By

MD

 Most autoimmune disease is female predominate In SLE female : male is ~ 10:1 SLE aects mostly in young females in childbearing

age (20-40 yr). The important is most autoimmune diseases include SLE dose not impaired fertility ability .

Cervera R, Balasch J. Bidirectional eects on autoimmunity and reproduction. Hum Reprod Update 2008;14:359e66.

Pathogenesis of SLE

(Harrisons 17 th Edi7on)

Scope
1. Eect of pregnancy on SLE. 2. Eect of SLE on pregnancy. 3. Flare of SLE 4. Lupus nephritis 5. Lupus anticoagulant 6. Neonatal lupus 7. Management and drugs use during pregnancy

Eect of pregnancy on SLE

Possibility factors that inuence the SLE; disease are

during pregnancy.

Sex hormones Dramatic of estrogens and progesterone. Immunological changes

a Th2-dominated state in late GA. (a Th1-dominated required for implantation and vascular ,tissue remodeling of the ut in eary GA)

Andrea T. Borchers, Stanley M. The implications of autoimmunity and pregnancy. Journal of Autoimmunity 34 (2010) J287eJ299

Eect of pregnancy on SLE

FLARE OF SLE

Challenges of SLE in Pregnancy

Normal manifestations of pregnancy SLE symptoms

VS

1. Common complications of pregnancy such as

preeclampsia may mimic exacerbations of SLE. 2. Laboratory interprete

Clinical mimic SLE Flare

Edema Arthralgia , arthritis Anemia Pregnancy induce hypertension HEELP Lab : CBC ; anemia ANA ,ESR Complement

Lupus nephri7s vs Pre-eclampsia

FLARE OF SLE
In the past occurred > 50 % during pregnancy. Rate of are now a day Most ares are mild, with cutaneous and joint

disease being the most common manifestations.

All these studies are rate was 30-50%

Timing of ares in SLE

during pregnancy
The risk of are depend on the level of maternal

disease activity in the 612 months before conception.

Rate of are 7 - 33 % in women who remission for at least 6 mos 61 - 67 % in women who active dz. at the time of conception.

Conclusion of SLE Flare

There are both positive and negative studies. Current concept agreement with no overall

increase in SLE are pregnancy.

Disease are can occur at any time during

pregnancy and postpartum without any clear pattern.

High Risk Lupus Pregnancy

Eect of SLE on pregnancy

Eect of SLE on pregnancy

Pregnancy of SLE patients can be complicated by a

number of obstetric and neonatal problems

Obstetric complications. Pre-eclampsia/eclampsia seems to be the most common Fetal complications. Pregnancy losses (spontaneous abortion or intrauterine fetal death), is the most common Premature birth IUGR

 casecontrol study consisting of 203 SLE patients with 481 pregnancies ,and 177 relatives with 566 pregnancies. Fetal outcome Pregnancy loss was more common in SLE (21 versus 14% ) Preterm birth (< 36 weeks) was more common in SLE (12 versus 4%)

J Med Assoc Thai 2007; 90 (10): 1981-5

68 61 ( 89.7)

27 ( 39.7) 15 ( 22.1) 7 ( 10.3)

20 (

29.4) 7 8 5

Autoan7bodies highly associated with fetal damage.

1. aPLs are the major risk factor for pregnancy loss in

patients with SLE and in those with primary APS.

2. anti-Ro/SS-A and anti-La/SSB antibodies,

responsible for neonatal lupus

ANTIPHOSPHOLIPID SYNDROME
APS may be primary or secondary with other connective tissue

diseases Approximately 30-40% of women with SLE have aPL antibodies

In pregnancy, aPL are specically associated with Recurrent miscarriage IUGR Olygohydramnios Pre-eclampsia, HELLP syndrome Placental abruption Fetal death

An7phospholipid Ab and normal pregnancy

In healthy non-pregnant have 5% of nonspecic

antiphospholipid ab in low titer

In normal pregnancy have 4.7% of nonspecic antiphospholipid

ab (the same of normal nonpregnant individual)

 Clinical One or more episodes of venous,

arterial, or small vessel thrombosis and/or morbidity with pregnancy.

1. Thrombosis Unequivocal imaging or histologic

evidence of thrombosis in any tissue or organ, OR

2. Pregnancy morbidity 1 unexplained fetal death GA >10wk 3 spontaneus abortion GA<10wk

1 preterm birth before 34wk dueto eclampsia , severe preeclampsia ,uteroplacental insuciency

Laboratory criteria** 1. Lupus anticoagulant (LA) present in plasma 2 occasions at least 12 wks apart 2. Anticardiolipin (aCL) antibody of IgG and/or IgM serum or plasma, in medium or high titer (i.e. >40 GPL or MPL, or >the 99th percentile), 2 occasions, at least 12 wks apart, 3. Anti-b2 glycoprotein-I antibody of IgG and/or IgM serum or plasma (in titer >the 99th percentile), 2 occasions, at least 12 weeks apart,

ANTIPHOSPHOLIPID SYNDROME
Previous Hx is an important predictor of future

obstetric performance.

Pregnancy losses > 50% of women with medium or

high titer IgG anticardiolipin (aCL)

IgM ,IgA-positive or Low positive IgG aCL are less

associated with pregnancy complications

 Thrombotic occlusion of placental vessels and

placental infarction are frequently reported.

Thrombotic Complications 70% of thrombotic events occur in the venous system

Obstetric Complica7ons of APS in Pregnancy

GESTATIONAL HYPERTENSION/PREECLAMPSIA 32%
Preeclampsia may develop as early as 15 to 17 weeks'

gestation

UTEROPLACENTAL INSUFFICIENCY AND PRETERM

BIRTH

IUGR approaches 30%

Early recurrent pregnancy loss

Treatment for An7phospholipid Syndrome during Pregnancy

Ideal treatment for APS during pregnancy
1. Improvement in maternal and fetal-neonatal outcome by preventing pregnancy loss, preeclampsia placental insuciency preterm birth 2. Reduction or elimination of the risk of thromboembolism

Pre pregnancy
Preconceptional couselling Discuss risk thrombosis , pregnancy loss , preterm

delivery , preeclampsia , UPI Informed risk/benet of heparin Lab

CBC,Plt , UA , urine for total protein & Cr for 24 hr

APS without previous thrombosis

1. Low-dose aspirin should be taken by all women

with aPL, (if possible)

Miscarriage Preeclampsia

before conception to decrease the risk of

2. Recurrent early miscarraige(<10 wk) Unfractionated Heparin 5000 -7500 u sc q 12 hr Or LMWH

Enoxaparin 40 mg sc OD

APS without previous thrombosis

3. Fetal death (>10wk) or

previous early delivery (<34wk) from severe preeclampsia or UPI

Unfractionated Heparin 7500 -10000 u sc q 12 hr in 1st trimester 10000 u sc q 12 hr in 2nd & 3rd trimester Or LMWH Enoxaparin 30 mg sc q 12 hr

APS with previous thrombosis

Standard Heparin
Every 812 hours, Target midinterval heparin levels

Low Molecular Weight Heparin

1) Weight-adjusted

enoxaparin 1/mg/kg q12h or dalteparin 200 U/kg q12h enoxaparin 40 mg once daily or dalteparin 5000 U once daily until GA 16 wks q12h at GA 16 wks

2) Intermediate dose

Labour and Delivery

O heparin 12 hr before induction labour
If plan SB -> o heparin 24 hr from last dose In case extremely thromboembolism

o heparin 2-4 hr before labour

add back heparin 6hr after Vg delivery 12hr after C/S

Post partum
1.

Warfarin keep INR 2-3 * 6 wk

2. Estrogen contain contraceptive = Contraindication 3.

Progestin only implants or DMPA injection provide eective contraception

Lupus nephri7s

Lupus nephri7s
Active nephritis has been shown to be an independent

factor for fetal mortality

Overall, this group has a high rate of fetal loss.

The risk of are is higher if LN is active at the time of

conception.

Disease activity in the 6 months prior to pregnancy

is an important predictor

Lupus nephri7s
Two studies carried out on 102 pregnancies in 75 SLE patients

with prior LN but in remission before conceptus.

Proteinuric are ranging between 45% and 50% Worsening of renal function in 1721%

Tandon A, Ibanez D, Gladman DD, Urowitz MB. The eect of pregnancy on lupus nephritis. Arthritis Rheum 2004 Soubassi L, Haidopoulos D, Sindos M et al. Pregnancy outcome in women with preexisting lupus nephritis. J Obs Gynaecol 2004

Eect of LN on pregnancy
Pre-existing renal impairment is associated with a poor fetal

outcome.1

Serum Cr > 140 mmol/L associated with a 50% pregnancy loss Serum Cr > 400 mmol/L associated with a 80% pregnancy loss

Nephrotic range proteinuria have tendency to deliver

prematurely.2

1) Burkett G. Lupus nephropathy and pregnancy. Clin Obstet Gynecol 1985 2) Lima F, Buchanan NM, Khamashta MA et al. Obstetric outcome in systemic lupus erythematosus. Seminars in Arthritis and Rheumatism 1995

Lupus nephri7s vs Pre-eclampsia

Neonatal lupus
Associated with maternal anti-Ro and anti-La

antibodies.

Even if the mother is asymptomatic.

Neonatal lupus
Skin manifests as Annular lesions similar to those of adult SCLE, usually on the face and scalp, appear after sun or ultraviolet light exposure in the rst 2 weeks of life. The rash disappears spontaneously within 6 months. Severe case Residual hypopigmentation or telangiectasia may persist for up to 2 years

Neonatal lupus
Other rarer features of neonatal SLE Abnormal liver function tests Thrombocytopenia

These manifestations are transient. Resolving by the age of 1 year. Infants are usually asymptomatic.

Congenital heart block

The most serious complication 24% mortality Occurs 2% of fetuses of women with anti-Ro Ab. Occurs between 18 - 30 weeks. Fetal echocardiography should be performed over

this period to enable early detection.

Congenital heart block

Complete heart block cannot be reversed. Second-degree heart block 1st degree block dexamethasone

50% surviving children require pacing in the 1 st year

of life.

Eect of SLE on fer7lity ability

Most autoimmune diseases include SLE dose not

impaired fertility ability . except when

1.

Renal impairment (creatinine clearance <50 ml/min), 2. Disease is very active 3. Cytotoxic therapy (cyclophosphamide). 4. High dose steroid.

Doria A, Iaccarino L, Arienti S et al. Th2 immune deviation induced by pregnancy: the two faces of autoimmune rheumatic diseases. Reprod Toxicol 2006;22:23441.

 The management should start before conception. The disease is not in itself a contra-indication to

pregnancy.
Disease should be inactive at least 6 months prior

to conception.

Contracep7on
Recommended Condom DMPA (Not excess 2 yrs because risk osteoporosis) TR Not recommended Oral pill IUD ( risk infec7on)

Contracep7on
Oral contraceptive pill
SLE are. thromboembolism in APS.

Before concep7on
Disease should be inactive at least 6 months prior to

conception.

The medication that the patient is taking to control her

disease would also need to be reviewed.

Drugs that are considered to be safe in pregnancy are: Prednisolone Azathioprine Cyclosporin A Hydroxychloroquine.

 Recommends a minimum of Q 1 mo visits until 28 weeks, Q 2 wks visits to 36 weeks Q 1 wks visits until labor. Lab: CBC, complement ,Anti-dsDNA ,UA During pregnancy, C3 and C4 may rise to

supranormal levels. SLE are may normal levels of C3 and C4.

If SLE are during pregnancy

Drugs that are considered in pregnancy : Corticosteroid Immunosupressive DMARDs NSAIDs

Prednisolone (B)
A systematic meta-analysis of studies of women who

used GCs during pregnancy reported an overall odds ratio for bearing a child with cleft palate of 3.4 (95% CI 1.97-5.69)

Pred > 20 mg/day risk pre-eclampsia and GDM
Park-Wyllie, L, Mazzotta, P, Pastuszak, A, et al. Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies. Teratology 2000; 62:385.

( =10 /1)

Azathioprine (D)
AZA in mothers used pass to fetal blood as inactive

metabolites. Placenta metabolizes AZA to thiouric acid. lactation ,so its contraindication.

After birth, AZA is metabolized to 6-MP and pass through

A retrospective study of pregnancies in women with

IBD on AZA also revealed no association with poor pregnancy outcomes.

Cyclosporin A

A 2001 meta-analysis of 15 studies of women who

received CSA during pregnancy reported major malformations in 4.1 % of ospring, a rate similar to that of the general population

Bar Oz, B, Hackman, R, Einarson, T, Koren, G. Pregnancy outcome after cyclosporine therapy during pregnancy: a meta-analysis. Transplantation 2001; 71:1051.

Hydroxychloroquine
HCQ crosses the placenta,but not appear to be fetal

toxicity.

It is a good steroid-sparing drug in SLE. Withdrawal in pregnancy is frequently associated with

later ares.

Therefore, should continue hydroxychloroquine

throughout pregnancy.

Non-steroidal an7-inammatory drugs

Generally safe during 1 st 2 nd trimester But should be avoided after 30 weeks of gestation
(due to risk of premature closure of the ductus arteriosus)

Cyclo-oxygenase-2-specic inhibitors.
Should be avoided There are inadequate data regarding safety in

pregnancy.

An7hypertensives
Drugs that are safe in pregnancy Methyldopa Labetalol Nifedipine

Immunosuppressive drugs
Methotrexate Mycophenolate mofetil Cyclophosphamide

Are teratogenic eect drugs. Should be stopped at least 3 months prior to

conception.

Post-partum and Lacta7on

The End