In utero opioid exposure and risk of infections in childhood: a multinational Nordic cohort study

Background: Little is known about long-term consequences of in-utero exposure to opioids. Opioids modulate the immune system by binding to opioid mu receptors; prenatal exposure to opioids may increase children’s susceptibility to infections later in life. The aim of this study was to examine the association between prenatal exposure to opioids and risk of infections in childhood, measured as antibiotic prescriptions and infection diagnosis in specialist healthcare.

Methods: As confounding by indication may be a key concern, we investigated the association within two distinct populations of pregnant women with two different indications: First, in a cohort of women with a history of opioid maintenance treatment (OMT) exposure, we compared OMT exposed with OMT discontinuers pre-conception. Second, in a cohort of women with analgesic opioid use during pregnancy, we compared long-term users with short-term users. We followed the corresponding cohorts of live born infants into childhood. Exposure during pregnancy was identified from linkage between the nationwide Birth Registries and Prescription Databases. Incidence rate ratios (IRR) for antibiotic prescriptions were calculated using Poisson regression with robust standard errors for 95% confidence intervals (CI). The association between exposure and the cumulative risk of infection diagnosis in specialist health care system was analyzed using Cox proportional hazard regression, with attained age as the time scale. Inverse-probability-of-treatment weights (IPTW) were applied to adjust for confounding.

Results: From Norway and Sweden we included 57 911, and from Denmark 11 998 live born infants of mothers with history of opioid use. The adjusted IRR for antibiotic prescriptions at any time during follow-up in OMT exposed compared with OMT discontinuers was 1.08 (0.81 to 1.44) in Norway and Sweden, and 0.74 (0.63 to 0.88) in Denmark, and was in the same range for all age groups. The adjusted HRs for the risk of diagnosis of infection in specialist health care was 0.83 (0.55 to 1.26) in Norway and Sweden, and 0.82 (0.62 to 1.10) in Denmark. The adjusted IRR for antibiotic prescriptions at any time during follow-up in long-term users compared with short-term users was 1.17 (1.14 to 1.21) in Norway and Sweden, and 1.06 (1.00 to 1.12) in Denmark, and the trend was similar for all age groups. The adjusted HRs for diagnosis of infection was 0.97 (0.93 to 1.00) in Norway and Sweden, and 0.82 (0.62 to 1.10) in Denmark.

Conclusions: In this population-based cohort study, we did not observe increased risk of infections among children prenatally exposed to OMT opioids when compared to OMT discontinuers, nor long-term analgesic opioids exposed when compared to short-term analgesic opioids exposed.