autoimmune disease pregnancy

Question 1

revised sapporo criteria /Sydney criteria for Anti phospholipid syndrome

Answer 1

need one clinical and one laboratory finding
- Clinical
vascular - one or more venous, arterial or small vessel thrombosis to any tissue or organ with unequivocal imaging or histological evidence of thrombosis (Not superficial venous thrombosis)
pregnancy related one of the following
3+ consecutive spont preg losses before 10 weeks otherwise unexplained
one morphologicaly normal fetal death at or after 10 weeks
PTB before 34 weeks due to eclampsia PET or placental insufficiency

-laboratory 
one of these antibodies on 2 occasions at least 12 weeks apart 
IgG or IgM anticardiolipin
anti beta 2 glycoprotein
lupus anticoagulant

Question 2

Why do people get APS

Answer 2

mutated HLA DR7 gene encodes the major histocompatability complex class 2 MHC class 2 - on surface of B cell
- makes B cell make APS antibodies
+
environmental trigger
eg infection (Hep C HIV Syphillis malaria)
Drugs - cardiovascular or antipsychotics

Question 3

What is the pathophysiology of APS

Answer 3

Main antibody is anti - beta2 - glycoprotein 1
This targets beta2glycoprotein 1. The function of this is to inhibit agglutination.
SO the antibody stops its inhibition therefore increasing platelet clumping and clotting.
Also anticardiolipin - binds to the lipid protein in phospholipid membrane cardiolipin that also binds beta2glycoprotein 1
Anti cardiolipid Antibodies are also + in syphillis and therefore can cause false + test for syphillis
can also target other blood products eg platelets and RBC causing anaemia and thrombocytopenia

Question 4

How does rheumatoid change with pregnancy

Answer 4

50% improve in pregnancy, 20% enter complete remission
Nodules can disappear and improvement is from T1
25 % significant disability in pregnancy
Disease activity in previous pregnancy can be predictive
Those who are + for RF and Anti CCp are less likely to improve in pregnancy
Worsening sx may be related to disease modifying anti rheumatic drugs (DMARDs)
90% suffer post partum exacerbations
? Due to T cell mediated immunity resurgence
There is increase incidence of first presentations of RA in the post partum period especially after a first pregnancy

Question 5

How is pregnancy affected by rheumatoid arthritis?

Answer 5

Not as bad a SLE
Increase PTB and SGA
Fertility or spont miscarriage rate is not significantly altered
Infants of woman with anti –Ro are at risk of neonatal lupus
Spinal subluxation is a rare complications for epidurals and rarely limitation of hip abduction is severe enough to impede vaginal delivery
Hip replacement is not an indication for cesarean
Main concern in pregnancy is medications used for RA

Question 6

NSAIDS in pregnancy
What are the risks?
can it every be used?

Answer 6

NSAIDS

Cause infertility through luteinized unruptured follicle syndrome or impaired blastocyst implantation

NSAIDS increase the risk of neonatal haemorrhage via inhibition of platelet function

NSAIDS lead to oligohydramnios via effects on the fetal kidneys and may cause premature of the ductus arteriosus – both of these things are reversible after stopping NSAIDS

NSAIDS are usually avoided especially in the third trimester

Occasionally used before 28 weeks

COX type 2 selectives have only minor renal and ductal effect but associated with CV risk and currently contraindicated

Question 7

Steroids in pregnancy

Answer 7

Steroids
Better them NSAIDS T3
Can use long acting IM steroids
Increased risk GDM and PPROM
Supplementary Vit D and calcium are important
If long term steroids a stress dose should be given in labour regardless of route of delivery (more then 7.5mg for more then 2 weeks)

Question 8

Can Azathioprine be used in pregnancy?
Why is it safe?

Can hydroxychloroquine be used?

Answer 8

Safe in pregnancy – the fetal liver lacks the enzyme to convert azathioprine to active metabolite
No fetal adverse effects
Breastfeeding not contraindicated
Can be added in pregnancy as a steroid sparing agent

Hydroxychloroquine is safe in pregnancy and breastfeeding

Question 9

Can MMF mycophenolate mofetil be used in pregnancy ?
What is it used for?
How to manage prenatally?

Answer 9

Antiproliferative immunosuppressant, more selective

USed in SLE and transplant patients

Teratogenic - cleft lip and palate, microtia with atresia of external auditary canal, micrognathia, hypertelorism

Woman should be switched from MMF to azathioprine at least 3 months before pregnancy

Question 10

Penicillamine
What is it?
can it be used in pregnancy ?
What disease is it used for in pregnancy ?

Answer 10

Chelating agent not really used anymore
Teratogenic at high doses
Used in Wilsons disease in pregnancy

Question 11

Is Sulfasalazine safe in pregnancy ?

How does it work?

Answer 11

Used in IBD  
May be safe in pregnancy and breast feeding  
 Increased risk NTD oral celfts, CVD 
High dose folate recommended 
Dihydrofolate reductase inhibitor

Question 12

Cytotoxic drugs include methotrexate, cyclophosphamide and chlorambucil
Can these be used?
What is the risk?
What is the exception?

Answer 12

MTX, cyclophosphamide and chlorambucil are contraindicated in pregnancy

Cyclophosphamide is an alkylating agent - Risk can be 20% congential defects - must be stopped 3 months before pregnancy. Can be used in late pregnancy as a chemotherapy for breast and other malignancies

MTX has a 15% risk of craniofacial, limb, CNS malformations, associated with miscarriage, and cong abnormalities

Question 13

Leflunomide

and pre pregnancy counselling

Answer 13

DMARD, tetratogenic, contraindicated

Long half life, delay conception for 2 years or eliminate the drug with cholestyramine or active charcoal

Question 14

Biological therapies can sometimes be used in pregnancy

Which is considered safest and why?

Answer 14

Biologic therapies

Eg etanercept, infliximab, adalimumab
Not teratogenic in animal studies
Infliximab and adalimumab are IgG and therefore are actively transported across the placenta and have high levels in the fetus
Delay live vaccine (BCG) for 6 months as they are immune suppressed
These agents do not cross into breast milk
They can be used in pregnancy but if can be stopped In the second trimester reduces the neonatal level

Certolizumab only crosses the placenta by passive diffusion as it lacks an Fc fragment therefore it is a safe option and can be carried on with throughout pregnancy

Rituximab is a B cell depletion therapy and the last dose should be given 6 months before birth to avoid neonatal B cell depletion

Question 15

What antibodies does SLE have?

Answer 15

Anti nuclear antibodies 96%

Most specific are antibodies to double stranded DNA 78% - increased risk of glomerulanephritis

Can have anti –ro, anti-La, or anticardiolipin

Question 16

How does SLE change in pregnancy ?

Answer 16

Effect of pregnancy on SLE
Increases likelihood of flare from 40-60% in pregnancy and puerperium
Flares involve skin and joints - more likely if a flare within 6 months
Sx of a flare can be masked by pregnancy sx
Flares are not prevented by prophylactic steroids
Less common in woman who continue Maintenance hydrochloroquine
In woman with renal involvement, pregnancy does not seem to worsen it
The risk of deterioration is higher the higher the starting Cr is
Risk of renal flare 30% - much higher if not well tx disease prepreg
Woman should delay pregnancy 6 months are a lupus nephritis flare

Question 17

How does SLE affect pregnancy?

What are the risks

Answer 17

SLE on pregnancy 
Increase risk of 
Spont miscarriage 
IUFD
FGR 
PET 
PTB

Question 18

What factors about SLE make it a higher risk pregnancy ?

Answer 18

Risk is related to
the presence of anticardiolipin antibodies or lupus anticoagulant,
lupus nephritis - Risk PTB + LBW is 30%
Increased risk fetal loss, PET, FGR esp if proteinuric or HTN
HTN,
active disease at conception
First presentation of SLE in pregnancy

Question 19

How to manage SLE in pregnancy

Answer 19

Preconception counselling
Knowledge of Anti –Ro, anti – La, anti-ds DNA, C3,4, baseline proteinuria, Cr, BP U+Es
Outcome is improved with disease remission
If lupus nephritis, aPLs or vasculitis they should have aspirin in pregnancy
MDT approach with physicians and obstetricians
Uterine artery doppler 20-24 weeks
Serial growth scans
Umbilical artery flow from 24 weeks
Monitor for flare of disease
Symptoms, rising dsDNA titre, RBC or cellular casts in urinary sediment, fall in complement (may help differentiate lupus from PET) 25% fall in C3 or 4 suggests SLE flare
Actively manage flares with corticosteroids
Control HTN

Question 20

Differentiating SLE from PET

Answer 20

Difficult
A doubling of baseline Cr can be expected in pregnancy – more then this indicates pathology
High urate, abnormal LFTs and low placental growth factor imply PET
Symptoms, rising dsDNA titre, RBC or cellular casts in urinary sediment, fall in complement 25% fall in C3 or 4 suggests SLE flare
Only definitive test is a renal biopsy
May be appropriate if pre viable, as if lupus can treat with azathiprine and steroids

Once viability reached need to consider delivery

Question 21

Neonatal lupus syndrome

Pathophysiology

Answer 21

Passively acquired autoimmunity

Autoantibodies cross the placenta – these are directed against cytoplasmic ribonucleoproteins Ro and La

Cutaneous Neonatal lupus syndrome is the most common
Congenital heart block is the most serious – they rarely co exist

Neonatal lupus is not linked to severity of maternal disease

Question 22

How common is Anti Ro and anti La ?
Who has them?
What is the risk of fetal effects?

Answer 22

out for woman with babies that have cutaneous neonatal lupus 90% of mothers have anti Ro (prevalence in population <1%) and 50-70% have anti La

These are present in 30% of woman with SLE – commonly associated with photo sensitivity, Sjogrens, subacute lupus erythematosis, ANA negative SLE

Not all woman with Ro/La have SLE – some have sjogrens, Raynauds or a photosensitive rash and a large proportion are asymptomatic (although may eventually develop connective tissue disease )

In woman with these antibodies the risk of CHB is 2% and neonatal lupus is 5%

Question 23

If you have had a child with neonatal cutaneous lupus - how common that the next child will be affected?

Answer 23

If a previous child was affected the risk rises to 16-18% and 50% if 2 children previously affected

Question 24

What may decrease the risk of CHB in Anti Ro + mums?

Answer 24

CHB may be reduced in woman taking hydroxychloroquine

Question 25

Cutaneous neonatal lupus

How does it present?

Answer 25

Manifests in the first 2 weeks of life
The infant develops typical erythematous geographical skin lesions similar to adult subacute cutaneous lupus – photosensitive (can follow sunlight exposure or light for jaundice Tx)
The rash disappears spontaneously 4-6 months
Scarring unusual but residual hypopigmentation can lasts for 2 years

Question 26

Congenital heart block
When does it occur?
mortality rate?
When Dx? How Dx

Answer 26

Occurs in utero
Permanent and can be fatal 20% mortality
Mechanism not completely understood
Dx 18-28 weeks – bradycardia recognised and detailed cardiac scanning shows AV dissociation

Question 27

What is the pathology of CHB

Answer 27

The pathology is inflammation and fibrosis of the conduction system – fibroblasts become unchecked proliferating myofibroblasts causing scarring of the AV node – a pancarditis with pericardial effusion can also occur

Development of CHB is associated with 52kDa Ro and the titres of these antibodies

It si likely the HB is progressive from 1st, 2nd before reaching 3rd and complete HB

Question 28

Tx for CHB?

Answer 28

Steroid or IVIG doesn’t help CHB once established

Dexamethasone may reverse lesser degrees of heart block / prevent progression

Salbutamol to the mother may help fetal bradycardia if the fetus is going into heart failure

If HF from myocarditis then dexamethasone and plasmaphoresis can be used but this doesn’t help the conduction defect

Perinatal mortality 20%
20% of live born children dying in the early neonatal period. 50% require a pacemaker in early infancy

All should be paced by early teens to avoid sudden death

Question 29

Affects of APS on pregnancy

Answer 29

Increase risk miscarriage 
More common when 3 or more miscarriages  
T2,3 IUFD 
Generally preceeded by FGR and oligo  
PET risk can be 10-40% depending on how their APS was dx  
PET is early and severe  
Abruption 
FGR

Question 30

How do we predict the risk in pregnancy for APS

Answer 30

Risk is associated with higher LA, and is related to titre particularly IgG aCL
Prev obs hx is the best predictor of outcome

Question 31

Effect of pregnancy on APS

Answer 31

Preexisting thrombocytopenia may worsen
Risk of thrombosis in the hypercoagulable state
If previous venous the risk is venous if previous arterial then the risk is arterial

Question 32

Pre pregnancy counselling APS

Answer 32

Woman with a hx of severe early onset PET IUFD, recurrent miscarriages, severe early onset FGR thrombosis should be screened for LA and aCL

Detailed hx to screen for causes – cervical incompetence, PTB

Aspirin pre conception for woman with aPLs (antibodies no clinical sx)
Aspirin pre conception for APS not on warfarin already

Question 33

What obstetric monitoring in APS

Answer 33

Fetal monitoring
Uterine artery at 20-24 weeks
Monthly growth from 28 weeks if raised or notched uterine artery
Regular monitoring BP and PCR

Question 34

Who gets heparin and who doesn’t for APS ?

Answer 34

Mixed evidence
CNP suggests
heparin once pregnant for prev thrombosis or dx made on IUFD / PET / Abruption / IUGR
(aspirin only for recurrent miscarriages and if they loose a baby on aspirin then can try them on clexane until maybe 20 weeks if UA doppler normal)

Question 35

Post natal plan for APS ?

Answer 35

If prev thrombosis for heparin for 6 weeks

If dx on obstetric outcome clexane for 10/7 to 6 weeks depending on other risk factors