Pregnancy and Rheumatological Diseases

Caroline Gordon

Rheumatological Diseases in Pregnancy

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

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

• Prescribing rheumatological drugs in pregnancy and lactation

Effect of pregnancy on the mother with rheumatic diseases

Rheumatoid Arthritis

Spondyloarthropathy

– peripheral arthritis

– uveitis

– spine

48-75% improve/remission

– may improve

– may improves

– 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 (Sjogren’s)

APS

Flare Hypertension Pre-eclampsia Diabetes Infection Thrombosis Pre-eclampsia Thrombocytopenia

Jain 2011, Clowse 2014, Ostensen 2015

Effect of pregnancy on the mother with vasculitic diseases

• Behcet’s disease

• Takayasu’s disease

• Polyarteritis nodosa

• Granulomatosis with polyangiitis

• Allergic granulomatosis with polyangiitis

thrombosis > activity (17-27% flare, more post-partum)

hypertension, valve d, heart failure stroke (thrombosis & bleed), renal

– disease onset in pregnancy or post-

partum – high mortality if onset in pregnancy – least risk if well controlled

(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

NOT Active lupus

features Pregnancy complications

Facial blush

Melasma

Palmar erythema

Erythema nodosum

gravidarum

Buyon 1999, Gordon 2004

Vasculitic rash 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 & vasculitis in pregnancy

• Proteinuria: 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 uric acid level Abnormal liver function tests No active sediment and normal serology 5% normal pregnancies (0.5% severe)

Neurological dilemmas: disease activity, thrombosis, eclampsia or

other pregnancy complication?

• Headache

• Seizure

• 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

platelets) 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 vomiting

• 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 abortions under 10 weeks

– miscarriages 10-19 weeks

– stillbirths 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

Fetal distress

Rupture of membranes

Spontaneous labour

De Man 2009, Jain 2011, Ostensen 2011

Therapy in pregnancy

Paracetamol (Codeine) Prednisolone Hydroxychloroquine Azathioprine Sulphasalazine Ciclosporin A Tacrolimus (Certolizumab) Aspirin Subcutaneous heparin

• Avoid NSAIDS*

• No Cyclophosphamide • No Methotrexate • No Lefluonamide • No MMF • No anti-TNF** • No Rituximab** • Avoid Warfarin*

* especially 1st, 3rd trimestre ** 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 position) – not metabolised by placental 11-OH steroid dehydrogenase

Ostensen 2006; Flint 2016

Maternal risks of corticosteroids in pregnancy

Premature rupture of membranes

Gestational diabetes

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 miscarriage (OR 2.4, Quebec)

Possible small increased risk of congenital abnormalities*

May prolong gestation

High doses: oligohydramnios, bleeding

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 placenta + 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 mothers

• 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 infant (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