Management Rheumatic Disease Around Pregnancy Carlos Zevallos Jr, DO Crystal Arthritis Center

Management Rheumatic Disease
Around Pregnancy
Carlos Zevallos Jr, DO
Crystal Arthritis Center
Akron, Ohio
Pregnancy in Rheumatic Disease
• Pregnancy causes shift from Th1 to Th2
lymphocyte dominance.
• Th1 disease like RA - remission
• Th2 diseases like SLE - flare
• High Risk: woman’s previous obstetric history,
organ damage, disease activity, serologic
profile, additional medical history
Fertility
• Fertility not generally affected except CKD 3-5,
eGFR<50ml/min, amenorrhea – due to
cyclophosphamide, active disease
• RA and scleroderma - lower birth rates
compared with the general population
• NSAIDs – stop when trying to conceive
• Assisted reproductive techniques – increase
risk of flare and thrombotic events –
particularly SLE
Systemic Lupus Erythematosis
• Plan pregnancy after remission for 6 months – active
lupus = inc risk of flare
– Active lupus nephritis and LN in remission = inc risk flare
– The higher Cr, the greater risk of deterioration
• Lupus flares generally non-severe = arthralgias, rash,
mild hematologic issues
– Severe flare with organ damage can occur
• Unless contraindicated, continue hydroxychloroquine
– Protects against organ damage, flares, thrombosis, bone
mass loss, long-term survival
Systemic Lupus Erythematosis
• Risk of multiple medical and obstetrical complications
during pregnancy, especially those with active disease
or nonreversible organ damage (CVA, CKD, PHTN,
Mod/Sev CM, Sev Rest Lung Dz
• Increased ESR due to high fibrinogen production in
liver
• C3 and C4 rise in pregnancy – increased liver
production (can be normal in active SLE)
• Pts with protein loss due to LN may have increased
proteinuria due to increased renal blood flow without
indicating active LN (expect double proteinuria levels)
Effect of SLE on Pregnancy
• 20 fold increased risk of maternal mortality, inc rate of HTN,
diabetes, renal impairment, PHTN, major infections, thrombotic
events, hematologic complications than general population
• 2-4 fold higher risk of preeclampsia, c-section, preterm labor, IUGR
(particularly in pts with chronic HTN, renal impairment, high dose
steroids)
– Those with SLE in remission without major organ issues likely have
normal pregnancy
• 25% of SLE pregnancies end in preterm delivery
• 6-35% incidence of small for gestational age babies
• Miscarriage in 20% (risk inc with HTN, proteinuria >500mg/d, low
plt, APS)
• 3-4 fold increased chance of preeclampsia
Rheumatoid Arthritis and Other
Arthritis
• 50-66% women with RA and the majority of women with
psoriatic arthritis and JIA improve in pregnancy. (When
both RF and CCP+ = less likely to improve)
• Women with ankylosing spondylitis stay unaltered during
pregnancy.
• Postpartum flares can occur within the first 4 months (new
onset RA 3-5 fold more likely to occur here)
• Women with active disease have a higher risk of preterm
delivery and small for gestational age babies.
• RA has a higher risk of hypertensive disorders during
pregnancy.
• Children more likely small for gestational age, preterm,
lower birth weight
Scleroderma
• Pregnancy does not seem to affect disease activity in
the majority of patients (63-72%).
– 1/3 will improve or worsen during pregnancy
• Associated with higher risk of hypertensive disorders
and higher rates of adverse pregnancy outcomes.
(preeclampsia)(Monitor for renal crisis)
• Raynauds improves, GERD worsens, Skin stays stable or
improves (may worsen postpartum)
• Recent onset dz, diffuse cutaneous dz, SCL70, RNA
polymerase 3 = increased risk of more active disease.
Scleroderma
• Pts with marked malabsorption, CKD (Cr>2.5-2.8), PHTN, mod/sev
CM (EF<30-40%), or severe RLD are at highest risk of medical and
obstetric complications and should be counseled against conception
• Renal crisis rate is same, but may need to treat with ACE inh if it
occurs
• Previous renal crisis does not contraindicate further pregnancy, but
should delay for several years after stabilized.
• Corticosteroid for lung maturation should not be given, may
precipitate renal crisis.
• SSC associated with increased risk of preterm delivery (14-29%)
– Inc risk of IUGR, miscarriage
Vasculitis
• If in remission prior to pregnancy, low rate of
complications and good pregnancy outcomes are
reported.
• Hypertensive disorders, including preeclampsia, are
associated with poorer outcomes.
• ESR not reliable, but CRP is reliable
• RX – Low dose steroids (<7.5-10mg) and azathioprine.
CYC if life threatening disease (contraindicated in 1st
and early 2nd trimesters – may need IVIG during this
time period)
• Behcet’s – mild ulcers to severe CNS involvement or
thrombosis(V/A).
Antiphospholipid Syndrome
• Antiphospholipid antibodies represent one of the
major risk factors for poor obstetric outcome.
– incr risk of preeclampsia, IUGR, prematurity,
miscarriage
– Recheck aPL shortly prior to pregnancy in SLE
• Double or triple positive antibodies, and/or those
with thrombotic antiphospholipid syndrome have
the worst obstetric outcomes.
• Rx – LDA, LMWH – for recurrent early
miscarriage, or previous fetal death >10 weeks
gestation and/or preterm <34 weeks
Undifferentiated Connective Tissue Disease,
Polymyositis,/Dermatomyositis, Mixed Connective
Tissue Disease
• Outcomes for UCTD and MCTD resemble
those of SLE. (increased risk of preeclampsia,
IUGR, preterm delivery)
• Active PM and DM is associated with preterm
delivery and pregnancy loss.
– 50% will flare
Neonatal Lupus
• In Anti-Ro and/or anti-La can cause neonatal lupus
syndrome affecting skin, heart, liver, cytopenias
• Cutaneous neonatal lupus is seen in approximately 5% of
offspring (resolve 3-6 months after birth), whereas
congenital heart block is seen in about 2% (risk is 18% if
prior child with CHB, 50% if 2 prior children with CHB) – risk
of perinatal death is 20% - will need permanent pacemaker
if survives.
– Abs cross placenta between 16th-30th week gestation
• Repeated fetal echocardiograms from the 16th week of
gestation recommended
• Rx – Fluorinated steroids – betamethasone and
dexamethasone (less metabolized by the placenta)
Pregnancy Management Plan
• Pre-pregnancy assessment is vital.
• Emphasis on previous obstetric and medical history,
serology profile, disease activity, and extent of organ
damage.
• Monitor UA for proteinura, assess HTN, labs – DNA, C3/4,
CRP, CBC, Cr, LFTs
• Higher risk of preeclampsia – may use LDA to decrease risk
• Calcium 1 gm daily showed >50% reduction in risk of
preeclampsia and 25% reduction in risk of preterm delivery
• Antenatal and postnatal plan and multidisciplinary team
input are essential to achieve good maternal and fetal
outcomes.
Postpartum
• Close surveillance for 2-3 months after
delivery is important owing to high risk of flare
and thrombosis.
• All women with aPL should receive
prophylactic LMWH for at least 7 days after
delivery
• Counseling on contraception.
Hydroxycholroquine
• Crosses the placenta
• Category C
• Found in human breast mild. Infant may be
exposed to 2% of maternal dose
• Rec – Continue HCQ during pregnancy and
lactation with SLE to help prevent flares
Sulfasalizine
• Crosses the placenta
• Category B/D
• Lactation – drug concentrations is 40% that of the
maternal level. Use with caution.
• Rec- Does not appear to increase the adverse
fetal outcome or have adverse affects during
lactation
– Concomitant folate supplementation is recommended
and the dose of SSZ should not exceed 2 gm per day.
NSAID and LDA
• Minimal fetal/maternal risk when use is limited to 1st
to end of 2nd TM
• Category C for 1st two TM
• Lactation – Excreted in breast milk in small amounts.
May be compatible with breast feeding, but use with
caution – See drug information guide for each drug
• Recs – avoid NSAIDs during planned conception cycle
until pregnant. NSAIDs may be associated with an
increased risk of spontaneous abortion before 20
weeks of gestation. Avoid after week 30.
Glucocorticoids
• Prednisone and prednisolone cross the placenta but appear in only
small amounts in cord blood
• Dexamethasone and betamethasone reach higher concentrations in
the fetus
• Prednisone is cat B. Other GC are cat C.
• May increase risk of cleft palate, adrenal hypoplasia
• May increase risk of premature rupture of membranes, intrauterine
growth restriction
• In MOM – pregnancy induced HTN, gest DM, OP, infection
• Lactation – excreted in breast milk. Discard breast mild for first 4
hours after pred dose >20mg.
• Recs – use lowest dose. Try to avoid during first TM when hard
palate is forming. May need stress dose during labor, delivery, and
immediately postpartum.
Azathioprine
• Cat D
• 64-93% of AZA mother dose in fetal blood as inactive
metabolite
– Placenta metabolizes AZA to thiouric acid – which is inactive
– Fetal liver lacks enzyme inosinate pyrophosphorylase which is
necessary to convert AZA and 6-MP to active metabolites
• Study of 101 pregnancies revealed no association with poor
pregnancy outcomes at doses of 100mg/d
• Recs – Manufacturer insert state excreted in breast milk.
More recent data suggests -Very low excretion in breast
milk.
TNF inh
• Pregnancy outcome, preterm birth rates,
spontaneous abortions, congenital abnormalities
similar to women with RA
• A case report suggested a possible association
with VACTERL (Vertebral anomaly, Anal atresia,
Cardiac defects, Tracheoesophageal fistula,
Esophageal atresia, Renal anomalies, Limb
dysplasia)
• Category B
• Lactation – insuf data
• Recs – Discontinue TNF inh prior to conception
IVIG
• Crosses the placenta after 30-32 weeks of
gestation
• Category C
• Lactation – Not known
• Recs – Reasonable to use during some preg
Cyclosporine
• Little or no transplacental transfer in some reports – other
yes
• Risk of teratogenicity is low
• Assoc with lower birth weights, inc maternal DM, HTN,
renal allograft rejection
• A report on 6 infants born to mother on cyclosporine found
that T, B, NK cell development and maturation were
impaired with effects still seen at 1 year – without
development of predominant health problems at
reproductive age
• Category C
• Lactation – is excreted in milk – not rec to breast feed
• Recs – When needed, use lowest dose.
Tacrolimus
• Cat C
• Lactation - not rec
• Long-term immunomodulatory effect on
offspring not known. Use smallest dose.
Monitor BP and renal fxn.
Cyclophosphamide
• Risk of infertility and amenorrhea associated with med
• Risk of ovarian failure depends on age - >31yo = highest risk; also
accumulative dose
• Animals – exopthalmos, cleft palate, skeletal abn, fetal resorption,
growth retardation,
• Risk of teratogenicity is high ~20%
• Used only when disease poses grave health threat to mother
• Normal children have been born to offspring exposed to CYC
• Risk of terat highest during 1st TM
• Cat D
• Lactation – avoid
• Recs – avoid except in life threatening disease without other
alternatives available
Chlorambucil
• Rodents – bone formation defects, renal
hypoplasia
• Case reports of healthy infants
• Cat D
• Lactation – not rec
• Recs – Strongly rec avoiding
Methotrexate
• Folate antagonist – inhibits dihydrofolate reductase and thus interferes
with folic acid metabolism and purine synthesis
• Embryotoxic in early preg
• Skeletal abnormalities and cleft palate later in preg
• Hydrocephalus, anecephaly, menigomyelopathy, congenital stenosis of
tubular bones, abn facial features, delayed ossification
• Rate of cong abn 9-17%
• Widely distributed in maternal tissues
• Persists in liver up to 4 months after exposure
• Discontinue med 3-4 months prior to conception
• Continue folic acid through preg
• Cat X
• Lactation- contraindicated
• Recs – Strongly rec against use during preg or lactation
Mycophenolate Mofetil
• Cleft lip/palate, microtia and external auditory
canals, anomalies – distal limbs, heart,
esophagus, kidneys
• Inc in 1st TM miscarriages
• Cat D
• Should discontinue at least 6 weeks before
conception is attempted
• Lactation – avoid
• Recs – don’t use
Leflunomide
• T1/2 15 days
• Teiflunomide (=major metabolite) undergoes extensive
enterohepatic circulation and remains detectable in serum
for up to 2 years
• Eliminate with use of cholestyramine 8g TID for 11d and
confirm level <0.02mg/L on 2 tests 2 weeks apart
• Embryotoxic and marked teratogenicity in animal studies
• Cat X
• Lactation – avoid
• Recs - Avoid Lef up to 2 years before preg. Do not use
during preg or lactation. Wait at least 3 menstrual cycles
after cholestyramine before attempting conception
Anakinra
• Recombinant human interleukin 1 receptor
antagonist
• Cat B
• Lactation – Insuf data –avoid
• Recs – avoid preg and lact
Rituximab
• Chimeric monoclonal ab
• Peripheral B cell depletion by targeting CD20
antigen on B lymphocytes
• Detected in high concentrations in umbilical
blood
• Cat C
• Lactation – Insuf data – avoid
• Recs – avoid preg and lact
Abatacept
•
•
•
•
•
CTLA4-Ig is an inhibitor of T-cell co-stimulation
Not teratogenic in animals
Cat C
Lactation – insuf data
Recs – Avoid in preg and lact
Tocilizumab
•
•
•
•
•
Interleukin 6 receptor inhibitor
Animals – may cause fetal harm
Cat C
Lact – insuf data
Recs – avoid in preg and lact
Summary - Medications
• Azathioprine, plaquenil, sulfasalizine, ciclosporin, and
tacrolimus, IVIG are safe in pregnancy and lactation.
• Steroids are safe but can have increased side effects
and complications if used for prolonged periods and at
doses >7.5mg daily. Limited boluses are safe.
– Nonfluorinated steroids (prednisone, methylprednisolone,
hydrocortisone) are largely metabolized by placenta and
thus minimal amounts reach fetal circulation – Cat B
– Dexamethasone and betamethasone cross the placenta
with similar maternal and fetal concentrations – Cat C
– At high doses of prednisone >20mg daily, wait until 4 hours
after the dose to breastfeed.
Summary - Medications
• Biologics – TNF inhibitors may be safe in the
1st and 2nd trimesters and lactation.
• Avoid – MTX, Arava, Rituxan, Cellcept,
Cyclophosphamide, Endothelin receptor
antagonisits, bisphosphonates
• Unknown – abatacept, tocilizumab,
belimumab
• NSAIDs are class B for intermittent use, but D
if >30 weeks gestation
Summary - Medications
• Mild disease
– Low dose prednisone 5-15 mg per day, Plaquenil, SSZ
• Moderate to Severe disease
– Plaquenil, GC, Azathioprine, Cyclosporine, IVIG
• Life-threatening disease
– High dose GC, Cyclosporine, Azathioprine, 6mercaptopurine,
– Cyclophosphamide if no other alternative available
• Avoid Leflunomide, Methotrexate, chlorambucil ,
mycophenylate mofetil
References
• Ateka-Barrutia O, et al. Management of
Rheumatologic Diseases in Pregnancy. Int J Clin
Rheumatol. 2012;7(5):541-558.
• Temprano K, et al. Anti-rheumatic Drugs in
Pregnancy and Lactation. Semin Arthritis Rheum
2005;35:112-121.
• Bermas B. Use of Anti-inflammatory and
Immunosuppressive Drugs in Rheumatic Diseases
During Pregnancy and Lactation. UpToDate 2013.