Anti Rheumatic Drug Safety During Pregnancy- An Update

1
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.

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Natural Course

• RA Spontaneous improvement during pregnancy
  Increased risk of postpartum flare
• AS Disease activity doesnt 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

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Rheumatoid Arthritis

• Biologic DMARDs
• -Anti TNF drugs
• -Tocilizumab
• -Abatacept
• -Rituximab

• Paracetamol
• Opiates
• NSAIDs
• Glucocorticoids
• Synthetic DMARDs
• -Methotrexate
• -Sulphasalazine
• -Leflunomide
• -Hydroxychloroquine

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Rheumatoid Arthritis

• Biologic DMARDs
• -Anti TNF drugs
• -Tocilizumab
• -Abatacept
• -Rituximab

• Paracetamol
• Opiates
• NSAIDs
• Glucocorticoids
• Synthetic DMARDs
• -Methotrexate
• -Sulphasalazine
• -Leflunomide
• -Hydroxychloroquine

6
SLE

• Biologic DMARDs
• - Rituximab
• - Belimumab

• Paracetamol
• Opiates
• NSAIDs
• Glucocorticoids
• Synthetic DMARDs
• - Hydroxychloroquine
• - Azathioprine
• - Mycophenolate
• Mofetil
• - Cyclophosphamide

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SLE

• Biologic DMARDs
• - Rituximab
• - Belimumab

• Paracetamol
• Opiates
• NSAIDs
• Glucocorticoids
• Synthetic DMARDs
• - Hydroxychloroquine
• - Azathioprine
• - Mycophenolate
• Mofetil
• - Cyclophosphamide

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•   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.

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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. 38370614.14Epub 2009 Mar 30.

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Opiates (FDA C)

• 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.
• HeinonenOPSloneDShapiroSBirth defects and drugs
  in pregnancyLittleton, MAPublishing Sciences
  Group1977
• BriggsGGFreemanRKYaffeSJDrugs in pregnancy and
  lactation6th edPhiladelphia, PALippincott
  Williams Wilkins200231920
• 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

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NSAIDs and Aspirin (FDA B)

• 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 pre-eclampsia 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, 76957-961.
• 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, 177256-2
  61.
• Østensen M, Khamashta M, Lockshin M et al.
  Anti-inflammatory and immunosuppressive drugs and
  reproduction. Arthritis Res. Ther. 8(3), 209
  (2006).

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Glucocorticoids (FDA C)

• Prednisolone, Methylprednisolone and
  Hydrocortisone are largely metabolised in
  placenta and lt10 of the dose reaches fetus.
• Safe during pregnancy at lowest effective doses
  (lt7.5mg/day)
• At gt20mg/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.

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Bisphosphonates (FDA C)

• 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, 6068-73.

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HydroxyChloroquine (FDA C)

• HCQ No reported fetal anomalies and is safe to
  use throughout pregnancy and lactation.
• Recent case series suggested that in mothers
  with anti-SSA/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.
• 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 543640.
• 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, 358813-814.
• 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).

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Sulphasalazine (SSZ) (FDA B)

• 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, 251078-1084.
• 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. Repr
  od. Toxicol.25,271275 (2008).

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Azathioprine (FDA D)

• Does not affect fertility in men or women.
• Safe during pregnancy at doses not more than
  2mg/kg.
• 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 19
  90, 99443-446. 

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Ciclosporin (FDA C)

• 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, 
  711051-1055.

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Tacrolimus (FDA C)

• 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 2006121138-43
• 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).

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Ivig (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, 191815-820.
• Østensen M, Khamashta MA, Lockshin M et
  al. Anti-inflammatory and immunosuppressive drugs
  and reproduction. Arthritis Res. Ther.8,209227
  (2006).Important summary and update about
  safety in pregnancy of drugs used in the
  rheumatological field

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Methotrexate (FDA X)

• 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-ind
  uced congenital malformations. J
  Pediatrics 1968, 72790-795.

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Leflunomide (FDA X)

• 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
  lt0.02mg/L 2 weeks apart)
• Neville CE, McNally J. Maternal exposure to
  leflunomide associated with blindness and
  cerebral palsy (letter). Rheumatology 2007461506
  .

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Mycophenolate mofetil (FDA D)

• MMF is contraindicated during pregnancy due to
  increased risk of 1st trimester pregnancy loss
  and congenital malformations.
• Discontinue 6 weeks before a planned pregnancy
• Breastfeeding is not recommended 
• 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 2006821698-702.
• Sebaaly ZE, Charpentier B, Snanoudi R. Fetal
  malformations associated with mycophenolate
  mofetil for lupus nephritis. Nephrol Dial
  Transplant 2007222722.

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Cyclophosphamide (SLE / VASCULITIS) (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, 522761-2767.

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Anti tnf drugs (FDA B)

• 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 relong-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.70,823826 (2011).
• Vinet E, Pineau C, Gordon C, Clarke AE, Bernatsky
  S. Biologic therapy and pregnancy outcomes in
  women with rheumatic diseases. Arthritis
  Rheum.61,587592 (2009).

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Rituximab (FDA C)

• Whether preconception or 1st trimester exposure
  to rituximab exposes the fetus to any risk is
  unclear.
• 2nd and 3rd trimester exposure causes B cell
  depletion in the fetus, with unknown long-term
  effects in the child.
• The manufacturer recommends discontinuation of
  rituximab 1 year before a planned pregnancy.
• Contraindicated during lactation.
• Vinet E, Pineau C, Gordon C, Clarke AE, Bernatsky
  S. Biologic therapy and pregnancy outcomes in
  women with rheumatic diseases. Arthritis
  Rheum.61,587592 (2009).
• Chakravarty EF, Murray ER, Kelman A, Farmer P.
  Pregnancy outcomes after maternal exposure to
  rituximab.Blood117,14991506 (2011).
• 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).

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Abatacept (FDA C)

• No data re its use in pregnancy is published.
• Discontinue 10 weeks prior to a planned
  conception
• Contraindicated during breast feeding

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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
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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
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Thank you
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