Antiphospholipid syndrome and SLE
Autoimmune and immunodeficiency disorders in pregnancy: antiphospholipid syndrome and SLE
Autoimmune disease in pregnancy for FCPS Part 1: placental IgG transfer, neonatal lupus, antiphospholipid syndrome and SLE antibodies and criteria. Also covers dermatomyositis, Schmidt syndrome, pemphigoid gestationis, HIV and primary immunodeficiency.
Immunity in pregnancy and IgG transfer
- The fetus is a semi-allograft. Trophoblast lacks classical HLA class I and II (it expresses HLA-G), and maternal immunity shifts towards Th2 and regulatory T cells. Rheumatoid arthritis improves from the second trimester and flares after delivery; antibody-driven SLE may flare.
- Only IgG crosses the placenta, actively via neonatal Fc receptors (FcRn) on syncytiotrophoblast, rising steeply after 32 weeks. IgM does not cross, so raised cord IgM means fetal infection.
- Maternal IgG protects the baby for about 6 months (so X-linked agammaglobulinaemia presents after 6 months) and lasts up to 18 months, so an HIV antibody test is not diagnostic in infants; use PCR.
- Any pathogenic maternal IgG can cause transient neonatal disease that clears as the IgG is catabolised (half-life about 3 weeks).
| Maternal IgG | Neonatal effect |
|---|---|
| Anti-Ro, anti-La (Sjögren, SLE, often a well mother) | Neonatal lupus: photosensitive annular rash and cytopenias that clear; congenital heart block is permanent |
| Anti-acetylcholine receptor | Transient neonatal myasthenia (weak suck, floppy) |
| Anti-platelet IgG (ITP) | Neonatal thrombocytopenia, lowest on days 2–5 |
| TSH receptor stimulating antibody | Neonatal thyrotoxicosis |
| Anti-D, anti-Kell | Haemolytic disease |
- Why heart block is permanent: anti-Ro binds fetal cardiac conducting tissue between about 18 and 24 weeks, causing inflammation that ends in fibrosis and calcification of the AV node. Fibrous tissue does not regenerate when the antibody disappears, so the baby needs a pacemaker, while the skin rash fades. Many mothers are asymptomatic and the antibody is found only after the birth.
- Neonatal ITP: maternal anti-platelet IgG crosses and destroys fetal platelets. As the neonatal spleen matures, clearance increases, so the count falls over the first days (a normal cord count does not exclude a later fall) and recovers over weeks. The mother's own count poorly predicts the baby's.
Antiphospholipid syndrome
- Autoantibodies are directed mainly against beta-2-glycoprotein I bound to anionic phospholipid on endothelium, platelets and trophoblast; they activate endothelium, platelets and complement, and impair trophoblast invasion.
| Antibody test | Comment |
|---|---|
| Lupus anticoagulant | Strongest single predictor of thrombosis and pregnancy loss |
| Anticardiolipin IgG or IgM | Also causes a false-positive VDRL with negative TPHA |
| Anti-beta-2-glycoprotein I | Triple positivity carries the highest risk |
- Laboratory paradox: the antibody binds the phospholipid in the test, prolonging the APTT without correction on mixing; in the body it causes thrombosis, not bleeding.
- Clinical criteria: venous or arterial thrombosis; or fetal death at 10 weeks or more, birth before 34 weeks for severe pre-eclampsia or placental insufficiency, or three or more consecutive losses before 10 weeks. Antibodies must be positive twice, 12 weeks apart.
- Placenta: spiral artery thrombosis and poor invasion give multiple infarcts, growth restriction and early pre-eclampsia.
- Treatment in pregnancy: low-dose aspirin plus prophylactic LMWH.
Systemic lupus erythematosus
- Origin: impaired clearance of apoptotic cells leaves nuclear antigens exposed; type I interferon drives anti-nuclear antibodies. Inherited deficiency of C1q, C2 or C4 predisposes.
- Damage: type III immune complexes (granular deposits) in kidney, skin, joints and serosa, with low C3 and C4 in active disease; type II for haemolytic anaemia (warm IgG), thrombocytopenia and leucopenia. Contrast Goodpasture disease: type II with linear IgG along the GBM.
| Antibody | Value |
|---|---|
| ANA | Most sensitive screen (over 95%), the best initial test for a woman with a malar rash; positive in many autoimmune diseases |
| Anti-dsDNA | Highly specific; titre rises with disease activity and lupus nephritis |
| Anti-Smith | Most specific; level stable, not related to activity |
| Anti-histone | Drug-induced lupus (hydralazine, procainamide, isoniazid) |
| Anti-Ro, anti-La | Neonatal lupus, heart block |
- Joints, skin and haematological changes are the commonest features; arthritis is non-erosive. A woman with malar rash and anti-dsDNA who develops foamy urine, proteinuria and haematuria has lupus nephritis; class IV diffuse proliferative is the most severe.
- Lupus nephritis versus pre-eclampsia: falling C3 and C4, rising anti-dsDNA and red cell casts favour lupus; raised uric acid, liver enzymes and a high sFlt-1:PlGF ratio favour pre-eclampsia.
- Drugs: continue hydroxychloroquine, azathioprine and sulfasalazine; stop mycophenolate, methotrexate and cyclophosphamide before conception.
Other autoimmune disorders
| Disorder | Key point |
|---|---|
| Dermatomyositis | Proximal weakness, heliotrope eyelid rash, Gottron papules over the knuckles; in adults screen for underlying malignancy (ovary, lung, gastrointestinal); anti-Jo-1 (anti-synthetase) predicts interstitial lung disease |
| Schmidt syndrome (autoimmune polyglandular syndrome type 2) | Addison disease with autoimmune hypothyroidism (and often type 1 diabetes); treat the Addison disease first, because thyroxine alone speeds cortisol clearance and can precipitate adrenal crisis |
| Myasthenia gravis | Avoid magnesium sulphate, which can precipitate crisis |
| Pemphigoid gestationis | Itchy periumbilical plaques then tense blisters; subepidermal blister with linear C3; IgG against BP180 (collagen XVII) in hemidesmosomes |
| Polymorphic eruption of pregnancy | Starts in striae, spares the umbilicus, no true autoantibody; benign |
| Hereditary angioedema | C1 esterase inhibitor deficiency, bradykinin; oestrogen worsens it |
Immunodeficiency
- HIV: most vertical transmission occurs around labour and delivery; maternal viral suppression prevents most. Zidovudine terminates viral DNA chains. Mixed feeding raises transmission more than exclusive breastfeeding.
- With CD4 under 200 per mm3, the commonest opportunistic infection is Pneumocystis jirovecii pneumonia; co-trimoxazole prophylaxis is given. Low CD4 causes tuberculin anergy.
- Primary defects: selective IgA deficiency is commonest (anaphylaxis to blood products with anti-IgA); XLA (BTK, no B cells); CVID (B cells present, all immunoglobulins low); DiGeorge 22q11 (absent thymus and parathyroids); SCID (avoid live vaccines, give irradiated blood).
- Placental malaria: parasites expressing VAR2CSA bind chondroitin sulphate A; primigravidae are most affected.
Remember Only IgG crosses the placenta, so every neonatal antibody disease is IgG-mediated and transient, except permanent heart block from anti-Ro.
Exam trap In antiphospholipid syndrome a long APTT means a clotting tendency, not a bleeding risk.
Exam trap Antiphospholipid antibodies must persist 12 weeks apart; one positive test or one miscarriage does not make the diagnosis.
How FCPS asks about this
- Most sensitive screening test for SLE: ANA; most specific and activity-linked: anti-dsDNA.
- Hypersensitivity type in SLE: type III immune complex (type II for cytopenias).
- Congenital heart block in the baby of an anti-Ro mother: permanent because the AV node is replaced by fibrosis.
- Neonatal thrombocytopenia from maternal ITP: maternal anti-platelet IgG crossing the placenta; nadir days 2–5.
- Addison disease with autoimmune hypothyroidism: Schmidt syndrome; replace steroid first.
- Dermatomyositis in an adult woman: screen for malignancy.
- Pemphigoid gestationis target antigen: BP180 (collagen XVII) in hemidesmosomes.
Test yourself on this topic
5 of the 65 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
In a malaria-endemic area, a primigravida with falciparum malaria has heavy parasitisation of the placenta and a growth-restricted baby, while women in later pregnancies are much less affected. Why are first pregnancies at greater risk?
Answer: No antibody yet to the placental variant
Infected red cells in pregnancy express a parasite protein, VAR2CSA, that binds chondroitin sulphate A on the syncytiotrophoblast, so they sequester in the intervillous space. Women in endemic areas have immunity to other variants but meet this one for the first time in their first pregnancy. Antibodies against VAR2CSA develop over successive pregnancies, which is why multigravidae are protected. Placental sequestration causes inflammation, anaemia and fetal growth restriction.
Malaria in the first pregnancy
- Parasite VAR2CSA binds CSA
- Sequestration in intervillous space
- Primigravidae lack specific antibody
- Immunity builds with each pregnancy
Remember A new placental target finds a mother without antibody.
Exam trap Adult immunity to malaria does not protect the placenta in a first pregnancy.
Why the other options are wrong
- Primigravidae have lower red cell counts Not the reason for placental sequestration.
- The first placenta lacks villous blood flow Not a recognised difference.
- Parasites cannot bind multigravid placentas Binding is possible, but antibodies prevent it.
- Primigravidae receive no antimalarials Not the biological explanation.
At 26 weeks, a primigravida develops intensely itchy plaques around the umbilicus that progress to tense blisters on the trunk. Biopsy shows a subepidermal blister with linear C3 along the basement membrane. Against which structure are her autoantibodies directed?
Answer: BP180 in hemidesmosomes
Pemphigoid gestationis is an autoimmune blistering disease of pregnancy. IgG antibodies bind BP180 (type XVII collagen) in the hemidesmosomes that anchor basal keratinocytes to the basement membrane; the antigen is also expressed in the placenta and amnion, which may trigger the response. Complement activation along the basement membrane separates the epidermis, giving tense subepidermal blisters that typically start around the umbilicus. The baby may have mild transient blisters from transferred IgG.
Pemphigoid gestationis
- Itchy periumbilical plaques
- Tense subepidermal blisters
- Antibody to BP180 (collagen XVII)
- Linear C3 on immunofluorescence
Remember Blisters starting at the umbilicus in pregnancy: pemphigoid gestationis.
Exam trap Do not confuse it with polymorphic eruption of pregnancy, which spares the umbilicus and does not blister this way.
Why the other options are wrong
- Desmoglein 3 in desmosomes Target in pemphigus vulgaris, with flaccid intraepidermal blisters.
- Type VII collagen in anchoring fibrils Target in epidermolysis bullosa acquisita.
- Tissue transglutaminase Linked with dermatitis herpetiformis and coeliac disease.
- Keratin in the stratum corneum Not an autoantibody target in blistering disease.
A woman has persistent lupus anticoagulant on two tests 12 weeks apart. Which of the following past obstetric events counts as a clinical criterion for antiphospholipid syndrome?
Answer: Delivery at 32 weeks for severe pre-eclampsia
The classification criteria accept three groups of obstetric events: one or more unexplained fetal deaths at or after 10 weeks, one or more premature births before 34 weeks because of severe pre-eclampsia, eclampsia or placental insufficiency, or three or more unexplained consecutive miscarriages before 10 weeks. These reflect placental thrombosis and poor placentation. A single early miscarriage is common and does not qualify, and metabolic or labour complications are unrelated.
APS obstetric criteria
- Fetal death at ≥ 10 weeks
- Birth < 34 weeks for pre-eclampsia or placental insufficiency
- ≥ 3 consecutive losses < 10 weeks
- Plus antibodies 12 weeks apart
Remember One late loss, one early severe pre-eclampsia, or three early losses.
Exam trap A single first-trimester miscarriage is not enough to meet the criteria.
Why the other options are wrong
- One miscarriage at 7 weeks One early loss is common and not a criterion; three are needed.
- Gestational diabetes in two pregnancies Not linked with antiphospholipid antibodies.
- Postpartum haemorrhage after a long labour Not a placental vascular event.
- A term baby weighing 3.9 kg A large baby does not suggest placental insufficiency.
A baby whose mother has anti-Ro antibodies is born with a heart rate of 55/min from complete heart block. The baby's facial rash fades within months, but the heart block remains and needs a pacemaker. Why is the heart block permanent?
Answer: The AV node has been replaced by fibrosis
Maternal IgG anti-Ro (and anti-La) crosses the placenta from mid-pregnancy and binds antigens exposed on fetal cardiomyocytes, especially in the conducting tissue. This sets up inflammation that ends in fibrosis and calcification of the atrioventricular node. Once the node is scarred, conduction cannot recover even after the maternal antibody is cleared. The skin rash, in contrast, is an active inflammation that fades as the antibody disappears.
Neonatal lupus heart block
- Maternal anti-Ro/anti-La IgG
- Inflames fetal AV node
- Ends in fibrosis: permanent
- Rash resolves; block does not
Remember Scar does not heal when the antibody leaves.
Exam trap Many mothers of affected babies have no symptoms; the antibody may be found only after the birth.
Why the other options are wrong
- Maternal antibody persists in the baby for life Maternal IgG is cleared over 6–8 months.
- The baby starts making its own anti-Ro The baby does not develop its own lupus antibodies in this way.
- The sinus node fails to develop Rate is slow from AV block, not sinus node agenesis.
- Digoxin given in pregnancy damaged the node Not a cause of congenital heart block.
A baby born at 27 weeks has much lower serum IgG than a term baby and is more prone to serious bacterial infections in the first months. Why is the IgG level low?
Answer: Most placental IgG transfer occurs after 32 weeks
IgG is carried across the syncytiotrophoblast by the neonatal Fc receptor (FcRn), and this transport increases steeply in the third trimester, especially after about 32 weeks. A baby born very preterm therefore misses much of this transfer and starts life with low IgG. Its own antibody production is also immature. This contributes to the high risk of sepsis in extremely preterm infants.
Placental IgG transfer
- Via FcRn on syncytiotrophoblast
- Rises steeply after 32 weeks
- Term baby IgG ≥ maternal
- Preterm baby: low IgG
Remember Early birth means less borrowed IgG.
Exam trap Do not assume a preterm baby has the same passive protection as a term baby.
Why the other options are wrong
- Preterm babies make IgG faster but lose it Preterm babies make little IgG of their own.
- IgG crosses only during labour Transfer occurs through pregnancy, mostly late.
- Preterm placentas transfer IgM instead IgM does not cross the placenta at any gestation.
- Maternal IgG is destroyed by fetal complement Not a recognised mechanism.
Where this sits in the CPSP syllabus
- Obstetrics & Gynaecology, Paper 2: General pathology in obstetrics, Autoimmune and immunodeficiency disorders in pregnancy: antiphospholipid syndrome, SLE
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