Preterm Birth and Infantile Appendicitis

This is a retrospective, multicenter, matched case-control study. The study was approved by the institutional review board at each participating institution. Because of the retrospective nature of the study, informed consent was waived by the institutional review boards. Our study adheres to the 1975 Declaration of Helsinki.

Cases were identified by a comprehensive search of the institutional databases of 3 children’s hospitals and 1 tertiary medical center with large pediatric delivery services. Both primary and final diagnoses were searched. Consecutive patients <1 year of age diagnosed with appendicitis and admitted between December 1, 2007 and May 31, 2023, were considered eligible. To maintain diagnostic accuracy and consistency, we included only cases of appendicitis confirmed by appendectomy, laparotomy, laparoscopic exploration, or autopsy. Exclusion criteria included (1) intraoperative finding of a normal appearing appendix, (2) pathology findings not consistent with appendicitis, (3) cases with diffuse abdominal inflammation in which it is uncertain whether appendicitis is the primary cause, (4) comorbid necrotizing enterocolitis (NEC), (5) comorbid immunodeficiency disease or malignancy, and (6) comorbid Meckel diverticulitis.

Patients were categorized as neonates (0 to 28 days) or older infants (>28 days and <1 year) on the basis of their age at the onset of symptoms or signs that were considered relevant to acute appendicitis. Data of interest were extracted by using a predetermined sheet.

For each case, 10 healthy controls were selected from a pool of >10 000 healthy infants in the outpatient child primary care department. Controls were randomly selected and matched on age. The exclusion criteria included (1) a history of acute or chronic appendicitis, (2) a history of appendiceal fecalith, and (3) comorbid immunodeficiency disease or malignancy.

Information regarding demographic data, birth history, and feeding history were extracted from the medical records of the cases and the health archives of the controls. Data collection was independently performed by 2 authors and cross-checked for accuracy. The pathological findings and surgical findings were both checked to confirm the diagnosis of appendicitis.

Potential confounding factors included sex, birth weight, season, feeding method, weight, weight-for-age z-score (WAZ), and comorbid congenital heart defects. The season of appendicitis occurrence and control subjects’ presentation was categorized as spring (March to May), summer (June to August), autumn (September to November), and winter (December to February). Infant feeding was classified as breast, formula, or a combination of both. Appendiceal perforation was defined by consensus as the visualization of a gross defect in the appendiceal wall as documented by attending surgeons.

Continuous variables are presented as the median and interquartile range (IQR), and categorical variables are presented as numbers and percentages. Comparisons were made by using the Mann–Whitney U test or χ-square test, as appropriate. Both univariable and multivariable conditional logistic regression analyses were performed to evaluate the association between each variable and the development of appendicitis. Variables with a significant association with appendicitis in the univariable analysis were included in the multivariable model for adjustment, avoiding multicollinearity. Variables with a Variance Inflation Factor >10 were deemed to have significant multicollinearity and were, thus, excluded from the multivariable analysis. The odds ratio (OR) was calculated with a 95% confidence interval (CI).

Additionally, we explored the association between preterm birth and perforated infantile appendicitis in 2 ways: (1) by assessing whether a history of preterm birth increased the risk of perforation among infants with appendicitis, and (2) by evaluating the correlation between preterm birth and the occurrence of perforated appendicitis, comparing cases with perforation against age-matched controls.

Statistical analyses were conducted by using SPSS for Windows version 26.0 (IBM., Armonk, NY, USA). A 2-sided α of <.05 was considered statistically significant.

A total of 106 infants (median age, 2.4 months; IQR, 0.5–6.0 months; 33 female infants [31.1%] and 73 male infants [68.9%]) diagnosed with appendicitis were evaluated, and 1060 age-matched healthy infant controls (median age, 2.4 months; IQR, 0.7–5.9 months; 492 female infants [46.4%] and 568 male infants [53.6%]) were included for comparison. The neonatal group encompassed 39 cases, and the older infant group encompassed 67 cases. Patient distribution based on age is depicted in Fig 1. The distribution based on corrected gestational age is presented in Supplemental Fig 5. The baseline characteristics of the cases and controls are presented in Table 1. The age was comparable between the 2 groups. The significance of the difference in seasonal distribution is marginal.

There were 36 (34.0%) infants with a history of preterm birth in the case group and 123 (11.6%) in the age-matched control group. Preterm birth was significantly associated with the development of appendicitis before 1 year of age, with an unadjusted OR of 4.23 (95%CI, 2.67–6.70) by conditional logistic regression analyses. The results are illustrated in Fig 2. Male infants (OR, 1.91; 95%CI, 1.25–2.94), lower birth weight (OR, 0.42; 95%CI, 0.31–0.57), and lower WAZ (OR, 0.72; 95%CI, 0.64–0.81) were all associated with a higher unadjusted risk of infantile appendicitis. Infants exclusively fed formula had a higher risk of developing appendicitis before 1 year of age than breastfed infants (OR, 2.95; 95%CI, 1.77–4.91). Appendicitis risk was highest during autumn, with an OR of 2.10 (95%CI, 1.19–3.69) compared with spring.

Six variables that were statistically significant in the univariate analyses were included in the multivariable analyses, and 4 variables were left in the final adjustment model (Fig 3). A history of preterm birth remained significantly associated with the development of appendicitis during the first year of life (adjusted OR, 3.32; 95%CI, 1.76–6.24). Other factors associated with infantile appendicitis included male sex (adjusted OR, 3.10; 95%CI, 1.85–5.19), formula feeding (adjusted OR, 1.80; 95%CI, 1.01–3.20), and weight (adjusted OR, 0.44; 95%CI, 0.23–0.83).

Both neonates (unadjusted OR, 3.43; 95%CI, 1.69–6.95) and older infants (unadjusted OR, 4.84; 95%CI, 2.70–9.04) exhibited significant associations between preterm birth and infantile appendicitis. After adjusting for sex (male, adjusted OR, 2.84; 95%CI, 1.35–5.99) in the neonatal group, and sex (male, adjusted OR, 2.00; 95%CI, 1.13–3.52) and WAZ (adjusted OR, 0.81; 95%CI, 0.68–0.97) in older infants, preterm birth remained significantly associated with the development of appendicitis before 28 days (adjusted OR, 4.56; 95%CI, 2.14–9.71) and between 1 and 12 months of age (adjusted OR, 3.63; 95%CI, 1.72–7.65). The results are illustrated in Fig 4.

Of the 106 infants diagnosed with appendicitis, 77 (72.6%) presented with perforated appendicitis. Among all infants with appendicitis, a history of preterm birth (25 cases) did not significantly influence the incidence of perforation (OR, 0.79; 95%CI, 0.32–1.91; P = .60).

When compared with age-matched controls using the conditional logistic regression analyses, preterm birth significantly correlated with the development of perforated appendicitis within the first year of life, with an unadjusted OR of 4.66 (95%CI, 2.70–8.03). After adjusting for sex and feeding method in a multivariable analysis, a history of preterm birth remained significantly associated with the occurrence of perforated infantile appendicitis (adjusted OR, 3.54; 95%CI, 1.86–6.76).

In the subgroup analysis, after adjusting for sex and WAZ, a history of preterm birth maintained a significant association with perforated infantile appendicitis both in neonates (adjusted OR, 4.17; 95%CI, 1.46–11.93) and older infants (adjusted OR, 3.30; 95%CI, 1.25–8.68).

In this matched case-control study, we showed a strong and previously unknown association between preterm birth and infantile appendicitis. Preterm infants have a 2.3 times higher risk of developing appendicitis than healthy controls before 1 year of age. However, the risk of perforation in infants with appendicitis was not significantly influenced by a preterm birth history. These findings offer new opportunities to understand the etiology of infantile appendicitis and to improve the timely diagnosis of appendicitis among preterm infants.

In previous reports and our study, it was not uncommon for patients with a preoperative diagnosis of NEC and bowel perforation to be diagnosed intraoperatively with perforated appendicitis. It may suggest that we may have failed to include NEC patients with nonperforated appendicitis who did not receive appendectomy or laparotomy, which may introduce selection bias to the current study. Another potential source of selection bias may derive from the infants who died of appendicitis but did not undergo an autopsy. It is worth noting that both of the scenarios could potentially lead to an underestimation of the true association between prematurity and appendicitis.

Some scholars believe neonatal appendicitis is an isolated form of NEC involving the appendix because some factors associated with NEC are shared as possible etiologies of neonatal appendicitis (eg, preterm).^14,15  However, the proportion of preterm neonates (34.0%) in the current study was lower than that reported in a pooled analysis of neonatal appendicitis (43%)¹¹  and much lower than that reported in NEC cases (70% to 90%).¹⁶  Additionally, this proportion is similar across the first several months of life, indicating that preterm is not only a possible etiology for appendicitis in neonates but also for appendicitis in older infants.

It has been speculated that seasonal outbreaks of enteric infections may be one of the etiologies of appendicitis.¹⁷  The incidence of appendicitis in children and adults is most prominent during the summer months, similar to summer peaks of enteric infections.^17,18  In this study, we observed an increased risk of infantile appendicitis during the autumn months, mirroring the seasonal peak observed in childhood diarrhea cases, suggesting a similar pattern between the two conditions.¹⁹ 

Another common etiology for appendicitis is luminal obstruction from lymphoid follicle hyperplasia, fecaliths, or parasites.²⁰  However, the chance of this etiology is minimal in the infant population, because children <1 year of age have much less prominent lymphoid tissue and funnel-shaped lumen of the appendix, which are less prone to appendiceal obstruction.

Preterm infants face an elevated susceptibility to infections because of various factors associated with their immature immune function, with the mucosal barrier of the gastrointestinal tract playing a critical role.^21,22  Compared with full-term infants, preterm infants exhibit fewer cilia cells and insufficient innervation of gastrointestinal motor complexes, leading to impaired mucociliary clearance and bacterial overgrowth.^22–25  Preterm infants demonstrate diminished levels of antimicrobial proteins and decreased production of antimicrobial peptides in their gastrointestinal tracts.²⁶  In addition, the dysregulation of tight junction proteins augments intestinal permeability, facilitating the translocation of bacteria across the epithelial layer.²⁷  Moreover, the altered composition and reduced microbial diversity of the gut microbiome can further impact barrier function and immune development.²⁸  In combination with the hypomotility of the appendix, these factors may significantly contribute to the heightened risk of appendicitis in preterm infants.²³ 

Studies have revealed that preterm infants fed with breast milk had reduced rates of sepsis, NEC, and mortality compared with those fed with formula.^22,29,30  Consistent with previous studies, the current study revealed that breastfed infants had a lower incidence of appendicitis. Human breast milk feeding plays a crucial role in protecting preterm infants against infections derived from the gastrointestinal tract. Breast milk contains numerous bioactive molecules, including antimicrobial peptides, such as β defensins 1 and lactoferrin, as well as specific secretory IgA antibodies.³¹  These components contribute to innate immune function and provide resistance against enteric pathogens.³²  Moreover, breast milk also stimulates plasma cells to produce anti-inflammatory cytokines and growth factors that support intestinal host defense.²¹  These factors may be the causes underlying the higher risk of appendicitis in formula-only-fed infants than in breastfed infants. Another possible reason is that preterm infants are more likely to be fed with formula than term infants, especially very or extremely preterm infants.

Appendicitis in infants has been a life-threatening condition, mainly because of its atypical presentation, high perforation rate, and delayed treatment. However, it has not been systematically studied. Another study of clinical features of infantile appendicitis is ongoing, further helping to extend knowledge of infantile appendicitis. Future prospective multicenter studies are needed to promote early diagnosis and diminish mortality in this young and vulnerable population.

The scope of this study was limited to children <1 year old for the following reasons: (1) these patients cannot verbalize any discomfort or localize pain (older children always have identifiable abdominal peritonitis signs and present to the hospital much earlier^33,34 ), (2) in young infants and neonates, the symptoms and signs of appendicitis and severe infection are often vague and nonspecific, (3) the anatomic funnel shape of the appendix in neonates and infants differs from that of children older than 1 or 2 years. The etiology and risk factors may differ between infants and older children.

This study has several limitations. First, this study is vulnerable to the inherent methodological pitfalls of retrospective research, including selection bias. We could not accurately determine the indications for surgery, and we might fail to include the appendicitis infants who did not undergo appendectomy. Second, the autopsy rate in China is low, further introducing selection bias.³⁵  Third, the rate of preterm birth in the control group is higher than previously reported in China, which may result in an underestimated correlation between preterm and infantile appendicitis.³⁶  However, this rate is consistent with the global preterm birth rate.²  Fourth, most patients were from children’s hospitals with transfer services, which may affect the generalizability. Fifth, case-control matching may lead to overadjustment and introduce intentional selection bias. Moreover, because of the limited number of preterm cases and controls, we could not perform subgroup analysis based on subcategories of preterm (extremely preterm, very preterm, and moderate to late preterm). However, the current study may evoke future focus and studies on appendicitis in young children and infants. This study is mainly strengthened by the relatively large sample size of patients <1 year.

Preterm infants have an increased risk of appendicitis during the first year of life. A preterm history should be considered in the diagnostic algorithm of infantile appendicitis. Future studies are warranted to extend the knowledge of infantile appendicitis and promote timely diagnosis.

We thank the patients, nurses, doctors, and administrators for their participation in the study. The authors would also like to acknowledge all doctors in the 4 institutions for their contributions in the treatment of children with appendicitis. YKL thanks his friends and family members for always accompanying him.

CI

confidence interval

IQR

interquartile range

NEC

necrotizing enterocolitis

OR

odds ratio

WAZ

weight-for-age z-score