Are biologics safe in pregnancy? Monika Ostensen National Center of Pregnancy and Rheumatic Disease University Hospital, Trondheim, Norway

Are biologics safe in pregnancy? Monika Ostensen National Center of Pregnancy and Rheumatic Disease University Hospital, Trondheim, Norway

Declaration of Interest The speaker has received fees for lectures from MSD, Roche and Pfizer.

What is a safe drug in In the mother: pregnancy? No additional side effects compared to non-pregnant patients For pregnancy: No induction of pregnancy complications like miscarriage or prematurity In the child: No short term or longterm adverse effects

Some basics Helping to understand transplacental transfer of different biologics

Most biological drugs are complete monoclonal antibodies (IgG 1 class) Rezeptor Certolizumab

Transfer of monoclonal antibodies during pregnancy Transfer by the placental Fc receptor In the 2. and 3. trimester Fetal and maternal levels equal at term Complete mab Infliximab Adalimumab Golimumab Tocilizumab Rituximab Fusion with Fc part Abatacept Etanercept

Transplacental passage of some TNF inhibitors (few studies ) Drug Infliximab 100% Etanercept Ca. 30% Certolizumab 1.6-8.8% Oussalah et al; Gut 2009;58:A8 Mahadevan et al; Abstract AGA 2009 % of maternal level in cord serum Differences in transfer at late pregnancy depend on the structure of the drug: Complete antibody, Fc part of IgG present or not

Certolizumab in pregnancy:animal studies Transfer of certolizumab compared to a complete monoclonal antibody Nesbitt A et al, Poster, Ann Rheum Dis 2007; 66 (Suppl 2):296

Case 1 A patient with RA is in remission on one of the monoclonal ab TNF inhibitors (infliximab, adalimumab or golimumab). She plans a pregnancy. MTX is discontinued. At what time would you stop treatment with the TNF inhibitor?

Qu 1: At which time point? 6 months before a planned pregnancy 3 months before a planned pregnancy At a positive pregnancy test In the 1st trimester Between gestational week 20-30 No stop at all

Transplacental passage of Infliximab: serum levels in a mother-child pair Pt with M. Crohn, Infliximab at gestational week 39. Vasiliauskas EA et al, Clin Gastroenterol Hepatol 2006

Avoid monoclonal abs in late pregnancy Conclusion: Placental transfer of Fc part containing monoclonal antibodies is much less when discontinued before gestational week 30 and avoids high levels in children after birth Kane et al, J Clin Gastr. 2009

TNF inhibitors in pregnancy > 750 pregnancies reported (case reports, cohort studies, pregnancy registries) including infliximab, etanercept, adalimumab, certolizumab Mostly exposure before conception or in 1. trimester Ca. 170 pregnancies exposed throughout No increase in birth defects

Infliximab in RA and CD pregnancies > 300 pregnancies from case reports, registries, cohort studies published Katz et al (2004). 96 pregnancies in patients with Crohn s disease or Rheumatoid arthritis Verstappen S et al. (ARD 2011): British pregnancy registry: 130 pregnancies anti-tnf exposed Infliximab given until conception or in the 1. trimester No increase in birth defects Katz JA et al, Am J Gastroenterol 2004, Djokanovic, N, Reproductive Tox 2011; Verstappen 2011

Adalimumab and Etanercept in pregnancy OTIS studies Adalimumab: 42 pregnant RA patients exposed compared to 58 non-exposed and 84 healthy women Etanercept: 139 pregnant RA patients exposed, 67 non-exposed No significant increase in prematurity or major birth defects. No recurrent pattern of malformations.

Golimumab and Certolizumab in Drug Golimumab Certolizumab pegylated Fab fragment pregnancy Published reports No adverse effect in animals and in unpublished human cases No adverse effect in animals, in published and unpublished human cases Safe in pregnancy? No conclusive data No conclusive data

AreTNF inhibitors harmful in early pregnancy? Outcomes of 140 pregnancies from the British Society for Rheumatology Biologics Register Verstappen S et al. (ARD 2011): Increased rate of miscarriage with TNF inhibitors at conception: 33% with and without MTX/LEF 24% versus 10% miscarriage in the non-exposed group of pregnant patients Data not confirmed by other studies

TNF inhibitors and congenital malformations Congenital malformations recorded to the FDA database until 12/2005: 41 reports on congenital malformations 1 VACTERLsyndrome, 2 incomplete VACTERL Problem: Proportion of treated patients unknown No patient control group, no comparison to healthy women No controlled study has found an increased rate of congenital malformations Carter JD et al. J Rheumatol 2008 Østensen M et al, Nature Clin Pract Rheum 2009

Children exposed to anti-tnf Late pregnancy exposure carries risk of infection BCG itis in a child exposed during late pregnancy After late pregnancy exposure to anti-tnf live vaccines should not be given during the first 6 months of life Children exposed in the 3. trimester to Infliximab showed normal immune system development and immune response, normal vaccination response to non-live vaccines, no increase of infections Vasiliauskas EA et al, Clin Gastroenterol Hepatol 2006; Chent et al. J Crohns Colitis 2010

Use of TNF inhibitors in pregnancy Depends on severity of disease risk/benefit Recommendation: Discontinue infliximab, etanercept, adalimumab, golimumab, certolizumab as soon as pregnancy is recognized since long term effects on exposed children are unknown In severe cases discontinue before week 30

Other biological drugs in pregnancy Antibodies against B cells Rituximab, Belimumab (no data) Tocilizumab Abatacept Anakinra

Rituximab (MabThera ): Structure Rituximab Chimerical monoclonal ab against CD20 on B cells IgG1 antibody Animal studies during pregnancy: B cell depletion, no risk of malformations

Rituximab in pregnancy Outcome of 153 pregnancies Chakravarty, Blood 2010 Women with malignant and autoimmune disease 90 (59%) live birth 33 (22%) miscarriage 28 termination of pregnancy Birth defects: one clubfoot, one cardiac malformation Neonatal infections: fever, bronchiolitis, CMV hepatitis, and chorioamnionitis Hematologic abnormalities in 11 neonates (peripheral B-cell depletion, neutropenia, lymphopenia, thrombocytopenia and anemia

Rituximab in pregnancy Exposure before conception or during early pregnancy: no B cell depletion of the child 2 nd or 3rd trimester exposure depletes B cells in the child Open question: carries 1st trimester exposure a risk for the child? Is discontinuation of RTX1 yr before pregnancy really necessary?

Abatacept and Tocilizumab: No human pregnancy experience published Tocilizumab Abatacept

Abatacept and Tocilizumab in pregnancy Drug Abatacept IgG1 ab inhibits Tcell activation Tocilizumab ab against IL-6R Published reports Autoimmunity in animals at high doses, no harm in unpublished human cases No adverse effect in animals and in unpublished human cases Safe in pregnancy? No conclusive data No conclusive data

Anakinra the IL-1 receptor antagonist in pregnancy No fetotoxic effects in animals with100 x human dose 2 case reports with 3 pregnancies have been published in patients with Still s disease healthy children No prophylactic withdrawal before pregnancy because of 4-6 hrs halflife

When to stop biological agents? Drug Anti-TNF Teratogenic risk Stop before/at conception At Conception Belimumab Anakinra Abatacept Rituximab Data insufficient to claim safety At Conception At Conception 3 mo before planned pregnancy 1 yr before (?) Tocilizumab 3 mo before

Which advice to a male AS patient on MTX and infliximab? The patient is in remission on a combination of MTX 20 mg/weekly and infliximab infusions every 6 weeks. The couple wants a child. Stop MTX and infliximab 6 months before a planned pregnancy Stop MTX 3 months before a planned pregnancy, continue infliximab Continue MTX and infliximab regardless of wish for children

Male fertility and infliximab 2 uncontrolled studies 1 controlled study in 26 men with SpA Mahadevan U et al. 2005: 13 men with M.Crohn Montagna et al, ARD 2006: 3 patients with AS Uncontrolled: INF reduced motility and increased abnormal forms of semen Controlled: no impairment of sperm quality

vitality [%] normal forms [%] sperm concentration [G/l] motility [%] Anti-TNF: No harmful effect on sperm quality Figure 1 A 800 B 100 p=0.007 p=0.001 600 80 60 400 40 200 20 0 HC SpA SpA/anti-TNF 0 HC SpA SpA/anti-TNF C 150 p=0.004 p=0.001 D 30 100 20 50 10 0 HC SpA SpA/anti-TNF 0 HC SpA SpA/anti-TNF Villiger et al, eingereicht in Annals Rheum Dis

Biological drugs and male reproduction Studied only for TNF inhibitors Some reviews and national guidelines recommend birth control for men treated with biologics This implies the view that they are mutagenic At present no study in animals or humans to support mutagenicity

Conclusion - 1 Still no proof that biological drugs are safe during pregnancy Lack of published pregnancy experience for several biologics :abatacept, tocilizumab, anakinra Longterm effects on the immune system (increase in autoimmunity? or lymphoid malignancy?) are still unknown.

Conclusion - 2 Animal studies and limited human experience has not shown teratogenicity for TNF inhibitors and rituximab. Data are still insufficient for most of the other biologics. More data are needed in regard to male reproduction, lactation and longterm follow-up of exposed children.

Summary: Discontinuation of biologics Infliximab Etanercept Adalimumab Golimumab Anakinra Rituximab Tocilizumab Abatacept pregnancy 12 months 3 months

The end. Thank you for your attention

Biological drugs and lactation Low levels of IgG1 found in milk

Biological drugs and lactation Drug TNF inhibitors Excreted in breastmilk Minute amounts (Etanercept&Adalimum ab) or not detected (Infl&Certolizumab) Recommendation Breastfeeding possible Rituximab Not studied No breastfeeding Abatacept Not studied No breastfeeding Tocilizumab Not studied No breastfeeding Anakinra Not studied?