Irma A.

Lee, MD, MHPhEd

Department of Obstetrics and Gynecology
Faculty of Medicine and Surgery
September 30, 2011
Connective Tissue Disorders
and
Renal Diseases
In Pregnancy
Autoantibodies
- Antibodies directed against self or normal tissues

- Maybe stimulated by bacterial or viral injury of
susceptible tissues tissue destruction
VIA
1. CYTOTOXIC MECHANISM antibody attachment
to specific surface antigen CELL INJURY
2. IMMUNE COMPLEX MECHANISM antigen-
antibody complex attaches to susceptible tissues
CASCADE OF CHEMOTACTIC RELEASE
Human Leukocyte Antigen (HLA)
- Genetic loci code for cell-surface glycoprotein for
self and non-self recognition

! Class I HLA-A, HLA-B, HLA-C
! Class II HLA-DR, HLA-DQ, HLA-DP
Systemic Lupus Erythematosus
- Heterogenous syndrome with genetic loci is on
1q and 6p
- Overactive ! lymphocytes autoantibody
production
- Prevalent in women; 1:500 during child-bearing
Table 54-1
Table 54-2
Table 54-3
Laboratory Tests:
1. Antinuclear antibody (ANA) best screening
but not specific
2. Double-stranded DNA (dsDNA) antibodies
Smith (Sm) antigen specific for SLE
3. CBC anemia, leukopenia, thrombocytopenia
4. Proteinuria, casts
5. APTT
6. Rheumatoid factor assay

Table 54-4
Goals During Pregnancy
1. 6 months remission prior to conception
2. No renal involvement
3. Prevent superimposed pre-eclampsia
4. No APA activity

Major Complications
1. Infection
2. Lupus flares
3. End-organ failure
4. Cardiovascular disease
DRUG-INDUCED LUPUS
- Lupus-like syndrome
- Procainamide
- Quinidine
- Hydralazine
- Alpha-methyldopa
- Phenytoin
- Phenobarbital
SLE Nephritis
- Proteinuria (75%), most common sign
hematuria or aseptic pyuria (40%),
urinary cast (33%)

- Diffuse proliferative glomerulopnephritis most
common and most serious histologic category
- " of women experienced renal deterioration

- 50% fetal loss rate if creatinine is >1.5mg/dl

Preeclampsia vs Lupus Nephritis
- It is difficult to differentiate SLE from
preeclampsia

- HPN and proteinuria common in all women
with SLE
- Superimposed preeclampsia is encountered in
those with nephropathy

Fetal Outcome
- Pregnancy loss
Associated with APS , LAC

- Preterm delivery
HPN, renal compromise and PROM

- IUGR

- IUFD
APS, hx of fetal death, active disease at the
time of conception, lupus nephropathy, HPN
Neonatal Outcome
- Congenital heart block
anti SSA/Ro antibody
anti SSB/La antibody

- Neonatal Cutaneous Lupus

- Hematologic - usually transient
hemolytic anemia, leukopenia,
thrombocytopenia
Management
- Antepartum surveillance
BPS, NST, CST, Doppler velocimetry

- !C3, C4 and CH50 associated with active disease

- Hemolysis (+) Coombs test, anemia, reticulocytosis,
unconjugated hyperbilirubinemia

- Thrombocytopenia

- Leukopenia

- Urine test
Pharmacologic Treatment
Analgesics
- arthralgia, serositis, arthritis, fever
- acetaminophen, NSAIDs, aspirin

Corticosteroid therapy
- for life threatening manifestations of SLE ex.
Nephritis, neurologic involvement,
thrombocytopenia, hemolytic anemia,
cutaneous manifestations
- Prednisone 1-2mg/kg/day 10-15mg/day
Pharmacologic Treatment
Immunosuppression
- azathioprine

Antimalarial
- interfere with normal phagocytic function and
antigen processing, inhibit platelet
aggregation and reduce serum lipids
- Hydroxychloroquine
A P A S
Autoimmune disorder characterized by circulating
antibodies against membrane phospholipid and
one or more specific clinical syndromes
Classification
Primary APS

occurs alone with associated
thrombo-embolic phenomena,
thrombocytopenia,
adverse obstetrical outcome
Classification
APS secondary to:
SLE
Drugs
Infections
Malignancies

Clinical Manifestations
- Pregnancy wastage due to decidual/placental
thrombosis or immune complex deposition
- Pre-eclampsia in 20-30%
- IUGR (50%), associated with moderate to high titer ACA
IgG, history of fetal demise, prednisone therapy
- Preterm delivery (25-40%) secondary to PPROM in
patients on steroids
- Thrombosis (20-60%)
Venous lower limb 55%
Arterial involves the brain in 50%, heart 25%,
renal 25%
Vascular occlusion from mitral or aortic valve 49%

Clinical Criteria for Definite APS
1. Vascular Criteria confirmed by imaging,
Doppler, or histopathology
2. Pregnancy Morbidity
a. > 1 unexplained death of a normal fetus > 10 weeks

b. > 1 premature births < 34 weeks due to pre-eclampsia
or placental insufficiency

c. > 3 consecutive spontaneous abortions < 10 weeks

International Consensus Statement on
Preliminary Criteria for
Classification of APS
Wilson, Arthritis Rheuma 1999
Laboratory Criteria for Definite APS
1. Lupus Anticoagulant (LAC)

! > 2 6 weeks apart

! Prolonged phospholipid-dependent coagulation
(aPTT, DRVVT, KCT, DPTT, Textarin Time)
International Consensus Statement on
Preliminary Criteria for the
Classification of APS
Wilson, Arthritis Rheuma 1999
Laboratory Criteria for Definite APS
2. Anticardiolipin Antibodies (ACA)

! > 2 6 weeks apart

! Medium to high titer IgG or IgM by ELISA
International Consensus Statement on
Preliminary Criteria for the
Classification of APS
Wilson, Arthritis Rheuma 1999




RESULT IgM (MPL) IgG (GPL)
Negative < 10 < 8
Low Positive 10-19 8-19
*Mid Positive 20-50 20-80
*High Positive > 50 > 80


ACA (ELISA) : 10-30% of ACA (+) will be LAC (+)
- predictive of adverse fetal outcome



LAC: 70-80% LAC (+) will be ACA (+)
- predictive of thrombosis

Prevalence of ACA

- Low titer ACA IgG
0-3% non-pregnant women
2-4% of pregnant women
4-5% with single unexplained early pregnancy
loss

- Moderate to High titer ACA IgG
5 20% > 3 spontaneous pregnancy losses
Classification System for Women with APS

1. Definite or Classic APS

- Patients with LA
- Medium to High levels of IgG or IgM ACL antibodies
- Fetal death
- Recurrent pre embryonic or embryonic pregnancy
with thrombosis
- Neonatal death secondary to preeclampsia severe or
fetal distress


2. Syndrome of low levels of IgG or IgM ACL antibodies
associated with fetal death or recurrent, pre embryonic or
embryonic pregnancy loss
3. Syndrome of APL other than LA and ACL antibodies
associated with fetal death or recurrent pre embryonic or
embryonic pregnancy loss
Classification System for Women with APS
Proposed mechanisms in pregnancy loss
in APS
TARGET
Eicosanoids


Antithrombin III
Protein C & S
Endothelial cells and
platelets

Annexin V
MECHANISM
Decrease prostacyclin & increase in
thromboxane production by endothelial cells

Inhibition of heparan sulfate heparin-
dependent activation of antithrombin III
Inhibition of the activation of Protein C-Protein
S- pathway
Activation of endothelial cells & platelets;
expression of adhesion molecules

Reduction of annexin V production, inhibition
of its function in placenta by APL antibodies
Therapeutic approach to APAS in
pregnancy
Objectives:

1. Improve maternal and fetal-neonatal outcome
by preventing pregnancy loss, pre-eclampsia,
placental insufficiency and preterm birth

2. Reduce or eliminate maternal thrombotic risk




Management of Classical APS

! Risks of fetal loss
! Thrombosis or stroke
! Preeclampsia
! IUGR
! Preterm delivery
1. Preconception Counseling


Management of Classical APS

! Prevention of pregnancy loss
! Thromboprophylaxis
! Prevention of complications of placental
insufficiency
! Postpartum treatment


2. Treatment Regimens

Treatment Guidelines
- Low dose aspirin, 80 mg daily
- blocks the conversion of arachidonic acid to
thromboxane A2 while sparing prostacyclin

- Heparin, 5000-10,000 units SC q 12 hours
- prevent venous and arterial thrombotic episodes

- Glucocorticoids use only if with connective tissue
disorder
- Immunoglobulin therapy 0.4 g/kg daily for 5 days
- use when 1
st
line therapies have failed
Treatment Guidelines
- Calcium and Vitamin D
- Prevent osteoporosis

- Fetal antepartum surveillance
- Fetal growth monitoring
- Biophysical profile scoring
- NST, CST
- Doppler velocimetry
Thromboprophylaxis
Postpartum Treatment
Sodium warfarin for 6 weeks postpartum

Lifelong Anticoagulation 2.5 to 3.0
International Normalized Ratio (INR)

Woman Diagnosed w/
APS desires pregnancy
Preconception consultation w/
Obstetrician & rheumatologist;
Inititate low dose aspirin
TVS to confirm live
embryo at 5.5-6.5 wks AOG
Initiate heparin treatment
DIAGNOSTIC TESTS CLINICAL CARE

Prenatal visit q 2-4 wks
until 20-24 wks then q
1-2 wks, thereafter

Monitor for fetal death,
Preeclampsia & IUGR

Rheumatology visit q 2-4 wks
Obstetric ultrasound q 3-4
weeks from 17-20 wks of
gestation
Assess fetal growth and AFI
Fetal surveillance weekly fr
30-32 wks earlier if placental
Insufficiency is suspected
SYSTEMIC SCLEROSIS (SCLERODERMA)

Multisystem disease with fibrosis and
thickening of the skin and visceral organ
due to accumulation of collagen

TYPES OF SYSTEMIC SCLEROSIS
1. Overlap Syndrome Systemic Sclerosis with
features of other connective tissue disease
2. Mixed Connective Tissue Disease Syndrome
with Lupus, Systemic Sclerosis, Polymyositis,
Rheumatoid Arthritis, high titers of Anti-RNP
antibodies
CLINICAL MANIFESTATIONS
- Reynauds Phenomenon
- Swelling of distal extremities and face
- Fullness & epigastric burning pain
- Dyspnea
- Renal
- CREST
MATERNAL COMPLICATIONS
1. Hypertension
2. Renal Failure
3. Cardio-pulmonary complications as a result of
pulmonary interstitial fibrosis with
vasculopathy ! Pulmonary hypertension
FETAL COMPLICATIONS
1. Preterm deliveries
2. Fetal growth restriction
3. Increase perinatal deaths
GOALS OF THERAPY
1. Improve organ function
2. Relieve symptoms
DRUG THERAPY
1. Corticosteroids myositis, pericarditis,
hemolytic anemia

2. ACE Inhibitors relief of hypertension and
renal failure
TABLE 5-3 page 137
URINARY TRACT INFECTIONS
1. Asymptomatic bacteriuria
2. Cystitis/Urethritis
3. Pyelonephritis
ASYMPTOMATIC BACTERIURIA
- Most common; 2-7% of pregnant women

- 25% infected ! symptomatic

- 100,000 organisms per mL = Bacteriuria

- Leukocyte esterase-nitrite dipstick " cost-effective

- Complications : Preterm births, LBW,
Hypertension, Maternal Anemia
CYSTITIS AND URETHRITIS
- Dysuria, urgency and frequency
- Pyuria, bacteriuria, hematuria
- 3 day regimen
- Chlamydia Trachomatis ! cause of urethritis w/
o growth on culture
ACUTE PYELONEPHRITIS
- Occurs at the 2
nd
trimester unilaterally and right-
sided
- Characterized by fever, chills, and lumbar pain
" CVA tenderness
- Organisms
! E.Coli 75-80%
! Klebsiella 10%
! Enterobacter 10%
! Proteus 10%
ACUTE PYELONEPHRITIS
- Bacteremia ! Sepsis syndrome
- Ampicillin + Gentamicin, Cefazolin or
Ceftriaxone
FIGURE 42-4 page 994
NEPHROLITHIASIS DURING PREGNANCY
- Pregnancy does not increase risk for stone
formation
- Presents with gross hematuria
- Sonography confirms suspected stone
- Intravenous Hydration & Analgesics
- Lithotripsy
ACUTE NEPHRITIC SYNDROME
- Characterized by hematuria and proteinuria with
renal insufficiency and salt-water retention !
edema, hypertension and circulatory congestion

- Acute poststreptococcal glomerulonephritis

- Membranous IgA and mesangial glomerulonephritis
are seen on renal biopsy

- Associated with fetal loss and perinatal mortality,
preterm delivery and growth restriction