Connective Tissue Disease and Antiphospholipid Syndrome in Pregnancy
Overview by Disease
| Disease | Maternal complications | Fetal complications | |---|---|---| | SLE | Flare in pregnancy and postpartum; hypertension; pre-eclampsia; deterioration of lupus nephritis | Ro/La positive: neonatal lupus, congenital heart block. FGR, fetal loss, preterm delivery | | Sjögren syndrome | Flare in pregnancy or postpartum | Ro/La positive: neonatal lupus rash, congenital heart block | | Rheumatoid arthritis | Postpartum flare; new-onset RA after pregnancy | FGR and preterm delivery if disease active | | Spondyloarthropathies (ankylosing spondylitis, psoriatic arthritis, IBD-related) | Back pain less likely to improve; arthritis may deteriorate; postpartum flare | — | | Systemic sclerosis | Deterioration of pulmonary hypertension; hypertension; renal crisis; postpartum flare | Fetal loss, premature delivery |
Adapted from Gayed and Gordon, Pregnancy and rheumatic disease (2007).
Rheumatoid Arthritis
Chronic inflammatory condition affecting mainly synovial joints.
Features: joint pain, morning stiffness. Extra-articular: fatigue, vasculitis, rheumatoid nodules, anaemia, pericarditis, pulmonary fibrosis, scleritis, Sjögren syndrome.
Diagnosis: joint involvement and symptom duration; rheumatoid factor positive in 80–90%; anti-CCP antibodies; ESR/CRP.
Pregnancy effect on RA: approximately 50% improve during pregnancy; seropositive disease is less likely to improve; 90% suffer postpartum exacerbation.
RA effect on pregnancy: FGR and preterm delivery if active. Anti-Ro/La relevant. Atlanto-axial subluxation is a specific anaesthetic hazard.
Management: ENA antibody screen, anaesthetic review, serial scans if disease active.
Medication: stop NSAIDs by 30 weeks; continue azathioprine and hydroxychloroquine; sulfasalazine with 5 mg folic acid; oral, depot or intra-articular steroids; biologics.
Systemic Lupus Erythematosus
Multisystem autoimmune disorder with periods of activity (flares) and remission, affecting skin, joints, kidney, brain and other organs.
Pregnancy effect on SLE: flare risk rises from around 40% to 60%, especially in those who flared in the 6 months before conception. Flares are difficult to distinguish from normal pregnancy changes.
SLE effect on pregnancy: risk relates to lupus nephritis, hypertension, antiphospholipid antibodies, and disease activity in the 6 months before conception. Miscarriage, stillbirth, FGR, pre-eclampsia, preterm delivery. Renal involvement affects outcomes even when quiescent, with roughly 30% risk of preterm delivery, pre-eclampsia or FGR.
Antibodies: ANA, anti-dsDNA.
Pre-pregnancy and baseline: ENA, antiphospholipid antibody status, dsDNA, complement levels, proteinuria, renal function, blood pressure. Delay pregnancy until in remission for 6 months.
Antenatal management: aspirin throughout, serial growth scans, active control of hypertension (labetalol, nifedipine, methyldopa), monitoring for disease activity.
Monitoring for flare: symptoms (arthralgia, rash, hair loss, ulcers, pleuritic pain); rising dsDNA titre; falling complement; urine for haematuria and proteinuria.
Medication: continue hydroxychloroquine — stopping may precipitate a flare. Azathioprine may continue. If on prednisolone above 5 mg for more than 2 weeks, give hydrocortisone 50–100 mg IV QDS in labour.
Distinguishing Nephritic Flare from Pre-eclampsia
Both cause hypertension, proteinuria, thrombocytopenia and renal impairment. Features favouring lupus nephritis flare:
- Rising dsDNA titre
- Falling C3 / C4
- Haematuria
- Other features of active SLE
- No rise in uric acid
- No abnormal liver function tests
- No reduction in PlGF
Neonatal Lupus Syndrome
Caused by maternal anti-Ro and anti-La antibodies crossing the placenta. Present in about 30% of mothers with SLE, and also in some with Sjögren syndrome or RA. Risk is increased by a previously affected child. There is no correlation between maternal disease severity and the incidence of neonatal lupus.
Cutaneous form — 5% risk if Ro/La positive
- Presents at about 2 weeks of life, resolves by 4–6 months
- Red geographical photosensitive lesions appearing after sun or UV exposure, usually face or scalp
- Residual hypopigmentation or telangiectasia may persist up to 2 years; scarring unusual
- Treatment: avoid sun and UV exposure, with or without topical steroid
Congenital heart block — 1% risk if Ro/La positive
- Inflammation and fibrosis of the conducting system (bundle of His) caused by anti-Ro/La
- Appears in utero and is permanent
- Perinatal mortality 20%
- Usually detected between 18 and 28 weeks as fetal bradycardia
- Maternal hydroxychloroquine may reduce the risk
- Refer to fetal medicine at 20 weeks; regular checks for fetal bradycardia
- If not developed by 28 weeks, the baby is usually unaffected
- Of survivors, 50–60% require pacemakers in early infancy
Drugs in Pregnancy
Safe to continue: steroids, azathioprine, ciclosporin, tacrolimus, hydroxychloroquine, sulfasalazine (with 5 mg folic acid), anti-TNF agents, IVIg.
Contraindicated: NSAIDs in the third trimester, cyclophosphamide, methotrexate, chlorambucil, gold, D-penicillamine, mycophenolate mofetil, leflunomide, rituximab, abatacept.
Long-term steroids
The HPA axis in pregnancy shows a three-fold rise in cortisol, highest in the third trimester, corresponding to maximal fetal organ maturation. Mechanisms: oestrogen stimulation of corticosteroid-binding globulin; placental CRH secretion; a positive feedback loop in which maternal cortisol increases placental CRH. Diurnal secretion is unchanged; the HPA response to stress is increased. The fetus is protected by placental 11β-hydroxysteroid dehydrogenase type 2, a mechanism that maternal anxiety, infection and inflammation may compromise. Postpartum, CRH falls sharply after placental delivery and normalises by 12 weeks; ACTH falls transiently then rises at 3–4 days.
Risks:
- Teratogenesis — no. Cleft lip and palate seen in animal studies; human data difficult to interpret. The Danish Birth Registry (51,973 first-trimester exposed pregnancies) found no increased risk of orofacial clefts. Even if a real effect existed, it would move isolated cleft lip from about 0.77 per 1000 births to roughly 1 in 400–500
- Preterm delivery — no proven causative effect; possible association at higher doses, confounded by underlying disease
- Growth restriction — no robust evidence, though an association cannot be excluded
- Gestational diabetes — yes, chronic use increases risk 5- to 10-fold
Interactions: avoid mifepristone (anti-glucocorticoid, stops steroid working). Oestrogen derivatives may increase systemic corticosteroid concentrations.
Breastfeeding: no adverse effects reported. To reduce exposure use prednisolone and delay feeding 4 hours after a dose; methylprednisolone with a 2–4 hour delay; avoid prednisone and betamethasone.
Peripartum steroid cover — for adrenal insufficiency or long-term oral steroids (prednisolone 5 mg or more daily for more than 3 weeks):
- Vaginal birth: continue regular oral steroids and, in established labour, hydrocortisone 50–100 mg IV or IM every 6 hours until 6 hours after birth
- Caesarean, planned or emergency: continue regular oral steroids; hydrocortisone at induction of anaesthesia — 50 mg if already had hydrocortisone in labour, 100 mg if not — then a further 50 mg IV or IM 6 hours after birth
- Do not give supplemental hydrocortisone to women on inhaled or topical steroids alone
Biologics
Maternal: infections may present atypically — screen and treat aggressively. Risk of reactivating latent infection, particularly tuberculosis. Poor wound healing and infection risk after delivery, so time the last dose around delivery and avoid for 5–7 days postpartum. Breastfeeding is permitted.
Fetal: most anti-TNF agents are actively transported across the placenta in the third trimester and have long half-lives, so they accumulate in the neonate. No evidence of teratogenicity or of an effect on neonatal lymphoid development. There is a potential risk of disseminated infection after live vaccines — if biologics were given beyond the recommended gestation, wait 6 months before BCG or rotavirus. Non-live vaccines are given as normal.
Antiphospholipid Syndrome (APS)
Acquired autoimmune disorder with antibodies to β2-glycoprotein I (apolipoprotein H) and prothrombin. The three tested antibodies are lupus anticoagulant, anticardiolipin, and anti-β2-glycoprotein I.
Procoagulant mechanisms: β2GPI–antibody complexes activate platelets, endothelial cells, monocytes and tissue factor expression; increase resistance to activated protein C; reduce fibrinolysis.
Obstetric mechanisms: placental thrombosis; displacement of annexin V from trophoblast, accelerating coagulation; defective placentation through effects on trophoblast migration, invasion and differentiation; and an inflammatory process in which antibodies bind trophoblast, initiate complement and increase C4 deposition — heparin may reverse this.
Epidemiology
- Female to male ratio 5:1, young to middle-aged, no racial predominance
- 5% of the general obstetric population have antiphospholipid antibodies
- 15% of the recurrent miscarriage population
- Asymptomatic non-pregnant aPL: under 1% thrombosis risk per year
- 30–40% of patients with SLE have aPL
- 30% of those with early-onset pre-eclampsia have aPL
Clinical features
Venous thrombosis (sometimes at unusual sites), arterial thrombosis, small-vessel disease such as renal thrombotic microangiopathy. Pregnancy morbidity: recurrent early miscarriage, second and third trimester loss, severe early-onset pre-eclampsia, severe placental insufficiency.
Diagnosis (revised Sapporo criteria)
Clinical — vascular thrombosis: at least one objectively confirmed episode of arterial, venous or small-vessel thrombosis. Histopathological confirmation requires thrombosis without vessel wall inflammation.
Clinical — pregnancy morbidity, any one of:
- One or more unexplained deaths of a morphologically normal fetus at or beyond 10 weeks
- One or more premature deliveries of a morphologically normal fetus before 34 weeks because of severe pre-eclampsia or eclampsia, or recognised features of placental insufficiency
- Three or more unexplained consecutive miscarriages before 10 weeks, with maternal and paternal anatomic, hormonal and chromosomal causes excluded
Laboratory: antiphospholipid antibodies on two or more occasions at least 12 weeks apart and no more than 5 years before the clinical manifestation — lupus anticoagulant, medium-to-high titre anticardiolipin (above 40 GPL/MPL or above the 99th centile) IgG or IgM, or anti-β2GPI IgG or IgM.
Not all APS is equal
- Persistent aPL with no clinical features of APS: pregnancy outcomes similar to controls
- Early obstetric APS (recurrent miscarriage plus aPL): preterm delivery 10%, pre-eclampsia 10%
- Late obstetric APS (SLE-associated, thrombotic, late intrauterine death, or severe early-onset pre-eclampsia, plus aPL): preterm delivery 30–40%, FGR over 30%, pre-eclampsia often severe and early onset
Management
Pre-pregnancy: confirm the diagnosis; exclude other causes of late miscarriage; assess associated conditions such as SLE; avoid pregnancy if recent thrombosis or pulmonary hypertension; VTE risk assessment.
Aspirin inhibits thromboxane and may reduce vascular thrombosis; logical and safe for all APS and aPL, started pre-conception on the basis that placental damage occurs early.
LMWH acts as an anticoagulant and as an anti-inflammatory by blocking complement activation. Weigh benefit against osteoporosis risk (0.4%), hypersensitivity, HIT, cost and daily injections.
| Scenario | Aspirin | LMWH | Postpartum | |---|---|---|---| | aPL, no clinical APS features | Yes | No | Yes, at least 10 days | | aPL with early losses not meeting APS criteria | Yes | No — if started earlier, stop at 12 weeks or the viability scan, whichever is first | Yes, at least 10 days | | 3 or more early (< 10 week) miscarriages, no VTE (early obstetric APS) | Yes | Yes per Green-top, BASHH and ACOG, though evidence is controversial and outcomes may be as good with aspirin alone | Yes, at least 10 days | | Adverse obstetric outcome — late loss, early pre-eclampsia, HELLP, FGR, delivery < 34 weeks, no VTE (obstetric APS) | Yes | Maybe — BASHH says no, but some evidence prophylactic LMWH reduces recurrence of placental-mediated complications | Yes, at least 10 days | | Thrombotic APS (often on long-term warfarin) | Yes | Recent thrombosis: therapeutic LMWH. Past venous: consider higher-dose prophylaxis. Past arterial: high-dose prophylaxis | At least 6 weeks; may switch back to warfarin 5–7 days after delivery | | Thrombotic APS with recurrent arterial thrombosis despite high-dose prophylaxis | Yes | Therapeutic LMWH on confirmation of intrauterine pregnancy; warfarin may be cautiously restarted after the first trimester for arterial or cerebral events | Yes; restart warfarin day 5–7 |
Surveillance: uterine artery Dopplers at 20 weeks, with 4-weekly growth scans from 28 weeks if notching or high PI. Serial growth scans from 28 weeks in thrombotic and late obstetric APS — not required for recurrent-miscarriage-associated APS. Close blood pressure and urine monitoring for pre-eclampsia.
Steroids, azathioprine, IVIg and plasmapheresis are not used therapeutically for obstetric APS — side effects, cost, and no evidence of improved outcome.
Screening: the Green-top guideline recommends screening for APS after unprovoked VTE, because detection alters thromboprophylaxis dosing. APS is not diagnosed unless lupus anticoagulant, anticardiolipin or anti-β2GPI is positive on two occasions 12 weeks apart. A Canadian study found APS carried an adjusted odds ratio of 12.9 for PE and 5.1 for DVT.
Catastrophic APS
Accelerated form with multi-organ failure from widespread, usually microvascular, thrombosis. Acute onset with three or more organ systems involved over days to weeks. Triggers include infection and surgery. Mortality 50%. Treatment: plasmapheresis, IVIg, corticosteroids and rituximab.
References
- Gayed and Gordon. Pregnancy and rheumatic disease. Rheumatology 2007
- RCOG Green-top Guideline 17, Recurrent Miscarriage
- RCOG Green-top Guideline 37a, Reducing the Risk of Thrombosis and Embolism
- Revised Sapporo classification criteria for antiphospholipid syndrome
- The Obstetrician & Gynaecologist (TOG), RCOG journal
Source: The Obstetrician & Gynaecologist (TOG), RCOG journal — see references below
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