Ustekinumab and Risk of Small for Gestational Age in Inflammatory Bowel Disease Pregnancies: Data from the DUMBO Registry

Study type

• Study topic:
  Disease /health condition

  Human medicinal product
• Study type:
  Non-interventional study
• Scope of the study:
  Safety study (incl. comparative)
• Data collection methods:
  Secondary use of data

Non-interventional study

• Non-interventional study design:
  Cohort

Study drug and medical condition

• Medicinal product name:
  STELARA
• Study drug International non-proprietary name (INN) or common name:
  USTEKINUMAB
• Anatomical Therapeutic Chemical (ATC) code:
  (L04AC05) ustekinumab

  ustekinumab
• Medical condition to be studied:
  Inflammatory bowel disease

Population studied

• Short description of the study population:
  9.2.2.1. Inclusion Criteria; The population under study will consist of women meeting the following criteria:;  Pregnant women with confirmed IBD (CD, UC, IBD-U) recruited into the DUMBO registry before week 28 of gestation. ;  Exposed to mesalazine, immunomodulators including corticosteroids, anti-TNFɑ agents, ustekinumab or not exposed to any treatment at any time during pregnancy or 3 months prior to conception;; 9.2.2.2. Exclusion Criteria; Women who meet any of the following criteria will not be eligible for this study:;  Patients exposed to known teratogens from conception through the first trimester of pregnancy (Gomes 2021).;  Patients exposed to targeted small molecules (eg. JAKi, S1P modulators), or biologics other than anti-TNFɑ agents or ustekinumab;  Lack of informed consent, or loss to follow-up prior to delivery.
• Age groups:
  • Adults (18 to < 65 years)
• Special population of interest:
  Pregnant women
• Special population of interest, other:
  Pregnant women with IBD
• Estimated number of subjects:
  954

Study design details

• Study design:
  Observational design, based on analysis of data from the DUMBO registry, a prospective Spanish cohort of pregnant women with IBD supported by Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa (GETECCU)
• Main study objective:
  To assess whether exposure to ustekinumab (and biosimilars) during pregnancy in women with inflammatory bowel disease (IBD) is associated with an increased risk of small for gestational age (SGA) infants compared to those exposed to anti-tumor necrosis factor (TNFɑ) agents (infliximab, adalimumab, golimumab, including biosimilars), immunomodulators and to those not exposed to either biologics or immunomodulators.
• Setting:
  DUMBO (Safety Of IB(D) Dr(U)gs During Pregnancy And Breastfeeding (M)others And (B)abies’ (O)utcomes) registry database.
• Comparators:
  exposure to anti-TNFɑ agents (primary comparator); exposure to immunomodulators or no immunomodulatory/biologic ; therapy (secondary comparators)
• Outcomes:
  The primary outcome is to assess small for gestational age (SGA). SGA is defined as birth weight below the 10th percentile for gestational age and sex. For term newborns (greater than or equal to [>=] 37 weeks) world health organization (WHO) growth standards will be used; for preterm infants (less than [<] 37 weeks) Fenton growth charts will be applied. Maternal demographic and clinical data (disease characteristics, activity and treatment) will be extracted at baseline.
• Data analysis plan:
  Descriptive analysis will include baseline characteristics of mothers of live-born infants which will be described for each exposure group using means and standard deviations (SD) or medians and interquartile ranges (IQR) for continuous variables, and frequencies (%) for categorical variables. Comparison of baseline characteristics between exposure groups will be performed to characterize differences before propensity score (PS) weighting. A description of the planned statistical methods to be used to analyze the data collected. The report will include descriptive data of the number of mothers of life-born infants who have entered the study in each of the treatment cohorts, trimester of exposure and counts and proportion of infants with SGA tabulated by exposure status at cohort entry. The associations between maternal characteristics and SGA will be assessed by univariate analysis. And to minimize confounding by indication multivariable analysis will be applied in order to achieve covariate balance between groups.
• Summary results:
  Results: A total of 954 pregnancies with 980 live births were included in the analysis. The overall incidence of SGA was 11%, and the proportion of infants classified as SGA was similar across treatment groups (37 cases [11%] in the non- treated group, 27 [11%] in the immunomodulator group, 37 [12%] in the anti-TNFɑ group, and 10 [11%] in the ustekinumab group). In multivariable analysis, ustekinumab exposure was not associated with an increased risk of SGA compared with anti-TNFɑ therapy, immunomodulators including corticosteroids, or no immunosuppressive treatment : compared with ustekinumab exposure, adjusted OR (95% CI) were: 1.17 (0.53–2.78) for immunomodulators/corticosteroids, 1.37 (0.65–3.16) for anti-TNFɑ therapy, and 1.37 (0.61; 3.33) for no immunosuppressive therapy. Independent predictors of SGA included female infant ; sex, and disease activity during pregnancy (higher risk of SGA).; Conclusions: In this prospective cohort of pregnancies in women with IBD, exposure to ustekinumab during pregnancy was not associated with an increased risk of SGA infants compared with other treatment groups. These findings provide reassuring real-world evidence regarding the fetal growth safety profile of ustekinumab in pregnancy.