sindrome antifosfolipido

Collagen Vascular
Diseases
CALLA HOLMGREN AND D. WARE BRANCH
CHAPTER 42

Systemic 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 and
Antiphospholipid 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.4

1080

Chapter 42 Collagen Vascular Diseases 1081

Several alterations in the human leukocyte antigen (HLA) Clinical Manifestations
system have been linked to the development of SLE,
and homozygous carriers of mutations responsible for DIAGNOSTIC CRITERIA
complement 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 is
CNS, 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 syndrome

ARA, 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 to
in about 50 percent of patients. Patients also may have 90 percent of patients with newly diagnosed SLE. When
a pruritic, maculopapular eruption, particularly in sun- elevated, these antibodies have been associated with a
exposed areas. Two distinct forms of cutaneous lupus are symptomatic flare in 80 percent of SLE patients followed
discoid and subacute. The lesions of discoid lupus mature prospectively.7,8 In pregnancy, anti-dsDNA antibodies
to clearly outlined papules and plaques, with a central correlate with flare and preterm delivery.8,9 Antibodies
area eventually becoming atrophied and depressed. Scar- to single-stranded DNA (ssDNA) are also found in a large
ring is the result. In contrast, subacute lesions appear proportion of untreated SLE patients but are less specific
as distinctly defined erythematous plaques that do not for SLE than anti-dsDNA. Patients with SLE may have
undergo central atrophy and scarring. Subacute lesions antibodies to RNA-protein conjugates, often referred to
are usually more widespread than discoid lesions, with as soluble or extractable antigens, because they can be
the latter tending to be confined to the face, neck, scalp, separated from tissue extracts. These antigens include the
and 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 patients
leading 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 patients
of renal involvement is proteinuria; about 40 percent of and patients with Sjögren’s syndrome, are of particular
patients with SLE renal disease have hematuria or pyuria, importance to obstetricians because they are associated
and 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 determining
prognosis and providing appropriate treatment. Renal Systemic Lupus Erythematosus
biopsy findings are used to group LN into four basic his- and Pregnancy
tologic 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. For
vival 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 preterm
to-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 intrauterine
tive 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 is
uncommon. Membranous glomerulonephritis typically
presents with moderate to heavy proteinuria but lacks THE RISK OF SYSTEMIC LUPUS ERYTHEMATOSUS
the active urinary sediment and does not cause renal EXACERBATION (FLARE)
insufficiency. Mesangial glomerulonephritis appears to
be the least clinically severe lesion and carries the best Whether or not pregnancy is associated with a higher
long-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 and
LABORATORY 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 in
presentation, is confirmed by demonstrating the presence women with SLE was associated with substantial risk for
of pertinent circulating autoantibodies. Most clinicians severe maternal morbidity and mortality and that this
initially 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 with
for 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 the
pattern of antibody binding. A homogeneous pattern is relationship of pregnancy to the rate and nature of SLE
found most commonly in patients with SLE (65 percent), exacerbations. Overall, 15 to 60 percent of women with
although its specificity is low. A peripheral pattern is SLE have a flare during pregnancy or the postpartum
the most specific for SLE, but is not very sensitive. The period.3,11–23 Several prospective studies deserve special
speckled and nucleolar patterns are more specific for consideration. Using a previously published scoring system
other 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 the
diagnosis of SLE, monitoring disease activity, and guiding flare score between the cases and controls, and a similar


number in either group required a change in their medica- Thus, from the available literature one can surmise that
tion. When only signs or symptoms specific for SLE were if pregnancy predisposes to a lupus flare, it does so only
included, exacerbations occurred in only 13 percent of modestly. A majority of studies of pregnant women with
cases. Mintz et al.13 prospectively studied 92 pregnancies SLE indicate that most flares are mild to moderate in
in women with SLE and used a similar group of nonpreg- nature and easily treated with glucocorticoids.11,13,15,16,20–22
nant SLE patients on oral contraceptives derived from a The routine or prophylactic use of glucocorticoids in
previous 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 results
a matter of policy, all pregnant women were started on achieved by others without the routine prophylactic
10 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 SLE
similar in both groups. Most of the exacerbations tended exacerbation, thorough and frequent clinical assessment
to be easily controlled with low to moderate doses of remains essential. The criteria for measuring an SLE flare
glucocorticoids, but seven patients (8 percent) had severe during pregnancy have been recently tested and found
exacerbations requiring more aggressive therapies. Inter- valid.24 Commonly presenting symptoms of flare during
estingly, 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).22,25
their experience comparing 79 pregnancies in patients Serologic evaluation of SLE disease activity may be
with active SLE with a matched control group of 59 non- beneficial in confirming a flare in confusing cases. As
pregnant active SLE women. They also compared these mentioned earlier, elevations in anti-dsDNA titers that
women with 216 women with inactive disease. Using a precede or accompany a lupus flare in more than 80
previously 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 evaluation
three groups. Georgiou et al.22 prospectively evaluated of complement components and activation products is
the 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 SLE
matched for parameters other than disease activity and exacerbation was signaled by a decline of C3 and C4
duration. Using accepted clinical criteria, they reported into the subnormal range.26,27 Buyon et al.28 found that
an SLE exacerbation in 8 (13.5 percent) of the preg- an SLE exacerbation was associated with an absence of
nant patients compared with 13 (22 percent) of the non- the usual increase in C3 and C4 levels during normal
pregnant 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 activation
ter; all exacerbations were mild and easily treated with products during pregnancy remains unproven. Lockshin
glucocorticoids. 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. Wong
two prospective series suggest that pregnant women et al.30 prospectively studied 19 continuing pregnancies
with SLE have higher rates of exacerbation. Petri et al.3 complicated by SLE and found that neither ANA nor
found SLE flares (flares per person years) to be more C3 or C4 levels predicted which patients were going to
common among pregnant women than among controls. have a flare, whereas Nossent and Swaak31 observed that
Fortunately, more than three quarters of the flares were fewer than half of the pregnancies with decreased serum
mild 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 hypocomplementemia
SLE 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 SLE
a matched control group of 50 nonpregnant women. or adverse pregnancy outcomes.35
Sixty-five percent of the patients experienced an exacer-
bation of SLE during pregnancy, for a flare rate of 0.082
per patient-month. In the control group, 42 percent of LUPUS NEPHRITIS EXACERBATION
the 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 risks
Derksen et al.19 reported that SLE exacerbation occurred of maternal and fetal complications. Those with chronic
in 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 whether
pregnancies and found that SLE exacerbations during the increased proteinuria represents an exacerbation of
pregnancy 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 not
of more than three severe flares before pregnancy. The renal flares are more common in pregnant women with
findings of several other studies support the notion that SLE remains controversial. Two studies have reported
women with active disease should postpone pregnancy high frequencies of renal flares (43 to 46 percent) during
until sustained remission can be achieved.20–22 pregnancy,25,30 but others have reported lower figures (9


to 28 percent).13,16,31,36 Three studies assessed the patients’ Table 42-3. Distinguishing Between Preeclampsia and
status during pregnancy in regard to whether the SLE was SLE/LN Flare
active or in remission prior to conception.37–39 In all three,
the rate of SLE exacerbation was lower in pregnancies in TEST PREECLAMPSIA SLE
which 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 CH50
term 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. Hematologic
The 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
anemia
women 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- Renal
lished 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 be
after pregnancy. It is important to note that the majority present; −, not present; LN, lupus nephritis; SLE, systemic lupus
of women in these studies had normal renal function, erythematosus.
mild proteinuria, and well-controlled hypertension before
conception. Petri and colleagues at the Hopkins Lupus
Pregnancy Center reported that only women who began risk of preeclampsia and early delivery. Moderate renal
pregnancy with nephrotic syndrome went on to renal insufficiency (creatinine 1.5 to 2.0 mg/dl) is a relative
failure 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 occurred
in 5 percent (1/20) of pregnancies in women with inac- PREGNANCY LOSS
tive LN before conception compared with 39 percent
(12/31) in women with active LN before conception. The In most retrospective studies, the rate of pregnancy
sole predictors for renal flare were a plasma creatinine loss appears to be higher in women with SLE than in
greater than 1.2 mg/dL or proteinuria equal to 500 mg the general obstetric population, ranging between 8 and
in 24-hour collection. Permanent deterioration occurred 41 percent, with a median of 22 percent.10,12,37,38,50–55 A
in two women with active LN before conception, one of large case-controlled study compared obstetric outcomes
whom 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 significantly
evidence of multiorgan dysfunction. Some of the features more often in women with SLE (21 percent) than in either
that may prove helpful in the distinction between the their healthy relatives (8 percent) or unrelated healthy
two conditions are listed in Table 42-3. Preeclampsia is controls (14 percent). However, the pregnancy loss rates
more likely in women with decreased levels of antithrom- observed in most prospective trials of lupus pregnancies
bin 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 SLE
preeclampsia.49 In the most severe and confusing cases, activity and routine antenatal surveillance. In the most
the correct diagnosis is possible only by renal biopsy. In recent, well-detailed, prospective trials, fetal deaths in the
reality, situations involving either the more severe cases second or third trimester accounted for between 10 to 40
of SLE flare or preeclampsia inevitably raise concerns percent of the total losses.22,23
about maternal and fetal well-being and often prompt Control of disease activity appears to have a helpful
delivery, thus rendering the distinction between the two effect on the rate of pregnancy loss,56 with one early study
clinically 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 with
syndrome, and severe hypertension are at considerable 88 percent in women with quiescent disease.37 In a more


recent, prospective study, pregnancy loss occurred in 75 FETAL GROWTH RESTRICTION
percent of women with active disease compared with 14
percent of women with inactive disease.22 Not surpris- Uteroplacental insufficiency resulting in IUGR and
ingly, pregnancy loss is more likely if SLE is diagnosed small-for-gestational-age neonates has been reported in
during 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 such
pregnancy loss in women with SLE, but loss rates vary as underlying renal insufficiency and chronic hypertension
widely 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 prospective
the 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 pregnancies
LN in pregnancy that included only women with inactive and healthy controls.22 In this study, glucocorticoids were
disease and normal renal function (serum creatinine less given only for symptomatic SLE flare.
than 0.8 mg/dl), the overall fetal survival rate was greater
90 percent, after exclusion of embryonic losses (losses
less than 10 weeks’ gestation).20 These results contrast PRETERM BIRTH
markedly to those of another study in which the rate of
fetal loss was 50 percent in pregnant women with LN PTB has been reported in as few as 3 percent and
and moderate-to-severe renal insufficiency (serum creati- as many as 73 percent of pregnancies complicated by
nine = 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 increase
women with LN, spontaneous abortion occurred in 26 the likelihood of PTB in women with SLE.22,23 Only
percent 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 SLE
than 80 ml/min, and proteinuria less than 1 g/day) and 36 than in a group of matched controls (12 percent vs 4
percent in women with “mild” impairment (clearance 50 percent) in one retrospective case-control study.55a In a
to 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 versus
SLE pregnancies is tied to the presence of antiphos- 15 percent),22 although PTB was more common among
pholipid 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 is
death,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 studies
the predictive value is more than 85 percent.60 In the most that provide sufficient detail suggest that between 28 to
recent prospective trial, the presence of any aPL was the 66 percent of preterm deliveries are indicated because of
single strongest predictor of subsequent pregnancy loss, preeclampsia and another 12 to 33 percent because of
even in women with active disease and underlying renal suspected or confirmed fetal compromise.23,52,55a,60,66 An
impairment.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.68
PREECLAMPSIA

It is difficult to estimate the exact incidence of preg- NEONATAL LUPUS ERYTHEMATOSUS
nancy-related hypertension associated with SLE. This is
in large part due to inconsistencies in the definition and Neonatal lupus erythematosus (NLE) is an infrequent
classification of these disorders, as well as the inclusion condition of the fetus and neonate, occurring in 1 of
of 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 passively
with SLE develop either gestational hypertension (GH) acquired immunity in pregnant women with circulating
or 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 cross
tible, probably owing to the known association between the placenta as early as 11 weeks’ gestation, and they
preeclampsia and underlying renal disease of any origin. are associated with congenital complete atrioventricular
In one prospective series, preeclampsia occurred in 7 heart block (CCHB), a neonatal lupus rash, and hepatic
of 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 percent
predispose SLE patients to GH or preeclampsia include mothers who deliver babies with NLE.70,72,73 A smaller
chronic hypertension, secondary antiphospholipid syn- percentage has only anti-La/SSB. Dermatologic NLE has
drome (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


who 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, this
infant 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 of
anti-Ro/SSA or anti-La/SSB, 1 to 5 percent deliver an fetal-neonatal alloimmune thrombocytopenia has led to
infant with CCHB. It is important to note, however, speculation that IVIG might be effective in preventing or
that 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 women
with anti-Ro/SSA-La/SSB antibodies who has never had
an affected child.73 Recurrence of dermatologic NLE is OBSTETRIC MANAGEMENT
approximately 25 percent.72,76
The skin lesions of NLE are erythematous, scaling Women with SLE who are contemplating pregnancy
annular, or elliptical plaques occurring on the face or should be counseled before conception about potential
scalp. They are analogous to the subacute cutaneous obstetric problems including pregnancy loss, gestational
lesions in adults. They typically appear in the first weeks hypertensive disorders, IUGR, and PTB. They should also
of life, probably induced by exposure of the skin to be informed of the risk of SLE flare and special concerns
ultraviolet light, and may last for up to 6 months.77 related to APS and NLE. Laboratory evaluation before
Hypopigmentation may persist for up to 2 years. Hema- pregnancy should include an assessment for anemia and
tologic 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 from
when 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, and
diography 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 drug
and 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 be
the more severely affected fetus, more widespread endo- discontinued.
myocardial damage leads to fibroelastosis and markedly The prenatal care of the patient with SLE should be
diminished 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 the
CCHB, 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, or
by fetal echocardiography and maternal tests for anti- suspicion of IUGR. Because of the risk of uteroplacental
Ro/SSA and anti-La/SSB antibodies. If the diagnosis of insufficiency, fetal ultrasonography should be performed
CCHB 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 amniotic
Maternal plasmapheresis, to reduce the antibody load, or fluid volume measurements) should be instituted at 30 to
invasive fetal pacing to increase the fetal ventricular rate 32 weeks’ gestation. More frequent ultrasonography and
also 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, or
tioned maternal treatments have known potential and APS. Fetal surveillance as early as 24 to 25 weeks may
real side effects. The efficacy of prenatal treatments is be necessary in patients with APS.80
being examined in a registry of cases collected by Dr. J.P. Management of SLE during labor and delivery is a
Buyon, Hospital for Joint Disease, New York University, continuation of antenatal care. Exacerbations of SLE can
New York City (jill.buyon@med.nyu.edu). 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 of
who have previously delivered an infant with CCHB cesarean delivery to all patients who have been treated
using 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 for
Because 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


managed 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 confirm
at delivery for problems associated with CCHB and other rare reports of these adverse fetal effects. And recent case
manifestations 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-controlled
SLE flare following delivery, and it probably best to trial, which compared the effects of in utero exposure to
maintain frequent contact with SLE patients in the post- hydroxychloroquine, were confirmatory.96 No differences
partum 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 infants
ately following delivery, at similar doses as during the regarding the number and type of defects identified at
pregnancy. Dose adjustments can be handled in the out- birth. There was also no difference in the percentages of
patient 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 be
Erythematosus 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 changed
pregnancy. 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 pregnancy
doses used in pregnancy are the same as those in non- in patients being treated with this agent.
pregnant patients. Tapering to the lowest dose required
to manage the disease is prudent because glucocorticoids
are associated with preeclampsia, gestational diabetes CYTOTOXIC AGENTS
mellitus, 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 the
practice is not evidence based, and comparable maternal most severely affected patients with SLE. Limited data
and 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 with
disease.82 IUGR98,99 and impaired neonatal immunity.100 Thus, in
Despite the fact that glucocorticoids have a low poten- women requiring chronic azathioprine, consideration of
tial for teratogenesis,83 they are not without risk during pregnancy demands that the patient and physician have
pregnancy. Patients requiring long-term therapy are best carefully weighed potential fetal risks against the benefits
treated with prednisolone or methylprednisolone because of the medication.
of their conversion to relatively inactive forms by the Cyclophosphamide has been reported to be teratogenic
abundant 11-β-ol dehydrogenase found in the human in both animal101 and human studies102,103; it should be
placenta. 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 proliferative
during pregnancy should be avoided. Recent analyses glomerulonephritis.104
suggest a very slight increased risk of cleft lip and palate Methotrexate is toxic to actively dividing trophoblast
associated 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 in
include weight gain, striae, acne, hirsutism, immunosup- up to 30 percent of surviving pregnancies when using
pression, 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 with
been 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 have
IUGR.89 Because of the increased risk of glucose intoler- also described cleft palate and deformities of the toes and
ance,87,88 women treated over the long term with glu- fingers when methotrexate is used in early pregnancy.106
cocorticoids 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 have
discontinued antimalarials before or during pregnancy NSAIDs are the most common type of analgesics used
because of concerns about teratogenicity, specifically in the treatment of SLE outside of pregnancy. Although


effective, they readily cross the placenta and can block ANTIPHOSPHOLIPID SYNDROME
prostaglandin synthesis in a wide variety of fetal tissues.
Maternal ingestion of normal adult doses of aspirin in Introduction
the 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 phospholipids
indomethacin 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 associated
After 32 weeks’ gestation, indomethacin can cause con- with hypercoagulability 50 years ago, and an association
striction 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 the
decreased fetal urinary output, oligohydramnios, and association of aPL with these clinical features. Over a
neonatal 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 international
should be avoided during pregnancy, especially after the consensus statement on preliminary criteria for definite
first 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 diagnosis
needed 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- Epidemiology
dose 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 derangement
of adverse fetal effects. MMF is a reversible inhibitor (primary APS) or in combination with other autoimmune
of inosine monophosphate dehydrogenase. It works by diseases (secondary APS), most commonly SLE. aPL are
blocking de novo purine synthesis. MMF is an Food and found in up to 5 percent of apparently healthy controls
Drug Administration (FDA) Category C drug, but terato- and in up to 35 percent of patients with SLE.115 The
genic risks are a concern because experiments in animals prospective risks associated with a positive test for aPL
revealed developmental toxicity, malformations, and antibodies in otherwise healthy subjects are unknown
intrauterine death at dosages that coincide with recom- (Table 42-5).
mended clinical dosages.98 Given this information, there
is a possibility of increased risk in humans, and therefore, Pathophysiology
MMF is contraindicated in pregnancy. Thalidomide is
strictly 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.


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, drugs

ELISA, enzyme-linked immunosorbent assay; HIV, human immunodeficiency virus.

subject of debate, although mounting evidence supports Diagnosis
a direct antibody-mediated effect. Working with mice,
some investigators found administration of human aPL CLINICAL MANIFESTATION
results in clinical manifestations of APS, including fetal
loss.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 clinical
pregnancy 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 must
the 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 three
ulation. Candidate molecules or pathways that might categories: (1) otherwise unexplained fetal death (10
be 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 associated
duction of arachidonic acid metabolites. Other evidence with aPL but are not considered specific enough to be
suggests 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 of
implying that aPL may participate in oxidant-mediated both the preembryonic-embryonic and the fetal-neonatal
injury 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 third
interference with trophoblastic annexin V,120 which is trimester (see Table 42-5). In the original description
abundant in the human placenta, or by impairing tropho- of APS, the single obstetric criterion for diagnosis was
blastic 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 recurrent
living cells do not express phospholipids bound by aPL pregnancy loss [RPL] including those occurring in the
on 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 of
vated 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.127–132
APS-related pregnancy loss, showing that C3 activation Complications occurring in the fetal-neonatal period
is required for fetal loss in a mouse model.122 Moreover, of pregnancies affected by APS can be serious. At least
the beneficial effect of heparin seen in this model appears 40 percent of pregnancy losses reported by women
to 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 those
prevent fetal loss in this murine system,123 suggesting that pregnancies complicated by APS with fetal survival
thrombosis may not be the immediate cause of pregnancy past 20 weeks’ gestation, the median rate of gestational
morbidity 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 as
effect of APS on human pregnancy appears to be tied to early as 15 to 17 weeks’ gestation,134 and two groups
abnormal 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 positive
thickening, acute atherosis, and fibrinoid necrosis in cases for aPL antibodies compared to healthy controls.141,142
of fetal loss associated with APS. Others have found Several investigators have relatively high rates of IUGR
extensive placental necrosis, infarction, and thrombosis. in association with aPL antibodies.134,138,141,143,144 Even


with currently used treatment protocols, the rate of used to make the diagnosis of APS. When they occur
IUGR approaches 30 percent.134,138 Pregnancies compli- alone, IgM results are widely considered to have reduced
cated by APS are also more likely to exhibit nonreas- specificity for APS. In spite of well-intentioned efforts at
suring fetal heart rate patterns during antenatal tests of standardization and the availability of positive standard
fetal well being and intrapartum monitoring.59,134,135 Not sera, substantial interlaboratory variation when testing
surprisingly, 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 as
refute the diagnosis of APS. As indicated in Table 42-5, subcategorization, of patients included in studies. This
a patient with APS should manifest at least one of three objective is crucial for credible investigative efforts and
laboratory 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 of
isotype anticardiolipin antibodies, or (3) medium to high laboratory testing, an area of proven concern in aPL. As
titers of IgG or IgM isotype anti-β2-glycoprotein I anti- with other autoimmune conditions, such as SLE, there
bodies. Very importantly, positive tests must be confirmed are individuals who present with one or more clinical or
on 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, experienced
clotting 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 standardized
enzyme-linked immunosorbent assay that measures β2- Pregnancy in Women with
glycoprotein I-dependent IgG and IgM anticardiolipin Antiphospholipid Syndrome
antibodies. The standard anticardiolipin antibody assay
detects β2-glycoprotein I-dependent anticardiolipin anti- Even with treatment, the potential complications of
bodies because β2-glycoprotein I is present in the diluted pregnancy in women with APS include RPL (including
patient 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 due
use 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 vary
ences in reactivity between anticardiolipin antibodies and depending on the population in which the diagnosis of
anti-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 insufficiency
tive tests for this antibody or group of antibodies, referred requiring PTB.14,145–149
to as anti-β2-glycoprotein I, are relatively specific for APS. These low-risk patients contrast with those patients
Thus, anti–β2-glycoprotein I antibodies are now included that have a history of medical problems (see discussion
as 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 and
anticardiolipin 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 50
for IgG binding and MPL for IgM binding). In most percent.134,139–141,143,150 Placental insufficiency requiring
laboratories, there is substantial concordance between delivery is also relatively frequent in some of these case
LA 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 previously
with definite APS having both LA and anticardiolipin or diagnosed with APS, aPL are not found in a statistically
anti–β2-glycoprotein I antibodies. However, the antibod- significant proportion of a general obstetric population
ies detected in three assays are likely not to be identical. presenting with preeclampsia151 or in women at moderate
As a general rule, LA and IgG anti–β2-glycoprotein I risk to develop preeclampsia because of conditions such
antibodies are more specific for APS, and anticardio- as underlying chronic hypertension or preeclampsia in a
lipin antibody detected in the standard enzyme-linked prior pregnancy.152
immunosorbent 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 Management
medium-to-high titers. Low positive results should be
viewed with suspicion because they may be found in up Given the array of potential complications in APS
to 5 percent of normal individuals and should not be pregnancy, appropriate obstetric care calls for frequent


prenatal visits, at least every 2 weeks before midgesta- regimen. A paradigm for the management of APS in
tion 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 heparin
other 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 daily
amniotic 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 of
earlier if the clinical situation is suspicious for placental heparin for women with APS diagnosed because of prior
insufficiency, and continue at least weekly until delivery. fetal loss or neonatal death after delivery at less than 34
Frequent rheumatologic consultation every 2 to 4 weeks weeks’ gestation, for severe preeclampsia or placental
during 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 reasonable
would (1) improve maternal and fetal-neonatal outcome that these cases receive sufficient thromboprophylaxis
by preventing pregnancy loss, preeclampsia, placental (see Table 42-6).
insufficiency, and PTB; and (2) reduce or eliminate the Low-molecular-weight heparins are an acceptable
maternal 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 in
has evolved considerably. Enthusiasm for glucocorticoids the United States, and there is little reason to suspect that
waned when a small, randomized trial found maternally one preparation would be better than the other if used
administered heparin to be as effective as prednisone.153 in regimens that provide equivalent anticoagulant effects
Maternally administered heparin is widely considered the over 24 hours. A direct comparison of standard heparin
treatment of choice at present (Table 42-6), usually initi- versus low molecular-weight-heparin in pregnancy is
ated in the early first trimester after ultrasonographic dem- lacking. The potential complications of heparin treatment
onstration of a live embryo. The dose of heparin required during pregnancy include hemorrhage, osteoporosis with
for 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 associated
recurrent preembryonic and embryonic pregnancy loss fracture is low, although cases have occurred, even with
and none of whom had a history of thromboembolic low-molecular-weight heparin.139 However, it is likely that
disease, a heparin dose of 5000 U twice daily was associ- the risk is higher in women with underlying autoimmune
ated 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.156
of 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 very
mately 1.5 times the control mean, was associated with high risk for thrombosis during pregnancy. In selected
an 80-percent live-birth rate.146 In most case series and such cases, we recommend the judicious use of warfarin
trials, 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)


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 ARTHRITIS
conjunction with heparin and low-dose aspirin, especially
in women with particularly poor histories or RPL during Introduction
heparin treatment.157 However, a randomized, controlled,
pilot study of IVIG treatment during pregnancy in Rheumatoid arthritis (RA) is a debilitating disease
unselected APS cases found no benefit to this expensive involving chronic symmetric inflammatory arthritis of
therapy 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 1
with 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 at
a majority of such women and found no difference in live- any age of life and the prevalence increases with age into
birth 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 some
women with APS and prior thrombosis is critical.160 We (Native American) and less common in others (Native
prefer switching the patient to warfarin thromboprophy- African). As with most autoimmune conditions, RA is
laxis as soon as she is clinically stable after delivery. In more common in women than in men, with a ratio of 2
most cases, an international normalized ratio of 2.0 to 3.0 to 3 female cases to one male.161
is desirable. There is no international consensus regarding Juvenile rheumatoid arthritis (JRA) is diagnosed in
the 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 typically
before 34 weeks’ gestation, or for severe preeclampsia resolves without serious disability in 70 to 90 percent of
or placental insufficiency, although all agree there is an children diagnosed.
increased risk of thrombosis. The recommendation in
the United States is anticoagulant therapy for 6 weeks
following delivery. The need for postpartum anticoagula- Pathophysiology
tion in women with APS diagnosed solely on the basis of
recurrent 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


with membrane thickening, edema, and fibrin deposition Clinical Manifestations and
as common early findings. Inflammatory damage at the Laboratory Findings
synovium 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 and
ily mediated by CD4+ T cells. The CD4+ T cells recognize somewhat rapid. Twice as many patients present during
unknown endogenous or exogenous antigens, are acti- winter months compared with the summer months, and
vated by these antigens, and stimulate monocytes, mac- trauma (including surgery) may be a precursor. The most
rophages, 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 of
ligands that stimulate osteoclastogenesis, as confirmed the wrists, knees, shoulders, and metacarpophalangeal
in animal models of RA.162 Activated CD4+ T cells also joints in an erosive arthritis that usually follows a slowly
stimulate 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 are
antibody in patients with RA. RF is present in the periph- especially obvious at the metacarpophalangeal joint and
eral 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 other
that RF autoantibodies form aggregates in synovial fluid, cells, present in 20 to 30 percent of affected patients
resulting in complement activation and local inflamma- and are usually located in the subcutaneous tissues of
tion, 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. These
percent of monozygotic twins and 5 percent of dizygotic extra-articular tissues include the lung (pleuritis, pleural
twins. 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, conduction
HLA-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 American
with 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, joint
pected 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. Criteria
one 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 rheumatoid
arthritis. Arthritis Rheum 31:315, 1988.


and, though too expensive for routine use, magnetic reso- There are no data to suggest that RA in remission is
nance imaging may detect synovial hypertrophy, edema, likely to have a better course during pregnancy than active
and 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 avoid
are 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-matched
only 10 percent of patients with RA without a positive controls, and found no significant differences between the
RF. 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 affects
with 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 no
and 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 are
Pregnancy and Rheumatoid Arthritis conflicting studies,178 and a double-blind crossover trial
found that estrogen did not benefit patients with RA.179
CLINICAL COURSE OF RHEUMATOID ARTHRITIS Sex hormones may interfere with immunoregulation and
DURING 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 are
percent, 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 globulins
least 50 percent of their pregnancies.166–173 For a major- eluted from placenta.182 Other investigators believe that
ity 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 during
pain.169 The peak improvement in symptoms generally pregnancy alters their inflammatory activity.184
occurs 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 with
subcutaneous 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 of
nancy 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 with
clinical course of RA during pregnancy is characterized only three of 12 whose condition remained unchanged
by short-term fluctuations in symptoms. Most but not all or worsened. The authors suggested that the maternal
patients who experience an improvement in RA during immune response to paternal HLA antigens may have a
pregnancy have a similar improvement in subsequent role in pregnancy-induced remission of RA.185
pregnancies. At present, there is no laboratory or clinical
feature that predicts improvement of RA in pregnancy,
and in a few patients, the disease worsens. Nearly three OBSTETRIC COMPLICATIONS
quarters of patients whose disease has improved during
pregnancy will suffer a relapse in the first several post- About 15 to 25 percent of pregnancies in women with
partum months.169,171 The level of disease during the first RA end in miscarriage,186,187 a figure that may or may
year 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 normal
had a worsening or reactivation of the disease associated women, even before the onset of their disease (25 versus
with 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.

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