Introduction

Appendicitis is the most common abdominal disease in children requiring surgery [1]. The lifetime risk of developing appendicitis is reported to be 8.7 % for males and 6.7 % for females [1]. The demographics of appendicitis changed in the early 2000s with a shift toward a smaller difference between men and women [2, 3]. The lower incidence among women is speculated to be related to female sex hormones, and a large case–control study showed a reduced incidence during pregnancy [4]. Further, it is known that girls and women have a higher risk of misdiagnosis, and the lifetime risk of appendectomy is 23 % for females compared to 12 % for males [1, 5]. However, a perforated appendicitis before the age of 15 years was shown to not affect fertility [6].

The gender difference in the incidence of appendicitis and the higher risk of misdiagnosis among females raise the question of whether there are gender differences between girls and boys regarding the presentation of appendicitis, the surgeons’ attitude, perioperative care, and postoperative outcome. Do anatomical or physiological differences play a role in the presentation of appendicitis? Are there any differences in the attitude toward girls and boys who are admitted to the emergency department for acute abdominal pain? Do outcomes after appendectomy differ between girls and boys? We are not aware of any reports about such gender differences in children.

The aims of this study were to: (1) compare the presentation of appendicitis in girls and boys; (2) investigate differences in the perioperative care between girls and boys; and (3) identify differences in outcomes after an appendectomy between girls and boys.

Material and method

Settings and children

All children were treated at a tertiary center for pediatric surgery. The center serves an area with 340,000 inhabitants with primary surgical care for children <15 years of age, and is the sole provider of tertiary pediatric surgery for children <15 years old in an area with 1.8 million inhabitants. During the study period, six attending surgeons were responsible for the appendectomies. All the responsible surgeons are specialists in general surgery or pediatric surgery. Every patient in the emergency room (ER), whether day or night, with suspected appendicitis, has a pediatric surgery consult, often carried out by a resident in pediatric surgery.

Study design

This study is an institution-based, retrospective study. A database of medical records of all children admitted to this tertiary center for pediatric surgery was analyzed. All children <15 years of age who underwent an appendectomy or who were treated conservatively for an appendiceal abscess, from 2006 to 2014, were searched using international classification of diseases (ICD-10) diagnosis codes (K35.2, K35.3, K35.8, K36.9, K37.9) and procedure codes (JEA00, JEA01, JEA10). The end point of the study was December 31, 2014. The diagnosis of appendicitis was based on operative and histopathological findings.

Medical and surgical records were reviewed and patient demographics, symptoms, preoperative management including time to appendectomy, surgical characteristics, and postoperative data including complications and length of hospital stay were abstracted. The Pediatric Appendicitis Score (PAS) [7] was calculated for each patient; based on the patient history, abdominal examination, and laboratory tests. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) using a cutoff value of six of the PAS was compared between the two groups. When analyzing postoperative parameters, patients with conservatively treated appendiceal abscess were excluded.

Definitions and classification

The presence of leukocytosis and/or neutrophilia, C-reactive protein (CRP) value, symptoms, information from the abdominal examination, and the PAS score were registered when the family first sought care for their child. Hence, some of the children had the operative decision taken later on at the ward. The PAS is a score that measures the probability of appendicitis in children [7]. It was originally developed for children ≥4 years of age, but has been evaluated in younger children [8, 9]. In the original article, the PAS had a sensitivity of 100 %, specificity of 92 %, PPV of 96 %, and an NPV of 99 % using a cutoff value of ≥6 [7]. Hence, this cutoff value was used in the present study. Sensitivity was defined as the frequency of having a PAS ≥6 among those with confirmed appendicitis [true positives/(true positive + false negatives)]. Specificity was defined as the frequency of having a PAS ≤5 among those not diagnosed with confirmed appendicitis [true negatives/(true negatives + false positives)]. PPV was defined as the frequency of confirmed appendicitis among those with a PAS ≥6 [true positives/(true positives + false positives)]. NPV was defined as the frequency of not having a diagnosis of confirmed appendicitis among those with a PAS ≤5 [true negatives/(false negatives + true negatives)].

The time interval from admission to the start of surgery was defined in two ways: (1) the interval from the time of the decision that the child should be transferred from the emergency room (ER) to the pediatric surgical ward to the start of the operation and (2) from the operative decision to the start of surgery.

The appendectomy was performed either laparoscopically, with one, two, or three ports, or as an open appendectomy with a laparotomy in the right lower quadrant. The usual approach in this department is to start with laparoscopy, which can be converted to open surgery when needed. Laparoscopic appendectomy was introduced at the department in the middle of the 1990s, long before this study period. The surgeons performing the operative interventions had a laparoscopic appendectomy as a routine operative intervention and, thus, the learning curve was not considered to be a confounding factor.

All laparoscopic operations that were converted to open surgery were analyzed separately regarding operative time, but counted as open appendectomies when comparing postoperative pain management. In each procedure, an attending, who was a specialist in pediatric surgery, was responsible for the operation. The routine antibiotic regime was preoperative prophylaxis with trimethoprim/sulfamethoxazole (16 + 80 mg/ml, dosage according to age) (Eusaprim®, Vitaflo Scandinavia AB, Gothenburg, Sweden) and metronidazole (20 mg/kg) (Flagyl®, Sanofi AB, Stockholm, Sweden). In cases of gangrenous or perforated appendicitis, the intravenous antibiotics were continued for 3 or ≥5 days postoperatively, respectively; additional doses were administered orally after discharge from the ward. There was no conservative treatment with antibiotics of patients with appendicitis that did not have an appendiceal abscess. Postoperative pain management after arrival at the inpatient ward from the postoperative unit was abstracted. There was no fixed protocol for postoperative pain management for appendicitis at the clinic. Operative complications included iatrogenic perforation of the appendix, diathermic injury, postoperative bleeding requiring reoperation, and intestinal injury. Postoperative complications included postoperative abscess, intestinal obstruction concomitant with the appendicitis or due to postoperative adhesions later on, wound infection, pleural fluid/empyema, and urinary tract infection (UTI). The length of hospital stay was calculated from the time of surgery to the time that the child left the ward.

Statistical analyses

Patient data were recorded in an Excel database. Statistical analyses were performed using SPSS Statistics. A power calculation was done indicating that we would need to study 165 girls and 220 boys to be able to reject the null hypothesis that the exposure rates for case and controls are equal with probability (power) 0.8 [10]. Fisher’s two-tailed exact test was used for dichotomous variables, and Student’s t test or the Mann–Whitney U test for continuous variables with or without a standard distribution, respectively. A p value < 0.05 was considered to be statistically significant.

Ethical statements

The study was approved by the Regional Ethical Review Board (registration number 2010/49). The data were anonymized prior to calculations and are presented without personal identifiers, so that it is impossible to identify any single patient. No protocols were used that would have required individual informed consent. Therefore, it was not necessary to obtain approval from the individual patient’s guardians. All evaluations, treatments, and procedures described in this report were standard care and were conducted at a tertiary center for pediatric surgery.

Results

From 2006 to 2014, 520 children either underwent an appendectomy or were conservatively treated for an appendiceal abscess. Eighty-seven patients were excluded because an incidental prophylactic appendectomy was performed during surgery for another diagnosis. Six other patients were excluded: two had a planned appendectomy due to chronic appendicitis, and four had an underlying severe disease making the symptoms, perioperative care, and length of hospital stay difficult to interpret (Table 1). Thus, 427 patients, 244 boys and 183 girls, were included in the study. The median follow-up time including both short- and long-term outcome was 40 (range 1–106) months.

Table 1 Reasons for exclusion and number of excluded patients
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There were no significant differences between the genders in age, age group frequencies, mean weight, and duration of long-term follow-up (Table 2). The median duration of symptoms before seeking care was 24 h for both girls and boys (range 2–240 and 4–336 h, respectively, p = 0.161). The frequency of doctor delay did not differ significantly by gender (12 and 9 %, respectively, p = 0.432).

Table 2 Baseline demographics such as age, age groups, and weight; and follow-up duration by gender
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The frequencies of specific symptoms did not differ significantly by gender, but girls had a tendency toward more frequent nausea/vomiting, and boys tended to present more frequently with fever. Based on abdominal examinations, boys had a significantly higher frequency of right lower quadrant (RLQ) tenderness produced by hopping, percussion, or coughing, but not a higher frequency of tenderness in the RLQ with palpation. Further, the frequencies of leukocytosis and neutrophilia, and CRP values did not differ between the genders (Table 3). In 9 girls and 17 boys, no blood tests for CRP, white blood cell count, and neutrophils were taken (Table 3).

Table 3 Symptoms, clinical findings, and laboratory tests in girls and boys admitted for abdominal pain and submitted for an appendectomy or treated conservatively for an appendiceal abscess
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The mean PAS did not differ between the two genders, regardless of whether patients with a negative appendectomy were included. The sensitivity of a PAS ≥6 was low and did not differ between the two groups. The specificity for a PAS ≤5 was also low in both groups, but was significantly higher in girls. The positive predictive value (PPV) for a PAS ≥6 was relatively high in both groups, especially in boys. The negative predictive value (NPV) was low in both groups, but the NPV was significantly higher in girls (Table 4).

Table 4 The Pediatric Appendicitis Score (PAS) by gender in children who underwent appendectomy for suspicion of appendicitis
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Preoperative imaging was used significantly more often for girls than for boys (Table 5). However, the use of specific imaging methods, ultrasound (US), or computed tomography (CT) did not differ by gender. There were no differences in time to appendectomy between the two genders for either definition of the time interval: from hospital admission to surgery or from operative decision to surgery (Table 5). There was no difference between boys and girls regarding the surgeon’s decision to use the laparoscopic technique (Table 5). Girls had significantly higher frequencies of negative appendectomy and gangrenous appendicitis, whereas boys had significantly higher frequencies of phlegmonous and perforated appendicitis and open appendectomy than girls. A normal appendix was found in 33 girls and 17 boys. The causes of abdominal pain are outlined in the footnote of Table 5, where there is a list of findings at negative appendectomies. The grade of inflammation was based on the surgeon’s report, and in 45 % of all cases histology was carried out. All negative appendectomies were verified with histology. Perforation was defined as a visual hole in the appendix. The mean operative time for laparoscopic appendectomy tended to be longer in girls; this difference almost reached significance (Table 5).

Table 5 Use of imaging, time to operation, grade of inflammation, method of operation, and operative time by gender in children operated on with appendectomy for suspected appendicitis
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The length of hospital stay did not differ between boys and girls. Girls had a significantly higher frequency of operative complications. When complications were related to the operative modality, a significant difference was observed between genders in open, but not laparoscopic appendectomy. Further, there were no significant differences in postoperative complications or the need for reoperation between boys and girls (Table 6).

Table 6 Duration of hospital stay and complications by gender in 408 children who underwent an emergency appendectomy for suspected appendicitis
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Regarding postoperative pain management, there were no clear trends or significant differences between the genders when analyzing the number of patients receiving morphine, the amount of morphine given, number of patients receiving nonsteroidal anti-inflammatory drug (NSAID) or paracetamol, or the number of paracetamol doses intravenously administered.

No significant differences were found between boys and girls in the duration of postoperative antibiotic treatment, either in patients with gangrenous (8.2 and 7.1 days, respectively, p = 0.203) or with perforated appendicitis (10.5 and 10.5 days, respectively, p = 0.965).

Discussion

This study revealed some significant gender differences in pediatric appendicitis; preoperative imaging, nature of the appendicitis, and operative outcomes differed. Girls had negative appendectomies more frequently, despite having more preoperative imaging, and had operative complications more often despite having less frequent perforations. Boys were found to have a perforation more often than girls, despite equal time to appendectomy.

As found by others [1, 5, 11, 12], girls had a significantly higher frequency of negative appendectomies. Of note, despite no difference in time to appendectomy, boys had a higher perforation frequency, which has been reported in adult men before [13, 14], but not in boys [12]. It could be speculated to be related to different immune responses or differences in the intestinal connective tissue between the genders. Gender differences in the immune response of the gut have been described [15], but not specifically regarding appendicitis. Boys underwent an open appendectomy significantly more often than girls, which has been described previously in adults [16–18]. In the present study, the gender differences between open and laparoscopic approaches could be due to the more frequent perforated appendicitis observed in boys. We found no difference in the frequency of laparoscopic appendectomy (LA) between the genders; in adults, women were reported to be more likely to have their appendix removed laparoscopically [16–18].

Girls had a significant higher frequency of operative complications; iatrogenic perforations accounted for the majority of these complications. This may be explained by more extensive surgery performed to find and examine the internal reproductive organs in females or by the higher frequency of gangrenous appendicitis observed in girls. Hence, it could be speculated that appendixes in girls induced a higher risk of iatrogenic perforation. The higher frequency of operative complications among girls is worrying when considering that they also have a higher number of negative appendectomies. No significant differences in postoperative complications between boys and girls were found; in contrast, others described a higher risk in boys of wound infection and postoperative abscess [19].

Being a retrospective study, a certain amount of missing data can be expected. However, every patient was examined to the same detail by the surgeon. All the children underwent the hopping test, or were examined with percussion in the RLQ, to examine whether this elicited pain. Thus, there were no missing values in these parameters. However, misclassification of symptoms cannot be excluded and the differences reported in clinical presentation may be biased. Further, there were a few patients with missing blood tests. However, this did not influence the results, since the decision to operate was based mainly on clinical findings.

Preoperative imaging was significantly more commonly used in girls. Similarly, a study of girls with a median age of 11 years reported that they were 4.5-fold more likely to have a preoperative ultrasound and CT than boys [20]. The same study found that in girls, ultrasound had a lower sensitivity for appendicitis. The possibility of a gynecological condition in girls may explain the more extensive preoperative assessment in girls compared to boys. This may also explain the finding of the lower sensitivity of ultrasound for appendicitis in girls; hence, ultrasound is used to exclude gynecological conditions and not primarily to confirm the suspicion of appendicitis [20]. More frequent use of preoperative imaging has also been described in adult females, contributing to a longer, delayed time to surgery, but not reducing the frequency of negative appendectomy [21]. From the present study, it does not seem that ultrasound reduces the rate of negative appendectomies, although this was not specifically looked at.

The mean operative time for LA tended to be longer in girls; perhaps, the higher frequency of negative appendectomies in girls resulted in more time spent inspecting the internal reproductive organs, abdominal cavity, and small intestines, to explore other etiologies when the appendix appeared normal. On the other hand, appendicitis that is more complicated could be expected to require a more lengthy surgery. This explanation is supported by our findings of a higher frequency of gangrenous appendicitis in girls, but not by our findings of a higher frequency of perforated appendicitis in boys. No other study was found that examined gender differences in operative time for LA, or any describing gender differences in the incidence of phlegmonous or gangrenous appendicitis.

The lengths of surgical delays did not differ between girls and boys; no gender differences were found in parental delay, physician delay, time from admission to appendectomy, and time from operative decision to surgery. In contrast, a longer delay to surgery has been described in adult females, when compared with adult men [22], and to both adult men and children [21]. Our finding of similar surgical delay in girls and boys could be explained by the lower incidence of gynecological conditions in girls compared to adult females, which could decrease the time needed to evaluate differential diagnoses. Another possibility may be that different genders are managed and treated more equally in children than in adults, but no study comparing gender differences in time to appendectomy in children were found.

Boys had significantly higher frequencies of peritonitis, tenderness in the RLQ, and tended to have a higher frequency of fever. This may be explained by the higher frequency of perforated appendicitis observed in boys.

No study has evaluated gender differences in the PAS before; we found that the PAS of girls had a significantly higher specificity and NPV. This is interesting because it may indicate that girls undergo surgery more often despite a lower probability of appendicitis. Surgeons may be more afraid of missing an appendicitis in girls, possibly due to either a misconception that perforated appendicitis leads to infertility later in life [6] or they may be concerned about ovarian pathology. Another clinical appendicitis score, the Alvarado score, has been described to have gender differences that favor males [23].

There were no significant differences between the genders in age or age groups; others reported a higher incidence of appendicitis among girls 0–4 years old [12].

Postoperative pain management, assessed after children arrived at the ward from the postoperative unit, revealed no gender differences. In adolescent patients undergoing surgery, one study found that girls reported more postoperative pain, but that gender did not influence the use of postoperative opioid analgesics [24]. Because our study is retrospective, it was not possible to evaluate the postoperative pain experience.

Because this study was retrospective, there were some limitations in the quality of data that was recorded in the medical records. However, the retrospective design might have less impact on well-recorded variables, such as the use of imaging and operative complications, but more impact on symptoms, indications for surgery, and postoperative pain management. On the other hand, a prospective study could have obscured gender differences if the surgeons involved were aware of the study aims and consequently attempted to manage genders as equally as possible. A retrospective study is never superior to a prospective study. However, awareness about a gender focus in studies might influence the treatment and subsequently the results to become more gender equal. Previous gender analyses on appendicitis in adults were retrospective cohort studies from databases and also retrospective analyses [13, 25]. In a prospective study, it would have been possible to evaluate postoperative pain management, including during the time in the postoperative unit. Further, one could have assessed the PAS at the time of the operative decision, and not only when the child was first seen in the emergency room.

Most studies in pediatric surgery research include gender as a demographic variable, but few evaluate the primary illness from a gender perspective. Few studies specifically evaluated gender differences in pediatric surgery [12, 13, 26, 27]. Evaluating gender differences in pediatric research is of great importance, because it can greatly affect surgical care and parent counseling. One study of over 100,000 children who underwent pediatric surgical operations, of which 81 % were appendectomies, revealed significant gender differences [27]. Female gender was associated with a 13 % reduction in postoperative morbidity, whereas male gender was linked to shorter hospital stay [27]. From the results of our present study, we cannot conclude that our pediatric surgery care has gender equality in spite of the evidence for a lack of gender inequality. On the other hand, the results from the present study do not require any immediate changes in the clinic. Further, it seems that conclusions drawn from other studies of appendicitis in children, without a gender perspective, do not need to be questioned. The findings may accurately be characterized as biological “disparities”, since inequality suggests differential treatment of the genders related to surgeon behavior, which was not the case.

Conclusion

There are important gender differences in children with appendicitis. Girls had a higher number of negative appendectomies, despite the more often use of preoperative imaging, and experienced operative complications more often despite a lower perforation frequency. Boys were found to have a higher frequency of perforation despite equal time to appendectomy. It is of importance to be aware of these differences in the clinical situation. These results should encourage further studies and evaluation of gender differences in appendicitis and other pediatric surgical conditions.