What is Association Between Preterm Delivery and JIA Development?

Researchers have found an association between premature birth and an increased risk of juvenile idiopathic arthritis (JIA) in a case-control study.¹ They found no association between previously reported risk factors of JIA, including exposure to smoking, infection early in life, or lack of breastfeeding. For this reason, the association between preterm delivery and JIA requires further investigation.

Other than prematurity, “the remainder of studied risk factors were not associated with increased JIA risk, including cigarette smoke exposure, early-life infections, presence of pets, breastfeeding, residential area, stressful life events, and other perinatal characteristics,” wrote Susan Shenoi, MB BS, MS, from the University of Washington School of Medicine and Seattle Children’s Hospital and Research Institute and colleagues. “Previous studies from Sweden² and Australia³ examined similar exposures; however, despite overlap in exposures studied, this study includes a substantially different population and provides external validation of previous findings.”

The researchers noted that this study examined JIA according to a broader representation, identified through rheumatology outpatient clinics rather than by hospital billing codes.

The researchers studied 225 participants with JIA and 138 controls identified through a major pediatric rheumatology outpatient clinic. Each participant with JIA was asked to identify 3 healthy playmates of the same gender and similar age to serve as controls.

Parents or caregivers completed questionnaires on various environmental and early-life exposures. Researchers then used conditional logistic regression adjusted for age and socioeconomic status to determine the odds ratio (OR) for developing JIA with 95% confidence intervals.

Compared with matched controls, preterm delivery (OR 1.8 [95% CI 1.2-2.7]) was associated with JIA. No association was found between JIA and maternal prenatal smoking, household smoking, breastfeeding, hospitalization with infection in the first year of life, daycare attendance before age 6, household pets, or residential area prior to the onset of JIA.

The modestly increased risk of JIA with premature birth contrasts with a previous study by Carlens et al² which found no association between prematurity and JIA, but instead found an increased risk of JIA with post-term gestational age (OR 1.2 [95% CI 1.0–1.34]). Contrary to the current study, Carlens et al also found an increased risk of JIA with early-life infections (OR 1.9 [95% CI 1.7–2.1]) using a case-control design identifying severe cases through hospitalized International Classification of Diseases JIA billing codes.

The researchers of the current study also noted that their study showed no association between stressful life events and JIA, and even found a significant protective effect for JIA with death in the family (OR 0.3 [95% CI 0.1–0.9]) and unemployment in the household (OR 0.2 [95% CI 0.1–0.6]). These findings contrast with previous research showing associations between stressful events and JIA.

Dr Shenoi and colleagues did find in their previous research that maternal smoking was not associated with an increased risk of JIA (OR 0.71 [95% CI 0.58–0.87]). This is unlike with adults, where personal smoking is a risk factor for seropositive rheumatoid arthritis. 

However, since the majority of JIA is seronegative, it may be plausible that smoking may not increase risk of seronegative JIA. It may also be possible that smoking only affects certain JIA categories, but the researchers were unable to examine this due to only small numbers of individuals in each category.

Summary & Clinical Applicability

In contrast to previous studies showing associations between smoking, early-life infection, or breastfeeding and an increased risk of JIA, researchers in this study found no association between these factors, finding instead an association between premature birth and an increased risk of JIA.¹

“Prematurity has been linked to later onset of other autoimmune diseases, like diabetes mellitus; mechanisms implicated include structural changes in organs and epigenetic mechanisms. Mechanistic reasons for the observed association of prematurity and JIA are unclear and should be further evaluated,” the authors concluded.

Limitations & Disclosures

• Potential introduction of selection bias, as JIA cases were identified primarily through outpatient rheumatology clinics
• Potential recall bias from using questionnaires that may not have been address by sensitivity analysis
• Control group was difficult to recruit, most recruited as friends of children with JIA, and instances of failure to return questionnaires were common; researchers attempted to correct  by repeating analyses with a frequency-matched control cohort
• Time period of environmental influence was defined as occurring within 1 year of symptom onset 
• Except for polyarticular RF-negative JIA, category-specific risks could not be calculated due to small numbers in each category

References

1. Shenoi S, Shaffer ML, Wallace CA. Environmental Risk Factors and Early-Life Exposures in Juvenile Idiopathic Arthritis: A Case-Control Study. Arthritis Care Res (Hoboken). 2016;68(8):1186-94. doi:10.1002/acr.22806.
2. Carlens C, Jacobsson L, Brandt L, Cnattingius S, Stephansson O, Askling J. Perinatal characteristics, early life infections and later risk of rheumatoid arthritis and juvenile idiopathic arthritis. Ann Rheum Dis. 2009;68:1159–64.
3. Ellis JA, Ponsonby AL, Pezic A, Chavez RA, Allen RC, Akikusa JD, et al. CLARITY: ChiLdhood Arthritis Risk factor Identification sTudY. Pediatr Rheumatol Online J. 2012;10:37.

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