimmune conditions, for example, SLE, scleroderma, tant in the amelioration of RA.166 However, there is noand mixed connective tissue disease. correlation between cortisol concentrations and disease state.176 Some studies suggest that estrogens or estrogens and progestagens favorably affect arthritis,177 but there arePregnancy and Rheumatoid Arthritis conﬂicting studies,178 and a double-blind crossover trial found that estrogen did not beneﬁt patients with RA.179CLINICAL COURSE OF RHEUMATOID ARTHRITIS Sex hormones may interfere with immunoregulation andDURING PREGNANCY interactions with the cytokine system.180 Promising data suggest that certain proteins circulating in higher con- Numerous studies (Table 42-8) show that at least 50 centrations during pregnancy or unique to pregnancy arepercent, and maybe as much as 75 percent, of patients associated with improvement of RA. These include preg-with RA demonstrate improvement in their disease in at nancy-associated a2-glycoprotein181 and gamma globulinsleast 50 percent of their pregnancies.166–173 For a major- eluted from placenta.182 Other investigators believe thatity of patients, the improvement in RA starts in the ﬁrst the placenta may modify RA by clearing immune com-trimester heralded by a reduction in joint stiffness and plexes183 or that modiﬁcation of immune globulins duringpain.169 The peak improvement in symptoms generally pregnancy alters their inﬂammatory activity.184occurs in the second or third trimester. Other aspects of In 1993, Nelson and coworkers185 reported that ame-the disease may also improve during pregnancy, including lioration of RA during pregnancy is associated withsubcutaneous nodules associated with RA.171 In addition, a maternal-fetal disparity in HLA class II antigens.Hazes and colleagues reported a protective effect of preg- Maternal-fetal HLA class II disparity was noted in 26 ofnancy in development of RA.174 the 34 pregnancies (75 percent) described as having remis- Even with the overall improvement in symptoms, the sion or improvement in their arthritis, compared withclinical course of RA during pregnancy is characterized only three of 12 whose condition remained unchangedby short-term ﬂuctuations in symptoms. Most but not all or worsened. The authors suggested that the maternalpatients who experience an improvement in RA during immune response to paternal HLA antigens may have apregnancy have a similar improvement in subsequent role in pregnancy-induced remission of RA.185pregnancies. At present, there is no laboratory or clinicalfeature that predicts improvement of RA in pregnancy,and in a few patients, the disease worsens. Nearly three OBSTETRIC COMPLICATIONSquarters of patients whose disease has improved duringpregnancy will suffer a relapse in the ﬁrst several post- About 15 to 25 percent of pregnancies in women withpartum months.169,171 The level of disease during the ﬁrst RA end in miscarriage,186,187 a ﬁgure that may or mayyear after delivery generally returns to that of a year not be slightly higher than in normal women. One con-before conception, but it may be worse.173 There are few trolled study found that women with RA have a sig-studies of JRA, but one found that only one case in 20 niﬁcantly higher frequency of miscarriage than normalhad a worsening or reactivation of the disease associated women, even before the onset of their disease (25 versuswith pregnancy.176 17 percent before disease, 27 versus 17 percent after Table 42-8. Improvement of Rheumatoid Arthritis in Pregnancy AUTHOR PATIENTS PATIENTS WITH IMPROVEMENT (%) PREGNANCIES PREGNANCIES WITH IMPROVEMENT (%) Hench161 22 20 (91) 37 33 (89) Oka168 93 73 (78) 114 88 (77) Betson164 21 13 (62) 21 13 (62) Ostensen171 10 8 (90) 10 9 (90) Ostensen175* 51 NA 76 35 (46)*Study of patients with juvenile rheumatoid arthritis.