This is possibly the most comprehensive study to date on neonatal risk factors in celiac disease. We found a positive association with elective, but not emergency, cesarean delivery and later celiac disease, indicating that the bacterial flora of the newborn may play a role in the development of celiac disease. In contrast to previous studies using retrospective data, we conclude that cesarean delivery per se is not a major risk factor for later celiac disease. Thus, our results should not alter delivery advice (i.e. indication for cesarean delivery). In the current study we also found a 21% increased risk of later celiac disease in children who were small for gestational age.
Interpretation of findings
We found a modest but statistically significant excess risk for celiac disease after elective,
but not emergency, cesarean delivery. Overall, cesarean delivery per se
was not a major risk factor for later celiac disease in the offspring, with risk estimates very close to one. While the association with elective cesarean delivery could be due to residual confounding, it could also reflect atypical patterns of initial bowel colonization, which typically occur in the birth canal. Animal data indicate that microbial exposures in the birth canal may be important for the development of homeostasis between host and colonizing flora. This is because perinatal colonization represents the first major exposure to microorganisms in the gut34
.The effect of a disturbed neonatal gut colonization can persist for many years35
and influences the intestinal immune response36
as well as the mucosal barrier function37
. This disturbed mucosal barrier function may be important in that translocation of gliadin peptides through the intestinal epithelium is a key element in the pathogenesis of celiac disease38
Although modest in magnitude, our findings that elective caesarean delivery predisposes to celiac disease are consistent with a similar association for pediatric Crohn’s disease observed in two studies39, 40
. In contrast to children born by elective cesarean delivery, children born by emergency cesarean delivery (where we found no association with later celiac disease) may have been in contact with the birth canal. By definition in the Swedish Medical Birth Register, elective cesarean delivery must occur before the onset of labor would include ruptures of the membranes, which would limit the possibility of initial contact with microorganisms in the birth canal.
To rule out that the association between elective cesarean delivery and celiac disease was due to a higher frequency of small for gestational age children among mothers with elective cesarean delivery we estimated the association between elective cesarean delivery in celiac disease among small for gestational age pregnancies and non-small for gestational age pregnancies, but with similar risk estimates in both groups.
In 2010, Decker et.al16
reported an increased risk of celiac disease after any cesarean delivery (adjusted OR = 1.80; p = 0.014); however, that study did not distinguish between elective and emergency cesarean delivery. This and other methodological issues may have contributed to the difference between our findings. First, Decker et.al
used retrospective interview-based data on 123 individuals with celiac disease, as compared with our prospectively recorded data on some 11,000 individuals with celiac disease. Second, we adjusted for maternal celiac disease. This adjustment is very important since mothers with celiac disease have an increased cesarean delivery rate30, 41
and convey an increased risk of celiac disease in offspring. The association between cesarean delivery and celiac disease has also recently been examined using British record-based pregnancy data. Although restricted to a limited number of inpatients with celiac disease (n = 90), in this study Roberts et.al
reported a non-significant decreased
risk of celiac disease after cesarean delivery (OR = 0.29; p = 0.064)17
. A causal effect between elective cesarean delivery and celiac disease would certainly have the most profound impact in countries with high cesarean delivery rates.
We found a 21% increased risk of celiac disease in children with small for gestational age. Because small for gestational age is a multi-factorial condition, many circumstances could have contributed to this result42
. Infants born small for gestational age have an altered cell-mediated immunological development43, 44
, which may influence the intestinal immunity but separate from the altered immune state associated with prematurity. The association between small for gestational age and celiac disease did not change when we excluded children with Down syndrome.
In contrast to the increased risk of celiac disease in children with small for gestational age, we found a modestly decreased risk of later celiac disease following preterm birth. Although this may be a chance finding, it could also reflect the different feeding practices among preterm compared with term infants, as well as compared with children born small for gestational age.
We found no increased risk of celiac disease after neonatal infection. Importantly, these results do not necessarily refute the hypothesis that infant
infections could influence the development of celiac disease because infections near the time of gluten introduction may have greater impact on celiac disease development29
In 2002, Sandberg-Bennich et.al18
reported a statistically significant increased risk of celiac disease after neonatal infection (OR =1.52), low birth weight (OR = 1.27), and small for gestational age (OR = 1.4), as well as a significantly decreased risk following preterm birth (OR = 0.82). With the exception of preterm birth, we found considerably lower risk estimates (all close to one) than Sandberg-Bennich et.al
. An important explanation for this discrepancy may be their restriction to inpatient celiac disease18
, where selection bias led to inclusion of more complicated celiac disease and comorbidity, possibly inflating risk estimates.
Strengths and limitations
A major strength of our study is the use of prospectively recorded exposure and outcome data, eliminating the risk of recall bias. Further, this is the largest study on neonatal risk factors in celiac disease to date, and the number of individuals with celiac disease (>11,000) greatly exceeds that of all earlier studies in this field combined. The strong statistical power improved the precision of our risk estimates and allowed us to adjust for several potential confounders, including maternal disease.
The use of biopsy data to identify patients with celiac disease enabled us to identify a representative population with celiac disease. In contrast, patients from inpatient registers or referral centers often suffer from surveillance or selection bias that may overinflate risk estimates because of co-morbidity. More than 95% of Swedish gastroenterologists and pediatricians perform a small intestinal biopsy before celiac disease diagnosis19
, implying that biopsy records have a high sensitivity for diagnosed
celiac disease. The great statistical power allowed for important subanalyses, such as stratification for calendar period of birth and early diagnosed celiac disease (before age 2 years).
We regard the risk of misclassification in celiac disease as low. In an earlier validation study 95% (108/114) of individuals with villous atrophy had celiac disease19
. A manual review of more than 1,500 biopsy reports showed that diagnoses other than celiac disease were rarely the cause of villous atrophy19
(inflammatory bowel disease was the most common comorbidity mentioned in 0.3% of biopsy reports with villous atrophy). A high specificity is crucial in minimizing the number of false-positive cases, which otherwise would result in a decrease of a true excess risk.
This study has some limitations. In nationwide registers, such as the Medical Birth Register, some of the individual data may be missing or have been erroneously registered. However, validation studies of the Medical Birth Register have concluded that, in general, it holds high-quality data45
. The proportion of infants with missing diagnosis has varied between 5 % and 15 %22
. We cannot rule out the possibility of missing diagnoses in individual infants, but this would only have a marginal effect on our statistical power. More importantly, potential misclassification of pregnancy data should not differ by celiac disease status and therefore not bias our results. With respect to neonatal infectious diseases, the Medical Birth Register foremost monitors severe infectious diseases, thus limiting our ability to study mild neonatal infectious disease and later development of celiac disease.
We adjusted for several potential confounders but not for breastfeeding. Although data on breastfeeding and celiac disease are inconsistent46, 47
, infant feeding may influence the development of celiac disease. We cannot exclude that lack of breastfeeding data might have influenced our risk estimates of celiac disease after small for gestational age.
In conclusion, we found a positive association with elective, but not emergency, cesarean delivery and later celiac disease, indicating that the bacterial flora of the newborn may play a role in the development of celiac disease. However, the risk of celiac disease was not influenced by cesarean delivery per se and therefore our result should not alter delivery guidelines. We also found a 21% increased risk of celiac disease in children born small for gestational age, whereas other pregnancy exposures did not increase the risk of future celiac disease.