Transcript A Case Presentation

ANTI RHEUMATIC DRUG SAFETY DURING
PREGNANCY- AN UPDATE
Dr Chethana Dharmapalaiah
Consultant Rheumatologist
Apollo Hospitals - Bangalore
22/12/13
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Best outcome can be expected when the
disease has been in remission for at least
6 months prior to conception.
Careful preconception planning and
advanced adjustment of medications is a
must.
Tailoring therapy as per disease activity
and organ involvement if any.
NATURAL COURSE
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RA: Spontaneous improvement during pregnancy
Increased risk of postpartum flare
AS: Disease activity does’nt seem to be influenced
by pregnancy
PsA: May improve or even remit during
pregnancy
SLE: increased risk of disease flares both during
pregnancy and post-partum period, especially in
patients with active disease at conception
RHEUMATOID ARTHRITIS
 Paracetamol
 Opiates
 NSAIDs
 Glucocorticoids
 Synthetic
DMARDs
-Methotrexate
-Sulphasalazine
-Leflunomide
-Hydroxychloroquine
 Biologic
DMARDs
-Anti TNF drugs
-Tocilizumab
-Abatacept
-Rituximab
RHEUMATOID ARTHRITIS
 Paracetamol
 Opiates
 NSAIDs
 Glucocorticoids
 Synthetic
DMARDs
-Methotrexate
-Sulphasalazine
-Leflunomide
-Hydroxychloroquine
 Biologic
DMARDs
-Anti TNF drugs
-Tocilizumab
-Abatacept
-Rituximab
SLE
 Paracetamol
 Opiates
 NSAIDs
 Glucocorticoids
 Synthetic
DMARDs
- Hydroxychloroquine
- Azathioprine
- Mycophenolate
Mofetil
- Cyclophosphamide
 Biologic
DMARDs
- Rituximab
- Belimumab
SLE
 Paracetamol
 Opiates
 NSAIDs
 Glucocorticoids
 Synthetic
DMARDs
- Hydroxychloroquine
- Azathioprine
- Mycophenolate
Mofetil
- Cyclophosphamide
 Biologic
DMARDs
- Rituximab
- Belimumab
US FDA categories for drug safety during pregnancy
A Adequate and well-controlled studies have failed to demonstrate a risk
to the fetus during the 1st or later trimesters).
B Animal studies have not demonstrated a fetal risk, but there are no
adequate, well-controlled studies in pregnant women. Or Animal
reproduction studies have shown an adverse effect, but adequate and
well-controlled studies in pregnant women have failed to demonstrate a
risk to the fetus.
C Animal studies have shown an adverse effect on the fetus, no studies in
humans, benefits may be acceptable despite its potential risks. Or There
are no animal reproduction studies and no adequate and well-controlled
studies in humans.
D There is positive evidence of human fetal risk based on adverse reaction
data from investigational or marketing experience or studies in humans,
but the potential benefits may be acceptable despite its potential risks.
X Studies in animals or humans have demonstrated fetal abnormalities or
there is positive evidence of fetal risk based on adverse reaction reports
from investigational or marketing experience, or both, and the risk of
the use of the drug in a pregnant woman clearly outweighs any possible
benefit.
PARACETAMOL (FDA B)
 Safe
at all stages of pregnancy
 Safe during lactation
Rebordosa C, Kogevinas M, Bech BH, Sørensen HT, Olsen J. Use of acetaminophen during pregnancy and risk
of adverse pregnancy outcomes Int J Epidemiol 2009. 383706–14.14Epub 2009 Mar 30.
OPIATES (FDA C)
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Limited studies in human pregnancies.
Therapeutic doses during pregnancy have not been linked to
elevated risk of major or minor malformations.
Neonatal withdrawal has been observed with use of codeine in late
pregnancy, even with therapeutic doses.
High doses in late pregnancy should be avoided, and the infant
should be observed carefully in the neonatal period for any signs of
withdrawal (neonatal abstinence syndrome).
Breast feeding: short term use seems safe. Watch for CNS
deppression in the neonate, use alternative analgesic.
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HeinonenOPSloneDShapiroSBirth defects and drugs in pregnancyLittleton, MAPublishing Sciences Group1977
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BriggsGGFreemanRKYaffeSJDrugs in pregnancy and lactation6th edPhiladelphia, PALippincott Williams & Wilkins200231920
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ShawGMMalcoeLHSwanSHCumminsSKSchulmanJCongenital cardiac anomalies relative to selected maternal exposures and
conditions during early pregnancyEur J Epidemiol19928575760
KhanKChangJNeonatal abstinence syndrome due to codeineArch Dis Child Fetal Neonatal Ed1997761F5960
ReynoldsEWRiel-RomeroRMBadaHSNeonatal abstinence syndrome and cerebral infarction following maternal codeine use
during pregnancyClin Pediatr (Phila)200746763945
NSAIDS AND ASPIRIN (FDA B)
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Pre-Conception: risk of impeding implantation by inhibiting COX
1 & 2 required for rupture of luteinized follicle$. Hence avoid
during a planned conception cycle.
Generally safe during pregnancy.
Avoid beyond 30 weeks: risk of premature closure of DA*, PHTN,
Oligohydramnios, GI bleed, prolongation of labour.
Low dose Aspirin (75-100mg): for obstetric indications like preeclampsia and APLS can be safely used till term.
Lactation: compatible.
COX2 inhibitors: Effects of 1st trimester use has not been
reported. No reliable data, best avoided.
$Uhler
ML, Hsu JW, Fisher SG, Zinaman MJ: The effect of non-steroidal antiinflammatory drugs on ovulation: a prospective,
randomized clinical trial. Fertil Steril 2001, 76:957-961.
*Vermillion ST, Scardo JA, Lashus AG, Wiles HB: The effect of indomethacin tocolysis on fetal ductus arteriosus constriction
with advancing gestational age.Am J ObstetGynecol 1997, 177:256-261.
Østensen M, Khamashta M, Lockshin M et al. Anti-inflammatory and immunosuppressive drugs and reproduction. Arthritis Res.
Ther. 8(3), 209 (2006).
GLUCOCORTICOIDS (FDA C)
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Prednisolone, Methylprednisolone and Hydrocortisone are
largely metabolised in placenta and <10% of the dose reaches
fetus.
Safe during pregnancy at lowest effective doses (<7.5mg/day)
At >20mg/day during 1st trimester: slightly increased risk of
oral clefts.
Consider stress dose GCs peripartum for those on long term
steroids.
Possible increased risk of PROM, IUGR, PIH, GDM,
Infections, Osteoporosis.
Lactation: Discard breast milk for 4 hours following ingestion
of a dose of pred ≥20 mg.
BISPHOSPHONATES (FDA C)
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In experimental animals, gestational exposure to BisP
led to decreased bone growth, fetal weight* and
hypocalcemia in the fetus.
Because of insufficient data, pregnancy should be
avoided for 6 months after discontinuation of BisP.
Breast feeding: contraindicated
Cacium & Vitamin D supplements: safe during
pregnancy.
*Patlas N, Golomb G, Yaffe P, Pinto T, Breuer E, Ornoy A: Transplacental effcts of bisphosphonates on
fetal skeletal ossification and mineralization in rats. Teratology 1999, 60:68-73.
HYDROXYCHLOROQUINE (FDA C)
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HCQ: No reported fetal anomalies* and is safe to use
throughout pregnancy and lactation.
 £ Recent
case series suggested that in mothers with antiSSA/Ro and/or anti-SSB/La antibodies and a previous child
with neonatal lupus, exposure to HCQ during a subsequent
pregnancy may decrease the risk of congenital heart block.
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Chloroquine: risk of maternal retinal and fetal ototoxicity at high doses$.
Recommended dose of 250mg/day is safe.
Mepacrine: to be avoided due to lack of safety data.
*Clowse ME, Magder L, Witter F, Petri M. Hydroxychloroquine in lupus pregnancy. Arthritis Rheum 2006; 54:3640.
$Klinger
G, Morad Y, Westall CA, Laskin C, Spitzer KA, Koren G, Ito S, Buncic RJ: Ocular toxicity and antenatal exposure to
chloroquine or hydroxychloroquine for rheumatic diseases. Lancet 2001, 358:813-814.
Levy RA, Vilela VS, Cataldo MJ et al. Hydroxychloroquine (HCQ) in lupus pregnancy: double-blind and placebo-controlled
study. Lupus 10(6), 401-404 (2001)• This double-blind, randomized controlled trial of 20 consecutive pregnant patients with lupus
provided important evidence for the benefit and safety of hydroxychloroquine when used during pregnancy.
£Izmirly
PM, Kim MY, Llanos C et al. Evaluation of the risk of anti-SSA/Ro-SSB/ La antibody-associated cardiac manifestations of neonatal
lupus in fetuses of mothers with systemic lupus erythematosus exposed to hydroxychloroquine. Ann. Rheum. Dis. 69(10), 1827-1830
(2010).
SULPHASALAZINE (SSZ) (FDA B)
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SSZ leads to reversible oligospermia$, reduced sperm
motility. This recovers at about 2 months after withdrawal
of the drug.
Safe during pregnancy* at dose of 2g/day however, with
high-dose folic acid in order to prevent neural tube defects.
Breastfeeding is safe for a healthy full term infant.
$O'Morain
C, Smethurst P, Doré CJ, Levi AJ: Reversible male infertility due to sulphasalazine: studies in
man and rat. Gut 1984, 25:1078-1084.
*Rahimi R, Nikfar S, Rezaie A, Abdollahi M. Pregnancy outcomes in women with inflammatory bowel disease
following exposure to 5-aminosalicylic acid drugs: a meta-analysis. Reprod. Toxicol.25,271–275 (2008).
AZATHIOPRINE (FDA D)
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Does not affect fertility in men or women.
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Safe during pregnancy at doses not more than 2mg/kg.
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A retrospective study* of 101 pregnancies in women with
IBD on AZP revealed no association with poor pregnancy
outcomes.
Lactation: best avoided
*Alstead EM, Ritchie JK, Leonard-Jones JE, Farthing MJG: Safety of azathioprine in pregnancy in
inflammatory bowel disease. Gastroenterology 1990, 99:443-446.
CICLOSPORIN (FDA C)
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CsA at a dose of 2.5-5.0 mg/kg/day can be given to treat
renal lupus during pregnancy. It is safe to the fetus, but
can be nephrotoxic to the mother. Maternal BP, renal
function need monitoring.
Lactation: Unsafe
Bar Oz B, Hackman R, Einarson T, Koren G: Pregnancy outcome after CsA therapy during pregnancy: a
meta-analysis. Transplantation 2001, 71:1051-1055.
TACROLIMUS (FDA C)
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Studies report absence of an increased risk of
miscarriage or congenital anomalies in transplant
recipients*
May be administered safely during pregnancy for renal
lupus flares at the lowest possible dose( 0.1 to
0.2mg/kg/day) whilst monitoring BP and renal
function.
Breastfeeding is probably possible!
Chistopher V, Al-Chalabi T, Richardson PD, et al. Pregnancy outcome after liver transplantation: a single-center
experience of 71 pregnancies in 45 recipients. Liver Transpl 2006;12:1138-43
*Bar J, Stahl B, Hod M, Wittenberg C, Pardo J, Merlob P. Is immunosuppression therapy in renal allograft
recipients teratogenic? A single-center experience. Am. J. Med. Genet. A 116A(1), 31-36 (2003).
IVIG
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(FDA C)
IVIG can be safely used in pregnancy and lactation, to
treat immune thrombocytopenia.
Radder CM, Roelen DL, van de Meer-Prins, Claas FH, Kanhai HH, Brand A: The immunologic profile of
infants born after maternal immunoglobulin treatment and intrauterine platelet transfusions for
fetal/neonatal alloimmune thrombocytopenia.Am J Obstet Gynecol 2004, 191:815-820.
Østensen M, Khamashta MA, Lockshin M et al. Anti-inflammatory and immunosuppressive drugs and
reproduction. Arthritis Res. Ther.8,209–227 (2006).
•Important summary and update about safety in pregnancy of drugs used in the rheumatological field
METHOTREXATE (FDA X)
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Associated with miscarriages, congenital anomalies*
and fetal growth retardation. Hence contraindicated
during pregnancy.
Stop 3 months prior to attempts at conception.
Supplement high-dose folic acid (5 mg/day) from 3
months prior to conception until at least the end of the
first trimester.
Lactation: Contraindicated.
*Milunsky A, Graef JW, Gaynor MF: Methotrexate-induced congenital malformations. J
Pediatrics 1968, 72:790-795.
LEFLUNOMIDE (FDA X)
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Contraindicated during pregnancy and lactation.
Long half life, detectable in plasma upto 2y after
discontinuation.
Cholestyramine washout with 8g TDS for 11 days or
until plasma levels are undetectable. (2 levels
<0.02mg/L 2 weeks apart)
Neville CE, McNally J. Maternal exposure to leflunomide associated with blindness and cerebral palsy
(letter). Rheumatology 2007;46:1506.
MYCOPHENOLATE MOFETIL (FDA D)
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MMF is contraindicated during pregnancy due to
increased risk of 1st trimester pregnancy loss and
congenital malformations.
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Discontinue 6 weeks before a planned pregnancy
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Breastfeeding is not recommended
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Sifontis NM, Coscia LA, Constantinescu S, Lavelanet AF, Mortiz MJ, Armenti VT. Pregnancy outcomes in solid organ
transplant recipients with exposure to mycophenolate mofetil or sirolimus. Transplant 2006;82:1698-702.
Sebaaly ZE, Charpentier B, Snanoudi R. Fetal malformations associated with mycophenolate mofetil for lupus
nephritis. Nephrol Dial Transplant 2007;22:2722.
CYCLOPHOSPHAMIDE (SLE / VASCULITIS)
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(FDA D)
CYC: can cause fetal malformations, gonadotoxic in men
and women.
Cryopreservation* of sperm and sperm banking in men
and co-administering a GnRH analogue in women is the
method of choice for preservation of gonadal function.
Attempts at conception should be delayed until 3 months
after the cessation of therapy.
Breastfeeding is contraindicated.
*Somers EC, Marder W, Christman GM, Ognenovski V, McCune WJ: Use of a gonadotropin-releasing hormone
analog against premature ovarian failure during cyclophosphamide therapy in women with severe
lupus. Arthritis Rheum 2005, 52:2761-2767.
ANTI TNF DRUGS (FDA B)
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In patients with active arthritis, anti TNF drugs can
be continued till pregnancy is confirmed.
Limited experience with treatment during pregnancy
and lack of knowledge re:long-term effects on exposed
children. TNF inhibitors should be discontinued as
soon as pregnancy is recognized
Breastfeeding is not recommended
Verstappen SM, King Y, Watson KD, Symmons DP, Hyrich KL; BSRBR Control Centre Consortium, BSR Biologics
Register. Anti-TNF therapies and pregnancy: outcome of 130 pregnancies in the British Society for Rheumatology
Biologics Register. Ann. Rhuem. Dis.70,823–826 (2011).
Vinet E, Pineau C, Gordon C, Clarke AE, Bernatsky S. Biologic therapy and pregnancy outcomes in women with
rheumatic diseases. Arthritis Rheum.61,587–592 (2009).
RITUXIMAB (FDA C)
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Whether preconception or 1st trimester exposure to
rituximab exposes the fetus to any risk is unclear.
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2nd and 3rd trimester exposure causes B cell depletion in
the fetus, with unknown long-term effects in the child.
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The manufacturer recommends discontinuation of
rituximab 1 year before a planned pregnancy.
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Contraindicated during lactation.
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Vinet E, Pineau C, Gordon C, Clarke AE, Bernatsky S. Biologic therapy and pregnancy outcomes in women with rheumatic
diseases. Arthritis Rheum.61,587–592 (2009).
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Chakravarty EF, Murray ER, Kelman A, Farmer P. Pregnancy outcomes after maternal exposure to rituximab.Blood117,1499–1506
(2011).
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Pham T, Fautrel B, Gottenberg JE et al. Rheumatic Diseases & Inflammation Group (Club Rhumatismes et Inflammation, CRI) of the
French Society for Rheumatology (Societe Francaise de Rhumatologie, SFR). Rituximab (MabThera) therapy and safety management.
Clinical tool guide. Joint Bone Spine 75(Suppl. 1), S1-S99 (2008).
ABATACEPT (FDA C)
 No
data re: its use in pregnancy is published.
 Discontinue 10 weeks prior to a planned
conception
 Contraindicated during breast feeding
WHEN TO STOP DMARDS
DRUG
RECOMMENDATION
METHOTREXATE
3 months prior to conception
LEFLUNOMIDE
discontinue when plaaning
pregnancy and perform a washout
INFLIXIMAB
discontinue after a positive
pregnancy test
ETANERCEPT
discontinue after a positive
pregnancy test
ADALIMUMAB
discontinue after a positive
pregnancy test
RITUXIMAB
discontinue 12 months before
pregnancy
ABATACEPT
discontinue 10 weeks before
pregnancy
BISPHOSPHONATES
discontinue after a positive
pregnancy test
TREATMENT OF A FLARE DURING PREGNANCY
TYPE OF FLARE
DRUGS
Acute mono or oligoarthritis
-Intra articular steroids
-NSAIDs – Diclofenac /
Ibuprofen / Naproxen
Pain
-Paracetamol
-Opiates
Systemic flare
-Oral Corticosteroids
-Hydroxychloroquine
-Sulphasalazine
-Azathioprine
-Ciclosporin / Tacrolimus
THANK YOU