Transcript pre-eclampsia

Connective tissue disease in pregnancy
Catherine Nelson-Piercy
Concerns in pregnancy
Effect of CTD disease on pregnancy outcome
Effect of pregnancy on CTD disease
Drugs
In pregnancy
While breast feeding
Connective Tissue Disorders
SLE
Systemic Lupus Erythematosus
RA
Rheumatoid arthritis
MCT
Mixed Connective Tissue disease
SS
Systemic sclerosis/scleroderma
Vasculitis
• Safety of Drugs
– In pregnancy
– While breast feeding
Pre-pregnancy counselling
‘Contraindications’ to pregnancy:
Pulmonary hypertension
SLE / scleroderma
Drugs:
•
Mycophenolate mofetil (MMF)
CKD stage 4/5
•
Methotrexate
Active lupus nephritis
•
Cyclophosphamide
Severe restrictive lung disease
•
Warfarin / NOAC
Pregnancy outcome in SLE
Disease activity
Lupus nephritis
Hypertension
Renal impairment
Anti Ro / La
Antiphospholipid antibodies
Cardiac / Lung involvement
SLE – Disease activity
Active disease at conception or first presentation of SLE in pregnancy
increases the risk of
• pre-eclampsia
• fetal growth restriction
• preterm delivery
Pregnancy increases the risk of disease flare
Flares more difficult to diagnose
Hair fall
facial erythema
Fatigue
anaemia
Oedema
raised ESR
Musculoskeletal pain
Renal involvement / hypertension
Increased risk of pre-eclampsia / FGR / preterm delivery
Even quiescent lupus nephritis increases risk of fetal loss, especially
if hypertensive or proteinuric
Risk of deterioration is higher with higher serum creatinine
Chance of successful outcome is lower with higher serum creatinine
SLE nephropathy may manifest for the first time in pregnancy
Delay pregnancy for 6 months after renal flare
CKD 1
CKD 3
eGFR <60
Stratta et al, J Nephrol 2006
Incidence of pre-eclampsia during pregnancy: comparison
between the normal population and nephropathic women.
Fig. 2
Lupus nephritis
Imbasciatti et al. Nephrol Dialysis Transplant 2009; 24: 519-25
113 pregnancies 81 women pre-existing biopsy-proven LN.
Renal Bx performed 7.2 +/- 4.9 years before:
6 class II,
8 class III,
48 class IV
19 class V.
At conception, 49% in complete and 27% partial remission.
9 MC, 1 SB, 5 NNDs.
31 (30%) preterm.
34 (33%) BW <2500 g
Lupus nephritis
Imbasciatti et al. Nephrol Dialysis Transplant 2009; 24: 519-25
34 (33%) renal flares (pregnancy & postpartum)
20 were reversible
3 progressive decline of GFR (1 on dialysis).
Pregnancy outcome was predicted by
-hypocomplementaemia at conception (RR 19.02; 90% CI 4.58-78.96)
-aspirin during pregnancy (RR 0.11; 90% CI 0.03-0.38).
Renal flare was predicted by renal status
partial remission RR 3.0; 90% CI 1.23-7.34,
Non remission RR 9.0; 90% CI 3.59-22.57.
SLE with and without Lupus Nephritis
SLE + Nephritis
SLE - Nephritis
Maternal Outcome
Pre-eclampsia
7 (20.6%)
10 (16.9%)
Thrombus
0
1 (1.7%)
Flare
14 (41.2%)
22 (37.3%)
Neonatal Outcome
IUD
1 (2.9%)
1 (1.7%)
NND
1 (2.9%)
0
Gestation
Mean±SD
36.7± 4.2
38.2 ± 3.0
% <34/40
6 (17.6%)*
4 (6.8%)*
% <37/40
10 (29.4%)
10 (16.9%)
Birth Weight (g)
Mean±SD
2715 ± 862
2963 ± 717
%<10th Centile SGA
10 (29.4%)
14 (23.3%)
Bramham et al. J
Rheumatol. 2011
Explain the risks of prematurity
Increasing proteinuria
Physiological
Secondary to discontinuation of ACEI
Pre-eclampsia
Nephritic flare
Nephritic flare / Pre-eclampsia
BOTH
SLE
Hypertension
Rising anti-DNA titre
Proteinuria
RCs or cellular casts in urine
Thrombocytopenia
Fall in C3 / C4
Renal impairment
No increase in uric acid
No abnormal LFTs
Other features of active SLE
Infection or Inflammation?
Infection
Raised CRP
Inflammation
Raised / reduced WC
Normal CRP (↑in pericarditis / lupus
pneumonitis / arthritis)
Fever
Reduced WC
Response to antibiotics
Fever
Raised procalcitonin (sensitivity 70%) Response to immunosuppression
Remember: most deaths in SLE are
due to overwhelming sepsis
Anti Ro / La antibodies (ENA)
Mother
Fetus / Neonate
30% of women with SLE
Risk of neonatal cutaneous
lupus = 5%
Associated with
photosensitivity, subacute
LE, Sjogren’s, Raynaud’s,
ANA- negative SLE
50% have CTD within 15yrs of
baby with CHB
Risk of congenital heart block
= 2%
Offer fetal cardiology scan
(18/20 and 28 weeks)
Neonatal cutaneous lupus
Manifests age 2-3 weeks
Geographical skin lesions (cf. Subacute cutaneous LE)
Face, scalp
After exposure to sun / UV light
Disappears spontaneously within 6 months
Residual hypopigmentation/telangiectasia for up to 2 yrs
No scarring
Congenital Heart Block (52Kd Ro, 60 Kd Ro, La)
Appears in utero; 18-20 weeks
Fetal bradycardia (1st or 2 nd degree precede)
Increased PNMR – 20%
50-60% of those who survive need pacemakers in early infancy (others
in early teens)
Pathogenesis; inflammation and fibrosis of conducting system; direct
effect on myocytes
Pancarditis and myocarditis associated
16% (10 fold) recurrence rate
No role for prophylactic steroids, IVIG, plasmapheresis (Brucato
Rheumatology 2008)
Autoimmune Congenital Heart Block: A Systematic Review
P. Brito-Zerón, P. Izmirly, M. et al. Nat Rev Rheumatol 2014 In press
1416 cases from 9 retrospective case series
Overall incidence of CHB in Ro + ve mothers = 20/729 = 2.74%
54% diagnosed 20-24 weeks
21% diagnosed 25-29 weeks
75% 20-29 weeks
19% mortality (of which 70% = in utero)
64% required pacemaker (of which 80% within 1st year of life and
67% within 10 days of birth)
Recurrence in subsequent pregnancy (97/574 = 17%)
86% of women with babies with ACHB are anti-Ro +
N = 1416
N =1216
Rest 14%:
-Others (ANA,FR,DNA…)
-Not tested for the 4 abs (Ro/SSA,La/SSB,Ro52,Ro60)
-Included some post-natal CHB
3 databases (US, UK, France)
Analysis of pregnancies following a child with cardiac NL
HCQ (started < 10/40 and continued) reduced recurrence of
CHB by 77% (OR 0.23; 95% CI 0.06-0.92; P=0.037).
N = 257
+ HCQ (40)
-HCQ (217)
Unaffected
37
171
Cardiac NL
3 (7.5%)
46 (21.7%)
Izmirly et al. Circulation 2012
Rheumatoid arthritis
Traditional teaching:
Pregnancy shifts Th1 dominance to Th2 dominance.
Th2 cells reduce IL and TNF.
Most improve in pregnancy (only 16% complete remission)
If improves, 90% suffer postpartum exacerbation
T-cell immunity reduced in pregnancy and returns in puerperium
First presentation of RA increased in first puerperium
Rheumatoid arthritis
Page 23
Prospective studies (UK, Netherlands):
Only 40-75% improve in pregnancy and < 25% achieve remission by
the third trimester.
•
Women without anti-cyclic citrullinated peptide (anti-CCP), or rheumatoid
factor (RF) more likely to improve in pregnancy. (75% vs 39%) (n=118)
•
Equally likely to improve post partum (42%vs 34%)
•
Anti-CCP, IgM and IgA-RF fall post partum.
de Man et al. Ann Rheum Dis 2010;69:420.
Rheumatoid arthritis
Medications
Continue Aza and HCQ
5 mg folate if taking sulfasalazine
Oral or Intra-articular steroids
NSAIDs until 32 weeks
Biologics safe
Refer obstetric anaesthetist
Atlanto-axial subluxation
Limitation of hip abduction
Flares post-partum are common
33% flare within 1/12 post-partum and 98% by 4/12
despite an increase of medications post-partum.
de Man et al. Arthritis Rheum 2008;59(9):1241-8.
Raynaud’s
Usually improves in pregnancy (increased skin blood flow; vasodilation)
Heated gloves
Nifedipine (10 mg SR BD)
Sjogren’s
Dry eyes/ dry mouth
Primary /secondary (SLE)
Check ENA (anti Ro/La)
Artificial tears / saliva
Scleroderma
Localized cutaneous
Systemic sclerosis
CREST (anticentromere Abs)
Calcinosis
Raynaud’s
E/Oesophageal involvement
Sclerodactaly
Telangiectasia
Systemic sclerosis
Progressive fibrosis involving oesophagus, lungs, heart, kidneys
High risk in pregnancy = early (< 4yrs) and renal involvement
Check FVC
Check echo (for pulmonary hypertension)
U3RNP (PHT) + Scl70/Topo (lung) markers
Check renal function
Beware postpartum deterioration
Fetal and maternal outcomes in Systemic Sclerosis
25 Italian centers, 99 women, 109 pregnancies (from 2000 to 2011)
Median disease duration at conception 60 months (range 2-193 months).
Taraborelli et al Arthritis Rheum. 2012
SSc (109)
Control (3939)
Preterm (%)
25
12
<34/40 (%)
10
5
FGR (%)
6
1
VLBW (%)
5
1
Preterm deliveries
Increased with steroids (OR 3.63, 95% CI [95% CI] 1.12-11.78)
Reduced with anti-Scl-70 antibodies (OR 0.26, 95% CI 0.08-0.85)
4 cases progression of disease within 1 year from delivery (all anti-Scl-70 +ve
3 had disease duration of <3 years).
Systemic sclerosis
Do not stop ACE inhibitors
Steroids (> 10 mg /day) can precipitate a renal crisis
Refer obstetric anaesthetist
Difficulty monitoring BP
Difficulty monitoring oxygen saturation
Difficult venous access
Difficult airway
Lung function
Don’t give steroids for fetal lung maturation
Vasculitis
Takayasu
43% PIH / Preeclampsia
Exclude PHT
Monitor with ESR / CRP
Continue immunosuppression (pred / aza)
Granulomatosis with polyangiitis GPA (Wegener’s)
Nose, sinuses, lungs, kidneys
45% flare
35% preterm
ANCA positive
Microscopic polyangiitis MPA
Rapidly progressive GN
p-ANCA and anti-MPO positive
Continue immunosuppression (pred / aza)
Cyclophosphamide
Rituximab
Gatto et al. Autoimmunity Reviews 2012
Vasculitis - pregnancy outcome
Page 32
66 pregnancies in 44 women from 8 centres in Italy
Livebirth rate 86%
8 miscarriages < 10/40; 1 fetal death
Disease related complications in 24(36%) in pregnancy
7 severe (3 TIAs)
20% post partum flare
Vasculitis
General Population
Preterm
29
12
Very preterm
16
5
Caesarean section
49
31
Fredi M et al. 2014
Medications
YES
NO
Steroids
NSAIDs (third trim)
Azathioprine
Cyclophosphamide (1st trim)
Cyclosporin / tacrolimus
Methotrexate, thalidomide
Hydroxychloroquine
Chlorambucil
Sulfasalazine
Gold, D-penicillamine
(Etanercept / infliximab)
Adalimumab)
Mycophenolate mofetil
IVIG
Rituximab / abatacept
Leflunamide
Ostensen M et al. Arthritis Research & Therapy 2006; 8: 209
Update: Rheumatology (Oxford). 2008 Jun;47 Suppl 3:iii28-31.
Guidelines for use of antirheumatic drugs in pregnancy
Page 34
Facial appearance of Mycophenolate Mofetil embryopathy
Microtia
External auditory
canal atresia
Orofacial clefts
Micrognathia
Hypertelorism
Cardiovascular
malformations
Digital hypoplasia
Anderka et al 2009 Am J Med Genet 149A:1241-48 Perez-Aytes A, Am J Med Genet A. 2008;146:1-7
Page 36
Page 37
Page 38
Risk for adverse pregnancy outcome increased with every
• mg of prednisone dosage [odds ratio (OR) 2.03] and
• single unit of SLEDAI score (OR 3.92).
Renal flares occurred post-partum in two women.
No patient developed worsening of renal function.
Mycophenolate Mofetil and Pregnancy
MMF not recommended
MMF should be reserved for when no more suitable alternative is available
MMF should be used in pregnancy only if potential benefit outweighs
potential risk to the fetus
Stop (switch to azathioprine) at least 6 weeks before planned pregnancy
(long half life, enterohepatic recirculation)
Page 40
Biologics in pregnancy
In pregnancy maternal antibodies are transported across placenta by
the neonatal Fc receptor
Immunoglobulin concentrations increase in fetal blood from early
second trimester until delivery
IgG1 is the most efficiently transported Ig subclass
Infliximab and adalimumab are IgG1 subclass anti TNFα antibodies
that are actively transported across the placenta (cord blood levels
~150% of maternal)
Etanercept soluble receptor fusion protein (murine Fc portion), much
shorter half-life, less binding to placental Fc receptors; etanercept
cord levels much lower at 3.5%-7.4%
Certolizumab pegol is pegylated Fab fragment of humanized anti
TNFα monoclonal antibody without an Fc portion. Therefore any
transport across the placenta is by passive diffusion
Hyrich KL, Verstappen SM. Biologic therapies and pregnancy:. Rheumatology 2013.
Biologics in pregnancy
Systematic review (for IBD)
58 studies; 33 case reports, 21 case series
>1533 patients (1 study 289 pregnancies IBD + other
indications)
No increase in adverse outcome
No increase in congenital malformations
No increase in RR infections in first year of life
Stop only in remission and use usual stopping criteria
Nielsen OH, et al. BMC Med. 2013;11:174.
Planning management
Page 43
When deciding whether to continue, restart, or stop biological therapy in
pregnancy, it is important to consider:
•
likely disease course in pregnancy
•
which other therapies may be available to women and are likely to
control the disease and symptoms
•
pharmocokinetics of individual biologic agent
Page 44
Biologic
Half life
Cord:maternal
blood ratio
Suggested
gestation to
discontinue
Infliximab
8-10 days
83-400%
21
Adalimumab
10-20 days
98-293%
28
Etanercept
4 days
3.6-7.4%
32
Certolizumab
14 days
1.5-24%
Don’t stop
Adapted from Soh MC & Nelson-Piercy C. High Risk Pregnancy
and the Rheumatologist. Rheumatology 2014.
Rituximab global drug safety database
Chakravarty EF et al. Blood 2011; 117(5):1499-506.
231 pregnancies with maternal rituximab exposure.
153 pregnancies with known outcomes
90 live births.
22 (24%) preterm (30-36 weeks)
1 NND at 6 weeks. (? Cause)
11 neonates hematologic abnormalities; 0 had infections.
4 neonatal infections were reported (fever, bronchiolitis, cytomegalovirus
hepatitis, and chorioamnionitis).
2 congenital malformations: clubfoot in one twin, and cardiac
malformation in a singleton birth.
1 maternal death from pre-existing ITP
Hierarchy of risk aversive behaviour
Page 46
Gastroenterologists
Continue in
pregnancy
Rheumatologists
Stop at conception
Dermatologists
Stop 6 months prior
to conception
Rheumatology
Alternatives in pregnancy
Ank spond
RA
SLE
Page 47
Azathioprine and breast feeding
Moretti, Verjee, Ito, Koren. Ann Pharmacotherap 2006; 40: 2269.
6MP undetectable in breast milk samples from 4 mothers taking
azathioprine
Used HPLC – limit of detection = 5ng/ml
Relative infant dose < 0.09% of weight adjusted adult dose
Singh, Qualie, Currie, Howarth, Khare. Obstet Med 2011; 4: 104.
10 mother –baby pairs. No adverse effects
BJOG 2007; 114: 498-501.
•31 breast milk samples from 10 women
•Low levels (2-10% therapeutic) of 6MP in 2
samples from 1 woman
•No detectable 6MP or 6TGN in any of the
neonatal blood samples
Is Infliximab safe to use while breast feeding?
Stengel et Arnold. W J Gastroenterol 2008;14:3085
22yo fistulizing ileocolonic CD
10mg/kg (1000mg) infliximab x 6 doses in pregnancy
Last dose 2 weeks prior to delivery
CS 39/40; BW 7lb 6 oz
Fully breast fed
Breast milk spiked with 40 ng/ml infliximab
Infliximab detected in all spiked samples (1:2, 1:4, 1:8) but not her unspiked
breast milk
Usual dose (10mg/kg) of infliximab given, breast milk collected daily for 30
days. NO INFLIXIMAB DETECTED
Methotrexate in men
Weber-Schoendorfer C1, Hoeltzenbein M, Wacker E, Meister R, Schaefer C.
Rheumatology (Oxford). 2013 Dec 24. [Epub ahead of print]
Prospective observational cohort study
113 pregnancies paternal low-dose methotrexate
412 non-exposed pregnancies
No increase in major birth defects or miscarriage
No difference in gestational age at delivery or birth weight
Findings do not support the necessity of a 3-month MTXfree interval until conception (Ann Rheumat Dis 2009; 68:1086-93.)
No excess risks in offspring with paternal preconception
exposure to DMARDS
Page 52
Linkage of data from a longitudinal observational study of patients with
inflammatory joint disease (the Norwegian Disease-Modifying
Antirheumatic Drug [NOR-DMARD] registry study) and the Medical Birth
Registry of Norway (MBRN)
1,796 men with inflammatory joint disease were associated with 2,777 births
110, paternal exposure to DMARDs within 12 weeks before conception
methotrexate (n = 49), sulfasalazine (n = 17), anti TNF (n = 57).
230, the father had never been exposed to DMARDs before conception.
Neither adverse pregnancy outcomes nor occurrence of congenital
malformations differed between patients and reference subjects in either
group.
Wallenius M1, Lie E, Daltveit AK, Arthritis Rheumatol. 2015 Jan;67(1):296-301.
Connective Tissue Disease in Pregnancy - summary
Pre-pregnancy counselling to explain risks and stratify
Outcome dependent on disease activity and systemic involvement
High risk pregnancies need multidisciplinary care
Most drugs are safe and errors of omission should be avoided
Page 53
Thank you for your
attention!