Collagen Vascular Disease in Prergnancy

Chapter 46
Collagen Vascular
Diseases in Pregnancy
JEANETTE R. CARPENTER and D. WARE BRANCH
Systemic Lupus Erythematosus 981 Drug Used to Treat Systemic Lupus Pregnancy Considerations 991
Epidemiology and Etiology 981 Erythematosus and Pregnancy Antirheumatic Drugs 992
Clinical Manifestations 982 Considerations 986 Management of Pregnancies Complicated
Diagnosis 982 Antiphospholipid Syndrome 987 by Rheumatoid Arthritis 993
Lupus Flare in Pregnancy 982 Clinical Presentation 988 Systemic Sclerosis 993
Lupus Nephritis in Pregnancy 983 Diagnosis 988 Clinical Manifestations 993
Pregnancy Complications 983 Management of Antiphospholipid Diagnosis 993
Neonatal Lupus Erythematosus 984 Syndrome in Pregnancy 989 Pregnancy Considerations 993
Management of Pregnancies Pregnancy Complications and Management of Pregnancies Complicated
Complicated by Systemic Lupus Surveillance 990 by Systemic Sclerosis 993
Erythematosus 984 Rheumatoid Arthritis 991 Sjögren Syndrome 994
Management of Congenital Heart Clinical Manifestations 991
Block 985 Diagnosis 991
KEY ABBREVIATIONS
Anti-β2–glycoprotein I antibody aβ2-GP-I Low-molecular-weight heparin LMWH
Anticardiolipin antibody aCL Lupus nephritis LN
American College of Obstetricians and ACOG Major histocompatibility complex MHC
Gynecologists Mycophenolate mofetil MMF
American College of Rheumatology ACR Methotrexate MTX
Antinuclear antibody ANA Neonatal lupus erythematosus NLE
Antiphospholipid antibody aPL Nonsteroidal antiinflammatory drug NSAID
Antiphospholipid syndrome APS Normal sinus rhythm NSR
Azathioprine AZA Preterm birth PTB
Catastrophic antiphospholipid syndrome CAPS Rheumatoid arthritis RA
Congenital heart block CHB Recurrent early miscarriage REM
C-reactive protein CRP Rheumatoid factor RF
Deep venous thrombosis DVT Small for gestational age SGA
Erythrocyte sedimentation rate ESR Systemic lupus erythematosus SLE
Estimated glomerular filtration rate EGFR Sjögren syndrome SS
Hydroxychloroquine HCQ Systemic sclerosis SSc
Intrauterine growth restriction IUGR Tumor necrosis factor alpha TNF-α
Intravenous immunoglobulin IVIG Regulatory T cell TREG
Lupus anticoagulant LAC Unfractionated heparin UFH
point during their reproductive years. Not infrequently, an

SYSTEMIC LUPUS ERYTHEMATOSUS initial diagnosis is made during the course of an evaluation for
Epidemiology and Etiology pregnancy complications or during pregnancy or the postpar-
Systemic lupus erythematosus (SLE) is a chronic inflamma- tum period. Significant racial differences are apparent in
tory and autoimmune disorder that can affect multiple organ disease prevalence: black women have a prevalence of 405
systems, including the skin, joints, kidneys, central nervous per 100,000 compared with a prevalence of 164 per 100,000
system, heart, lungs, and liver. among white women.1
SLE is more prevalent among women than men, and most Genetic predisposition appears to be an important contrib-
women who are affected by the disease manifest it at some uting factor to the development of SLE in that 5% to 12%
981
Downloaded for Beryliana Maya Anisa (beryliana.maya91@gmail.ui.ac.id) at University of Indonesia from ClinicalKey.com by Elsevier on October 12, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
982 Section VI Pregnancy and Coexisting Disease
of relatives of SLE patients also have the disease. The con- TABLE 46-1 REVISED AMERICAN COLLEGE OF
cordance for SLE is high (~25%) among monozygotic twins. RHEUMATOLOGY CRITERIA FOR
Rare genetic factors such as deficiencies in complement com- CLASSIFICATION OF SYSTEMIC LUPUS
ponents and mutations in the TREX1 gene, which encodes ERYTHEMATOSUS (1982 AND 1997)
a DNA-degrading enzyme—as well as more common single
Malar rash Fixed erythema, flat or raised, over the malar eminences
nucleotide polymorphisms (SNPs) in the major histocompatibil- that tends to spare the nasolabial folds
ity complex (MHC)—are associated with the development of Discoid rash Erythematous raised patches with adherent keratotic
SLE.2 Although an individual may be genetically predisposed to scaling and follicular plugging; atrophic scarring may
develop SLE, the cause appears to be multifactorial. Studies have occur in older lesions
Oral ulcers Oral or nasopharyngeal ulceration, usually painless
identified various exposures—such as to the Epstein-Barr virus, Arthritis Nonerosive arthritis involving two or more peripheral
ultraviolet (UV) light, and silica dust—as having associations joints, characterized by tenderness, swelling, or
with SLE.3 Emerging research suggests that such exposures may effusion
mediate the development of SLE through epigenetic changes Serositis Pleuritis (convincing history of pleuritic pain, rubbing
that cause sustained alterations in gene expression.3 heard by a physician, or evidence of pleural effusion)
Pericarditis documented by ECG or rub or evidence of
Consistent with the higher prevalence of SLE among women, effusion
hormonal factors appear to play an important role. Early Renal Persistent proteinuria greater than 0.5 g/day or greater
menarche, oral contraceptives, and postmenopausal hormone than 3+ if quantitation is not performed
replacement have all been associated with an increased risk Cellular casts: Red cell, hemoglobin, granular, tubular, or
mixed
for SLE.4 Neurologic Seizures in the absence of offending drugs or known
metabolic derangements (e.g., uremia, ketoacidosis,
Clinical Manifestations or electrolyte imbalance)
The clinical course of SLE is characterized by periods of Psychosis in the absence of drugs or metabolic
disease “flares” interspersed with periods of remission. The derangements
Hematologic Hemolytic anemia with reticulocytosis
most common presenting symptoms of SLE include arthral- Leukopenia <4000/mm3 on two or more occasions
gias, fatigue, malaise, weight change, Raynaud phenomenon, Lymphopenia <1500/mm3 on two or more occasions
fever, photosensitive rash, and alopecia. Constitutional symp- Thrombocytopenia <100,000/mm3 in the absence of
toms will be present in nearly all women at some point in their drugs
Immunologic Anti-DNA: Antibody to native DNA in abnormal titer
disease course. More than 90% of individuals with SLE will Anti-Sm: Presence of antibody to Sm nuclear antigen
experience arthralgias, which are typically migratory and most Positive finding of antiphospholipid antibodies based
commonly involve the proximal interphalangeal and metacar on* (1) an abnormal serum level of IgG or IgM
pophalangeal joints, wrists, and knees. The arthralgias of SLE anticardiolipin antibodies, (2) a positive test result for
typically improve as the day progresses. Most patients also lupus anticoagulant using a standard method, or (3) a
false-positive serologic test for syphilis for 6 months
have skin manifestations at some point in the course of the Antinuclear An abnormal titer of ANA by immunofluorescence or
disease, and the classic presentation is a malar “butterfly” antibody an equivalent assay at any point in time and in the
rash that worsens with sun exposure. For women who present absence of drugs known to be associated with
in the postpartum period, some SLE symptoms—such as fatigue drug-induced lupus syndrome
and hair loss—may be easily overlooked. More severe but less For the purposes of enrollment in clinical studies, a person is defined as having systemic
common manifestations include discoid lupus (inflammatory lupus erythematosus (SLE) if four or more of the 11 criteria are present, serially or
simultaneously.
skin lesions that result in scarring), lupus nephritis (LN), pleu- *Testing for antiphospholipid antibodies should also include IgG and IgM anti-β2–
risy, pericarditis, and seizures or psychosis. glycoprotein I antibodies.
ANA, antinuclear antibody; ECG, electrocardiograph; Ig, immunoglobulin.
Diagnosis
The American College of Rheumatology (ACR) has devised a
set of diagnostic criteria for SLE. These criteria were most the setting of a disease flare, whereas Anti-Sm antibodies are
recently revised in 1997 (Table 46-1) and are highly sensitive detected in 30% to 40% of individuals with SLE and are associ-
and specific for SLE. To be diagnosed with SLE, a patient must ated with LN. Antiribonucleoprotein (anti-RNP) antibodies are
have at least four of the 11 clinical and laboratory criteria, associated with myositis and Raynaud phenomenon. Patients
either serially or simultaneously. It should be emphasized, with either SLE or Sjögren syndrome may also have anti-Ro/
however, that some women with features of SLE might not SSA and anti-La/SSB antibodies, which are particularly rel-
meet the strict diagnostic criteria but can still be at risk for evant to the obstetric patient because of the association with
pregnancy complications. These women may benefit from neonatal lupus erythematosus (NLE) and congenital heart
increased surveillance and even treatment. block (CHB).
Because nearly all individuals with SLE will have a positive
antinuclear antibody (ANA) titer, this is a reasonable initial Lupus Flare in Pregnancy
screening test for women with suggestive symptoms. If the Studies on the risk of SLE flare in pregnancy have yielded incon-
ANA test is negative, a diagnosis of SLE is highly unlikely. sistent results. In the 1960s and 1970s, studies suggested a sig-
However, an elevated ANA titer is not specific for SLE because nificant risk for disease flare in pregnancy with accompanying
it can also be seen in other autoimmune conditions such as high rates of adverse maternal and fetal/neonatal outcomes.
Sjögren syndrome, scleroderma, and rheumatoid arthritis (RA). However, more recent studies indicate that pregnancy may not
Anti–double-stranded DNA (anti-dsDNA) and anti-Smith significantly increase the risk of an SLE flare.5,6 If flares do occur
(anti-Sm) antibodies are more highly specific for SLE, albeit in pregnancy, they are generally not severe and are relatively
less sensitive. Anti-dsDNA titers are frequently elevated in easily treated.7 The best predictor of the course of SLE during
Chapter 46 Collagen Vascular Diseases in Pregnancy 983
gestation is the state of disease activity at the onset of preg- Distinguishing between a flare in SLE (and LN) and pre-
nancy. In one study, approximately one third of women who eclampsia can pose a clinical dilemma. Both entities can
were in remission for at least 6 months prior to pregnancy suf- present with hypertension and proteinuria. If the pregnancy is
fered an SLE flare compared with two thirds of women with at or near term, delivery may be the most prudent strategy.
active disease at the beginning of pregnancy.8 Thus women with Preeclampsia should resolve after delivery. However, if the preg-
SLE should be counseled to delay pregnancy until their nancy is still very preterm, distinguishing between a disease flare
disease has been in remission for at least 6 months. and preeclampsia is more critical. A SLE flare can usually be
The detection of SLE flare in pregnancy requires frequent treated, such as with corticosteroids, to prolong the pregnancy
clinical assessment and astute clinical judgment. Flares in preg- and optimize neonatal outcomes. Because elevated anti-dsDNA
nancy most commonly manifest as fatigue, joint pain, rash, titers and low complement levels are often seen in active SLE,
and proteinuria. Assessing anti-dsDNA titers and comple- assessing them may aid in distinguishing between a disease flare
ment (C3 and C4) levels may provide additional evidence of and preeclampsia. However, it should be emphasized that hypo-
disease flares in women with clinical symptoms. The routine complementemia can also be seen in preeclampsia.14 Examina-
assessment of anti-dsDNA and complement levels in asymp- tion of the urine sediment may also provide useful information
tomatic women is of doubtful clinical utility.9 because hematuria and cellular casts often accompany an LN
flare but are not characteristic of preeclampsia. Renal biopsy may
Lupus Nephritis in Pregnancy be considered in difficult cases but is usually avoided during
Renal manifestations are present in approximately half of pregnancy unless management of the pregnancy is incumbent
all patients with SLE. Although LN may be suspected based upon the results.
on hematuria, proteinuria, and casts on urinalysis, confirma- Women with severe LN are often treated with mycopheno-
tion of the diagnosis requires a renal biopsy. According to the late mofetil (MMF), a significant teratogen that is contrain-
International Society of Nephrology and the Renal Pathology dicated in pregnancy. MMF is typically replaced by azathioprine
Society, six classes of LN have been defined, with the most (AZA) when a pregnancy is planned or soon after conception in
common and severe form being class IV, or diffuse LN.10 All an unplanned pregnancy. In one study, preconceptional replace-
patients with active diffuse LN have proteinuria and hematuria, ment of MMF with AZA among women with inactive disease
and a significant subset of patients will progress to nephrotic did not lead to an increase in LN flares in the 3 to 6 months
syndrome, hypertension, and renal insufficiency. Women with prior to a confirmed pregnancy.15
LN, particularly active disease, are at especially increased
risk for adverse pregnancy outcomes that include hyperten- Pregnancy Complications
sive disorders of pregnancy, disease flares, low birthweight Women with SLE do not appear to be less fertile than women
infants, and indicated preterm delivery.11 Similar to SLE in without SLE, but they are at increased risk for multiple ad-
general, the activity of LN during pregnancy is related to disease verse pregnancy outcomes that include pregnancy loss, PTB,
status at conception. In one study, an LN flare was seen in only preeclampsia, and intrauterine growth restriction (IUGR).
9% of cases in which the disease was in remission for at least
5 months prior to pregnancy, compared with 66% of cases Pregnancy Loss
in which disease was clinically active at conception.12 Women Studies from the 1960s and 1970s reported pregnancy loss rates
with baseline renal insufficiency are at greatest risk. Ideally, as high as 50% among women with SLE. Although rates of
assessment of baseline renal status—serum creatinine and urine pregnancy loss appear to have declined over the decades, prob-
protein excretion—is done prior to planning a pregnancy. If ably related to improved treatment and surveillance, women
the patient is already pregnant, assessment as early as feasible with SLE are still at greater risk for pregnancy loss compared
in the pregnancy is recommended. As a general rule, a serum with women who do not have SLE. One study found that even
creatinine of 1.4 to 1.9 mg/dL (estimated glomerular filtration women with disease remission at the onset of pregnancy had a
rate [EGFR] ~30 to 59 mL/min/1.73 m2) is a relative contrain- risk of miscarriage or fetal death of 17% compared with 5% for
dication to pregnancy given the substantial risk of midterm women without SLE.16 A meta-analysis reported a spontaneous
pregnancy complications that might require preterm deliv- abortion rate of 16% and a stillbirth rate of 3.6% among women
ery. Most experts consider a serum creatinine of 2.0 mg/ with SLE.11 The National Institutes of Health (NIH) sponsored
dL or greater (EGFR ~15 to 29 mL/min/1.73 m2) to be an Predictors of Pregnancy Outcome: Biomarker In Antiphospho-
absolute contraindication to pregnancy, again because of lipid Antibody Syndrome and Systemic Lupus Erythematosus
the substantial risk of pregnancy complications requiring (PROMISSE), a study that followed a cohort of women with
extreme preterm birth (PTB) and the threat to long-term inactive or mild-to-moderate SLE activity at conception. Because
renal function. Women with moderate and especially severe patients were enrolled in the late first or early second trimesters,
baseline renal insufficiency should be counseled regarding the early pregnancy loss was not assessed. However, the overall fetal
small (5% to 10%) but real risk of an irreversible decline in death rate among these women was 4%, and the neonatal
renal function during pregnancy.13 death rate was 1%.17
Women with LN often have increasing proteinuria across Active disease at the onset of pregnancy confers an increased
gestation, related in part to increased glomerular filtration. risk for pregnancy loss. Among a cohort of 267 pregnancies
However, an isolated increase in proteinuria without new-onset followed between 1987 and 2002, 77% resulted in a live birth
or worsening hypertension or a significant rise in serum creati- among women with high-activity SLE compared with 88%
nine should not be an indication for preterm delivery. Further- among those with low-activity disease.18 In addition to disease
more, the American College of Obstetricians and Gynecologists activity, LN, hypertension, and antiphospholipid antibodies
(ACOG) no longer considers proteinuria a necessary diagnostic (aPLs) are all associated with an increased risk for pregnancy loss
criterion for preeclampsia. (see Chapter 27).19
Intrauterine Growth Restriction the early neonatal period and may persist for 1 to 2 months.
The increased risk for stillbirth among women with SLE is likely Less common manifestations of NLE include hematologic
related to higher rates of placental insufficiency and IUGR (see abnormalities (leukopenia, hemolytic anemia, thrombocytope-
Chapter 33), particularly among pregnancies complicated by nia) and hepatosplenomegaly. Fortunately, the incidence of NLE
active disease, hypertension, LN, and/or antiphospholipid syn- is low. Among all pregnant women with SLE, the risk of NLE
drome (APS). Although the rate of IUGR among pregnancies is less than 5%. Of those women with SLE who test positive
complicated by SLE has been reported to be as high as 40%,20 for anti-Ro/SSA and anti-La/SSB antibodies, at most 15% to
modern treatments and improved pregnancy surveillance 20% will have an affected newborn. Many mothers of newborns
have probably decreased this rate. A study from the National with NLE will not carry a current diagnosis of SLE. However,
Inpatient Sample analyzed over 16 million hospital admissions a significant number of these women will develop symptomatic
for childbirth and found that 5.6% of women with SLE carried autoimmune disease, often Sjögren syndrome, in the future.
a diagnosis of IUGR, compared with 1.5% among women They should therefore be counseled to seek medical evaluation
without SLE (this difference was not statistically significant).21 if symptoms of SLE or Sjögren syndrome develop.
In the PROMISSE study, 8% of infants of women with mild to The most serious manifestation of NLE is complete heart
moderate SLE were small for gestational age (SGA).17 Chronic, block. It is most frequently diagnosed at a routine prenatal
high-dose glucocorticoid treatment is also a risk factor for visit when a fixed fetal bradycardia of 50 to 80 beats/min is
IUGR. Because of the increased risk for IUGR and stillbirth, it detected. CHB is most commonly diagnosed between 16 and
is standard practice to assess fetal growth intermittently with 24 weeks’ gestation, and it is rarely diagnosed in the third
ultrasound after 20 weeks and to perform antenatal testing (non- trimester. It is caused by the binding of antibodies to antigens
stress tests or biophysical profiles) in the third trimester. in fetal cardiac tissue with subsequent damage to the cardiac
conduction system and, ultimately, complete atrioventricular
Preterm Birth (AV) dissociation. Some cases progress to endocardial fibroelas-
Women with SLE have an approximately threefold increased tosis, which can result in cardiac failure that leads to fetal
risk for PTB.22 In the PROMISSE study, 9% of pregnancies hydrops and fetal death. Among women with anti-Ro/SSA and
delivered before 36 weeks.17 Most of these PTBs are not spon- anti-La/SSB antibodies, the risk for CHB in the fetus is only
taneous but are rather iatrogenic, the result of fetal or maternal 1% to 2%. However, women with a prior affected child have a
indications (IUGR, preeclampsia, disease flare, deteriorating recurrence risk for CHB of 15% to 20% in subsequent pregnan-
renal function, etc.). Women with active disease, aPLs, LN, and cies.26 Fetal genetic factors, such as certain human leukocyte
hypertension are at particular risk for PTB. In one study, a full- antigen (HLA) polymorphisms, may modify susceptibility to the
term delivery was achieved in only 26% of women with high- development of CHB.27 Although many clinicians routinely
activity SLE compared with 61% of women with low-activity test pregnant women with SLE for anti-Ro/SSA and anti-La/
disease or remission.23 High-dose glucocorticoids have also been SSB antibodies, this practice is not without controversy given
associated with an increased risk for preterm premature rupture that CHB is infrequent, antenatal treatment to alter outcome
of membranes. is of uncertain efficacy, and a positive test result may cause
unnecessary maternal anxiety.
Hypertensive Disorders of Pregnancy Complete CHB is irreversible and is associated with an
Hypertensive disorders (gestational hypertension or preeclamp- overall mortality rate of at least 20% (5% stillborn).28 The
sia) occur in 10% to 30% of pregnancies with SLE.5,21 The majority of survivors require a pacemaker. In one series of 102
risk for preeclampsia is particularly increased in women with LN cases, a prenatal diagnosis of CHB was associated with a 43%
and/or chronic hypertension. Preeclampsia may develop in as risk of mortality in the first two decades of life.29 Among a
many as two thirds of women with LN23 and is a frequent indi- registry of 325 offspring with cardiac manifestations of NLE,
cation for iatrogenic PTB. It appears that preeclampsia is also predictors of a stillbirth or postnatal death included hydrops,
more likely to develop at an earlier gestational age among women endocardial fibroelastosis, earlier diagnosis, and a lower ventricu-
with a history of LN compared with those without such a history lar rate.30 In addition, the case fatality rate was significantly
(37.5 weeks vs. 34.5 weeks in one study24). Daily low-dose higher among minorities (32.1% for blacks compared with
aspirin (typically 81 mg in the United States) beginning early 14.3% for whites).30
in pregnancy is recommended for women with SLE, partic
ularly those with renal manifestations, because evidence Management of Pregnancies Complicated
suggests this may modestly decrease the risk of developing by Systemic Lupus Erythematosus
preeclampsia.25 Because SLE commonly affects women at some point during
As mentioned previously, it may be difficult in some cases to their reproductive years, the clinician should be familiar with
distinguish between an SLE flare and preeclampsia, and astute the high-risk nature of these pregnancies and the altered man-
clinical judgment is required. Hospitalization for maternal and agement and increased surveillance required. Ideally, women
fetal monitoring, administration of antenatal steroids, and with SLE would present for a preconceptional visit such that
thoughtful determination of the need for delivery is frequently disease remission could be ensured, medications reviewed,
indicated in these cases. and counseling performed.
Table 46-2 outlines recommendations for the management of
Neonatal Lupus Erythematosus pregnancies complicated by SLE. Key components include the
Neonatal lupus erythematosus is an acquired autoimmune assessment of disease activity and renal manifestations, sur-
condition related to the transplacental transfer of anti-Ro/ veillance for preeclampsia, surveillance of fetal growth, and
SSA and anti-La/SSB antibodies. NLE most commonly pres- antenatal testing. Co-management with a rheumatologist is
ents as an erythematous, scaling, plaquelike rash that begins in particularly important for women with severe manifestations
TABLE 46-2 RECOMMENDATIONS FOR MANAGEMENT role in deciding upon the nature and frequency of such
OF PREGNANCIES COMPLICATED BY monitoring.
SYSTEMIC LUPUS ERYTHEMATOSUS Even with early detection of cardiac conduction abnor-
malities or new-onset CHB, no credible evidence suggests
Baseline assessment • Antiphospholipid antibodies: Lupus
anticoagulant, anticardiolipin IgG/IgM, and that medical interventions alter outcomes. Current treat-
anti-β2–glycoprotein I IgG/IgM ment recommendations are based on expert opinion and rela-
• Review current medications and risks tively small studies, all nonrandomized. Several case series have
• Consider testing for anti-Ro/SSA and described use of fluorinated steroids such as dexamethasone
anti-La/SSB antibodies (controversial)
Lupus nephritis • Serum creatinine every 4 to 6 weeks
for the treatment of either cardiac conduction abnormalities
• Baseline urine protein assessment (24-hour or new-onset CHB.31-33 The PR Interval and Dexamethasone
urine collection or spot protein/creatinine Evaluation (PRIDE) study enrolled 40 women with anti-Ro/
ratio) SSA antibodies and a fetus with any degree of heart block diag-
• Urine culture each trimester* nosed echocardiographically.31 Thirty women were treated with
• Increased surveillance for signs and
symptoms of preeclampsia dexamethasone and 10 declined treatment. No cases of CHB
Intrauterine growth • Monthly ultrasonographic assessment of fetal reverted, treated or untreated. Among six treated fetuses with
restriction (IUGR) growth after 24 to 28 weeks second-degree block, three remained in second-degree block,
Stillbirth • NST/AFI or BPP beginning at 32 weeks two reverted to normal sinus rhythm (NSR), and one progressed
unless indicated earlier (e.g., due to IUGR)
• Delivery by 39 weeks unless indicated earlier
to complete block. Two treated fetuses had first-degree block,
(e.g., due to IUGR, preeclampsia, worsening and both reverted to NSR after initiation of dexamethasone.
renal function) However, the one untreated fetus with first-degree block was in
Chronic steroid • Early and repeated screening for gestational NSR at birth. Although case selection in this nonrandomized
therapy diabetes study likely played a role, no perinatal deaths were reported
• Stress-dose steroids at delivery, particularly
for women on more than 20 mg/day of in the nontreated group compared with deaths (20%) in the
prednisone for more than 3 weeks† dexamethasone group. Treatment with steroids was associated
Antiphospholipid • Daily low-dose aspirin with more preterm and SGA infants; the potential adverse
antibodies • Consideration of prophylactic or therapeutic effects of steroids must thus be weighed against the limited
heparin, depending on laboratory results and
clinical history (see section on
data that support a benefit in cases of early cardiac conduction
antiphospholipid syndrome) abnormalities.
Lupus flare • Continuation, or possibly initiation, of Although experts generally agree that steroid treatment
hydroxychloroquine should not be expected to reverse CHB, at least one group
• Postpartum monitoring for increased disease of investigators has concluded that steroid treatment might
activity
reverse or improve hydrops, reduce morbidity, and improve
*Sulfa antibiotics may exacerbate lupus symptoms in some patients. Consider other 1-year survival.32 Others disagree.30,34 In addition to steroid
antibiotics for the treatment of urinary tract infections.
†
Intravenous hydrocortisone 100 mg every 8 hours for 2 to 3 doses is one regimen.
treatment, β-stimulation—such as with terbutaline, ritodrine,
AFI, amniotic fluid index; BPP, biophysical profile; IG, immunoglobulin; or salbutamol—has been administered in some cases of a very
IUGR, intrauterine growth restriction; NST, nonstress test. low fetal heart rate (<55 beats/min) in an attempt to increase
the heart rate and prevent hydrops. Once again, data to support
this treatment strategy are very limited.32 Table 46-3 outlines
or active disease. Furthermore, some women experience a management strategies for CHB.
disease flare in the postpartum period; therefore the obstetrician Strategies to prevent conduction abnormalities altogether
should carefully assess disease activity at postpartum visits, and would certainly seem attractive, and three preventive treat-
follow-up with rheumatology in the 1 to 3 months following ments have been considered. Glucocorticoids are not recom-
delivery is usually recommended. mended as preventative treatment for women at high risk of
CHB due to lack of proven benefit and because most fetuses will
Management of Congenital Heart Block not develop CHB. Furthermore, chronic glucocorticoid therapy
Given that complete CHB is irreversible and that the prognosis is associated with some maternal and fetal risks, including poten-
is grave, efforts have focused on trying to predict and prevent tial programming effects on offsprings’ hypothalamic-pituitary-
the development of CHB. Some experts have proposed serial adrenal axis and neurodevelopment (see Chapter 5).
fetal echocardiograms with Doppler monitoring of the PR inter- Two multicenter prospective observational studies have evalu-
val or kinetocardiography in women with anti-Ro/SSA and ated intravenous immunoglobulin (IVIG) as a preventative
anti-La/SSB antibodies, particularly in those with a prior fetus agent.35,36 The two studies enrolled a total of 44 women at high
affected by CHB. However, these practices are controversial, and risk for CHB. The results do not indicate that IVIG is effective
no formal guidelines for the type and frequency of monitoring at preventing the development of CHB, and it should not be
have been established. Neither fetal Doppler PR interval moni- used for this purpose outside of approved research protocols.
toring nor kinetocardiography have been associated with proven More recent data suggest a potential benefit of hydroxychlo-
benefit, in part because progression to CHB can occur rapidly roquine (HCQ) in decreasing the risk of NLE cardiac com-
and without discernable progression through first- and second- plications among high-risk women.37-40 In a historic cohort of
degree block. In spite of this, many experts—including expert 257 pregnancies in women with anti-Ro/SSA antibodies and
rheumatologists and pediatric cardiologists—recommend serial a previous child affected with CHB, HCQ use beginning in
PR interval monitoring of the fetus in a woman with anti-SSA/ the first trimester was associated with significantly decreased
Ro and anti-SSB/La antibodies. In our experience, the inclina- odds of cardiac NLE (0.23; 95% confidence interval [CI],
tions of the local pediatric cardiology team play a dominant 0.06 to 0.92), defined as second- or third- degree block or
TABLE 46-3 MANAGEMENT APPROACHES FOR thus required lower doses of glucocorticoids. Evidence also sug-
CONGENITAL HEART BLOCK gests that HCQ may prevent CHB in at-risk fetuses.37,38,40 Given
the possible benefits and the apparent lack of harm, many
Anti-Ro/SSA, anti-La/ • Risk of CHB is 1%-2%, routine
SSB antibodies, no monitoring of the fetal PR interval is experts now recommend that women on HCQ who become
previously affected usually not recommended (controversial) pregnant continue the medication during pregnancy. It is also a
child favored agent for the treatment of SLE flares in pregnancy, and
Anti-Ro/SSA, anti-La/ • Risk of CHB is 15%-20% HCQ is compatible with breastfeeding.
SSB antibodies, • Give hydroxychloroquine beginning in the
previously affected first trimester (400 mg/day)
child • Consider serial monitoring of the fetal PR GLUCOCORTICOIDS
interval (controversial) with weekly pulsed SLE flares in pregnancy are most commonly treated with
Doppler echocardiography* glucocorticoids. Nonfluorinated steroids, such as prednisone
First-degree heart • Patient may revert to normal sinus rhythm; and methylprednisolone (both FDA category C) are preferred
block† monitor for progression
• Consider dexamethasone treatment at in pregnancy because the placenta metabolizes these agents to
4 mg/day (controversial) an inactive metabolite, which results in limited fetal exposure.
Second-degree heart • Monitor for progression Some studies have reported a small increased risk of cleft lip and
block† • Consider dexamethasone treatment at palate with first-trimester glucocorticoid use,43 but other studies
4 mg/day upon diagnosis
• Discontinue dexamethasone if condition
have not confirmed these findings.44 If the risk for orofacial clefts
progresses to complete block except with is increased, this increase appears to be small. Prolonged use of
evidence of hydrops glucocorticoids is associated with an increased risk for mater-
• Given potential adverse effects, consider nal bone loss, gestational diabetes, hypertension and pre-
discontinuation of dexamethasone if heart eclampsia, and adrenal suppression. The use of prednisone in
block reverts
First-degree (complete) • Monitor for hydrops moderate to high doses may be associated with preterm rupture
heart block† • Give dexamethasone if hydrops develops of membranes (PROM) and fetal growth restriction.45 Women
• Consider oral terbutaline (2.5-7.5 mg every taking glucocorticoids should be screened early for gestational
4-6 hr) for an FHR <55 beats/min‡ diabetes, and the test should be repeated at the usual 24 to 28
*Highest risk period for development of CHB is between 18 and 24 weeks’ gestation. weeks if normal. Those on 20 mg/day or more of prednisone for
†
‡
Fetal echocardiography is recommended to rule out structural heart disease. at least 3 weeks are at greatest risk of adrenal suppression and
Caution is warranted with chronic terbutaline therapy because of reported serious
maternal adverse events. Terbutaline should especially be avoided in women with
should receive stress-dose steroids during labor and delivery.
diabetes, hypertension, hyperthyroidism, seizures, or a history of arrhythmias. One stress-dose regimen is 100 mg of intravenous (IV) hydro-
CHB, congenital heart block; FHR, fetal heart rate. cortisone every 8 to 12 hours for two to three doses. The risk of
adrenal suppression for women taking 5 mg or less per day of
prednisone is very small, and stress-dose steroids are not indi-
isolated cardiomyopathy.38 Given the low risk for fetal harm cated. For women who take more than 5 mg and less than
(see the section on medications) and potential benefit, initia- 20 mg per day, many clinicians still administer stress-dose ste-
tion of HCQ in the first trimester should be considered among roids, although simply continuing women on their daily steroid
women positive for anti-Ro/SSA antibodies who have had a dose is probably adequate. In general, prednisone is compatible
prior affected child. with breastfeeding, although for women who take more than
20 mg per day, it may be prudent to delay feeding for 4 hours
Drug Used to Treat Systemic Lupus after the dose.
Erythematosus and Pregnancy Considerations
It should be noted that as of June of 2015, the U.S. Food and NONSTEROIDAL ANTIINFLAMMATORY DRUGS
Drug Administration (FDA) Pregnancy and Lactation Labeling Nonsteroidal antiinflammatory drugs (NSAIDs) are consid-
Final Rule requires that the pregnancy safety letter categories of ered first-line treatment for autoimmune disease symptoms
A, B, C, D, and X be removed from drug labels and replaced such as arthralgias or arthritis. First trimester NSAID exposure
by a risk summary, clinical considerations, and available data. was not associated with an increase in the rate of congenital
The goal of this change is to better assist health care providers malformations or a decrease in infant survival in several large
in assessing the benefits versus risks of medications in pregnancy. population-based studies.46,47 It is controversial as to whether
This rule also requires that labels be updated when the informa- first- and early second-trimester use of NSAIDs is associated
tion is outdated. with an increased risk of spontaneous abortion. Third-trimester
NSAID use may cause premature closure of the fetal ductus
Drugs with Acceptable Risk Profiles in Pregnancy arteriosus, particularly after 30 weeks’ gestation, and oligo-
(See Chapter 8) hydramnios. For these reasons, NSAIDs are FDA category C
HYDROXYCHLOROQUINE before 30 weeks and category D thereafter. NSAIDs should
Past concerns regarding HCQ being associated with fetal be used judiciously in the late first and second trimesters of
ocular toxicity and ototoxicity (FDA category C) have not pregnancy and should be generally avoided after 28 to 30 weeks.
been confirmed by studies published within the past 15 The single exception is low-dose aspirin, which can be taken
years.39,41 One study of 114 HCQ-exposed pregnancies, most safely throughout pregnancy. Daily low-dose aspirin may
in the first trimester, compared with 455 unexposed pregnancies provide modest risk reduction for the development of pre-
found no significant difference in the rate of congenital anoma- eclampsia among high-risk women.48 Data are limited regard-
lies.41 Moreover, the continuation of HCQ during pregnancy ing cyclooxygenase 2 (COX-2) inhibitors such as celecoxib in
may be beneficial; one retrospective analysis42 showed that pregnancy, and it is recommended that these agents be avoided.
women who remained on HCQ had less severe SLE flares and NSAIDs are compatible with breastfeeding.
AZATHIOPRINE placental insufficiency. Diagnosis of APS is confirmed by

Azathioprine (FDA category D) is used in the prevention of persistently positive aPLs, a heterogeneous group of autoanti-
transplant rejection and in the treatment of SLE and LN. bodies directed against either negatively charged phospholipids
Although teratogenicity has been documented in animal studies, or glycoproteins bound to these phospholipids. The diagnosis
the human placenta lacks the enzyme that metabolizes AZA to of APS is confirmed by the detection of one or more of three
its active metabolite, 6-mercaptopurine. As a result, very little aPLs: lupus anticoagulant (LAC), anticardiolipin antibodies
active drug reaches the fetal circulation. Human studies have not (aCL), and anti-β2–glycoprotein I (aβ2-GP-I) antibodies.
found an increased risk for teratogenicity. Some studies have The classification criteria for APS were most recently revised in
found increased rates of IUGR, PTB, and impaired neonatal 2006 (Box 46-1).50
immunity with AZA use in pregnancy. However, it is difficult
to determine whether these outcomes are related to AZA use or
the underlying disease.49 AZA, often in combination with glu-
cocorticoids, is thus the preferred treatment for severe or BOX 46-1 REVISED CLASSIFICATION CRITERIA FOR
active SLE in pregnancy. Most experts consider AZA to be THE ANTIPHOSPHOLIPID ANTIBODY SYNDROME*
compatible with breastfeeding, although long-term follow- Clinical Criteria
up of exposed infants is limited. Avoiding feeding for 4 to
Vascular Thrombosis†
6 hours after a dose will markedly decrease the amount of drug 1. One or more clinical episodes of arterial, venous, or
in breastmilk. small-vessel thrombosis in any tissue or organ and
2. Thrombosis confirmed by objective, validated criteria
CYCLOSPORINE A (i.e., unequivocal findings of appropriate imaging
Cyclosporine A (FDA category C) is a calcineurin inhibitor studies or histopathology) and
sometimes used in the treatment of LN or severe arthritis. The 3. For histopathologic confirmation, thrombosis should be
drug is an immunosuppressive that inhibits the production and present without significant evidence of inflammation in
release of interleukin 2 (IL-2). Animal studies have demon- the vessel wall
strated very low transplacental transfer of cyclosporine. Human
PREGNANCY MORBIDITY
studies are conflicting, but probably very little drug enters the
1. One or more unexplained deaths of a morphologically
fetal circulation. Data obtained primarily from organ trans- normal fetus at or beyond the 10th week of gestation,
plant patients indicate a very low risk of teratogenicity, but with normal fetal morphology documented by
the risk for PTB and SGA infants may be increased.45 The ultrasound or by direct examination of the fetus or
drug may also cause a rise in maternal creatinine. Women on 2. One or more premature births of a morphologically
cyclosporine are generally discouraged from breastfeeding, normal neonate at or before the 34th week of gestation
although data are limited regarding adverse outcomes. because of eclampsia or severe preeclampsia or
placental insufficiency‡ or
Drugs with Uncertain or Higher Risk Profiles 3. Three or more unexplained consecutive spontaneous
in Pregnancy abortions before the 10th week of gestation with
CYCLOPHOSPHAMIDE maternal anatomic or hormonal abnormalities and
paternal and maternal chromosomal causes excluded
Cyclophosphamide (FDA category D) is an alkylating agent
used in the treatment of LN and vasculitis. This drug is tera- Laboratory Criteria
togenic and should not be used at all in the first trimester. 1. Lupus anticoagulant present in plasma on two or more
Use of cyclophosphamide may be considered in the second and occasions at least 12 weeks apart, detected according
third trimesters in the rare patient with very severe and progres- to the guidelines of the International Society on
sive disease manifestations. Cyclophosphamide is not compat- Thrombosis and Hemostasis
ible with breastfeeding. 2. Anticardiolipin antibody of IgG and/or IgM isotype in
blood present in medium or high titer (i.e., >40 GPL or
Drugs Contraindicated in Pregnancy MPL or >99th percentile) on at least two occasions at
MYCOPHENOLATE MOFETIL least 12 weeks apart, measured by standardized ELISA
3. Anti-β2–glycoprotein I antibody of IgG and/or IgM
Mycophenolate mofetil (FDA category D) is an inhibitor of isotype in serum or plasma (in titer >99th percentile)
purine biosynthesis and is used in the treatment of LN. MMF present in medium or high titer on at least two
is absolutely contraindicated in pregnancy due its abortifa- occasions at least 12 weeks apart, measured by
cient and teratogenic properties. MMF is associated with an standardized ELISA
increased risk for cleft lip and palate, micrognathia, microtia,
and abnormalities of the ear canals. Women should avoid preg- Modified from Miyakis S, Lockshin MD, Atsumi T, et al. International
nancy until they have been off MMF for at least 6 weeks. No consensus statement on an update of the classification criteria for defi-
nite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4:
data are available regarding MMF use and breastfeeding, and 295-306.
it is considered contraindicated. *Must meet at least one clinical and one laboratory criterion for diagnosis
of “definite” APS.
†
Superficial venous thrombosis is not included in the clinical criteria.
‡
Features of placental insufficiency may include: (1) abnormal or nonreas-
ANTIPHOSPHOLIPID SYNDROME suring fetal surveillance, such as a nonreactive nonstress test; (2) abnor-
mal Doppler flow in the umbilical artery (e.g. absent end-diastolic flow);
Antiphospholipid syndrome (APS) is an autoimmune condi- (3) oligohydramnios; or (4) infant birthweight below the 10th percentile
tion associated with venous and arterial thrombosis, and for gestational age.
adverse pregnancy outcomes that include recurrent early ELISA, enzyme-linked immunosorbent assay; GPL, IgG phospholipid
units; Ig, immunoglobulin; MPL, IgM phospholipid units.
miscarriage (REM), fetal death, early preeclampsia, and
Clinical Presentation respectively, in their next observed pregnancy in spite of treat-

APS may occur as a primary condition or in association with ment with enoxaparin and low-dose aspirin.
another autoimmune disease, most commonly SLE. Prevalence
and incidence are uncertain, although definite APS in the Placental Insufficiency
absence of other autoimmune conditions is probably no more The association between aPL and PTB before 34 weeks due
common than SLE. If low-titer positive tests for one or more of to severe preeclampsia or placental insufficiency (manifested as
the three aPLs (usually aCL or aβ2-GP-I) are included, aPLs are IUGR) is somewhat uncertain because studies are flawed by poor
found in a small percentage (<5%) of healthy women51 and in standardization of laboratory tests, concerns related to cases and
up to 40% of patients with SLE.52 In the absence of a history controls selection, and the variable definitions of preeclampsia
of thrombosis or pregnancy morbidity, the risks associated and placental insufficiency. These issues notwithstanding, several
with an incidentally identified positive test for aPL among studies suggest that a median of 7.9% of women with severe
otherwise healthy women are not well understood, and these preeclampsia have positive tests for aPL, compared with 0.5%
women should not be diagnosed with APS. for controls.60,61 In the NOH-APS study, 10% of women with
The most common thrombotic presentation of APS is deep well-characterized APS developed severe preeclampsia in spite
venous thrombosis (DVT) of the lower extremity, which rep- of enoxaparin and low-dose aspirin treatment.59 So although
resents about two thirds of thrombotic APS cases.53 The most PTB before 34 weeks’ gestation due to severe preeclampsia or
common arterial presentation is stroke; positive aPL results are placental insufficiency is included in the clinical criteria for APS,
found in up to 20% of ischemic stroke patients younger than experts agree that further study is warranted.57
50 years of age.54 Small vessel thrombosis may present as The most serious but rare thrombotic presentation of APS
nephropathy. Compared with heritable thrombophilias, APS is is catastrophic APS (CAPS). This condition is characterized by
more likely to manifest with thromboses in diverse or unusual rapid-onset, often small vessel thrombosis, multiorgan dysfunc-
locations such as the intracranial (stroke), hepatic, and intraab- tion, a systemic inflammatory response, involvement of unusual
dominal venous or arterial circulations. organ systems (e.g., renal or hepatic), and a high mortality rate.
APS should be considered in the differential diagnosis of Although not included in the international diagnostic criteria,
venous or arterial thrombosis and also with any of the fol- aPLs are associated with other clinical features that include
lowing adverse pregnancy outcomes: immune thrombocytopenia, hemolytic anemia, cardiac valvular
• Three or more otherwise unexplained recurrent early miscar- disease, chronic skin ulcers, myelopathy, chorea, migraine, epi-
riages, defined as preembryonic or embryonic losses at less lepsy, and cognitive impairment, particularly among patients
than 10 weeks’ gestation with SLE.
• One or more otherwise unexplained fetal deaths (≥10 weeks’
gestation) Diagnosis
• A history of PTB occurring at less than 34 weeks’ gestation Definite Antiphospholipid Syndrome
secondary to severe preeclampsia or placental insufficiency As defined by the international criteria, at least one clinical
criterion and positive aPL are required for the diagnosis of
Recurrent Early Miscarriage definite APS (see Box 46-1).50 Clinicians should recognize that
Although studies have found that up to 15% of women with the clinical criteria are relatively common and nonspecific for
REM have positive aPL results,55 the data are flawed by poor APS, such that the final diagnosis of APS ultimately rests on
standardization of aPL assays, inclusion of women with other positive aPL. Specifically, the laboratory criteria require that a
causes of REM, inconsistent selection of controls, variability patient have medium to high titers of aCL IgG or IgM antibod-
in the type of aPLs or isotypes tested, and variable definitions ies, aβ2-GP-I IgG or IgM antibodies, or LAC. Because other
of aPL positivity and REM.56 As a result, women with REM conditions can result in transiently positive aPL, persistently
should only be diagnosed with APS if they meet accepted inter- positive results on two or more occasions at least 12 weeks apart
national criteria.57 This topic is discussed in greater detail in are needed. Laboratories are required to delineate medium or
Chapter 27. high titer results for aCL and greater than 99% results for aβ2-
GP-I antibodies. The development of standard calibrators and
Stillbirth international “units” for the aCL assay has established greater
In a recent analysis from the Stillbirth Collaborative Research than 40 IgG units (“GPL”) or IgM units (“MPL”) as being a
Network’s multicenter, population-based case-control study of medium or high titer. The status of IgA isotypes is a matter of
stillbirths and live births, 9.6% of fetal death cases at 20 or ongoing investigation, but currently IgA aCL or aβ2-GP-I anti-
more weeks’ gestation were associated with a positive test for bodies are not recognized as diagnostic of APS.
aPLs (aCL or aβ2-GP-I antibodies) compared with 6% of live It should also be emphasized that LAC is a better predictor
birth cases—a statistically significant difference.58 Among of pregnancy morbidity or thrombosis than aCL or aβ2-GP-I
otherwise unexplained cases, immunoglobulin G (IgG) aCL and antibodies.62,63 False-positive LAC results may occur in the
IgM aCL antibodies were associated with fivefold and twofold setting of anticoagulant drugs. Higher titers and the IgG isotype
increased odds of fetal death, respectively. Positive IgG aβ2-GP-I of aCL and aβ2-GP-I antibodies are more specific for APS-
antibodies were associated with a threefold increased odds of related clinical manifestations. Finally, some experts hold that
fetal death. The authors concluded that 14% of otherwise triple aPL positivity (LAC, aCL, and aβ2-GP-I) is of greater
unexplained fetal deaths were attributable to APS. In the clinical significance than double or single aPL positivity.
recently published prospective Nimes Obstetricians and Hema-
tologists Antiphospholipid Syndrome (NOH-APS) study,59 Catastrophic Antiphospholipid Syndrome
women with well-characterized APS who had either REM or a Catastrophic antiphospholipid syndrome (CAPS) can occur
prior fetal death suffered an 8.3% and 15.9% rate of fetal loss, in pregnancy and should be considered in the differential
diagnosis that includes hemolytic uremic syndrome (HUS) early delivery (<34 weeks’ gestation) because of severe pre-
and thrombotic thrombocytopenic purpura (TTP). Accord- eclampsia or placental insufficiency. Most experts recommend
ing to international criteria, the diagnosis of CAPS is based prophylactic-dose heparin and low-dose aspirin for these
on thromboses in three or more organs in less than a week, patients.
microthrombosis in at least one organ, and persistent aPL Heparin treatment to improve obstetric outcomes in
positivity.64 In practice, features of microthrombosis vary from women with APS is not without controversy. Four heparin
biopsy-proven thrombosis in small vessels to clinical ischemia treatment trials have been conducted in women diagnosed with
resulting from occlusion of arterioles and capillaries. Given the APS predominantly based on REM.65-68 In two of these, the
often vague features of microthromboses and the substantial proportion of successful pregnancies substantially improved
mortality rate associated with CAPS, a high index of suspicion with the addition of unfractionated heparin (UFH) to low-dose
is warranted in patients who present with fewer than three organ aspirin.65,66 The other two trials used low-molecular-weight
systems involved. heparin (LMWH) and did not find a significant benefit when
combined with low-dose aspirin,67,68 primarily because the live
Possible or Probable Antiphospholipid Syndrome birth rates in the patients treated with aspirin only were quite
and Equivocal Cases good (70% to 75%). Two studies have compared UFH with
In certain scenarios, it may not be prudent to wait 12 weeks to LMWH, each paired with low-dose aspirin, in women with
confirm initially positive aPL results before considering treat- predominant REM and found no differences in outcomes.69,70
ment. For example, after weighing the risks and potential ben- Furthermore, several studies have reported successful pregnancy
efits, thromboprophylaxis might be considered in a woman with outcomes in excess of 70% among women with predominant
a history of fetal death who is newly pregnant and initially tests REM who were treated with low-dose aspirin alone.71,72 A
positive for aPL. In the case of CAPS, the high mortality rate Cochrane systematic review concluded that although the
should prompt consideration of aggressive treatment without quality of available studies was not high, “combined UFH
waiting for confirmation of persistently positive aPL. and aspirin may reduce pregnancy loss by 54%” in women
At the other end of the clinical spectrum are patients who with APS based on REM.73 The American College of Chest
meet the clinical criteria for APS but have “equivocal” aPL Physicians recommends antepartum administration of prophy-
results. One frequent scenario is the woman with REM and lactic or intermediate-dose UFH or prophylactic LMWH in
persistently low-positive aCL or aβ2-GP-I antibody results (i.e., women who fulfill the laboratory criteria for APS and meet the
aCL result of 20 to 39 GPL or MPL units). In such cases, clini- clinical criteria for REM.74 In contrast, a recent ACOG practice
cians are often faced with the difficult decision as to whether bulletin states that for women with APS without a preceding
low-dose heparin “treatment” in the next pregnancy is reason- thrombotic event, either clinical surveillance or prophylactic
able, in spite of the lack of evidence of efficacy in such cases. heparin may be used in the antepartum period but that
“prophylactic doses of heparin and low-dose aspirin during
Management of Antiphospholipid pregnancy…should be considered.”75
Syndrome in Pregnancy Treatment to prevent adverse pregnancy outcomes in women
Treatment during Pregnancy with APS and fetal death (≥10 weeks’ gestation) or previous early
Management of APS during pregnancy is aimed at mini delivery (<34 weeks’ gestation) due to severe preeclampsia or
mizing or eliminating the risks of thrombosis, miscarriage, placental insufficiency has not been established by well-designed
fetal death, preeclampsia, placental insufficiency, and iatro- trials. So although heparin treatment is frequently initiated in
genic preterm birth. With currently recommended manage- such patients, professional guidelines have avoided making
ment strategies, the likelihood of a successful pregnancy unequivocal recommendations for its use in the prevention of
(delivery of a viable infant) in a woman diagnosed with APS these later adverse pregnancy outcomes.74,75
exceeds 70%. Box 46-2 summarizes the recommended treatment regimens
The combination of a heparin agent and low-dose aspirin for APS in pregnancy. Three important clinical points are
is the current recommended treatment for APS in preg- relevant with regard to treatment aimed at preventing adverse
nancy because it serves to provide thromboprophylaxis and outcomes in pregnant women with APS. First, women with
may improve pregnancy outcomes. Ideally aspirin is started APS and prior thrombosis represent a high-risk population
preconceptionally because of its possible beneficial effects on that should be treated with appropriate anticoagulant agents
implantation. Because some patients with APS have immune during pregnancy and the postpartum period.74,75 Second,
thrombocytopenia, the platelet count should be assessed prior even in the absence of a prior thrombosis, women with
to starting treatment. Heparin is usually begun in the early repeatedly positive tests for LAC or medium to high titers
first trimester after demonstrating either an appropriately of aCL or aβ2-GP-I antibodies are at increased risk for
rising serum human chorionic gonadotropin (hCG) or the pregnancy-associated thrombosis, which favors at least
presence of a live embryo on ultrasonography. Most APS prophylactic UFH or LMWH during pregnancy and the
patients with a history of thrombosis are maintained on long- postpartum period. Finally, even in the absence of prior
term anticoagulation, frequently warfarin. To minimize the risk thrombosis, most women with a history of REM, fetal death,
of warfarin embryopathy, these patients should be transitioned or early PTB due to severe preeclampsia or placental insuf-
from warfarin to a heparin agent either prior to or very early ficiency will opt for “treatment” if it is felt to be relatively
in pregnancy. safe. Considering that prophylactic UFH or LMWH regimens
Women with APS diagnosed on the basis of obstetric criteria are rarely associated with serious adverse effects such as clinically
who do not have a history of thrombosis may be classified into significant osteopenia, significant bleeding, or heparin-induced
one of two groups: (1) those with REM or (2) those with one thrombocytopenia, most clinicians are agreeable to treatment in
or more previous fetal deaths (≥10 weeks gestation) or previous these patients.
BOX 46-2 RECOMMENDED TREATMENT REGIMENS FOR for grave maternal risks and the need for extremely premature
ANTIPHOSPHOLIPID SYNDROME DURING PREGNANCY delivery in subsequent pregnancies. One group reported a 60%
rate of successful pregnancies in 18 women with refractory
Recurrent Preembryonic and Embryonic Loss, obstetric APS when prednisolone was added to standard low-
No History of Thrombotic Events dose aspirin and heparin treatment in the first trimester.81
Lose-dose aspirin alone or together with: Because inflammation appears to be a key component of
• UFH 5000 to 7500 U/12 hr or aPL-related adverse pregnancy outcomes, modulators of
• LMWH (usual prophylactic doses)
excessive inflammation may be beneficial. The authors are
Prior Fetal Death or Preterm Delivery Because of familiar with a handful of anecdotal reports of successful preg-
Severe Preeclampsia or Severe Placental Insufficiency, nancies using such agents as IVIG, HCQ, and etanercept (a
No History of Thrombotic Events tumor necrosis factor [TNF] inhibitor) in addition to low-dose
Low-dose aspirin plus: aspirin and a heparin agent. Statin agents are being investigated
• UFH 7500 to 10,000 U every 12 hours in the first for the prevention of recurrent preeclampsia, and therapy trials
trimester and 10,000 U every 12 hours in the second and are currently underway (e.g., NCT01717586). Fluvastatin treat-
third trimesters or ment reduces proinflammatory and prothrombotic biomarkers
• UFH administered every 8 to 12 hours at a dose to in persistently positive aPL patients.82 Complement inhibitors
maintain the midinterval aPTT* at 1.5 times the control such as eculizumab or pexelizumab may hold promise, but data
mean or
are extremely limited, potential adverse effects exist, and such
• LMWH (usual prophylactic doses)
agents are costly.
Anticoagulation Regimens for Women with a History
of Thrombotic Events Catastrophic Antiphospholipid Syndrome
Low-dose aspirin plus: The management of suspected or proven CAPS requires a mul-
• UFH administered every 8 to 12 hours to maintain the tidisciplinary approach with hematologic and rheumatologic
midinterval aPTT* or anti-Xa activity in the therapeutic expertise. The optimal management of CAPS is not well defined.
range or However, because the mortality rate is so high, aggressive empiric
• LMWH (preferred) treatments are typically pursued that include anticoagulation
• Weight-adjusted therapeutic doses (e.g., enoxaparin with IV heparin, high-dose steroids, and plasma exchange. A full
1 mg/kg/12 hr or dalteparin 200 U/kg/12 hr) discussion of the management of CAPS is beyond the scope of
*
Women without a lupus anticoagulant in whom the activated partial
this chapter.
thromboplastin time (aPTT) is normal can be monitored with the aPTT.
Women with lupus anticoagulant should be monitored with anti-factor Pregnancy Complications and Surveillance
Xa activity.
LMWH, low molecular weight heparin; UFH, unfractionated heparin.
In addition to the risk of fetal loss, women with definite APS
are at significantly increased risk of developing preeclampsia and
placental insufficiency. Case series of highly selected patients,
many of whom had prior thrombosis or SLE, indicate that
Postpartum thromboprophylaxis with UFH, LMWH, or hypertensive disorders or placental insufficiency complicate
warfarin (international normalized ratio [INR] 2 to 3) should 20% of pregnancies with APS and lead to a high rate of iatro-
be strongly considered in all women with APS and is abso- genic PTB.77 In the prospective, observational PROMISSE
lutely indicated in women with prior thrombosis, most of study, 144 women with aPL, APS, or SLE and confirmed,
whom will restart their long-term anticoagulation regimen.75 In repeatedly positive aPL were identified.62 Despite contemporary
patients with no previous thrombosis, treatment is usually con- management, usually with UFH or LMWH and low-dose
tinued for 6 weeks following delivery. Both heparin and war- aspirin, 19.4% of these women suffered an adverse obstetric
farin are safe for breastfeeding mothers. In patients with outcome; among these, 8% suffered a fetal death after 12 weeks,
obstetric APS and without prior thrombosis, recent data suggest and 8% required delivery prior to 34 weeks because of hyper-
that long-term low-dose aspirin may decrease the risk of an tensive disorders. Risks of adverse obstetric outcome were par-
initial thrombosis event.76 ticularly elevated among women with repeatedly positive LAC,
In the past, case series and small trials indicated that gluco- a history of SLE, or prior thrombosis. The NOH-APS study
corticoid treatment of APS in pregnancy results in outcomes included 500 women with obstetric APS and excluded women
comparable to those achieved with heparin.77,78 However, glu- with a history of thrombosis.59 All were treated with low-dose
cocorticoids are associated with adverse effects that include aspirin and prophylactic LMWH. Overall, including miscar-
gestational diabetes, weight gain, and premature rupture of riages at less than 10 weeks’ gestation, the live birth rate was just
membranes. Randomized trials have not demonstrated a benefit under 70%, similar to controls, but PTBs were observed in
from the use of IVIG, when either added to heparin or used nearly 25% of APS cases (12% at less than 34 weeks’ gestation).
alone.56,79,80 PTBs were largely the result of severe preeclampsia with or
without IUGR. Among women with ongoing pregnancies at 20
Refractory Obstetric Antiphospholipid Syndrome weeks, 25% went on to suffer preeclampsia, IUGR, abruption,
Experienced clinicians are likely to encounter patients with or a combination of these, compared with a rate of 17.5% in
recurrent fetal death or extreme PTB due to severe preeclampsia the controls.
or placental insufficiency despite treatment with low-dose aspirin The risk of APS-related pregnancy complications is
and heparin. Such “refractory obstetric APS” cases are extremely dependent on the population in which the diagnosis of
challenging because little evidence is available to guide treat- APS is made. Women who meet criteria for APS because
ment. These women should be counseled regarding the potential of REM but who are otherwise healthy are not at high
risk of thrombosis, fetal death, preeclampsia, or placental TABLE 46-4 2010 AMERICAN COLLEGE OF
insufficiency.65-67 In the NOH-APS study, severe preeclampsia RHEUMATOLOGY/EUROPEAN LEAGUE
occurred in less than 3% of women with a diagnosis of APS AGAINST RHEUMATISM CLASSIFICATION
based on REM.59 CRITERIA FOR RHEUMATOID ARTHRITIS
Serial ultrasounds to assess fetal growth and amniotic fluid
TARGET POPULATION SCORE
volume are recommended in pregnancies complicated by APS.
In pregnancies without evidence of maternal hypertension or 1. Patients with at least one joint with definite clinical synovitis (swelling)
2. Patients with synovitis not better explained by another disease
fetal compromise, surveillance with nonstress tests or biophysi-
cal profiles should begin at 32 weeks. In the setting of suspected CLASSIFICATION CRITERIA
IUGR, hypertension, or thrombocytopenia, earlier institution (Score-based algorithm: Add score of categories A through D; a score of 6
of fetal surveillance is warranted. out of 10 or greater is needed for classification of definite RA)
A. Joint involvement
1 large joint 0
2 to 10 large joints 1
RHEUMATOID ARTHRITIS 1 to 3 small joints (with or without involvement of large 2
Rheumatoid arthritis (RA) is an autoimmune disease char- joints)
acterized by chronic, symmetric inflammatory arthritis of 4 to 10 small joints (with or without involvement of large 3
joints)
the synovial joints. RA affects 1% to 2% of U.S. adults, and More than 10 joints (at least one small joint) 5
as with SLE, RA is more common among females than males. B. Serology (at least one test result is needed for classification)
Although the incidence of RA increases with age, it is still Negative RF and negative ACPA 0
occasionally encountered among reproductive-aged women. A Low-positive RF or low-positive ACPA 2
genetic susceptibility to RA is evidenced by the higher disease High-positive RF or high-positive ACPA 3
C. Acute-phase reactants (at least one test result is needed for
concordance among monozygotic twins compared with dizy- classification)
gotic twins (15% vs. 3.6%).83 Also, relatives of individuals with Normal CRP and normal ESR 0 0
RA are at increased risk for RA as well as for other connective Abnormal CRP or normal ESR 1 1
tissue diseases. Several variant alleles of the HLA-DRB1 gene D. Duration of symptoms
Less than 6 weeks 0
appear to play primary roles in disease susceptibility.84 At least 6 weeks 1
Clinical Manifestations Modified from Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis
classification criteria: an American College of Rheumatology/European League Against
The onset of RA is often insidious, with the gradual develop- Rheumatism collaborative initiative. Arthritis Rheum. 2010;62:2569-2581.
ment of symmetric peripheral polyarthritis and morning ACPA, anticitrullinated protein antibody; CRP, C-reactive protein; ESR, erythrocyte
sedimentation rate; RA, rheumatoid arthritis; RF, rheumatoid factor.
stiffness. Involvement of the metacarpophalangeal and proxi-
mal interphalangeal joints is characteristic, and significant
deformity of these joints may become apparent as the disease
progresses. Systemic symptoms occur commonly and include of the general, healthy population will test positive for RF.
fatigue, weakness, weight loss, and malaise. Rheumatoid nodules Furthermore, RF may be detected in the setting of certain viral
develop in 20% to 30% of patients. These local proliferations infections and in other autoimmune conditions such as SLE and
of small vessels, fibroblasts, and histiocytes within the subcuta- Sjögren syndrome. Antibodies to citrullinated peptides/proteins
neous tissue occur most commonly on pressure points such as (ACPAs) have better specificity for RA and sensitivity similar to
the extensor surfaces of the forearms; they may be painful and that of RF. The laboratory evaluation for RA also includes testing
may interfere with joint and nerve function. Treatment involves of acute phase reactants such as C-reactive protein (CRP) and
local injections of glucocorticoids and an anesthetic and, in rare erythrocyte sedimentation rate (ESR). Elevations in CRP and
cases, surgical excision. A minority of patients with RA develop ESR suggest an aberrant inflammatory response. Patients with
extraarticular manifestations that include pleuritis, pericarditis, RA frequently also have anemia, thrombocytosis, leukocytosis,
neuropathy, vasculitis, scleritis, and renal disease. and a positive antinuclear antibody (ANA).
Diagnosis Pregnancy Considerations

In 2010, the ACR, in collaboration with the European League The majority of women, perhaps as many as 80% to 90%,
Against Rheumatism, released revised classification criteria for experience some improvement in their RA symptoms during
RA (Table 46-4).85 These new diagnostic criteria represent a shift pregnancy, although only approximately 50% have more
in focus to the early features of RA that are most predictive of than moderate improvement. Improvements in joint pain and
later erosive disease. “Definite” RA is based on confirmed stiffness generally begin in the first trimester and persist through
synovitis in at least one joint, absence of another cause for several weeks postpartum. Women who experience symptom
the synovitis, and a score of at least 6 out of 10 on a standard- improvement in one pregnancy will usually observe similar
ized assessment in four clinical domains: (1) degree of joint improvements in subsequent pregnancies. Most women who
involvement; (2) serologic testing; (3) response from acute experience an improvement in symptoms during pregnancy
phase reactants; and (4) duration of symptoms. will relapse postpartum, typically in the first 3 months. It
Seventy to eighty percent of patients with RA test positive does not appear that pregnancy has any significant effects on
for rheumatoid factor (RF) antibodies. RF immunoglobulins the long-term course of RA.
are produced from B cells stimulated by CD4+ T-cell cytokines. RA patients have been shown to have functionally defective
These CD4+ T cells are activated by unknown antigens and play regulatory T cells (TREGS), critical inhibitors of autoimmunity
a key role in the inflammatory damage seen in RA. However, that suppress CD4+ and CD8+ T-cell cytokine production and
RF antibodies are somewhat nonspecific because 5% to 10% B-cell immunoglobulin production. The generally favorable
course of RA in pregnancy may be related to the normal increase BIOLOGIC AGENTS

in circulating TREGS that occurs during pregnancy. Hormonal This continually expanding class of agents includes anakinra
changes may also modulate RA disease activity. Many women (interleukin-1 receptor antagonist, FDA category B), rituximab
experience improvement in RA symptoms during the luteal (chimeric monoclonal antibody leading to B-cell depletion,
phase of the menstrual cycle, when progesterone levels are FDA category C), abatacept (inhibitor of T-cell co-stimulation,
highest. FDA category C), and tocilizumab (interleukin-6 receptor
Not only do RA symptoms usually improve during preg- inhibitor, FDA category C). These drugs may be used to treat
nancy, but RA disease activity does not appear to signifi- autoimmune disease not sufficiently controlled with tradi-
cantly impact pregnancy outcomes. Women with RA typically tional therapies, but data regarding the use of these medica-
have uneventful pregnancies without increased risks for PTB, tions in pregnancy are extremely limited. Case reports in
preeclampsia, or IUGR. Certain antirheumatic medications, humans generally suggest little fetal risk.89-91 According to the
however, are associated with increased pregnancy risks. Disease manufacturer, when given to monkeys during organogenesis,
activity and medication use should ideally be assessed during tocilizumab caused abortion (embryo or fetal death) at doses just
a preconceptional visit. above those used in humans. Rituximab treatment later in preg-
nancy can cause B-cell lymphocytopenia in the neonate that
Antirheumatic Drugs persists for several months.92 Given the overall relatively limited
Drugs With Acceptable Risk Profiles in Pregnancy experience with these medications in pregnancy, it is prudent
The use of NSAIDs, glucocorticoids, and HCQ in pregnancy to avoid their use unless the woman is refractory to other
were discussed in the section on SLE. therapies and the severity of disease warrants continuation.
Likewise, the safety of breastfeeding while taking these medica-
SULFASALAZINE tions is unknown. Patients who choose to breastfeed should
Sulfasalazine (FDA category B) is a combination of a sulfa anti- do so only after a thorough discussion of potential risks and
biotic and salicylate. Most of the data regarding safety in preg- benefits.
nancy come from women with inflammatory bowel disease.
Although sulfasalazine and its metabolite sulfapyridine cross the Drugs Contraindicated in Pregnancy
placenta, large studies have not found an increase in congenital METHOTREXATE
malformations with use in pregnancy.86 Because sulfasalazine Methotrexate (MTX, FDA category X) is a folate antagonist
acts as a dihydrofolate reductase inhibitor, it is recommended used for long-term, maintenance immunosuppression in patients
that women considering pregnancy take at least 0.4 mg of folic with autoimmune conditions, including SLE and RA. MTX is
acid daily. Sulfasalazine is compatible with breastfeeding. an abortifacient in early pregnancy and a potent teratogen
associated with craniofacial anomalies, neural tube defects,
Drugs with Uncertain or Higher Risk Profiles abnormal facies, and neurodevelopmental delay. The greatest
in Pregnancy risks are with exposure prior to 10 weeks, with one study report-
TUMOR NECROSIS FACTOR-α INHIBITORS ing a 9% rate of congenital anomalies and a 25% risk of miscar-
Several TNF inhibitors (all FDA category B) are used for the riage.45 The drug is widely distributed in maternal tissues and
long-term control of RA. These include infliximab, etaner- may persist for up to 4 months in the liver. All reproductive-
cept, adalimumab, certolizumab, and golimumab. Inhibition of aged women taking MTX should be warned of its teratogenic
TNF-α increases circulating TREG cells and restores their capac- risks and advised to remain on effective contraception. For
ity to inhibit cytokine production. All of the TNF inhibitors those considering pregnancy, conception should be delayed for
except certolizumab are transferred across the placenta. Animal at least three menstrual cycles after discontinuation of MTX.
studies of infliximab, adalimumab, and certolizumab have not MTX is found in low levels in breastmilk and is considered
demonstrated an increase in congenital anomalies. An associa- contraindicated in breastfeeding.
tion between TNF inhibitors and fetal vertebral anomalies,
anal atresia, cardiac defects, tracheoesophageal fistula, esopha- LEFLUNOMIDE
geal atresia, renal anomalies, and limb dysplasia (VACTERL) Some patients with RA are treated with leflunomide, an FDA
syndrome has been reported,87 but a subsequent study from a category X disease-modifying antirheumatic drug (DMARD).
European congenital malformation database did not confirm Leflunomide is sometimes also used to treat lupus-related skin
these findings.88 Indeed, published experience with hundreds manifestations. The drug’s mechanism of action is inhibition of
of pregnancies exposed to TNF inhibitors suggests that these dihydroorotate dehydrogenase, an enzyme necessary for pyrimi-
agents are not teratogenic and are not associated with adverse dine biosynthesis. Leflunomide is teratogenic in humans and
pregnancy outcomes. Proceedings of the ACR Reproductive is absolutely contraindicated in pregnancy. In a recent report,
Health Summit stated that although human data are some- 2 of 16 exposed offspring had major anomalies and 3 had minor
what limited, “TNF inhibitors are considered to be compat- anomalies.93 The major metabolite (teriflunomide) is detectable
ible with pregnancy.” Some providers recommend avoiding in the serum of patients for up to 2 years after discontinuation
TNF inhibitors in the third trimester in order to limit early of the drug. Patients on leflunomide should be counseled to
postnatal exposure, but this should be weighed against the risk of avoid pregnancy until serum drug levels are less than 0.02 mg/L
an increase in disease activity without treatment. Small amounts on two tests performed 2 weeks apart. This may take up to 2
of etanercept, infliximab, and adalimumab have been reported years. Drug elimination can be hastened by administering cho-
in breast milk, although it is uncertain whether this poses a risk lestyramine (8 g orally three times daily for 11 days) with
to the neonate. The choice to breastfeed while taking TNF follow-up of serum drug levels to assure elimination. No data
inhibitors should be made after a thorough discussion of are available regarding leflunomide and breastfeeding, and it
potential risks and benefits. is considered contraindicated.
Diagnosis
Management of Pregnancies Complicated The ACR and European League Against Rheumatism released
by Rheumatoid Arthritis classification criteria for SSc in 2013.94 These criteria were pri-
Because the majority of women with RA have improvement in marily designed to identify SSc patients for inclusion in studies.
their disease during pregnancy, many can discontinue their anti- Because significant clinical heterogeneity exists among SSc
rheumatic drugs. Mild to moderate joint pain can usually be patients, it should be noted that some individuals might not
managed with acetaminophen or low-dose glucocorticoids. meet these strict diagnostic criteria. According to these criteria,
Physical therapy may be helpful in some cases. No alterations the presence of skin thickening of the fingers extending
to routine prenatal care are necessary for women with mild, proximal to the metacarpophalangeal joints is sufficient for
uncomplicated RA. Routine serial ultrasounds to assess fetal the diagnosis of SSc. The diagnosis is supported by visceral
growth and antenatal testing are unnecessary. Because the risk organ involvement and the presence of certain autoantibodies.
of postpartum disease exacerbation is high, it is important Most patients with SSc have a positive ANA. Antitopoisom-
to assess symptoms at postpartum visits and to arrange erase I, anticentromere, and anti-RNA polymerase III antibodies
appropriate follow-up with rheumatology. Some experts rec- are highly specific for SSc but have only moderate sensitivity.95
ommend reinitiating antirheumatic drug treatment after deliv- Individuals with SSc may also be positive for aPL.
ery in all women with RA, regardless of disease activity.
Pregnancy Considerations
Because pregnancy in women with SSc is uncommon, relatively
SYSTEMIC SCLEROSIS few data are available regarding the impact of pregnancy on
Systemic sclerosis (SSc), or systemic scleroderma, is a hetero- the disease and the risk of pregnancy complications. If SSc is
geneous autoimmune disorder characterized by small vessel clinically stable at the onset of pregnancy and the woman is
vasculopathy, the presence of characteristic autoantibodies, without obvious renal, cardiac, or pulmonary disease, mater-
and fibroblast dysfunction that leads to increased extracel- nal outcomes are generally good. Raynaud phenomenon may
lular matrix deposition and progressive fibrosis of the skin improve in pregnancy related to greater vasodilation, although
and visceral tissues. The small vessel vasculopathy manifests gastrointestinal manifestations related to esophageal dysmotility
most commonly as Raynaud phenomenon and in severe cases may become more prominent. The risk for renal crisis during
as renal crisis. SSc is rare and occurs in only 1 to 2 per 100,000 pregnancy is probably not increased for women without preex-
individuals in the United States annually. Similar to other isting kidney disease, but distinguishing this complication from
autoimmune disorders, it is more common in women than in preeclampsia may be challenging. In the case of renal crisis, the
men. But in contrast to SLE, SSc is infrequently encountered urine sediment is either normal or shows only mild proteinuria
in pregnancy because the peak age of onset is in the fifth with few cells or casts. Hemolytic-uremic syndrome can also
decade. have a similar presentation to SSc renal crisis and should be part
of the differential diagnosis, particularly in postpartum patients.
Clinical Manifestations Some authors have reported that women with SSc have an
Early symptoms of SSc include subcutaneous swelling with increased risk of spontaneous abortion both before and after
muscle and joint pain, and more than 90% of patients will their diagnosis.96,97 Other studies have not confirmed these find-
experience Raynaud phenomenon. When combined with skin ings,98 although women with late, diffuse SSc probably do have
thickening, Raynaud phenomenon is specific for SSc; however, a higher rate of miscarriage.98
the phenomenon also occurs in 5% of the general population, PTB is more common among women with SSc, particu-
and thus will frequently be seen by obstetricians. larly those with diffuse disease.98 The risks for preeclampsia
Two main subsets of SSc have been recognized: diffuse cutane- and IUGR are threefold higher among women with SSc when
ous SSc usually involves cutaneous fibrosis of the forearms and compared with the general population, likely related to the
is associated with a greater risk for serious internal organ mani- vascular pathology of the disease and frequent renal involve-
festations such as renal crisis, pulmonary fibrosis, and myocar- ment.99 One of the largest published series found that pregnan-
dial fibrosis; limited cutaneous SSc involves fibrosis of the distal cies in women with SSc, compared with the general obstetric
extremities and face and is associated with digital ulcerations. population, were significantly more likely to complicated by
CREST syndrome—calcinosis of the skin, Raynaud phenome- PTB (25% vs. 12%) and IUGR (6% vs. 1%).100 Indeed, PTBs
non, esophageal dysmotility, sclerodactyly, and telangiectasias— among women with SSc are usually indicated, rather than spon-
falls under this latter category. taneous, due to hypertensive complications and IUGR.
The most frequent visceral symptoms of SSc are heartburn
and dysphagia related to esophageal dysmotility. Involvement Management of Pregnancies Complicated
of the lower gastrointestinal tract can lead to malabsorption, by Systemic Sclerosis
diarrhea, and constipation. Cardiopulmonary manifestations Preconceptional counseling is critical for women with SSc.
(i.e., pulmonary hypertension, cardiac arrhythmias) are of par- Those with diffuse, progressive disease and significant cardiac,
ticular concern in pregnancy. pulmonary, or renal involvement are at particularly high risk for
Renal involvement is usually mild, but 10% to 20% of adverse maternal and fetal outcomes. Women should be evalu-
patients with diffuse disease will develop renal crisis, which ated for pulmonary hypertension, which is a contraindica-
manifests as acute onset of severe hypertension, progressive renal tion to pregnancy. Active renal disease increases the risk for
insufficiency, and hemolytic anemia. Renal crisis results in pro- crisis during pregnancy with the accompanying risks of end-
gression to end-stage renal disease in a significant proportion of stage renal disease and mortality.
affected individuals and is a major cause of mortality in SSc Even among nonpregnant individuals, the treatment of SSc
patients. is challenging and noncurative. Treatment of diffuse disease is
typically organ specific. Symptomatic relief of arthralgias and

myalgias should be limited to acetaminophen or low-dose glu- KEY POINTS
cocorticoids if possible. Ultraviolet light therapy, topical gluco- ◆ SLE is the most common serious autoimmune disease
corticoids, and vitamin D analogues may be used to treat that affects women of reproductive age.
cutaneous manifestations. Many women take proton pump ◆ SLE disease activity at the onset of pregnancy is the
inhibitors (FDA category C) for upper gastrointestinal symp- most important determinant of the course of the disease
toms, and they can be continued in pregnancy because data do in pregnancy.
not suggest significant fetal risks. Raynaud phenomenon is often ◆ Women with SLE should be counseled to postpone
treated with oral vasodilators, in particular calcium channel pregnancy until a sustained remission for at least 6
blockers (CCBs). Although definitive proof of fetal safety is months has been achieved.
lacking, CCBs are FDA category C drugs and are probably safe ◆ For women with lupus nephritis, moderate renal insuf-
to continue in pregnancy. Avoidance of cold, stress, nicotine, ficiency (serum creatinine 1.5 to 2 mg/dL) is a relative
caffeine, and sympathomimetic decongestants may also improve contraindication to pregnancy, and advanced renal
Raynaud symptoms. insufficiency (creatinine >2 mg/dL) should be consid-
Renal crisis is specifically treated with angiotensin- ered an absolute contraindication to pregnancy.
converting enzyme (ACE) inhibitors. Although these agents ◆ The risk for NLE, and in particular CHB, in fetuses or
are usually contraindicated in pregnancy because of risks of tera- neonates of women with SLE is low. The highest-risk
togenicity and effects on fetal renal function, SSc renal crisis group for CHB is seen in women with anti-Ro/SSA or
carries such a high risk of morbidity and mortality that the anti-La/SSB antibodies and a prior affected child (15%
use of an ACE inhibitor in pregnancy may be justified in this to 20% recurrence).
specific circumstance. In patients with renal crisis, intensive ◆ Women with SLE who become pregnant on hydroxy-
care admission with continuous fetal monitoring may be indi- chloroquine should generally continue this medication
cated. Many patients will also require dialysis. Decisions regard- because it may decrease the risk of disease flares.
ing delivery should be guided by maternal stability and prognosis, ◆ The diagnosis of APS is incumbent upon either arterial
gestational age, and results of fetal monitoring. or venous thrombosis or obstetric morbidity and repeat-
No evidence-based guidelines have been established for edly positive testing for lupus anticoagulant and/or
prenatal care in women with SSc. Clinicians should have a medium to high titers of anticardiolipin or anti-B2–gly-
low threshold to investigate any new and unusual symptoms, coprotein I IgG or IgM antibodies.
especially as they might relate to visceral organ involvement. ◆ All women with APS and prior thrombosis should
Particular attention should be paid to those women with receive full anticoagulation during pregnancy and
diffuse disease, and an increase in the frequency of prenatal postpartum.
visits to every 1 to 2 weeks is prudent. Women should be ◆ Pregnant women with an APS diagnosis based upon
closely monitored for preeclampsia because SSc appears to recurrent early miscarriage without prior thrombosis
increase this risk. Serial ultrasounds after 18 to 20 weeks to assess should receive either low-dose aspirin alone or com-
fetal growth and antenatal testing at 30 to 32 weeks are also bined with a prophylactic dose of heparin.
reasonable. ◆ Pregnant women with an APS diagnosis based upon
Delivery among women with advanced skin disease may be fetal death, early preeclampsia, or placental insufficiency
complicated by poor wound healing. Some women will be at and without prior thrombosis should generally receive
increased anesthetic risk because of problems with IV access, low-dose aspirin combined with prophylactic heparin.
difficult intubation, and increased risk for aspiration. Among ◆ Most women with rheumatoid arthritis will experience
those with diffuse and severe disease, a multidisciplinary an improvement in symptoms during pregnancy, but
approach with rheumatology, anesthesiology, and even the risk for postpartum relapse is high.
nephrology, cardiology, or pulmonology (depending on the ◆ Women with systemic sclerosis generally have favorable
specific organs involved) is recommended. Intensive care man- pregnancy outcomes but should be carefully assessed
agement may even be necessary in some cases. for visceral organ (i.e., renal, cardiac, or pulmonary)
involvement.
SJÖGREN SYNDROME
Sjögren syndrome (SS) is a chronic autoimmune disorder
characterized by decreased lacrimal and salivary gland func-
tion, which leads to dry eyes and dry mouth. Extraglandular
manifestations commonly include fatigue, arthralgias, myalgias,
and Raynaud phenomenon. Less common extraglandular mani- REFERENCES
festations include interstitial lung disease, dysphagia, liver func- 1. Chakravarty EF, Bush TM, Manzi S, Clarke AE, Ward MM. Prevalence
of adult systemic lupus erythematosus in California and Pennsylvania in
tion abnormalities, nephritis, central and/or peripheral nervous 2000: estimates obtained using hospitalization data. Arthritis Rheum.
system manifestations, and an increased risk for lymphoma in 2007;56:2092-2094.
the long term. SS occurs in a primary form and in a secondary 2. Moser KL, Kelly JA, Lessard CJ, Harley JB. Recent insights into the
form associated with other autoimmune conditions, primarily genetic basis of systemic lupus erythematosus. Genes Immun. 2009;10:
SLE and RA. Pregnancy outcomes among women with SS are 373-379.
3. Costenbader KH, Gay S, Alarcon-Riquelme ME, Iaccarino L, Doria A.
similar to those without the disease. However, women with Genes, epigenetic regulation and environmental factors: which is the most
SS may be positive for anti-Ro/SSA antibodies, with the relevant in developing autoimmune diseases? Autoimmun Rev. 2012;11:
accompanying risks for NLE and CHB. 604-609.
4. Costenbader KH, Feskanich D, Stampfer MJ, Karlson EW. Reproductive 30. Izmirly PM, Saxena A, Kim MY, et al. Maternal and fetal factors associated
and menopausal factors and risk of systemic lupus erythematosus in with mortality and morbidity in a multi-racial/ethnic registry of anti-
women. Arthritis Rheum. 2007;56:1251-1262. SSA/Ro-associated cardiac neonatal lupus. Circulation. 2011;124(18):
5. Lockshin MD. Pregnancy does not cause systemic lupus erythematosus to 1927-1935.
worsen. Arthritis Rheum. 1989;32:665-670. 31. Friedman DM, Kim MY, Copel JA, Llanos C, Davis C, Buyon JP. Prospec-
6. Urowitz MB, Gladman DD, Farewell VT, Stewart J, McDonald J. Lupus tive evaluation of fetuses with autoimmune-associated congenital heart
and pregnancy studies. Arthritis Rheum. 1993;36:1392-1397. block followed in the PR Interval and Dexamethasone Evaluation (PRIDE)
7. Petri M, Howard D, Repke J. Frequency of lupus flare in pregnancy. The Study. Am J Cardiol. 2009;103:1102-1106.
Hopkins Lupus Pregnancy Center experience. Arthritis Rheum. 1991;34: 32. Jaeggi ET, Fouron JC, Silverman ED, Ryan G, Smallhorn J, Hornberger
1538-1545. LK. Transplacental fetal treatment improves the outcome of prenatally
8. Hayslett JP. Maternal and fetal complications in pregnant women with diagnosed complete atrioventricular block without structural heart disease.
systemic lupus erythematosus. Am J Kidney Dis. 1991;17:123-126. Circulation. 2004;110:1542-1548.
9. Clowse ME, Magder LS, Petri M. The clinical utility of measuring comple- 33. Saleeb S, Copel J, Friedman D, Buyon JP. Comparison of treatment with
ment and anti-dsDNA antibodies during pregnancy in patients with sys- fluorinated glucocorticoids to the natural history of autoantibody-
temic lupus erythematosus. J Rheumatol. 2011;38:1012-1016. associated congenital heart block: retrospective review of the research
10. Weening JJ, D’Agati VD, Schwartz MM, et al. The classification of glo- registry for neonatal lupus. Arthritis Rheum. 1999;42:2335-2345.
merulonephritis in systemic lupus erythematosus revisited. J Am Soc 34. Eliasson H, Sonesson SE, Sharland G, et al. Isolated atrioventricular block
Nephrol. 2004;15:241-250. in the fetus: a retrospective, multinational, multicenter study of 175
11. Smyth A, Oliveira GH, Lahr BD, Bailey KR, Norby SM, Garovic VD. A patients. Circulation. 2011;124:1919-1926.
systematic review and meta-analysis of pregnancy outcomes in patients 35. Pisoni CN, Brucato A, Ruffatti A, et al. Failure of intravenous
with systemic lupus erythematosus and lupus nephritis. Clin J Am Soc immunoglobulin to prevent congenital heart block: Findings of a multi-
Nephrol. 2010;5:2060-2068. center, prospective, observational study. Arthritis Rheum. 2010;62:
12. Jungers P, Dougados M, Pelissier C, et al. Lupus nephropathy and preg- 1147-1152.
nancy: report of 104 cases in 36 patients. Arch Intern Med. 1982;142: 36. Friedman DM, Llanos C, Izmirly PM, et al. Evaluation of fetuses in a
771-776. study of intravenous immunoglobulin as preventive therapy for congenital
13. Moroni G, Quaglini S, Banfi G, et al. Pregnancy in lupus nephritis. Am heart block: Results of a multicenter, prospective, open-label clinical trial.
J Kidney Dis. 2002;40:713-720. Arthritis Rheum. 2010;62:1138-1146.
14. Mellembakken JR, Hogasen K, Mollnes TE, Hack CE, Abyholm T, Videm 37. Izmirly PM, Kim MY, Llanos C, et al. Evaluation of the risk of anti-SSA/
V. Increased systemic activation of neutrophils but not complement in Ro-SSB/La antibody-associated cardiac manifestations of neonatal lupus
preeclampsia. Obstet Gynecol. 2001;97:371-374. in fetuses of mothers with systemic lupus erythematosus exposed to
15. Fischer-Betz R, Specker C, Brinks R, Aringer M, Schneider M. Low risk hydroxychloroquine. Ann Rheum Dis. 2010;69:1827-1830.
of renal flares and negative outcomes in women with lupus nephritis 38. Izmirly PM, Costedoat-Chalumeau N, Pisoni CN, et al. Maternal use of
conceiving after switching from mycophenolate mofetil to azathioprine. hydroxychloroquine is associated with a reduced risk of recurrent anti-
Rheumatology. 2013;52(6):1070-1076. SSA/Ro-antibody-associated cardiac manifestations of neonatal lupus.
16. Georgiou PE, Politi EN, Katsimbri P, Sakka V, Drosos AA. Outcome Circulation. 2012;126:76-82.
of lupus pregnancy: a controlled study. Rheumatology. 2000;39: 39. Costedoat-Chalumeau N, Amoura Z, Duhaut P, et al. Safety of hydroxy-
1014-1019. chloroquine in pregnant patients with connective tissue diseases: a study
17. Buyon JP, Kim M, Guerra M, et al. Predictors of pregnancy outcome in of one hundred thirty-three cases compared with a control group. Arthritis
a prospective, multiethnic cohort of lupus patients. Ann Intern Med. Rheum. 2003;48:3207-3211.
2015;163:153-163. 40. Tunks RD, Clowse ME, Miller SG, Brancazio LR, Barker PC. Maternal
18. Clowse ME, Magder LS, Witter F, Petri M. The impact of increased lupus autoantibody levels in congenital heart block and potential prophylaxis
activity on obstetric outcomes. Arthritis Rheum. 2005;52:514-521. with anti-inflammatory agents. Am J Obstet Gynecol. 2013;208(1):
19. Clowse ME, Magder LS, Witter F, Petri M. Early risk factors for pregnancy 64e1-64e7.
loss in lupus. Obstet Gynecol. 2006;107:293-299. 41. Diav-Citrin O, Blyakhman S, Shechtman S, Ornoy A. Pregnancy outcome
20. Agaarwal N, Sawhney H, Vasishta K, et al. Pregnancy in patients with following in utero exposure to hydroxychloroquine: a prospective com-
systemic lupus erythematosus. Aust N Z J Obstet Gynaecol. 1999;39: parative observational study. Reprod Toxicol. 2013;39:58-62.
28-30. 42. Clowse ME, Magder L, Witter F, Petri M. Hydroxychloroquine in lupus
21. Clowse ME, Jamison M, Myers E, James AH. A national study of the pregnancy. Arthritis Rheum. 2006;54:3640-3647.
complications of lupus in pregnancy. Am J Obstet Gynecol. 2008;199:127 43. Carmichael SL, Shaw GM, Ma C, et al. Maternal corticosteroid use and
e121-127 e126. orofacial clefts. Am J Obstet Gynecol. 2007;197:585e1-585e7.
22. Clark CA, Spitzer KA, Laskin CA. Decrease in pregnancy loss rates in 44. Bay Bjørn AM, Ehrenstein V, Hundborg HH, Nohr EA, Sørenson HT,
patients with systemic lupus erythematosus over a 40-year period. J Rheu- Nørgaard M. Use of corticosteroids in early pregnancy is not associated
matol. 2005;32:1709-1712. with risk of oral clefts and other congenital malformations in offspring.
23. Nossent HC, Swaak TJ. Systemic lupus erythematosus. VI. Analysis of the Am J Ther. 2014;21:73-80.
interrelationship with pregnancy. J Rheumatol. 1990;17:771-776. 45. Ostensen M, Khamashta M, Lockshin M, et al. Anti-inflammatory
24. Bramham K, Hunt BJ, Bewley S, et al. Pregnancy outcomes in systemic and immunosuppressive drugs and reproduction. Arthritis Res Ther. 2006;
lupus erythematosus with and without previous nephritis. J Rheumatol. 8:209.
2011;38:1906-1913. 46. Kozer E, Nikfar S, Costei A, Boskovic R, Nulman I, Koren G. Aspirin
25. Schramm AM, Clowse ME. Aspirin for prevention of preeclampsia in consumption during the first trimester of pregnancy and congenital anom-
lupus pregnancy. Autoimmune Dis. 2014;2014:920467. alies: a meta-analysis. Am J Obstet Gynecol. 2002;187:1623-1630.
26. Buyon JP, Clancy RM, Friedman DM. Autoimmune associated congeni- 47. Nezvalova-Henriksen K, Spigset O, Nordeng H. Effects of ibuprofen,
tal heart block: integration of clinical and research clues in the manage- diclofenac, naproxen, and piroxicam on the course of pregnancy and
ment of the maternal / foetal dyad at risk. J Intern Med. 2009;265: pregnancy outcome: a prospective cohort study. Br J Obstet Gynaecol.
653-662. 2013;120:948-959.
27. Meisgen S, Ostberg T, Salomonsson S, et al. The HLA locus contains novel 48. Askie LM, Duley L, Henderson-Smart DJ, Stewart LA, PARIS Collabora-
foetal susceptibility alleles for congenital heart block with significant pater- tive Group. Antiplatelet agents for prevention of pre-eclampsia: a meta-
nal influence. J Intern Med. 2014;275(6):640-651. analysis of individual patient data. Lancet. 2007;369:1791-1798.
28. Buyon JP, Hiebert R, Copel J, et al. Autoimmune-associated congenital 49. Goldstein LH, Dolinsky G, Greenberg R, et al. Pregnancy outcome of
heart block: demographics, mortality, morbidity and recurrence rates women exposed to azathioprine during pregnancy. Birth Defects Res A Clin
obtained from a national neonatal lupus registry. J Am Coll Cardiol. Mol Teratol. 2007;79:696-701.
1998;31:1658-1666. 50. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus state-
29. Jaeggi ET, Hamilton RM, Silverman ED, Zamora SA, Hornberger LK. ment on an update of the classification criteria for definite antiphospho-
Outcome of children with fetal, neonatal or childhood diagnosis of iso- lipid syndrome (APS). J Thromb Haemost. 2006;4:295-306.
lated congenital atrioventricular block. A single institution’s experience of 51. Lockwood CJ, Romero R, Feinberg RF, Clyne LP, Coster B, Hobbins JC.
30 years. J Am Coll Cardiol. 2002;39:130-137. The prevalence and biologic significance of lupus anticoagulant and
anticardiolipin antibodies in a general obstetric population. Am J Obstet 74. Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik
Gynecol. 1989;161:369-373. PO, et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy.
52. Branch DW, Gibson M, Silver RM. Clinical practice. Recurrent miscar- Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American
riage. N Engl J Med. 2010;28(363):1740-1747. College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
53. Andreoli L, Chighizola CB, Banzato A, Pons-Estel GJ, Ramire de Jesus G, Chest. 2012;141(2 suppl):e691S-e736S.
Erkan D. Estimated frequency of antiphospholipid antibodies in patients 75. Antiphospholipid syndrome. Practice Bulletin No. 132. American
with pregnancy morbidity, stroke, myocardial infarction, and deep vein College of Obstetricians and Gynecologists. Obstet Gynecol. 2012;120:
thrombosis: a critical review of the literature. Arthritis Care Res (Hoboken). 1514-1521.
2013;65:1869-1873. 76. Arnaud L, Mathian A, Ruffatti A, et al. Efficacy of aspirin for the primary
54. Bushnell CD, Goldstein LB. Diagnostic testing for coagulopathies in prevention of thrombosis in patients with antiphospholipid antibodies: An
patients with ischemic stroke. Stroke. 2000;31:3067-3078. international and collaborative meta-analysis. Autoimmun Rev. 2014;13:
55. Clark CA, Laskin CA, Spitzer KA. Anticardiolipin antibodies and recur- 281-291.
rent early pregnancy loss: a century of equivocal evidence. Hum Reprod 77. Branch DW, Silver RM, Blackwell JL, Reading JC, Scott JR. Outcome of
Update. 2012;18:474-484. treated pregnancies in women with antiphospholipid syndrome: an update
56. Triolo G, Ferrante A, Ciccia F, et al. Randomized study of subcutaneous of the Utah experience. Obstet Gynecol. 1992;80:614-620.
low molecular weight heparin plus aspirin versus intravenous immuno- 78. Cowchock FS, Reece EA, Balaban D, Branch DW, Plouffe L. Repeated
globulin in the treatment of recurrent fetal loss associated with antiphos- fetal losses associated with antiphospholipid antibodies: a collaborative
pholipid antibodies. Arthritis Rheum. 2003;48:728-731. randomized trial comparing prednisone with low-dose heparin treatment.
57. de Jesus GR, Agmon-Levin N, Andrade CA, et al. 14th International Am J Obstet Gynecol. 1992;166:1318-1323.
Congress on Antiphospholipid Antibodies: Task Force Report on Obstet- 79. Branch DW, Peaceman AM, Druzin M, et al. A multicenter, placebo-
ric Antiphospholipid Syndrome. Autoimmun Rev. 2014;13(8):795-813. controlled pilot study of intravenous immune globulin treatment of
58. Silver RM, Parker CB, Reddy UM, et al. Antiphospholipid antibodies in antiphospholipid syndrome during pregnancy. The Pregnancy Loss Study
stillbirth. Obstet Gynecol. 2013;122:1-18. Group. Am J Obstet Gynecol. 2000;182:122-127.
59. Bouvier S, Cochery-Nouvellon E, Lavigne-Lissalde G, et al. Comparative 80. Vaquero E, Lazzarin N, Valensise H, et al. Pregnancy outcome in recurrent
incidence of pregnancy outcomes in treated obstetric antiphospholipid spontaneous abortion associated with antiphospholipid antibodies: a com-
syndrome: the NOH-APS observational study. Blood. 2014;123: parative study of intravenous immunoglobulin versus prednisone plus
404-413. low-dose aspirin. Am J Reprod Immunol. 2001;45:174-179.
60. Lee RM, Brown MA, Branch DW, Ward K, Silver RM. Anticardiolipin 81. Bramham K, Thomas M, Nelson-Piercy C, Khamashta M, Hunt B.
and antibeta2-glycoprotein-I antibodies in preeclampsia. Obstet Gynecol. First-trimester low-dose prednisolone in refractory antiphospholipid
2003;102(2):294-300. antibody-related pregnancy loss. Blood. 2011;117:6948-6951.
61. Cerevera R, Piette UC, Font J, et al. Antiphospholipid syndrome. Clinical 82. Erkan D, Willis R, Murthy VL, et al. A prospective open-label pilot study
and immunologic manifestations and patterns of disease expression in a of fluvastatin on proinflammatory and prothrombotic biomarkers in
cohort of 1,000 patients. Arthritis Rheum. 2002;46:1019-1027. antiphospholipid antibody positive patients. Ann Rheum Dis. 2014;73:
62. Lockshin MD, Kim M, Laskin CA, et al. Prediction of adverse pregnancy 1176-1180.
outcome by the presence of lupus anticoagulant, but not anticardiolipin 83. Silman AJ, MacGregor AJ, Thomson W, et al. Twin concordance rates for
antibody, in patients with antiphospholipid antibodies. Arthritis Rheum. rheumatoid arthritis: results from a nationwide study. Br J Rheumatol.
2012;64:2311-2318. 1993;32(10):903-907.
63. Pengo V, Ruffatti A, Legnani C, et al. Incidence of a first thromboembolic 84. De Vries N, Tijssen H, van Riel PL, van de Putte LB. Reshaping the shared
event in asymptomatic carriers of high-risk antiphospholipid antibody epitope hypothesis: HLA-associated risk for rheumatoid arthritis is
profile: a multicenter prospective study. Blood. 2001;118:4714-4718. encoded by amino acid substitutions at positions 67-74 of the HLA-DRB1
64. Asherson R, Cervera R, de Groot P, et al. Catastrophic antiphospholipid molecule. Arthritis Rheum. 2002;46(4):921-928.
syndrome: international consensus statement on classification criteria and 85. Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classifica-
treatment guidelines. Lupus. 2003;12:530-534. tion criteria: an American College of Rheumatology/European League
65. Kutteh WH. Antiphospholipid antibody-associated recurrent pregnancy Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62:
loss: treatment with heparin and low-dose aspirin is superior to low-dose 2569-2581.
aspirin alone. Am J Obstet Gynecol. 1996;174:1584-1589. 86. Viktil KK, Engeland A, Furu K. Outcomes after anti-rheumatic drug use
66. Rai R, Cohen H, Dave M, et al. Randomised controlled trial of aspirin before and during pregnancy: a cohort study among 150,000 pregnant
and aspirin plus heparin in pregnant women with recurrent miscarriage women and expectant fathers. Scand J Rheumatol. 2010;41:196-201.
associated with phospholipid antibodies (or antiphospholipid antibodies). 87. Carter JD, Ladhani A, Ricca LR, Valeriano J, Vasey FB. A safety assessment
Br Med J. 1997;314:253-257. of tumor necrosis factor antagonists during pregnancy: a review of
67. Farquharson RG, Quenby S, Greaves M. Antiphospholipid syndrome in the Food and Drug Administration database. J Rheumatol. 2009;36:
pregnancy: a randomized, controlled trial of treatment. Obstet Gynecol. 635-641.
2002;100:408-413. 88. Crijns HJ, Jentink J, Garne E, et al. The distribution of congenital anoma-
68. Laskin CA, Spitzer KA, Clark CA, et al. Low molecular weight heparin lies within the VACTERL association among tumor necrosis factor
and aspirin for recurrent pregnancy loss: results from the randomized, antagonist-exposed pregnancies is similar to the general population.
controlled Hep/ASA trial. J Rheumatol. 2009;36:279-287. J Rheumatol. 2011;38:1871-1874.
69. Stephenson MD, Ballem PJ, Tsang P, et al. Treatment of antiphospholipid 89. Chakravarty EF, Murray ER, Kelman A, Farmer P. Pregnancy outcomes
antibody syndrome (APS) in pregnancy: a randomized pilot trial compar- after maternal exposure to rituximab. Blood. 2011;117:1499-1506.
ing low molecular weight heparin to unfractionated heparin. J Obstet 90. Ostensen M, Brucato A, Carp H, et al. Pregnancy and reproduction in
Gynaecol Can. 2004;26:729-734. autoimmune rheumatic diseases. Rheumatology. 2011;50:657-664.
70. Noble LS, Kutteh WH, Lashey N, et al. Antiphospholipid antibodies 91. Ojeda-Uribe M, Afif N, Dahan E, et al. Exposure to abatacept or ritux-
associated with recurrent pregnancy loss: prospective, multicenter, con- imab in the first trimester of pregnancy in three women with autoimmune
trolled pilot study comparing treatment with low-molecular-weight diseases. Clin Rheumatol. 2013;32:695-700.
heparin versus unfractionated heparin. Fertil Steril. 2005;83:684-690. 92. Friedrichs B, Tiemann M, Salwende H, Verpoort K, Wenger MK, Schmitz
71. Silver R, MacGregor SN, Sholl JS, Hobart JM, Neerhof MG, Ragin A. N. The effects of rituximab treatment during pregnancy on a neonate.
Comparative trial of prednisone plus aspirin versus aspirin alone in the Haematologica. 2006;91:1426-1427.
treatment of anticardiolipin antibody-positive obstetric patients. Am J 93. Cassina M, Johnson DL, Robinson LK, et al. Pregnancy outcome in
Obstet Gynecol. 1993;169:1411-1417. women exposed to leflunomide before or during pregnancy. Arthritis
72. Pattison NS, Chamley LW, Birdsall M, Zanderigo AM, Liddel HS, Rheum. 2012;64:2085-2094.
McDougall J. Does aspirin have a role in improving pregnancy outcome 94. Van den Hoogen F, Khanna D, Fransen J, et al. 2013 Classification criteria
for women with the antiphospholipid syndrome? A randomized controlled for systemic sclerosis: An American College of Rheumatology/European
trial. Am J Obstet Gynecol. 2000;183:1008-1012. League Against Rheumatism Collaborative initiative. Arthritis Rheum.
73. Empson MB, Lassere M, Craig JC, Scott JR. Prevention of recurrent 2013;65:2737-2747.
miscarriage for women with antiphospholipid antibody or lupus antico- 95. LeRoy EC, Black C, Fleischmajer R, et al. Scleroderma (systemic sclerosis):
agulant. Cochrane Database Syst Rev. 2005;(2):Art. No.CD002859. classification, subsets and pathogenesis. J Rheumatol. 1988;15:202-205.
96. Silman AJ, Black C. Increased incidence of spontaneous abortion and 99. Chakravarty EF, Khanna D, Chung L. Pregnancy outcomes in systemic
infertility in women with scleroderma before disease onset: a controlled sclerosis, primary pulmonary hypertension, and sickle cell disease. Obstet
study. Ann Rheum Dis. 1988;47:441-444. Gynecol. 2008;111:927-934.
97. Giordano M, Valentini G, Lupoli S, et al. Pregnancy and systemic sclero- 100. Taraborelli M, Ramoni V, Brucato A, et al. Brief report: successful preg-
sis. Arthritis Rheum. 1985;28:237-238. nancies but a higher risk of preterm births in patients with systemic
98. Steen VD. Pregnancy in women with systemic sclerosis. Obstet Gynecol. sclerosis: an Italian multicenter study. Arthritis Rheum. 2012;64(6):
1999;94:15-20. 1970-1977.

Collagen Vascular Disease in Prergnancy

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Collagen Vascular Disease in Prergnancy

Uploaded by

Copyright:

Available Formats

Chapter 46

point during their reproductive years. Not infrequently, an

AZATHIOPRINE placental insufficiency. Diagnosis of APS is confirmed by

Clinical Presentation respectively, in their next observed pregnancy in spite of treat-

Diagnosis Pregnancy Considerations

course of RA in pregnancy may be related to the normal increase BIOLOGIC AGENTS

typically organ specific. Symptomatic relief of arthralgias and

You might also like