In-utero events can affect early life immune responses,26, 27
the development of atopic diseases in the offspring,2-5
and even result in epigenetic effects on subsequent generations.6
To date, no prospective studies have examined the joint effect of prematurity and chorioamnionitis in relation to the development of respiratory morbidity and atopic diseases in early childhood. In this study, we found that while prematurity was associated with recurrent wheezing in this cohort of children in the first few years of life, this association was greatly augmented by the severity of prematurity and presence of chorioamnionitis. The children who were very preterm and had chorioamnionitis had the greatest risk of recurrent wheezing. Furthermore, this association was much stronger in African American children. Our findings provide new information to a long-standing clinical and public health challenge, that is, increased risk of respiratory morbidities in African American children.
There were a number of features of our cohort which allowed us to carry this study out. We carried out a thorough evaluation of prenatal factors including placental pathology which provided a very sensitive indicator of intrauterine infection or inflammation. Ours is one of the few prospective studies with large enough numbers to allow stratification by severity of prematurity and presence of chorioamnionitis. Our study also has significant minority representation, with a high frequency of African Americans. Like asthma,28, 29
prematurity and chorioamnionitis disproportionately affect the African American community (IOM report 2006). Our findings underscore the importance of examining the role of in-utero factors on the later development of respiratory morbidities. They also raise questions about whether the persistent and high prevalence of prematurity and chorioamnionitis, especially in African Americans, are linked in a causal fashion to the asthma epidemic and ethnic disparity in respiratory outcomes.
Caution is needed in interpreting our findings because of a number of potential limitations. Although we have shown associations with physician diagnosed asthma, we focused on recurrent wheezing given the average age of the children (around 2 years). It would be important to evaluate if the associations persist as we continue to follow these children and if increased rates of recurrent wheezing correlate with increased rates of asthma diagnoses at later ages. We were not able to follow all of the patients in the initial cohort as recruitment into the follow up cohort is ongoing. Subjects already enrolled in the follow up study showed no differences from those not yet recruited in key variables including birth-weight, gestation and percent of the cohort with chorioamnionitis.
This study focused on two prominent prenatal factors (prematurity and chorioamnionitis). While our analyses attempted to adjust for many potential covariates, we need to recognize that there are many other important prenatal factors that could affect the associations, such as intrapartum antibiotics and mode of delivery. Intrapartum antibiotics and mode of delivery can affect types of commensal organisms present in the mother30
, and atopic disease prevalence.32-34
However, we do not feel that mode of delivery or intrapartum use of antibiotics influenced our findings; intrapartum antibiotics was included as a covariate in our analyses. Also, modification of the commensal flora by antibiotics or mode of delivery should affect allergic diseases in general, not just wheezing. Since a significant proportion of the diagnoses of chorioamnionitis were made by histological diagnosis alone and represent subclinical inflammation, these mothers would not have had a clinical indication to receive intera-partum antibiotics. Notably, subclinical chorioamnionitis, determined by placental pathology, makes up the majority of our cases, and our analyses suggest that this is a stronger determinant than maternal fever alone. Finally, our findings compare subjects of similar gestational age, thereby decreasing any differential distribution of delivery mode. While we have controlled for modifiable risk factors such as smoking and breastfeeding in the analysis, we have insufficient sample size to stratify by all of these variables or evaluate interactions between all of these variables in addition to our main variables of interest, prematurity and chorioamnionitis. Further studies with increased sample size may be able to address these potential interactions.
Other potential mechanisms which need to be considered include possibilities such as increased susceptibility to early life respiratory infections and pneumonias such as RSV and the impact of these events on our findings. Also, further studies are needed to determine if the effects associated with chorioamnionitis are due to the administration of antipyretics in the perinatal period.
Several important points merit further discussion with respect to the prior literature. Prematurity has been associated with later childhood asthma in a number of studies3, 9-11
While the effect of gestational age has not been consistent in all studies12, 13
, a recent meta-analysis of 19 studies reported that preterm infants are more likely than term infants to develop asthma, with preterm infants having a 7% increased risk8
. One potential reason for discrepant results in the literature is that these studies did not evaluate the causes of prematurity. As emphasized in the 2006 IOM (Institute of Medicine) report, chorioamnionitis is a major pathway leading to the development of preterm birth.14-16
The potential role of chorioamnionitis as a cause of respiratory morbidity has been evaluated in only a few studies to date. In these studies, febrile episodes in pregnancy (especially the third trimester) were associated with subsequent development of asthma in offspring.17, 18
In keeping with the fact that chorioamnionitis is much more common in very preterm infants,35
we found our greatest effect in this group of infants.
Secondly, we did not find an association of prematurity and chorioamnionitis with atopic dermatitis or food allergy. This is also consistent with other published studies. A number of studies of prematurity suggest either no association with atopic diseases36
or decreased risk of atopic outcomes including atopic dermatitis37
, and allergic rhinitis.38
The differential associations for respiratory morbidities vs. non-respiratory atopic diseases suggest differential pathways of disease promotion. In our study, chorioamnionitis increased the risk of wheezing and physician diagnosed asthma, but not atopy. While this outcome is important in itself, it may or may not equate to asthma later in life. If it does predispose to persistent asthma, it would suggest that some prenatal factors may lead to asthma via non-atopic pathways such as fetal programming or epigenetic effects in-utero. However, the biological links between prematurity or chorioamnionitis and wheezing are not well established.
Finally, there is some biological rationale for our findings. Chorioamnionitis is associated with a strong pro-inflammatory response with increased levels of TNF-α, IL-6, and IL-8.39, 40
These inflammatory cytokines may be a response to infection and also a trigger for premature delivery. Specifically, human decidual cells increase the production of delivery promoting factors such as PGE2 and PGF2 in response to inflammatory cytokines including IL1a, IL1b, and TNF-α.41
In animal models, administration of a PDE4 inhibitor prevents preterm delivery.42
Some of the same cytokines which are a response to infection may be involved in chronic respiratory disease development. Of these inflammatory cytokines, TNF-alpha variants have been found to be associated with recurrent wheezing after RSV bronchiolitis.43
IL-8 levels were increased in children who developed wheezing illnesses in response to Rhinovirus,44
and in another cohort, individuals who wheezed with Rhinovirus were at additional risk of persistent wheezing till follow up at age 3 years.45
Thus, the same cytokines which are generated as part of the inflammatory response to chorioamnionitis may play a role in asthma and responses to respiratory viral illness.
In summary, we found a strong joint effect of prematurity and chorioamnionitis on early childhood recurrent wheezing. This effect was even stronger in African Americans. Further investigation is warranted to evaluate if the associations persist as we continue to follow these children to older age and if increased rates of recurrent wheezing correlate with increased rates of later asthma. Our findings remain to be confirmed by future studies in other populations.