Lupus With Pregnancy

Presenter-Dr. Nilay Kumar Chatterjee

Chairperson-Dr.Sumit Kr. Chakraborty
Associate Professor
Dept. of General Medicine
 SLE affects the women of childbearing age group.

 Pregnancy is a dilemma often faced in this group of patients.

 In past,patients with SLE were advised to avoid pregnancy because

of high fetal and maternal mortality.

 Because of advancement in medical management,majority SLE

pregnancies now yield a healthy infant and mother.
Immunobiologic Implications of Pregnancy
 Physiologic Alterations of Pregnancy

 Blood volume increases by 50% Heart Rate,C.O,Renal and Pulmonary Blood Flow

Lupus patient with damaged cardiopulmonary system can’t manage this high blood vol.

 Decreased peripheral vascular resistance and decrease B.P leading to Presyncope.

 Alteration of salt concentration in latter half of pregnancy leads to edema(d/d- Preeclampsia,DVT)

 Thrombotic Risk increases 2-3 fold.

With SLE,1% patient experiences DVT,0.32% stroke,0.4% Pulmonary Thromboembolism.
Risk continues for 6wks after delivery.
 Immunologic Mechanisms of Pregnancy-
 Fetus is an allograft
 But maternal response to new antigen doesn’t occur d/t some regulatory
mechanisms or immunological shift.

HLA-G Modified
antigen antibody
presentation produced

 Mechanisms that improve Increases

no. and Binds to
fetomaternal tolerance activity of paternal
may increase rheumatologic disease regulatory T- antigen
Cells selectively
SLE Activity in Pregnancy
 50% of SLE patients have flare.

 Among the flare patient’s most are mild flare of skin and joint.
 Skin- 25-90%
 Joint-25% will have severe arthritis
 Hematological-Thrombocytopenia and neutropenia in 10-40%.
 Nephritis-Overall risk is 4%-30%

 20% have severe flare – Renal,Severe arthritis,Hematological

involvement,Serositis.
Am J Reprod Immunol, 28(3-4):205–207, 1992
Arthritis Rheum 52(2):514–521, 2005
Predictors of SLE activity-
 Increased SLE activity 3-6 months before conception.
Patients having mild activity results in flare in 8% of cases,severe activity
results in flare in 56% of cases
Active SLE at time of conception – 2 fold increased risk of flare during
pregnancy.

 Discontinuation of needed immunosuppressant(like HCQS) during

pregnancy.

 h/o frequent and significant flares.

Lupus Nephritis
 overall risk for developing lupus nephritis ranges from 4% to 30%

 A history of lupus nephritis increases the risk of relapse during pregnancy to 20% to 30%.

 h/o lupus nephritis leads to nonelective pregnancy loss in 8-36% patients.

 Fetal loss correlates with maternal renal function and proteinuria.

 C/F- arthritis,fever,rash,edema,hypertension.

 How to differentiate from preeclampsia?

H/o lupus nephritis increases chance of both.Clinical presentation is similar but t/t is different.

Pregnancy outcome in lupus nephropathy. Arch Gynecol Obstet 271(3):222–226, 2005.

Maternal and foetal outcomes in pregnant patients with active lupus nephritis. Lupus 18(4):342–347,
2009.
 Management in Lupus Nephritis with pregnancy-
 When the pregnancy is near full term and disease is not
confirmed,delivery may be the best option.

 If symptoms continue >48hours after delivery aggressive treatment for

lupus nephritis is started.

 If occurs in earlier stages of pregnancy, however, a better approach may

be to administer high-dose steroids.

Lupus activity in pregnancy. Rheum Dis Clin North Am 33(2):237–252, v, 2007.

Pregnancy Outcomes in SLE
 FETAL OUTCOME and
COMPLICATIONS
 PREGNANCY LOSS-
 Approximately 20% of patients will result in pregnancy loss.

 May be Stillbirth(after 20wks) or Miscarriage(before 20wks)

 Stillbirth risk increases 3 fold.

 Main predictor of pregnancy loss is APS and SLE activity.

 If disease is active during pregnancy, 40% will have Pregnancy Loss.

 Other risk factors are 1st trimester HTN,Proteinuria,Thrombocytopenia.

J Rheumatol 32(9):1709–1712, 2005

 PRETERM BIRTH –
 SLE patients will have 20-54% risk of preterm deliveries(<37wks).

 Active SLE is the primary risk factor.

 Quiescent SLE have 33% risk. SLE flare have 66% risk.

 Other Risk Factors are Hypertension and high glucocorticoid dosage.

 Immediate cause of preterm birth may be Medical intervention or spontaeneous.

 For spontaeneous,main cause is PROM.

 Chorioamnionitis PROM inflammation dissolution of fetal membrane Cervical ripening

 Active SLE can produce inflammation in uteroplacental unit similar to chorioamnionitis.

 Neonatal Lupus Syndrome-
 Occurs in lupus patients with Anti RO(RO52>RO60)and Anti LA antibodies.

 They cross placenta 16wks onwards and produce Neonatal lupus Syndrome.
 ASSOCIATIONS
Age≥35 years increase the odds
ratio for CHB compared to age<24
years.

Risk of CHB increases 6-10 fold in

Ro/La positive women with
previous CHB pregnancy

Risk of CHB increases in 18-24

wks.
Maternal HLADRB1*03 is an
association
Fetal TNF-α polymorphism and
HLA –Cw3 is associated with high
risk
 Other Cardiac Manifestations-
1. Ventricular dilation and systolic dysfunction
2. Myocardial hypertrophy
3. Endocardial fibroelastosis (EFE)
 Fetal Screening and Surveillance-
 Using standard ultrasound equipment, atrial and ventricular depolarizations are identified
indirectly by their mechanical or hemodynamic consequences.

 A specific schedule has not yet been tested or established

 Most experts recommend repeated fetal ECG examinations between weeks 16 and 18, between
weeks 24 and 26, and even into the third trimester.
Prevention and Therapy
 Early transplacental treatment with fluorinated steroidal agents has been observed to inhibit progression
or even reverse first- and second-degree AVB

 dexamethasone plus sympathomimetic drugs for fetuses with heart rates lower than 55 bpm has been
demonstrated to increase 1-year survival from 46%-90%.

 IVIG may show promise in EFE and DCM

 LONG TERM OUTCOME is poor and needs permanent pacemaker placement.

PR Interval and Dexamethasone Evaluation (PRIDE) prospective study. Circulation 117(4):

485–493, 2008.
Cutaneous Manifestations-
25% of infants exposed to SSA/Ro antibodies in utero will develop neonatal lupus
skin lesions similar to SCLE.

Erythematous, slightly scaly, and usually annular with the middle of each lesion
faded.

Predilection for the face(not particularly in a malar distribution)

Can also occur on the trunk, diaper area, or extremities.
Confluence of the lesions in the periorbital area gives the appearance of a
“raccoon mask” or “owl eye.”
Lesions are photosensitive but can also occur in areas without sun exposure.
Noticed within 2months and resolved within 6months without scarring but with
hyperpigmentations and telengiectasia.

T/t- low-potency topical steroids

Maternal Outcome and Complications
Lupus Nephritis and Flare
 PRE-ECLAMPSIA-
Hypertension(>140/90) and proteinuria(>300mg/24hour) occuring in third trimester and resolving
postpartum.
 Risk factors are- 1st Pregnancy H/O preeclampsia
Active SLE +ve anti ds-DNA
+ve Anti RNP Obesity
Low complement Lupus nephritis history

 Pathophysiology is vascular dysfunction in placenta d/t poor implantation and diminished

trophoblast invasion of uterine septal arteries.

 Marker is PGF and sFlt-1

 T/t- Primary Prevention by use of low dose aspirin(81mg/day) in all pregnant women with Lupus
Secondary Prevention by Termination of Pregnancy.

Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database
Syst Rev (2):CD004659, 2007.
 Gestational Diabetes-
 Risk is increased in women treated with steroid(more if >10mg/day)

 Increased risk in Asian background and family history of diabetes.

 Osteoporotic Fractures-
 Risk of osteoporotic fractures are increased in patients treated with LMWH or glucocorticoids.

 Dyspepsia-
 Gets worsened as the patient is treated with asspirin and steroids.
The Risk 2006
revised of Thrombosis andtheAntiPhospholipid
criteria for APS include following: Antibody-
APLA present
(1)laboratory in 25-50%
criteria: patients
LA and aCL of SLE
antibodies but less than
or anti–beta half of these
2 glycoprotein patients
I (anti–β2 developon
GPI) positive APS
two or
more occasions at least 12 weeks apart
 APS may manifest clinically as thrombotic or obstetric complication along with one
serological test Lupus anticoagulant(LAC), anticardiolipin antibodies (ACL) or Anti beta 2
(2) vascular thromboses: at least one unequivocal episode of arterial, venous, or small-vessel thrombosis
glycoprotein 1, positive in medium to high titer on two occasions 12 weeks apart
 Aps induced pregnancy loss occurs due to
(3)obstetric criteria: ≥1 unexplained deaths of a morphologically healthy fetus after 10 wks
≥1 births before
 APLA 34 wks as
interaction a result
with of preeclampsia
platelet or placental insufficiency
membrane phospholipids
≥3consecutive spontaneous
 Inhibition abortions before 10 wks without chromosomal, anatomical,
of annexin-V
hormonal, or other causes  to Direct
explaininhibition
the RPL. of protein S
 Altered regulation of the complement cascade
 APS leads to recurrent 1st trimester fetal loss,early development of severe
preeclampsia,Arterial and Venous Thrombosis.
 Risk of thrombosis also persists 6wks postpartum.
 LAC is a better predictor of adverse pregnancy outcome as compared to other APLs.

Antiphospholipid antibodies and pregnancy loss: a disorder of inflammation. J Reprod

Immunol 77(1):51–56, 2008.
 Management of APLA Syndrome with Pregnancy-
 In obstetric APS group aspirin and heparin reduced the risk of pregnancy loss by 54%
 Only Antibody Positive- Low Dose Aspirin.
 Antibody+ve,Pregnancy Complication+ve,without thrombosis-
Low dose aspirin(81mg/d)+ 0.5mg/kg/d LMWH or 5000U BD UFH
TARGET Anti Factor Xa activity 4hours after last dose 0.2-0.6U/ml

 Antibody+ve,Pregnancy Complication+ve,With Thrombosis-

Low dose aspirin + 1mg/kg LMWH BD or 1.5mg/kg/d
or 10-12000 U UFH BD
or Dalteparin 100U/kg sc BD or 200/kg sc OD
Target Anti Factor Xa Activity 0.5-1.1U/ml(if BD dose) or 1-2U/ml if OD dose

Antiphospholipid Syndrome during pregnancy: the state of the art. J Prenat Med 2011; 5:41–53
 Treatment will begin at conception and to be continued 6-12wks postpartum or
indefinitely(if history of thrombosis is present)

 Thrombocytopenia is common.
HIT
HELLP
Active SLE
Maternal APS

 APS with Thrombocytopenia <50000/uL treated with IVIG,Control of

Hypertension and early delivery.
Management of Lupus Pregnancies
Fertility Concerns in Lupus Patients

 Delay in pursuing Pregnancy

 Medications
 Diminished ovarian reserve(if cyclephosphamide was used)
 Fetal/Neonatal Loss
 Disease Activity.
 Patient,Physician and Psychosocial factors.
Cyclophosphamide and Fertility
 Better fertility is observed in
 Patients age<30yrs(specially<20yrs)
 Six or fewer monthly iv pulses.
 Cumulative dosage <7gm
 Lack of amenorrhoea before or during drug administration.

 Use of GnRH agonist was associated with 68% increase in the rate of presesrved ovarian function.

 22% of women receiving GnRH agonist therapy later achieved pregnancy, compared with 14% of
women who did not receive GnRH agonist therapy

 T/t with GnRH agonist may initially lead to estrogen surge f/b lupus flare,hypertension and
thrombotic complications.

Ovarian preservation by GnRH agonists during chemotherapy: a meta-analysis. J

Womens Health (Larchmt) 18:311–319, 2009.
ART in Lupus
 ART includes ovarian stimulation and induction through HCG,progesterone and GnRH agonists.

 Initial surge of estrogen after GnRH therapy may complicate an ART procedure.

 Ovarian stimulation regimens should be tailored to avoid high level of estradiol.

 High risk for ART includes exogenous estrogen use,uncontrolled HTN,Smoking,APS,Active SLE

 Healthy egg donor/egg retrieval/surrogate mother is an option for high risk individuals.
 Before Conception
 Pregnancy contraindicated in
 Pregnancy should be deferred if
 Before Planning Pregnancy
1. Renal insufficiency (serum creatinine level >2.8
mg%)
2. Severe pulmonary hypertension (systemic
pulmonary artery pressure >50 mmHg or
symptomatic)
3. Severe restrictive lung disease (forced vital
capacity <1 L)
4. Severe cardiac disease leading to heart failure
5. History of severe preeclampsia or HELLP syndrome
1) Severe disease flare within past 6 months
2) Recent stroke within past six weeks
3) Active lupus nephritis
Acl and lAC
Anti-Ro and La
Anti dsDNA and C3 (to assess disease activity)
S. Free T3, T4 and TSH
Best Practice and Research Clinical Rheumatology 2013; 27:435–447.
 Concerns about Drugs-
Drugs Recommendations

Rituximab 6month before conception

Bisphosphonate 3-6months before conception

Warfarin When Pregnancy is confirmed

ACEI When Pregnancy is confirmed

NSAID When trying to conceive as risk of Luteinized

unruptured follicle syndrome.
Lupus UK 2017
 During Pregnancy
 Antenatal Monitoring- to be done 4-6 wks/more frequently in active
diseases
1. Blood pressure monitoring (more frequent if there is history of
hypertension, nephritis or pre-eclampsia)
2. Complete blood counts
3. Serum uric acid
4. Serum urea,creatinine,LFT
5. C3,C4,anti-dsDNA
6. Urine examination,spot urine protein/creatinine ratio
7. Lupus anticoagulant (LA),aCL
8. USG monitoring for foetal growth and well being (between 16-20
weeks of gestation)
9. AntiRo Antibody if positive –Fetal heart rate monitoring (16-
28wks)and Fetal echocardiography weekly from week 16-26, then
biweekly till delivery
10.h/o Preeclampsia–Uterine artery Doppler (at week 20 and then 4
weekly)
Drugs NOT TO BE STOPPED
 HCQS-
 Decrease the risk of an SLE flare, improve the prognosis of SLE nephritis, and prevent death.
 HCQ has perhaps the best side-effect profile of all available SLE medications
 It has been recommended in pregnant women with SLE.
 Pregnant patients with SLE who stop taking HCQ increase their risk for flares
 Hopkins lupus pregnancy cohort reported no increase in fetal abnormalities after HCQ exposure
 Corticosteroids-
 Mild SLE activity is easily treated with prednisone in low doses (less than 20 mg per day)
 Mother can be treated with higher doses of corticosteroids, including pulse-dose steroids, in the
presence of more severe lupus activity.
 Systemic corticosteroid use carries a two- to three-fold increase in the risk for cleft lip or
palate, although the absolute risk remains low (approximately 3 per 1000 infants exposed to
corticosteroids)
Drugs that can be Used
 Azathioprine-
 Azathioprine crosses the maternal-fetal membranes largely in the form of
thiouric acid, an inactive metabolite.
 No significant increase in congenital anomalies were documented
 The enzyme required to metabolize azathioprine into its active form
cannot be produced by the fetal liver
 Continuation of azathioprine treatment through all three trimesters is
recommended if it was started before pregnancy.
 Switching from MMF to azathioprine therapy before conception is also
advisable to avoid the teratogenicity of MMF.
 Tacrolimus-
 Treatment with tacrolimus in pregnant lupus patients corrected various
risk factors and came out to be efficacious in recent studies.
Key Points
 Before pregnancy occurs:
• Get disease activity under control (six months)
• Screen for kidney involvement (and treat)
• Exclude serious lung or heart problems
• Ensure normal blood pressure
• Explain all risks including autoantibodies and thrombosis (blood clots)
• Rationalise all drug therapy
• Plan for support in pregnancy and after
 During pregnancy:
• Monitor disease activity, especially kidney
• Continue steroids, azathioprine, hydroxychloroquine
• Screen for pre-eclampsia and congenital heart block and foetal growth restriction
• Beware blood clots (thrombosis)
 After pregnancy:
 • Advice on breast-feeding and contraception • Beware blood clots and lupus flare
THANK YOU