Children born to women who have rheumatoid arthritis (RA) are at increased risk for developing certain chronic diseases during childhood and adolescence, a nationwide Danish study found.
Specifically, those children had elevated risks for thyroid diseases, with an adjusted hazard ratio of 2.19 (95% CI 1.14-4.21), and for epilepsy, with a hazard ratio of 1.61 (95% CI 1.16-2.25), according to Line R. Jølving, a PhD student at the University of Southern Denmark in Odense, and colleagues.
In addition, and most conclusively, the children had an almost threefold risk for developing RA themselves (HR 2.89, 95% CI 2.06-4.05), the researchers reported in Arthritis Care & Research.
Rheumatoid arthritis is three times more common among women than men, and is a common concern during pregnancy, when women worry about the potential effects of the disease or its treatment on the fetus.
It has been shown that the intrauterine environment can have negative fetal effects such as growth restriction and low birth weight, which have been linked with later chronic disease. However, “early adverse fetal life exposures, such as maternal chronic disease, might thus program not only adverse birth outcomes but also have a lifelong impact on the health status of the exposed children,” the investigators wrote.
Little research has focused on the health of children whose mothers had RA, although genetic factors are likely to be involved, “as the aggregation of RA in families is evident,” Jølving told MedPage Today.
To explore a possible link between maternal RA and specific chronic diseases in offspring, she and her colleagues analyzed data from national Danish registries, including the birth registry and National Registry of Patients for the years 1989 to 2013. The mothers had to have been residents of Denmark for at least 10 years for their children to be included in the analysis.
Potentially relevant chronic diseases among children included diabetes, thyroid and parathyroid diseases, polycystic ovary syndrome, lupus, inflammatory bowel disease, multiple sclerosis, lung disorders including asthma, epilepsy, and psychiatric disorders including schizophrenia and affective mood disorders.
The analysis included 2,106 children born to 1,504 women with RA, and 1,378,539 children of 751,816 healthy women. Median follow-up time was 13.7 years, with a maximum of 25.9 years.
A total of 7.4% of the exposed children were born in the earliest years of the analysis (1989 to 1993), with the numbers increasing and the largest number, 34.5%, born in the latest years (2009 to 2013). An increasing number of women with RA were older when giving birth, with 58.6% being ages 30 to 39 at the time of birth compared with 46.9% of those without RA.
The authors said they were unsure why women in the exposed cohort were relatively older than women in the unexposed cohort, but suggested that those with RA may have been less fertile or may have postponed pregnancy in order to attain low disease activity.
Children who were exposed to maternal RA in utero more often were born by cesarean section (28.2% versus 15%), were preterm (10.1% versus 6.2%), and were small for gestational age (5.1% versus 3.8%).
Among the 2,106 exposed children, 46 had chronic lung disease such as asthma, 35 had epilepsy, 34 had RA, 28 had anxiety and personality disorders, and nine had thyroid disease. After adjustment for sex, year of birth, maternal age, type of delivery, preterm birth, and small for gestational age, only RA, epilepsy, and chronic lung diseases remained significant.
A sensitivity analysis limited to mothers who had received a diagnosis of RA at least twice before childbirth had similar results, except that thyroid disease was no longer significant.
“Genetic factors have pleiotropic effects and predispose to a number of different diseases, but the fetal adaption as a consequence of maternal RA might also induce epigenetic changes that increase accumulation of diseases such as RA in the offspring,” the researchers wrote.
As for the specific diseases found to be associated, Jølving noted that an earlier Danish study also found an increased risk of epilepsy among children of mothers with RA, suggesting an autoimmune or inflammatory influence on the risk.
“Concerning the increased risk of thyroid disorders, my only suggestion would be the autoimmune kinship between the diseases RA and thyroid disorders,” she said.
The researchers concluded that the findings are relevant for pediatricians, rheumatologists, and general practitioners “in order to have special awareness of early symptoms of RA, thyroid disease, and epilepsy in offspring of mothers with RA.”
A limitation of the study, the team added, was the lack of information about medical treatments and socioeconomic factors among the mothers.
The study was supported by the Region of Southern Denmark, the University of Southern Denmark, Center for Clinical Epidemiology, Odense University Hospital, the Colitis-Crohn Association in Denmark, the Director Jacob Madsen and Olga Madsen Foundation, and Else Poulsens memorial scholarship.
The authors reported having no conflicts of interest.
F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner