MATERNAL MEDICAL COMPLICATIONS
| ANTIPHOSPHOLIPID ANTIBODY SYNDROME —Carl V. Smith, MD, Professor and Chair, Department
of Obstetrics and Gynecology, University of Nebraska Medical Center, Omaha
|
| Antiphospholipid antibodies: family of autoantibodies to various combinations of phospholipid antibodies
and binding proteins; anticardiolipin (ACL) antibodies and lupus anticoagulant—subset of antiphospholipid
antibodies used to make diagnosis of antiphospholipid antibody syndrome (APS); relationship between autoimmune
disease and prevalence of antiphospholipid antibodies; lupus anticoagulant—misnomer; refers
to prolongation of partial thromboplastin time (PTT) on screening test; prolongation not corrected by addition
of normal plasma; promotes clotting, not bleeding
|
| Antiphospholipid antibody syndrome: requires presence of moderate levels of antibody and vascular
thrombosis or complication of pregnancy; primary—no evidence of underlying autoimmune disease;
secondary—presence of systemic lupus erythematosus (SLE) or other autoimmune diseases; clinical
criteria—vascular thrombosis, unexplained fetal death >10 wk, ≥3 spontaneous abortions (SABs) in first
trimester, or preterm delivery (<34 wk); laboratory criteria—moderate or high levels of IgG or IgM antibodies
on ≥2 occasions at least 6 wk apart or detectable lupus anticoagulant on ≥2 occasions at least 6 wk
apart
|
| Epidemiology: antiphospholipid antibodies seen in 1% to 5% of normal controls; lupus anticoagulant seen
in up to one third of patients with SLE; ≈70% of patients with SLE develop APS within 20 yr; ACL antibodies
seen in about one third of patients with SLE; patient with SLE may benefit from prophylaxis for
deep venous thrombosis (DVT); therefore, speaker recommends obtaining antibody levels; low-positive
ACL antibodies—view with suspicion; only patients with moderate- to high-positive IgG or IgM antibodies
should be considered to have APS
|
| Candidates for testing: patients with ≥3 first trimester SABs, unexplained fetal death, history of severe intrauterine
growth restriction (IUGR), DVT related to oral contraceptive pills, and young patient with history
of thrombotic cerebrovascular accident (CVA); unknown whether patient with early-onset severe
preeclampsia or those with thrombosis should be tested; preconceptional counseling strongly recommended
for patient with APS considering pregnancy
|
| Management: initiate low-dose aspirin once diagnosis confirmed; transvaginal ultrasonography (US) at 5.5
to 6.5 wk of gestation; prenatal visits at least every 2 wk until 20 wk gestation and weekly after 20 to 24
wk; liberal use of US to diagnose IUGR; assess amniotic fluid volume and Doppler umbilical artery blood
flow; close surveillance of patients with rheumatologic disease; US recommended at least every 3 to 4 wk,
beginning at 17 to 20 wk gestation; fetal surveillance utilizing either nonstress test (NST), US for amniotic
fluid volume, or biophysical profile (BPP) assessment on weekly to twice-weekly basis
|
| Pregnancy complications: recurrent pregnancy loss, fetal death, preeclampsia, placental insufficiency, maternal
thrombosis (including CVA), and fetal growth restriction
|
| Therapy: goals—improve maternal-fetal outcome, prevent pregnancy loss, preeclampsia, placental insufficiency,
and preterm birth, and reduce or eliminate maternal thrombotic risk; anticoagulation—warfarin relatively
to absolutely contraindicated; some evidence warfarin may be preferred anticoagulation agent
during pregnancy in woman with mechanical heart valve; adjusted-dose heparin or regular unfractionated
heparin and low-dose aspirin currently treatment of choice (not low-molecular-weight heparins [LMWHs]);
fetal warfarin syndrome—incidence 10% to 25%; associated with mental retardation, fetal and neonatal
bleeding, midface abnormalities, and long-bone abnormalities
|
| Prophylactic regimens: unfractionated heparin—7500 to 10,000 U administered subcutaneous (SC) every
12 hr in first trimester; increase to at least 10,000 U every 12 hr in second and third trimester; alternative
therapy—enoxaparin (Lovenox) 40 mg daily or 30 mg bid; better pregnancy outcome with unfractionated
heparin, not Lovenox; dalteparin 5000 U daily or bid; patients with history of thrombosis—unfractionated
heparin; adjust dose every 8 to 12 hr to achieve therapeutic PTT twice normal at 6 or 10 hr after last dose;
most patients in third trimester require dosing at least every 8 hr throughout pregnancy to achieve full anticoagulation;
enoxaparin 1 mg/kg bid requires no monitoring of PTT and theoretically has less risk for osteopenia
than unfractionated heparin
|
| Prenatal management: early endovaginal US to establish delivery date; prenatal visits every 2 to 4 wk until
20 wk, then every 1 to 2 wk, as determined by clinical situation; US for anatomy at 20 wk; serial growth
scans every 3 to 4 wk; surveillance using either NST, amniotic fluid volume, or BPP beginning no later
than 32 wk; delivery—if surveillance reassuring, deliver at term, but not beyond; if patient on heparin, consider
induction of labor after 39 wk to reduce bleeding and increase possibility of conduction anesthesia
|
| Miscellaneous issues: consider magnetic resonance imaging (MRI) of brain to look for evidence of DVT in
patients with vague and confusing neurologic complaints; up to 25% of patients with APS have noninfectious
cardiac valvular vegetations; consider echocardiography to evaluate
|
| SYSTEMIC LUPUS ERYTHEMATOSUS, PREGNANCY, AND ANTIPHOSPHOLIPID SYNDROME —
Maurice L. Druzin, MD, Charles B. and Ann L. Johnson Professor, Chief, Division of Maternal-Fetal Medicine,
and Associate Dean for Academic Affairs, Stanford University School of Medicine, Stanford, California
|
| General considerations: SLE occurs predominantly in women during childbearing years; dramatic improvement
in mortality rates; criteria for diagnosis—malar rash, discoid rash, photosensitivity, painless oral ulcers,
arthritis in ≥2 joints, serositis, renal disorder, central nervous system (CNS) disorder, hematologic
disorder, immunologic disorder, and presence of antinuclear antibody (ANA); at least 4 symptoms needed
for diagnosis, either serially or singularly; involvement of brain, lungs, kidney, or heart worsens prognosis;
often, 3 to 5 yr before diagnosis made, patient may initially have only positive ANA
|
 | Autoantibodies: ANA—not specific for SLE; anti-DNA—specific for lupus clinical activity; anti-Smith (Sm)
antibody response—specific for lupus (present in only 30% of patients with SLE); Anti-SS-A (Ro) and Anti-
SS-B (La)—frequency 30% for Ro and 10% for La; some women have Sjögren’s syndrome, not SLE; associated
with neonatal lupus syndrome; antiphospholipid antibodies—ACL and lupus anticoagulant;
present in 15% to 26% of patients with SLE; associated with much worse outcome for mother and fetus;
Russell’s viper venom test for lupus anticoagulant
|
| Effect of pregnancy on SLE: lupus exacerbation uncommon during or after pregnancy; prematurity and fetal
death greatest hazards; most women with SLE do well during pregnancy; flares—data show increased
risk for flares during pregnancy; can occur in any trimester and postpartum; small percentage of flares severe,
requiring ≥20 mg additional prednisone (safest in pregnancy); exacerbation common, but usually
mild and manageable with changes in medication; disease activity at conception most important predictor
of flares; counsel patient to avoid pregnancy, unless disease in remission; predictors of flares—active disease
at conception, rating on SLE Disease Activity Index (SLEDAI), and immunosuppression at conception;
maternal and fetal outcomes related to major end-organ involvement; poorer prognosis with renal
involvement, hypertension, APS, and especially CNS involvement
|
| Lupus nephropathy: kidney most commonly involved organ; good prognosis if patient in remission; 50%
develop hypertensive disease, ie, preeclampsia, gestational hypertension; some patients have transient and
reversible worsening of renal function; some have irreversible renal deterioration and progress to end-stage
renal disease faster than expected; predictors of serious decompensation—high serum creatinine, low creatinine
clearance, and significant proteinuria; pregnancy not recommended for patients with this clinical picture
until kidney function improves
|
| CNS lupus: higher risk for maternal and fetal outcomes; study done at speaker’s institution concluded CNS
lupus appears to represent especially severe manifestation of SLE with greater maternal and fetal risks than
other end-organ involvement; effect of SLE on pregnancy—increased incidence of maternal complications,
eg, hypertension, preeclampsia, gestational diabetes, preterm delivery; for fetus, increased risk for adverse
outcomes, eg, premature rupture of membranes (PROM; appears more prevalent in patients on prednisone),
preterm birth, IUGR, and pregnancy loss; adverse outcome more likely with end-organ disease, active disease
at conception, and presence of Anti-Ro, Anti-La, and antiphospholipid antibodies
|
| Antiphospholipid antibody syndrome (APS): ACL antibodies and lupus anticoagulant; same predictive
reliability for bad outcome, ie, placental infarction, IUGR, and fetal death; APS occurs in 25% of patients
with SLE; increased risk for spontaneous loss, fetal demise, and placental insufficiency syndromes; postpartum
syndrome—autoimmune exacerbation of SLE; characterized by fever, pulmonary infiltrates, and
pleural effusion; catastrophic APS—accelerated coagulation vasculopathy; high mortality; treatment—use
anticoagulation regimen of heparin and low-dose aspirin daily in patient with history of thrombotic events,
and prophylactic heparin for poor pregnancy outcome; unfractionated heparin or enoxaparin (Lovenox)
treatment options
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| Clinical predictors of prematurity and preeclampsia: thrombocytopenia associated with preeclampsia;
predictors of premature delivery—severe flare and need for antihypertensive medications or prednisone at conception
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| Neonatal lupus: correlated with transplacental passage of SS-A and SS-B autoantibodies at 14 to 16 wk; occurs
in 10% of patients with these autoantibodies; most cases cutaneous lupus (transient neonatal rash) and
thrombocytopenia; congenital heart block—most serious manifestation; 15% recurrence risk if sibling affected;
difficult to predict because no correlation with SS-A autoantibodies; Stanford University protocol—
early fetal echocardiography screening from 16 to 26 wk of gestation looking for early evidence of myocardial
dysfunction (prevents administering dexamethasone to all patients)
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| Medications: patient should not discontinue SLE medications during pregnancy; cyclophosphamide and
methotrexate—should be avoided; azathioprine (Imuran)—considered safe in pregnancy; used as second- or
third-line drug; prednisone—considered safest of all immunosuppressive drugs; hydroxychloroquine
(Plaquenil)—effective; Canadian study group concluded that patients on Plaquenil less likely to have clinical
flare if maintained on drug; no evidence of fetal effects; improved pregnancy outcome; heparin and aspirin—
considered safe in pregnancy; treatment—medication to maintain remission; low-dose aspirin and heparin; full
anticoagulation with history of thrombotic event; preconceptional counseling—counsel about importance of remission
at conception; pregnancy should be comanaged by obstetrician and rheumatologist; perform US,
monthly laboratory evaluation, and fetal surveillance; counsel patient that successful pregnancy possible
|
Educational Objectives
| The goal of this program is to educate the listener about pregnancies that are complicated by antiphospholipid
antibody syndrome (APS) and systemic lupus erythematosus (SLE). After hearing and assimilating this program,
the clinician will be better able to:
|
| 1. List the diagnostic criteria for APS.
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| 2. Identify pregnancy complications associated with APS and patients who should be screened for APS.
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| 3. Discuss obstetric management for patients with APS.
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| 4. List the diagnostic criteria for SLE.
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| 5. Care for pregnant patients with SLE.
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Discussed on This Program
Azathioprine (AZA) [Imuran]
Cyclophosphamide [Cytoxan, Cytoxan Lyophilized, Neosar]
Hydroxychloroquine sulfate [Plaquenil, Plaquenil Sulfate]
Dalteparin sodium [Fragmin]
Enoxaparin sodium [Lovenox]
Heparin sodium injection Heparin sodium lock flush solution [Heparin Lock Flush, Hep-Lock, Hep-Lock U/
P]
Low-molecular-weight heparins (LMWHs) – dalteparin [Fragmin], enoxaparin [Lovenox], tinzaparin
[Innohep]
Prednisone [Deltasone, Liquid Pred, Meticorten, Orasone, Panasol-S, Prednicen-M, Prednisone Intensol
Concentrate, Strerapred DS]
Suggested Reading
Avcin T et al: The antiphospholipid syndrome. N Engl J Med 347(2):145, 2002; Chakravarty EF et al: Factors
that predict prematurity and preeclampsia in pregnancies that are complicated by systemic lupus erythematosus. Am J
Obstet Gynecol 192(6), 1897, 2005; Disla E et al: Hydroxychloroquine in systemic lupus erythematosus. N Engl J
Med 325(14):1046, 1991; El-Sayed YY et al: Central nervous system lupus and pregnancy: 11-year experience at
a single center. J Matern Fetal Neonatal Med 12(2):99, 2002; Gomez-Puerta JA et al: Long-term follow-up in
128 patients with primary antiphospholipid syndrome: do they develop lupus? Medicine (Baltimore) 84(4):225, 2005;
Megan et al: Early risk factors for pregnancy loss in lupus. Obstet Gynecol 107(2):293, 2006. No authors listed:
A randomized study of the effect of withdrawing hydroxychloroquine sulfate in systemic lupus erythematosus. The
Canadian Hydroxychloroquine Study Group. N Engl J Med 324(3):150, 1991.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant
financial relationship with the manufacturer or provider of any commercial product or service discussed.
For this issue, the faculty reported nothing to disclose.
Dr. Smith was recorded at Clinical Approaches to Obstetrics and Gynecology sponsored by the Medical College
of Georgia and held on July 11-14, 2005, in Kiawah Island, South Carolina. Dr. Druzin was recorded at Antepartum
& Intrapartum Management sponsored by the University of California, San Francisco, School of
Medicine and held on June 9-11, 2005, in San Francisco. The Audio-Digest Foundation thanks the speakers
and the sponsors for their cooperation in the production of this program.
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