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Home , Eclampsia, HELLP syndrome, Melasma, Rupture of membranes

and Rheumatological Diseases

Caroline Gordon

Rheumatological Diseases in Pregnancy

• Effects of pregnancy on with rheumatic disease – Distinguishing flare from pregnancy complications

• Effects of rheumatic disease on fetal outcome – Fetal loss, growth restriction and prematurity

• Prescribing rheumatological and lactation Effect of pregnancy on the mother with rheumatic diseases

Rheumatoid Arthritis 48-75% improve/remission Spondyloarthropathy – peripheral arthritis – may improve – uveitis – may improves – spine – 25% deteriorate

Risk of flare and of developing RA and AS is increased post-partum De Man 2008, Jain & Gordon 2011 Ostensen 2015 Effect of pregnancy on the mother with rheumatic diseases SLE Flare (Sjogren’s) Pre-

Infection

Thrombosis APS Pre-eclampsia

Jain 2011, Clowse 2014, Ostensen 2015 Effect of pregnancy on the mother with vasculitic diseases

• Behcet’s disease thrombosis > activity (17-27% flare, more post-partum)

• Takayasu’s disease hypertension, valve d, heart failure stroke (thrombosis & bleed), renal

• Polyarteritis nodosa – disease onset in pregnancy or post- partum • Granulomatosis with – high mortality if onset in pregnancy polyangiitis – least risk if well controlled • Allergic granulomatosis with polyangiitis

(Jain 2011, Ostensen 2015) Rheumatic disease flare: What is the risk in pregnancy?

• 20-80% • depends on how flare is defined • probably a bit higher than in controls • least risk if disease inactive at onset • less risk if no history of renal disease

Need to distinguish activity from pregnancy changes and complications

Active NOT Pregnancy complications features Facial blush Palmar

Erythema nodosum gravidarum

Buyon 1999, Gordon 2004 Vasculitic not pregnancy Arthritis

-arthralgia and myalgia- unreliable

-synovitis

-beware carpal tunnel syndrome

Beware pulmonary hypertension

Often deteriorates in pregnancy Most common in patients with lupus anticoagulant 50% mortality in pregnancy

McMillan 2002, Prabu 2008 Renal lupus & in pregnancy • : increase >500 mg/24hr (>50mg/mmol) – or doubling of baseline value • Haematuria and proteinuria (pyuria) • Red cell casts (best)

• Hypertension (not initially)

• Active disease elsewhere or active serology

Jain and Gordon 2011 Pre-eclampsia • Pregnancy-induced hypertension (140/90) – or rise of 30 mmHg systolic &/or 15 mmHg diastolic • Proteinuria (>300mg/24hr; PCR 30mg/mmol) • Oedema

Rising serum level Abnormal No active sediment and normal serology 5% normal (0.5% severe)

Neurological dilemmas: disease activity, thrombosis, eclampsia or other pregnancy ? • • • Impaired level of consciousness

• Transient ischaemic attack • Cerebral infarction

• Role of anti-phospholipid antibodies Thrombocytopenia in pregnant rheumatic disease patients

Pre-eclampsia and eclampsia HELLP syndrome (haemolysis, elevated liver enzymes, low )

Abruptio placentae Fetal demise

SLE Anti-phospholipid syndrome

Heparin therapy Normal pregnancy ~9% Serological tests for active autoimmune disease in pregnancy

• C3 and C4 usually rise 10-50% in pregnancy • Fall of 25% suggests active disease

• Rising anti-dsDNA antibodies best in SLE • Rising ANCA in Wegener’s

• Leucopenia or lymphopenia supportive in SLE Jain & Gordon 2011 Systemic sclerosis • May develop in pregnancy or post-partum • Pulmonary hypertension- contra-indication (screen) • Dyspnoea worse in third trimestre • Gastro-oesophageal reflux common – Risk of Mallory-Weiss tears on • Raynaud’s improves and often skin • Hypertension may cause renal crisis (early, diffuse) – Proteinuria suggests pre-eclampsia – ACE inhibitors life-saving

Steen 1999, Gordon 2004. Ostensen 2015 Post-partum flare

• Inflammatory arthropathies • Spondyloarthropathies • SLE • Sjogren’s syndrome • Vasculitides Fetal Outcome in SLE, APS, Vasculitides & Systemic sclerosis

• Fetal loss – spontaneous under 10 weeks – 10-19 weeks – 20 weeks onwards

• Premature delivery – <37 weeks Determinants of Fetal Outcome

Previous fetal loss Anti-phospholipid antibodies &/or low platelets Disease activity at conception & during pregnancy – RA, SLE, vasculitides, systemic sclerosis Maternal systemic or pulmonary hypertension Pre-eclampsia PROM and maternal diabetes – Steroids

Lockshin 2005, De Man 2009, Jain 2011, Ostensen 2015 Causes of premature delivery (9-55% pregnancies in women with RA, SLE, SS or vasculitis)

Poor growth (10-30% premature deliveries) Pre-eclampsia (13-32%) Reduced liquor Spontaneous labour

De Man 2009, Jain 2011, Ostensen 2011 Therapy in pregnancy

Paracetamol (Codeine) • Avoid NSAIDS* Prednisolone Hydroxychloroquine • No Cyclophosphamide • No Methotrexate Azathioprine • No Lefluonamide Sulphasalazine • No MMF Ciclosporin A • No anti-TNF** Tacrolimus • No Rituximab** (Certolizumab) • Avoid Warfarin* * especially 1st, 3rd trimestre Subcutaneous heparin ** especially 3rd trimestre

Corticosteroids Do not impair fertility

Prednisolone oral/IV/IM/IA OK in pregnancy - Inactivated by 11-OH-steroid dehydrogenase - <10% crosses placenta

Prednisolone OK in pregnancy and in breast-feeding – American Academy of Paediatrics approved – British Society for Rheumatology guidelines for drugs in rheumatic diseases in pregnancy/breast-feeding

Caution with dexamethasone and betamethasone used to mature lungs (florinated at 9 alpha ) – not metabolised by placental 11-OH steroid dehydrogenase

Ostensen 2006; Flint 2016 Maternal risks of in pregnancy Premature rupture of membranes Hypertension/pre-eclampsia Osteoporosis (especially with heparin) Infection

• Give Calcium and Vit D3 prophylaxis

NSAIDs Avoid in first trimestre: May prevent or retard ovulation Small increased risk (OR 2.4, Quebec) Possible small increased risk of congenital abnormalities* May prolong gestation High doses: , Stop at 32 weeks gestation: Constriction or premature closure of ductus arteriosus Consider intermittent paracetamol &/or codeine

Ostensen 2006, *Nakhai-Pour 2008,Jensen 2010, Nakhai-Pour 2011, Daniel 2012, Nezvalova-Henriksen 2013, Van Marter 2013, Flint 2016 (BSR guidelines) Hydroxychloroquine

Long half life (>40 days) + crosses + low levels <1% in breast milk Prevents flare and complications from active disease Has useful steroid-sparing & anti-thrombotic effects No effects on fertility No congenital malformations No adverse effects on other pregnancy outcomes & reduces recurrent CHB in anti-Ro/La pregnancies No long term complications Motta 2005, Sperber 2005, Clowse 2006, Ruiz-Irastorza 2010, Irmzly 2012, Diav- Citrin 2013, Cooper 2014, Flint 2016 Azathioprine • Used in pregnancy: SLE and vasculitides transplants inflammatory bowel disease haematological malignancies

No effect on fertility No effect on miscarriages/stillbirths Not metabolised by fetal liver to active metabolites Sim 2011, Jain 2011, de Meij 2013, Ostensen 2013, Casanova 2013, Fischer-Betz 2013, Flint 2016 Risks of azathioprine in lactation

Low concentrations in breast milk (not active) Leucopenia/thrombocytopenia rare Liver dysfunction rare Immunosuppression not confirmed Risk of carcinogenesis uncertain

• Doses <2mg/kg/day given to women appear safe but little long term data published

Gardiner 2006, Sau 2007, Motta 2008, Jain 2011, Ostensen 2013, Flint 2016 Outcome of lupus pregnancies exposed to hydroxychloroquine and azathioprine in UK

• Standardised questionnaire – retrospectively • 10 UK centres • 285 live children born to 199 • 150 HCQ , 135 not exposed (non-HCQ) • 87 AZA, 198 not exposed (non-AZA). • Maternal renal disease, hypertension, steroid use and aspirin exposure were increased in AZA group & babies were smaller median 2.75 v 3.00 kg & born earlier (median 37 v 38 weeks gestation).

Gayed et al, M Res 2015

Outcome of UK pregnancies • No significant differences in congenital anomalies, congenital heart block, neonatal lupus or developmental problems between treatment groups. • Infection requiring hospital management occurred in 69/274 (25%) of children. • Rate of infection appeared higher in the AZA group: 32/86 (37%) compared to 37/188 (20%) in non-AZA (p= 0.002) but there was no significant difference when multifactor logistic regression was used to adjust for confounders (OR 1.91, p=0.095, 95% CI 0.89-4.09). Gayed et al, M Res 2015

Mycophenolate mofetil

• Animal studies show high rate of malformations, IUGR, IUD at clinical doses

• Human data accumulating (>60 pregnancies reported) miscarriages (first trimestre) congenital malformations in 26% - 50% (eg facial dysmorphia, malformations of ears & eyes & digits, cleft lip & palate, micrognathia).

• Should be stopped 6-12 weeks before conception Not recommended pregnancy or lactation

Ostensen 2013, Flint 2016

Anti-TNF therapies

No abnormalities in animal studies Most exposures in first trimestre ~85% infliximab or adalimumab (>100% cord) ~15% with etanercept (~7% maternal) 139 pregnancies with certolizumab (4% cord, Fab) No data for golimumab Risk of infection in newborn if exposed to MAb and immunised with BCG at 3 months Mahadevan 2011, Ostensen 2013, Flint 2016 Anti-TNF therapy • Certolizumab : safest as very little crosses placenta

• Etanercept : increasing uneventful pregnancies • Adalimumab : no toxicity in cynomolgus monkeys or humans so far – Do not cross placenta until week 16 onwards Can be continued until pregnancy confirmed and up to end of second trimestre (IBD data*)

• Infliximab : no risk of congenital malformations but long half life and risk of infection in (stop in first trimestre)

None recommended during lactation… Vinet 2009, *Mahadevan 2011 & 2013, Ostensen 2013, Flint 2016 Rituximab • No evidence of teratogenesis

• Second/third trimester exposure is associated with neonatal B cell depletion

• RTX should be stopped 6/12 before conception but unplanned exposure in the first trimester is not likely to be harmful

• Not recommended during lactation

Chakravarty 2011, Ostensen 2013, Pendergraft 2013, Sangle 2013, Flint 2016 Management of arthritis, SLE, PSS, SS & vasculitides in pregnancy

Before pregnancy occurs: Get disease activity under control Screen for renal involvement & hypertension Exclude pulmonary hypertension Note risks associated with autoantibodies Rationalise drug therapy Ensure potential complications are discussed

Management of arthritis, SLE, PSS, SS & vasculitides in pregnancy

During pregnancy: Monitor disease activity especially renal Beware thrombo-embolic disease & IUGR

After pregnancy: Advice on breast-feeding and contraception Pregnant patients require planned pregnancies, careful monitoring and co-ordinated management to ensure successful outcome for mother and baby