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Early life factors have been associated with risk of developing autoimmune disease in adulthood. We investigated the association of preterm birth and being breastfed with the incidence of rheumatoid arthritis (RA) in two large prospective cohorts.
We studied participants from the Nurses’ Health Study (NHS) and the Nurses’ Health Study II (NHSII) who provided information on perinatal factors. The NHS (n=121,701) and NHSII (n=116,608) are large prospective cohorts of women followed since 1976 and 1989, respectively. Incident RA was confirmed using the American College of Rheumatology criteria and a medical record review. Cox models were used to estimate the hazard ratio of RA associated with being born preterm, being breastfed, and its duration, adjusting for potential confounders. Random effects meta-analytic methods were used to compute combined estimates from the two cohorts.
We found no statistically significant association between preterm birth and incident RA (RR=1.1, 95% CI: 0.8, 1.5). Being breastfed was not associated with increased incidence of RA (RR=1.0, 95% CI: 0.7, 1.4), regardless of the breastfeeding duration.
In these cohorts of women, neither being preterm birth nor breastfed were associated with the onset of RA.
Rheumatoid arthritis (RA) is three to five times more prevalent in women and its incidence increases with age(1). It is hypothesized that the pathogenesis of RA may be related to early life factors such as birth weight and breastfeeding that contribute to the development and shaping of the immune system(2).
Recent population-based case-control studies have explored a number of perinatal factors in association with RA(3, 4). Breastfeeding started in the hospital after delivery was associated with a dramatic 80–90% lower incidence of RA with a median age at onset of 46 years, suggesting that exposure to breast milk during this period may affect the state of the immune system and in turn, influence the risk of autoimmunity later in life, including in adulthood(4). Whether continuation of breastfeeding after hospital discharge is associated with RA risk has not been studied. In addition, rheumatoid factor (RF), an antibody associated with RA, was inversely associated with breastfeeding in an otherwise healthy pediatric population(5). Gestational age, which may be related both to fetal exposures such as maternal smoking or exposure to infection and in utero maturation, did not appear to be significantly associated with RA(3, 4). However, high birth weight, as a reflection of in utero exposures, was associated with an increased risk of RA(4). This finding was replicated in one(6), but not all studies(3). We therefore considered the role of two other perinatal factors, preterm birth and having been breastfed, on RA incidence in two large prospective cohorts, the Nurses’ Health Study (NHS) and the Nurses’ Health Study II (NHSII). In these cohorts high birth weight and preterm birth were recently found to be risk factors for adult-onset systemic lupus erythematosus, a related rheumatic autoimmune condition(7).
Established in 1976 with 121,701 participants initiatially recruited aged 30 to 55 years, NHS collects extensive data biennially from female nurses across the U.S. In 1989 a second, similarly designed cohort of 116,608 female nurses between the ages of 25 and 42 were enrolled in NHSII. Details on these cohorts can be found elsewhere(8–10). In the present study we excluded those who reported other systemic rheumatic diseases at cohort baseline, had missing diagnosis date, or self-reported RA that was not confirmed (nnhs= 837; nnhs2=573). We further excluded those who did not complete the questionnaire that ascertained exposures during infancy (nnhs=27803; nnhs2= 8991) - The primary reason for not completing the series of questions about perinatal exposures was death or loss to follow-up, rather than selectively ignoring the questions. Additionally anyone who did not report being a singleton birth (i.e. not part of a multiple birth) was excluded as the fetal environment for twins is different from singletons and data to further characterize these multiple births as monozygotic or dizygotic was missing (nnhs=6623; nnhs2=8913). An additional 123 records from NHS were excluded due to data inconsistencies. Thus 86,315 NHS and 98,131 NHSII participants were included in our study population.
In the 1991 NHSII and 1992 NHS questionnaires participants were asked to report early life exposures including whether they were born two or more weeks premature. When self-reports of preterm birth were compared to similar data collected from a sample of mothers of the participants, approximately 90% agreement was found(11).
In the 1991 NHSII and 1992 NHS questionnaires, participants were also asked whether they had been breastfed (response categories: no/yes/not sure) and for how long (response categories: no/≤3 months/4–8 months/≥ 9 months/not sure). Participants who were not sure if they were breastfed did not answer the duration question; Therefore those uncertain of their duration of being breastfed were among those responding yes to the first breastfeeding question. In a sample of NHSII participants, Troy and colleagues validated self-report of being breastfed against mother’s report with 82% sensitivity and 86% specificity. The correlation between mother’s and daughter’s reports of breastfeeding duration was 0.74(12).
On each biennial follow-up questionnaire, participants were asked about a variety of doctor-diagnosed health conditions. Those reporting any systemic rheumatic disease were asked to complete a previously validated Connective Tissue Disease Screening Questionnaire (CSQ) which previously demonstrated 85% sensitivity for RA (13) and for permission to review their medical records. The medical records of participants who screened positively for the signs and symptoms of both typical and atypical connective tissue diseases were evaluated independently by two rheumatologists, blinded to perinatal exposures, with disagreements resolved by consensus. The presence of at least four of seven ACR criteria documented in the medical record constituted confirmed RA (14). A total of 913 incident RA cases were confirmed during follow-up: 727 NHS participants through May 31, 2004 and 186 NHSII participants followed through May 31, 2003.
In secondary analyses we also studied whether the associations between perinatal exposures and rheumatoid arthritis were similar for those subjects who were documented to be RF-positive and those who were RF-negative(15).
In NHS, data were available on the following potential confounders and effect modifiers: parents’ occupation (as a proxy for childhood socioeconomic status), maternal history of diabetes (as a proxy for gestational diabetes), childhood exposure to cigarette smoke (as a proxy for smoke exposure in utero), race/ethnicity, and birth weight. In NHSII similar data were available except that parents’ occupation was not collected, and passive exposure to smoke in utero was ascertained explicitly.
Cohort characteristics were summarized using descriptive statistics stratified by breastfeeding exposure and preterm birth status. We estimated hazard ratios as a measure of relative risk (RR) of incident RA using age-stratified Cox proportional hazards models and multivariable Cox models adjusted for the following covariates: race, parents’ occupations, early life exposure to passive cigarette smoke, and birth weight. These covariates were adjusted for as potential confounding factors and chosen because they satisfied the following criteria and believed a priori to be associated with the exposure of interest at that time point (perinatal period), independent risk factors of the outcome, and not on the hypothesized causal pathway between exposure and disease. The proportional hazards assumption was evaluated using the Wald test to assess the significance of the interaction between time and each perinatal exposure(16). In the primary analysis, among subjects free of RA at baseline (1976 in NHS or 1989 in NHSII), participants were followed from return of the baseline questionnaire until date of diagnosis of confirmed incident RA, date of death, or until the return of their last questionnaire. Random effects meta-analysis methods were used to combine data from the two cohorts to account for possible heterogeneity in the effect of exposure across the two cohorts (17).
Statistical interaction terms were used to test for effect modification by a number of factors. We examined effect modification by maternal smoking during childhood to account for the possibility of cigarette smoke altering the composition, biological effects, or metabolism of breast milk. We examined effect modification by maternal diabetes history(considered as a proxy for gestational diabetes). In gestational diabetes the fetal environment may affect perinatal factors such as birthweight, and intrauterine growth. And lastly we assessed effect modification by preterm birth status since a preterm infant’s immune system is less developed and may function differently with regard to tolerance and antigen processing during breastfeeding.
Perinatal exposure data were obtained years after enrollment in both cohorts, raising the possibility that RA diagnosed before perinatal factors were assessed, might lead to differential recall of perinatal exposures. We therefore performed sensitivity analyses restricting follow-up to a prospective period after perinatal exposure data were collected to consider the possible role of such recall bias. We conducted an additional secondary analysis in the NHS cohort to consider possible selection bias related to excluding prevalent RA at baseline.
We confirmed 913 incident cases of RA in our study population during follow-up. The average age at diagnosis was 58 in NHS and 45 in NHSII. Thirty percent of NHS and 25% of NHSII participants with RA had radiographic changes consistent with erosive disease, and 59% were RF-positive at diagnosis in both cohorts. Being born preterm was associated with early life cigarette smoke exposure and low birth weight in these data (Table 1). Women who were breastfed in their infancy were less likely to have parents who smoked and were less likely to have low birth weight (Table 2).
Preterm birth was not associated with RA incidence in either cohort. The combined relative risk was (RR=1.1, 95% CI: 0.8, 1.5) in multivariable adjusted models (Table 3). Results were comparable for RF-positive and RF-negative RA (Table 4). There appeared to be no interaction by maternal smoking or maternal diabetes (data not shown).
Being breastfed was not associated with RA in either cohort. The combined relative risk (RR) was 1.0 (95% CI: 0.7, 1.4) (Table 3). The combined RR of RA for three months or less of being breastfed versus no breastfeeding was 0.8 (95% CI: 0.6, 1.1) (Table 3). There appeared to be no effect modification by maternal smoking, maternal diabetes, or preterm status (data not shown). Estimates were essentially unchanged when we considered RF-positive RA as a secondary outcome (Table 4). In the NHS cohort being breastfed was associated with a reduced rate of RF-negative RA (RR=0.7, 95% CI: 0.5, 0.9). None of the breastfeeding duration categories appeared to be significantly associated with RA (all, RF-positive, and RF-negative) with the exception of long duration of breastfeeding (≥9 months) protecting against RF-negative RA in the NHS cohort (RR=0.6, 95%CI: 0.4, 0.9).
When follow-up was restricted to the periods after exposure ascertainment (prospective analysis), results were similar in both NHS and NHSII. Additionally we found nearly identical results when 19 confirmed prevalent RA cases were included as cases in the NHS study population (data not shown).
In our study we found no statistically significant association between either preterm birth or being breastfed with the onset of RA. To our knowledge the only other study assessing the relationship between the perinatal characteristics of being breastfed and preterm birth and RA is the population-based case-control study by Jacobsson and colleagues(4). Using birth records and a disease register in Malmo, Sweden, the investigators identified 77 RA cases (67 cases included in the multivariable analysis) and 308 population-based controls. Records were used to classify their participants’ perinatal characteristics where data for a number of the perinatal factors were recorded at time of delivery minimizing the possibility of recall bias. Having breastfeeding initiated in the hospital was associated with a striking 80–90% reduction in odds of RA. In contrast, using data from two large prospective cohorts, with over ten times the number of cases, we found no association between being breastfed and RA incidence. However, comparing results from Jacobsson et al. to NHS results for another perinatal exposure, birth weight, demonstrated similar results(4, 6).
Study design, exposure assessment, and other analytic considerations may explain the disparate findings for breast feeding exposure. NHS and NHSII participants are predominantly American women while Jacobsson et al’s study population included Swedish men and women. By design, Jacobsson’s study captured both early and late adult onset RA whereas our participants were women free of RA at enrollment between the ages of 25 and 55. The median age at diagnosis was 46 in their study, similar to that in the NHSII cohort (median age 45). Nearly 80% of the cases in the present study, however, came from NHS where the median age at diagnosis was 58. The Swedish study used data from a local register of patients seen either as outpatients at Malmö University Hospital or one of three private rheumatologists in the city. RA cases in Jacobsson’s study might have had more severe RA – 76% were RF-positive and 85% had erosions compared with 59% RF-positive and 29% with erosions at RA diagnosis in the present study. However, the Swedish cases included prevalent RA which might be associated with longer disease duration and more radiographic findings. When we restricted our case definition to only include RF-positive RA, our results were relatively unchanged. When we defined our outcome as RF-negative RA, we found that being breastfed and for longer duration may be protective against developing RF-negative RA among the older cohort of NHS participants. One might expect that if we were to find an association it would be for the RF-positive outcome because the previous study which found a strong protective effect had over 75% RF-positive RA. Furthermore, the exposures assessed in these two studies differ. The Jacobsson study does not explicitly examine duration of breastfeeding, which our study does. If the protective effect were from immune modulating effects of prolonged exposure to maternal immunoglobulins, hormones, cytokines, and numerous antigens(18, 19), then prolonged exposure to breast milk would be likely to be relevant etiologically. However, if first exposure is more important, then breastfeeding initiation is capturing that risk factor better. On the other hand, we would expect to observe an association in our data, if one were present, among the ever breastfed category which we only find in one of the cohorts for our secondary outcome of RF-negative RA.
The present study population was restricted to adult women in the U.S. not diagnosed with RA at enrollment (age range 25–55 at enrollment), therefore limiting our generalizability to adult-onset RA after age 25 in women. Being breastfed was protective in some (4, 20) but not all studies (21, 22) for juvenile onset RA. If being breastfed does protect against the development of RA in childhood or early adulthood, then women who were not breastfed and more likely to have developed RA may be underrepresented in our study either because they did not go on to become nurses or they were less likely to participate in the Nurses’ Health Studies because of prevalent RA at baseline. When 19 confirmed prevalent RA cases satisfying the multiple exclusion criteria in NHS were included in the analysis we found that the results were essentially unchanged. When approximately 250 additional prevalent self-reports were included in the NHS study population, results were comparable though centered closer to the null and with wider confidence intervals.
Although validation studies suggest that these self-reported perinatal exposures are valid, we cannot exclude the possibility of exposure misclassification. The validation study by Troy and colleagues did not consider the older NHS population which may not reported with the same accuracy as the younger NHSII sample. Furthermore the mother’s self-report may not be the ideal gold standard. Imperfect reporting of breastfeeding exposure and its duration may have also lead to some exposure misclassification. This is likely to be non-differential but the direction of potential bias is difficult to predict as most perinatal characteristics in the present study had at least three categories: yes/no/don’t know. Missing or uncertain perinatal exposures were considered as their own category of exposure. Although not shown in Tables 1 and and2,2, there appeared to be little difference in cohort characteristics among those with missing and non-missing exposure data. Additionally, it is possible that the women who were not breastfed were exposed to different infant feeding alternatives, cow’s milk based vs. soy-based formulas for instance, and the available data do not adequately characterize this. Preterm birth was defined using participants’ identification of being born as at least two weeks preterm, as worded on the questionnaires. This definition does not conform to the definition of preterm birth currently recommended by the American College of Obstetrics and Gynecology of at least three weeks preterm; therefore we were unable to consider moderate versus severe prematurity as a risk factor. We also cannot exclude the possibility of misclassification of RA diagnosis, but there is no reason to believe that this would differ by perinatal characteristics. When we use RF seropositivity to define subtypes of RA, we found that being breastfed and for a longer duration may be associated with a lower rate of RF-negative RA. We cannot exclude the possibility that this is a false positive finding because of the number of outcomes and exposures we considered in the present study; however, the effect estimate was relatively modest and statistically significant despite decreased power.
Our analysis is based on observational data and therefore one cannot exclude the possibility that there remains bias due to confounding by measured or unmeasured factors. For instance, the type of breast milk alternative available in the US has had secular changes, but other unmeasured confounders could have changed over time as well. Breastfeeding practices in the U.S. changed with time and are, in part, related to social factors which we cannot adequately adjust for due to limited data on socio-economic factors during the nurse participant’s infancy and childhood. However, adjustment for available potential confounders did not appreciably change the estimated associations for any of the perinatal factors we considered. We cannot exclude the possibility that heterogeneity of the association between breastfeeding and incident RA in women exists in relation to the two cohorts, which represent two distinct birth cohorts.
This study found that neither preterm birth nor being breastfed was significantly associated with RA incidence. Well powered with over 900 confirmed incident cases of RA, we showed consistent findings with previous work for a null association between RA and gestational age, but were unable to confirm the previously published protective effect of being breastfed.
Funding: JF Simard is supported by the Arthritis Foundation Doctoral Dissertation Award. EW Karlson is supported by NIH grants R01 AR49880, K24 AR0524-01. KH Costenbader is the recipient of NIH K12 HD051959 and an Arthritis Foundation/American College of Rheumatology Arthritis Investigator Award. M. Liang is supported by grants from Rheuminations, NIH Multipurpose Arthritis Center Grant, and the Arthritis Foundation.
Competing Interests: All authors declare no competing interests.
Key Messages: -Being born preterm is not significantly associated with incident rheumatoid arthritis in adults.
-Whether being breastfed in infancy protects one against later rheumatoid arthritis is unc