Ustekinumab Levels in Pregnant Women With IBD

Abstract and Introduction

Abstract

Background: Ustekinumab is increasingly used in pregnant women with inflammatory bowel disease (IBD). Existing safety data are reassuring, but the stability of ustekinumab levels in pregnancy, degree of transfer to the infant and time to infant clearance are unknown.

Methods: In this prospective observational study, ustekinumab-exposed women with IBD had trough levels measured in each trimester of pregnancy and at delivery. Infant ustekinumab levels were measured at delivery and ongoing until clearance was achieved. Trough ustekinumab level stability in individuals across pregnancy was compared by Skillings-Mack test. Spearman coefficients were used to correlate maternal and infant delivery levels, and median time to infant ustekinumab clearance was defined.

Results: 19 pregnant women receiving ustekinumab were included. There was no difference in ustekinumab levels across pregnancy in those with two or more representative trough levels (P = 0.83, n = 11). Infant delivery ustekinumab levels were higher than maternal levels, with a median infant:maternal ratio of 1.79 (IQR 1.26–3.1). There was a positive correlation between maternal and infant delivery ustekinumab levels (r = 0.75, P = 0.001) and an inverse correlation between the number of days from final antenatal dose and delivery infant ustekinumab level (r = −0.65, P = 0.006). Median time of infant ustekinumab clearance was 9 (range 6–19) weeks (n = 9).

Conclusion: Ustekinumab drug levels appear stable in pregnancy, with a delivery infant:maternal ratio similar to that of anti-TNFs. Infant ustekinumab clearance was complete by 20 weeks post-partum, however, infants exposed in utero should avoid live vaccination before 12 months of age until further clearance data are obtained.

Introduction

Inflammatory bowel disease (IBD) commonly affects women of childbearing age, with the maintenance of disease remission prior to and during pregnancy important in order to optimise maternal and neonatal outcomes.^[1] Ustekinumab, a human IgG1 kappa antibody against interleukin-12/23p40, is increasingly used in the management of IBD. IgG1 antibodies are actively transported across the placenta via interaction with placental Fc receptors from the second trimester, resulting in foetal exposure.^[2] Existing safety data for the continuation of ustekinumab in pregnancy are reassuring.^[1,3] Continuation of ustekinumab during conception and pregnancy is recommended for most women with IBD, although practice patterns of administering or withholding ustekinumab doses during the third trimester vary.^[1,3]

Data regarding the stability of ustekinumab levels in pregnancy, its degree of transfer to exposed infants and the subsequent rate of infant clearance remain limited to case reports and small cohorts.^[1,4,5] Observed physiologic changes in pregnancy, including increased plasma volume and decreased plasma albumin concentration, may theoretically alter the pharmacokinetics of biologic agents.^[2] It is unclear whether ustekinumab levels remain stable throughout pregnancy, and if adjustment of the timing of the final antenatal ustekinumab dose to reduce infant exposure is necessary or effective. Infant ustekinumab clearance is important to inform when live vaccination is safe. Thus, the current study aimed to evaluate ustekinumab pharmacokinetics in women with IBD during pregnancy and in the exposed infant.

Authors and Disclosures

Table 1. Participant characteristics, maternal and infant ustekinumab levels
Disease characteristics
Age at start of pregnancy (years)	31 (IQR 27–33)
Disease duration (years)	9 (IQR 7–12)
Ustekinumab exposure duration (months)	22 (IQR 12–26)
Perianal disease (n)	5/19
Stricturing disease (n)	5/19
Prior anti-TNF exposure (n)	12/19
Prior vedolizumab exposure (n)	7/19
Prior thiopurine exposure (n)	15/19
Ongoing thiopurine combination therapy (n)	2/19
Median Trough ustekinumab levels in pregnancy (μg/mL)
Trimester 1 ustekinumab level (n = 4)	2.1 (range 1.3–2.4)
Trimester 2 ustekinumab level (n = 14)	2.2 (range 1.0–4.5)
Trimester 3 ustekinumab level (n = 9)	1.9 (range 1.6–4.6)
Delivery outcomes and median delivery ustekinumab levels
Gestation at final ustekinumab dose (weeks)	32.2 (range 24.86–35.71)
Time from final antenatal dose to delivery (days)	44.5 (range 20–106)
Infant delivery levels (μg/mL) (n = 16)	3.9 (IQR 1.45–5.7)
Maternal delivery level (μg/mL) (n = 15)	1.6 (IQR 0.67–4.4)
Infant:maternal delivery level ratio (n = 15)	1.8 (range 0.96–7.13)
Gestational age at delivery (weeks) (n = 16)	39 (IQR 38–39.43)
Birthweight (grams) (n = 16)	3338.5 (IQR 3030–3625)
Time to ustekinumab clearance (weeks) (n = 9)	9 (range 6–19)

Emma Flanagan^1,2, Ralley Prentice^1,3,5, Emily K. Wright^1,2, Peter R. Gibson^4,5, Alyson L. Ross¹, Jakob Begun⁶, Miles P. Sparrow^4,5, Rimma Goldberg^3,5, Ourania Rosella⁴, Megan Burns³, Katerina V. Kiburg⁷ and Sally J. Bell^2,3,5

¹Department of Gastroenterology, St Vincent's Hospital Melbourne Pty Ltd, Melbourne, Australia
²University of Melbourne, Melbourne, Australia
³Department of Gastroenterology, Monash Health, Melbourne, Australia
⁴Department of Gastroenterology, Alfred Health, Melbourne, Australia
⁵Monash University, Clayton, Australia
⁶Department of Gastroenterology, Mater Hospital Brisbane, Brisbane, Australia
⁷Department of Medicine, St Vincent's Hospital Melbourne Pty Ltd, Melbourne, Australia

Correspondence
Dr Ralley Prentice, Department of Gastroenterology, Monash Health, 246 Clayton rd, Clayton, Vic 3168 Australia. Email: ralley.prentice@monashhealth.org

Author Contributions
Emma Flanagan contributed to the design of the study, acquisition of data and critically reviewed the manuscript. Ralley Prentice contributed to the acquisition and interpretation of data and drafted the manuscript. Emily Wright contributed to the acquisition and interpretation of data and critically revised the manuscript. Peter Gibson contributed to the interpretation of data and critical revision of the manuscript. Miles Sparrow, Jakob Begun, Rimma Goldberg and Ourania Rosella contributed to the acquisition of data and critical revision of the manuscript. Katerina Kiburg contributed to the statistical analysis and interpretation of data. Alyson Ross and Megan Burns contributed to the acquisition of data. Sally Bell contributed to the conception and design of the study, acquisition and interpretation of data and critical revision of the manuscript. All authors approved the final manuscript, including the authorship list.

Declaration of personal interests
Peter Gibson has served as a consultant or advisory board member for Anatara, Atmo Biosciences, Falk Pharma, Immunic Therapeutics, Janssen, Novozymes, Pfizer and Takeda. He has received research grants for investigator-driven studies from Atmo Biosciences. He holds shares in Atmo Biosciences. Miles Sparrow has received educational grants or research support from Ferring, Orphan and Gilead; speaker's fees from Janssen, Abbvie, Ferring, Takeda, Pfizer and Shire; and served on advisory boards for Janssen, Takeda, Pfizer, Celgene, Abbvie, MSD and Emerge Health. Jakob Begun has received educational grants or research support from Ferring, Janssen and Pfizer; speaker's fees from Janssen, Abbvie, Ferring, Takeda, Pfizer and Chiesi; and served on advisory boards for Janssen, Takeda, Pfizer, Celgene, Abbvie, MSD, BMS and Chiesi. Sally Bell has received consultation fees from AbbVie and Janssen, has received research grants for other investigator-driven studies/clinical trial funding from AbbVie, Janssen and Shire and has received speaker's fees from AbbVie and Janssen. The other authors disclose no conflicts.