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OP004 Adalimumab and infliximab levels in neonates (ERA study)

M. Julsgaard*1, 2, L.A. Christensen1, P.R. Gibson3, R. Gearry4, J. Fallingborg5, J. Kjeldsen6, S. Wildt7, L. Svenningsen8, W. Connell2, C.L. Hvas1, M.P. Sparrow3, A. Walsh9, S.J. Connor10, G. Radford-Smith11, I. Lawrence12, J.M. Andrews13, K. Ellard14, O. Rosella3, A. Grosen1, J. Santamaria15, S.J. Bell2

1Aarhus University Hospital, Department of Hepatology and Gastroenterology, Aarhus, Denmark, 2St Vincent's Hospital & University of Melbourne, Department of Gastroenterology, Melbourne, Australia, 3Alfred Hospital and Monash University, Department of Gastroenterology, Melbourne, Australia, 4University of Otago, Christchurch Hospital, Department of Medicine and Gastroenterology, Christchurch, New Zealand, 5Aalborg Hospital, Department of Gastroenterology, Aalborg, Denmark, 6Odense University Hospital, Department of Gastroenterology and Hepatology, Odense, Denmark, 7Koege Hospital, Department of Gastroenterology, Koege, Denmark, 8Herning Hospital, Department of Medicine and Gastroenterology, Herning, Denmark, 9St. Vincent's hospital , Department of Gastroenterology, Sydney, Australia, 10Liverpool Hospital & University of NSW, Dept. of Gastroenterology, Sydney, Australia, 11Royal Brisbane & Women's Hospital, Department of Gastroenterology, Brisbane, Australia, 12Fremantle Hospital, Centre for Inflammatory Bowel Disease, Fremantle, Australia, 13Royal Adelaide Hospital, University of Adelaide , IBD Service, Dept of Gastroenterology & Hepatology & School of Medicine, Adelaide, Australia, 14Royal North Shore Hospital, Department of Gastroenterology, Sydney, Australia, 15St Vincent's Hospital & University of Melbourne, Department of Intensive Care, Melbourne, Australia

Background

Limited data on anti TNF alpha therapy (ATNF) during pregnancy exist. We examined drug levels of ATNF in cord blood of newborns exposed in pregnancy and correlated these with maternal levels, duration of ATNF and time to drug clearance.

Median (range) drugs levels at birth according to time of cessation of anti-TNF3.

IFX level (mcg/ml)ADA level (mcg/ml)
Last infusion prior to GW 30Last infusion at or after GW 30P valueLast injection prior to GW 30Last injection at or after GW 30P value
N=17N=24N=6N=28
Mother0.6 (0.0–3.3)4.0 (0.0–22.2)< 0.0010.3 (0.0–0.7)2.0 (0.0–10.0)< 0.004
Cord Blood1.9 (0.1–8.9)9.6 (1.9–28.7)0.00010.5 (0.0–1.2)2.4 (0.0–12.1)< 0.02

 

Methods

Pregnant IBD women exposed to Remicade (IFX) or Humira (ADA) were included during 2012-14 at 14 sites in Denmark, Australia and New Zealand. Drug levels were measured by ELISA at delivery (Matriks Biotek). If positive at birth, infants were tested 3 monthly until negative. Demographics, disease activity, medication, and pregnancy outcomes were prospectively collected. Multivariate and logistic regression analysis determined factors correlated with drug levels at birth in mothers and newborns and time to clearance in newborns.

Results

Of 89 women recruited, 5 (5.6%) miscarried, 4 failed blood collection, leaving 80 mother-baby pairs (44 IFX, 36 ADA). 49% were on thiopurines. There were 3 (4%) preterm births, 3 (4%) small for gestational age and 2 (2.5%) congenital malformations. Development was normal in all babies using routine infant checks. There was an inverse correlation between duration since last dose and both cord drug levels (IFX: r = -0.58; ADA: r = -0.41, both p <0.0001) and maternal levels (IFX: r = -0.63; ADA: r = -0.64, both p <0.0001). Cord blood and maternal drug levels also correlated (IFX: r = 0.67; ADA: r = 0.64, both p < 0.0001). Last ATNF dose was at median gestational week (GW) 30 in IFX, (8-37) and 35 in ADA (14-41) treated mothers. Drug was ceased prior to GW 30 in 31% of mothers. Cessation prior to GW30 did not increase the risk of disease activity in the 3rd trimester or postpartum. Median maternal and cord drug levels were 2 (0-22.2mcg/ml) and 5.9 (0.12-28.7mcg/ml) for IFX and 1.5 (0-10mcg/ml) and 2 (0-12.1mcg/ml) for ADA. Levels were significantly lower when drug was stopped prior to GW30.

Conclusion

No increased risk of adverse pregnancy or developmental outcomes. Maternal and cord ATNF levels inversely correlated with duration since last exposure. Cord blood levels correlated with maternal level at delivery. Maternal cessation of ATNF prior to week 30 significantly reduced fetal exposure without disease exacerbation. However, clearance took up to 12 months. Therefore, live vaccinations should be avoided prior to 1 year unless drug clearance is documented.

44 (55%) babies have cleared drug, 36 are still in testing. Median time to clearance was 6 months (0-12) for both drugs. Drug type and weeks since last dose predicted clearance by 3 months (AUROC 0.81, p=0.002)

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