ANTI RHEUMATIC DRUG SAFETY DURING PREGNANCY- AN UPDATE

Dr Chethana Dharmapalaiah

Consultant Rheumatologist

Apollo Hospitals - Bangalore

22/12/13

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

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 pregnancySafe 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)

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

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, 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)

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)

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)

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; 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)

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)

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 1990, 99:443-446. 

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, 71:1051-1055.

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 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 (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)

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)

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)

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 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) (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)

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)

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.61,587–592 (2009).

Chakravarty EF, Murray ER, Kelman A, Farmer P. Pregnancy outcomes after maternal exposure to rituximab.Blood117,1499–1506 (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).

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