Download Optimizing the care of the care of the reproductively

Optimizing the care of the care of the
reproductively active rheumatic
patient
Salahuddin Kazi
The Epidemiology of Fertility,
Pregnancy and Outcomes in
Rheumatic Patients
Pregnancy and lupus
~4500 pregnancies in women with SLE each year in the
United States
one third will result in a cesarean section
33% will have preterm birth
more than 20% will be complicated by preeclampsia
Clowse M.E.B., Jamison M.G., Myers E., et al: National study of medical complications
in SLE pregnancies. Arthritis Rheum 54. (9 Suppl): S263-S264.2006
Pregnancy in scleroderma
the overall success rate ( live birth) was:
84% in women who had limited scleroderma
77% in women who had diffuse scleroderma
84% in the historical controls.
Steen V.D.: Pregnancy in women with systemic sclerosis. Obstet Gynecol 94. (1):
15-20.1999
The spectrum of
reproduction
The patient preventing/postponing reproduction
The patient preserving fertility
The patient actively planning pregnancy
The pregnant patient
The postpartum patient
The lactating/nursing patient
The patient preventing/postponing
pregnancy
Oral Contraceptives – likely safe
SELENA trail – 1 year placebo controlled study in SLE
Patients with inactive or stable active lupus
Women with moderate anticardiolipin or the lupus
anticoagulant were excluded
No increase in lupus flares
Depo-Progesterone – effective and safe for short term use
FDA advised that the use be limited to 2 years because of an
increased risk of osteoporosis with long-term use
IUD - a woman with SLE who has a single partner and who is not
on immunosuppressive drugs other than low-dose prednisone is
considered an appropriate candidate
The patient preserving
fertility
Less important issue with decreasing use of
cyclophosphamide and shorter durtaion of therapy
The PREGO study – ongoing – will compare monthly
injection of gonadotropin-releasing hormone
analogue (GnRH-a) to placebo in young SLE patients
during cyclophosphamide therapy
The only established method for preservation of
child-bearing potential in women at risk of gonadal
failure is embryo cryopreservation
Immunosuppressive Drugs
in Pregnancy
Contraindicated
Potentially Safe:
Caution Advised
Insufficient Data
Methotrexate
Glucocorticoids
TNF inhibitors
Leflunomide
Azathioprine
Anakinra
CellCept
6- mercaptopurine
Rituximab
?NSAIDs
Sulfasalazine
Abatacept
Cytoxan
Hydroxychloroquine
Intravenous immune
globulin
The patient actively planning
pregnancy
When to discontinue medications
Methotrexate – 3 months
Leflunomide – 2 years! + washout if < 2 years
CellCept – 3 months
NSAIDS – 2 weeks
Anti-TNF – after pregnancy confirmed
The pregnant patient
The patient with well controlled disease
The patient with active disease
The special case of the SSA/Ro positive patient
The patient with antiphospholipid antibodies
Patient with well controlled RA
on an anti-TNF agent
JW is a 32 year old woman with RF+ve, CCP + RA
She avoided methotrexate and has been on Humira
monotherapy – with well controlled disease for 18
months
She is now keen to start a family
Should she stop/continue anti-TNF therapy?
Table 1 Pregnancy risk categories (adapted
from FDA Consumer60) associated with
antirheumatic drugs
Skomsvoll JF et al. (2007) Drug Insight: anti-tumor necrosis factor therapy for inflammatory arthropathies
during reproduction, pregnancy and lactation
Nat Clin Pract Rheumatol 3: 156–164 doi:10.1038/ncprheum0426
Skomsvoll JF et al. (2007) Drug Insight: anti-tumor necrosis factor therapy for inflammatory arthropathies
during reproduction, pregnancy and lactation
Nat Clin Pract Rheumatol 3: 156–164 doi:10.1038/ncprheum0426
Key Points
No increased risk of adverse pregnancy outcome has been
demonstrated in patients treated with anti-tumor necrosis
factor (anti-TNF) drugs
In general, anti-TNF therapy should be stopped before
pregnancy, as there are limited data concerning the risk to
the fetus
Anti-TNF therapy might, however, be used in selected
patients with inflammatory arthropathies where there is
high disease activity, according to an individual risk–
benefit analysis, until early pregnancy is detected
(although this might result in possible exposure in early
pregnancy)
VACTERL and anti-TNF therapy
The authors examined reports of congenital abnormalities
submitted to the US FDA over a 5–10 year period, and
identified 41 children with birth defects born to mothers
who received infliximab or etanercept at some point
during their pregnancy
Of these children, 24 had a set of anomalies that, in the
view of the authors, constituted part of the so-called
VACTERL association, a nonrandom association of birth
defects comprising vertebral, anal, cardiac, tracheal,
esophageal and renal malformations or problems
Carter, J. D. et al. A safety assessment of tumor necrosis factor antagonists
during pregnancy: a review of the FDA database. J. Rheumatol.
doi:10.3899/jrheum.080545 (2008)
VACTERL and anti-TNF therapy
The VACTERL association occurs spontaneously in 0.3–2.1
per 10,000 live births, and its multiple malformations
originate during the early weeks of pregnancy
The design of the Carter study makes it impossible to
judge whether or not TNF inhibitors taken during
pregnancy increase the risk for birth defects
The main limitation is the unknown number of total
pregnancy exposures to TNF inhibitors, which precludes a
meaningful assessment of the magnitude of risk (if any)
Carter, J. D. et al. A safety assessment of tumor necrosis factor antagonists
during pregnancy: a review of the FDA database. J. Rheumatol.
doi:10.3899/jrheum.080545 (2008)
The Patient with active
disease/flare in pregnancy
Prednisone is largely metabolized by the placenta - fetal exposure
is small
Doses greater ≥20 mg increase the risk of both preeclampsia and of
gestational diabetes in SLE pregnancy
Intravenous methylprednisolone, 1000 mg daily for 3 days, given
over 90 minutes, can help achieve quick control of an SLE flare
Fetal exposure to corticosteroids may not be completely benign
Cognitive impairment has been found in premature infants
exposed to corticosteroids
This must be balanced against the severe risks experienced by very
preterm babies
The Patient with active
disease/flare in pregnancy
It is well know that nonsteroidal anti-inflammatory drugs
(NSAIDs) should be avoided during the second and third
trimesters because of their effect on the ductus arteriosus
NSAIDs must be avoided even in the first trimester
NSAIDs rarely have a deleterious effect on fertility
Ofori B., Oraichi D., Blais L., et al: Risk of congenital anomalies in pregnant users of nonsteroidal anti-inflammatory drugs: a nested case-control study. Birth Defects Res B Dev
Reprod Toxicol 77. (4): 268-279.2006
The Patient with active
disease/flare in pregnancy
Antimalarials: Initially, there was concern because of
case reports of congenital malformations in
pregnancies with chloroquine exposure
Both chloroquine and hydroxychloroquine cross the
placenta, and both are also present in breast milk
Hydroxychloroquine should be continued during
pregnancy because cessation of hydroxychloroquine
leads to increased disease activity, lupus flares, and
preterm birth
The Patient with active
disease/flare in pregnancy
Azathioprine has a long track record of use in pregnancy with
an acceptable safety profile – rare reports of neonatal
immunosuppression.
Mycophenolate mofetil has been associated with rare fetal
malformations of the corpus callosum and digit - advisable to
switch to azathioprine before conception
Cyclophosphamide must be avoided during the first and early
second trimesters – use in the third trimester in several patients
who had severe lupus nephritis not responding to high-dose
corticosteroids and other immunosuppressive drugs was
followed by intrauterine fetal demise
Cyclosporine has been associated with growth restriction - may
reflect the underlying maternal diseases for which it was
prescribed
The patient with SSA/Ro
antibodies
ML is a 22 year old nursing student with SLE (+ANA,
+dsDNA, + SSA/Ro, pericarditis) – on HCQ alone
She is now 12 weeks pregnant
What is the risk for neonatal lupus syndromes?
How should she be managed?
SLE
35%
SCLE
80%
SS
70%
Frequency of
Anti-Ro Antibodies
Neonatal Lupus Syndromes
95%
Asymptomatic
Women
0.44%
The patient with SSA/Ro
antibodies
Neonatal lupus is a passively transferred
autoimmune disease that occurs in about 1 to 2
percent of babies born to mothers with SSA/Ro
antibodies
The incidence of congenital complete heart block
appears to be more common in women with high
titers of anti-Ro/SSA and anti-La/SSB
The incidence of heart block rises to about 18 percent
in women with anti-Ro/SSA and/or anti-La/SSB
antibodies who have had a previous child with
congenital heart block
The patient with SSA/Ro
antibodies
Antibodies with a specificity for the 52 kD
component of the Ro/SSA protein are more
frequently found and are present at higher
concentrations in the serum of children with
congenital heart block and their mothers
The combination of anti-Ro/SSA and anti-La/SSB
antibodies may increase the likelihood of cutaneous
manifestations of neonatal lupus
The patient with SSA/Ro
antibodies
Complete heart block generally persists despite
steroid therapy
incomplete heart block often is reversible, but may
progress to complete heart block despite therapy
Glucocorticoids may suppress the associated
pleuropericardial effusion or hydrops, and may
improve outcomes
The patient with SSA/Ro
antibodies
Complete heart block generally persists despite steroid therapy
incomplete heart block often is reversible, but may progress to
complete heart block despite therapy
Glucocorticoids may suppress the associated pleuropericardial
effusion or hydrops, and may improve outcomes
There are no formal guidelines for the type or the frequency of
testing to detect fetal heart block
Dr. Jill Buyon recommends performing weekly pulsed Doppler
fetal echocardiography from the 16th through the 25th week of
pregnancy and then every other week until 32 weeks
Dr. Buyon is a great resource
if you have questions
Dear Dr. Buyon,
I'm following a very interesting 33 year old patient with Sjogren's syndrome
who is positive for ANA, anti-SSA and anti-SSB. She is especially
interesting because she presented with hypokalemia and was found to
have a renal tubular acidosis approximately 11 years ago. She
subsequently developed sicca symptoms and in 2006 successfully
delivered a baby without any complications. She has a Masters in Library
Sciences and read about the differences between 52 kD and 60 kD Ro and
the varying risk for congenital heart block. She is interested in determining
what kind of anti-SSA/Ro antibody she may be carrying. I recognize that
this is a research assay and not commercially available. All the same, both
she and I are curious if your lab or any other lab that you are aware off is
able to perform this determination. She would also be interested in
participating in any research study that would enroll her.
Thanks!
Dino Kazi
Dr. Buyon is a great resource
if you have questions
Dear Dino,
Thank you for your email. The long and short of it is that I am not in
agreement that your patient really needs any testing beyond anti-Ro and
La. Here is why. Her risk of a child with CHB is 2% if she has high titer
anti-Ro (almost all anti-Ro is high titer). If she also has anti-La it may be 45%, no more. The presence of antibodies to Ro52 is common in mothers
of children with CHB but in FACT it does not jack the risk up any higher
than 5%. Almost every mother in our PRIDE study (Circulation) had anti52Ro and as you will see the incidence was as expected, no higher. She
should have weekly PR intervals done on her fetus from 16-26 weeks if
possible. Thereafter the risk is decreased. If PR greater than 150msec she
should have her Peds Cards call me urgently. There is no reliable
prophylactic med and we are currently studying HCQ and IVIG. The
recurrence rate is about 19%. Hope this all helps.
Jill
The patient with SSA/Ro
antibodies
If the fetus develops incomplete heart block, prenatal treatment
should be considered with the administration of fluorinated
glucocorticoids that are not inactivated by placental 11-beta
hydroxysteroid dehydrogenase (eg, oral dexamethasone 4 mg daily
or betamethasone 2 or 3 mg per day), beginning as soon after
detection as feasible, and continuing through the end of
pregnancy.
If heart block does not improve despite several weeks of
glucocorticoid therapy, and if there is no other indication for their
use, they may be discontinued.
Careful observation of infants whose atrioventricular block has
been reversed in utero is necessary in the postnatal period, as there
is still a risk of progression to a higher degree heart block, even
with clearance of maternal autoantibodies
The patient with positive
antiphospholipid antibodies
Antibodies alone
Antibodies + pregnancy-related event (early severe
preclampsia, IUGR)
Antibodies + recurrent embryonic loss
Antobodies + late fetal loss
Antibodies + prior VTE
Antiphospholipid
antibodies alone
Therapeutic options for these women include no therapy, low
dose ASA alone, or low dose ASA and prophylactic heparin
Advisory Board of the 10th International Congress on aPL
favored using low dose ASA alone in these patients
The American College of Chest Physicians Evidence-Based
Clinical Practice Guidelines concluded these women are
probably at increased risk of developing pregnancy-related
venous thrombosis and suggested they be managed
antepartum with either close clinical surveillance, prophylactic
unfractionated heparin, or prophylactic low molecular weight
heparin, and that they receive postpartum anticoagulation
APL + history of severe
pre-eclampsia or IUGR
Low dose aspirin (50-100 mg) in 2nd and 3rd trimester
Consider prophylactic LMWH or UFH in cases of ASA
failure or when placental examination shows
extensive thrombosis
APL + late fetal loss
For women with laboratory criteria for aPL and one
or more fetal losses after 10 weeks of gestation
Combined therapy with low dose ASA (81 mg per day
begun as soon as conception is attempted) and
prophylactic LMWH
Low dose ASA and prophylactic or intermediate dose
unfractionated heparin is a reasonable alternative
APL + recurrent embryonic
losses
Management of women with laboratory criteria for
aPL and multiple embryonic losses (less than 10
weeks of gestation) is controversial, as there are
many causes of early recurrent pregnancy loss
If the woman has had three or more such losses and a
structurally normal uterus and documentation of
euploid losses
low dose ASA and prophylactic or intermediate-dose
heparin therapy or low dose ASA and prophylactic
LMWH heparin during pregnancy can be offered
APL + prior VTE
Women with laboratory criteria for aPL and a prior
history of arterial or venous thrombosis are at high
risk of recurrence and are generally on lifelong
anticoagulation with warfarin
These women should receive thromboprophylaxis
during pregnancy and postpartum
Dosing Heparin with
prior VTE
For most pregnant women a low molecular weight
heparin (LMWH)-based regimen, rather than an
unfractionated heparin (UFH)-based regimen is
recommended
Continue therapy postpartum for 6 weeks
The postpartum patient
Watch for disease flares
Screen for thyroid disease
Continue anticoagulation (if applicable) for 6 weeks
Discuss resumption of medications
Discuss resumption of contraception
Lactation/Nursing
Prednisone is excreted into the breast milk, but use during lactation is
deemed compatible by the American Academy of Pediatrics (AAP) if
justified by the potential benefit to the health of the mother
Azathioprine is likely safe – very low levels in infants
Sulfasalazine is safe – folate supplementation recommended
HCQ - HCQ is found in human breast milk. Breastfed infants may be exposed
to 2 percent of the maternal dose The AAP considers use of HCQ
compatible with breastfeeding
CSA is excreted in breast milk, and therapeutic levels have been reported in
breastfed infants - the use of CSA by lactating mothers is not recommended
Methotrexate, leflunomide, CellCept and Cytoxan are all contraindicated
The lactating/nursing
patient