Appendectomy during pregnancy: rates, safety, and outcomes over a five-year period. A hospital-based follow-up study

Abstract Introduction Appendicitis is the most common acute abdominal complication during pregnancy. If appendix perforation occurs there is an increasing risk of preterm delivery and other pregnancy complications. Objective To assess the outcome of pregnancy after appendectomy, the mode of surgery used, appendectomy rates, and complications. Methods A prospective cohort study of pregnant women with, or without, appendectomy at South Stockholm General Hospital, December 2015 to February 2021 in a setting where pregnant women are prioritized for surgery and laparoscopic surgery was standard of care in first half of pregnancy. Data on preoperative imaging, surgical method, intraoperative findings, microscopic findings, hospital stay, pregnancy, and 30-day complications were prospectively recorded in a local appendectomy register. A non-pregnant control group was gathered comprising women of fertile age in the same study interval. Results During the study period 50 pregnant women, of whom 44 gave birth, underwent appendectomy of 38 199 women giving birth. There were no differences between women with or without appendectomy in proportion of preterm delivery (4.5% vs. 5.6%), small-for-gestational age (2.3% vs. 6.2%), or Cesarean delivery (18.2% vs. 20.4%). The rate of appendix perforation was 19% in non-pregnant control group compared to 12% among pregnancy. There was no case of perforated appendix in the second half of pregnancy. However, women with gestational age > 20 weeks more frequently had an unaffected appendix compared to those operated ≤ 20 gestational weeks (4/11 vs. 2/39, p = .005). Laparoscopic surgery was used in 97% of non-pregnant control group, 92% of appendectomies ≤ 20 weeks gestation, and in 27% >20 weeks. As compared to first half, the appendectomy rate was three times lower during the second half of pregnancy. Pregnant women had priority for surgery < 6 h compared to < 24 h among non-pregnant women, this resulted in a shorter time-to-surgery among pregnant women (p < .001) Conclusion Routine laparoscopic surgery and time priority for pregnant surgery is associated with a low risk of perforation, preterm birth and other complications. However, a low threshold for surgery may increase the risk of a negative exploration.


Introduction
Appendicitis is one of the most common acute abdominal conditions, with a lifetime incidence of 7-9%. Pregnancy is said to protect against appendicitis [1,2]. Standard treatment for appendicitis is laparoscopic (LapApp) or open appendectomy (OpenApp). Appendicitis during pregnancy requires accurate diagnostics, timely appropriate choice of management, and good communication between obstetrician, anesthetist, and surgeon. Clinical examination, laboratory testing, and imaging (ultrasound scanning and computer tomography) are routine in non-pregnant women [3]. Computer tomography scan during pregnancy is rarely performed since it exposes the fetus to radiation, making acute appendicitis more difficult to diagnose accurately. Furthermore, in the second half of pregnancy, LapApp is difficult and time-consuming [4].
There are models for predicting the presence and severity of appendicitis in pregnant women [5]. An increased platelet: lymphocyte ratio has been reported in pregnant women with appendicitis [6]. Previous studies have shown that hyponatraemia (low S-Sodium) is a negative predictive factor in appendicitis in children [7]. A Swedish population-based study suggested that pregnancy is protective against appendicitis, with a lower risk during pregnancy and an increased risk in the peri-and postpartum periods [2].
The aim of this study was to assess the outcome of pregnancy after an appendectomy, mode of surgery, appendectomy rates, and complications associated with appendectomy during pregnancy.

Methods
At the Department of Surgery, South Stockholm General Hospital, Sweden, information on all patients undergoing appendectomy for acute appendicitis is prospectively recorded in a quality register [8]. South Stockholm General Hospital provides emergency medical care to a catchment area of approximately 700 000 inhabitants. The department of Gynecology and Obstetrics has approximately 7000 deliveries every year. Data on preoperative imaging, surgical approach, intraoperative findings, microscopic findings, hospital stay, and 30-d complications are recorded prospectively in the appendectomy register. Pregnant women with suspected appendicitis are routinely given priority for surgery, within 6 h after decision to operate compared to 24 h for non-pregnant women without suspicion of peritonitis.
We included all women giving birth with and without appendectomy at South Stockholm General Hospital between December 2015 and February 2021. Women not giving birth in Sweden with appendectomy were excluded in analysis of birth outcome. Appendicitis rates were determined based on all pregnant and non-pregnant women with appendectomy in the Stockholm region. For comparisons of times and complication rates, we also identified a control group of non-pregnant fertile women, aged 18-45 years undergoing appendectomy.
There is a lack of evidence regarding duration and type of antibiotics in patients with complicated appendicitis and there are no specific routines for pregnant women [8]. Nevertheless, the standard routines for antibiotic administration at South Stockholm General Hospital apply to both pregnant and non-pregnant women. Routine antibiotic treatment is based on the degree of inflammation of the appendix at surgery. When no inflammation is suspected, no antibiotics are given. If the appendix is phlegmonous, one dose of 1.5 gm metronidazole i.v. is given, and for gangrenous appendix, three doses of Piperacillin Tazobactam i.v. are given. In cases of perforated appendix, Piperacillin Tazobactam i.v. three times daily is given until bowel function is restored, and thereafter Ciprofloxacin 500 mg x 2 and metronidazole 400 mg x3 by mouth. Thromboembolic prophylaxis is recommended for one week after surgery during pregnancy according to the Swedish algorithm for pregnant women [9].
To assess risk factors for adverse outcomes due to appendectomy within 30 days after surgery, including surgical or medical complications, readmission, and need for surgical reintervention, we reviewed data obtained from the electronic medical records, TakeCare (CompuGroup Medical, Helsinki, Finland) and Obstetrics (Cerner Sverige AB, Stockholm, Sweden) registers. Data concerning surgical procedures and background variables were transferred automatically from the Surgical Department's planning software (Orbit 5, TietoEvry, Kristianstad, Sweden).
Initial sodium levels, C reactive protein (CRP), white blood cell count, and ultrasound (US) were investigated for their possible predictive value in the diagnosis of appendicitis during pregnancy.

Statistical analysis
We present results as number (percentages), mean (±standard deviation) or median (interquartile range). We used v 2 or Fischer-exact test to compare proportions and Students t test or Mann Whitney U test to compare means and medians between the groups as appropriate. Comparisons were made in SPSS version 28. To calculate incidence rates (IR) for appendectomy for the years 2016-2020 we used numerators from the quality register [8] and denominator from statistics Sweden. Estimates and confidence intervals for the IR were done in open Epi version 3.01. A p-value < .05 was considered as a significant difference.

Results
Out of a total 38199 births during the study period, 44 were appendectomized and further six pregnant women were appendectomized (pregnant App group). The 38 155 who gave birth without appendectomy comprised our pregnant reference group. During the same period, 793 non-pregnant fertile women underwent appendectomy for suspected acute appendicitis (non-pregnant control group). Of the pregnant App group, 39 (78%) were operated during the first half and 11 (22%) during the second half of pregnancy (54% were in the first trimester, 36% in the second, and 10% in the third trimester). The pregnant women were 32 ± 5-years-of-age, and the non-pregnant control group 31 ± 8 years.
Details of pregnancy, outcome, and complications among women with and without appendectomy are presented in Table 1. There was one case of legal abortion after appendectomy, one extrauterine pregnancy, one spontaneous miscarriage (4th gestational week), and two cases with abortus imminens (fetal death before surgery). One woman was a tourist in Sweden and continued the pregnancy in her home country. These six women were excluded from the pregnancy outcomes. In comparing pregnant women with and without appendectomy (pregnancy App group vs. pregnant reference group) there were no differences in birth or pregnancy complications between the two groups. Table 2 shows grade of appendicitis, type of surgery, complications, and prophylactic treatment among the pregnant App group and non-pregnant control group. LapApp was used in 39 of 50 (78%) pregnant women and in 770 of 793 (97%) non-pregnant women (p < .001). OpenApp was used in 11 pregnant women (8 of these > 20 weeks of gestation), and 7 non-pregnant women. In four women surgery was converted from LapApp to OpenApp, three before 20 weeks, all due to difficulties during surgery. Twelve per cent (n ¼ 6) of pregnant women operated on had an unaffected appendix, 4 (36%) > 20 weeks gestation and 2 (4%) 20 weeks). The corresponding figure in the nonpregnant control group was 2.1% (p < .001).
In pregnant App group, the rate of perforated appendicitis was 12% (6/50), where no perforation was seen in the second half of pregnancy. In the non-pregnant control group, the rate was 19% (p ¼ 0.2). Three pregnancy complications were noted: one case of early fetal loss (4th week), one case of contractions, and one newborn with flaccid moderate hypoxic ischemic encephalopathy (HIE ¼ 2). Early neonatal lumbal puncture showed signs of meningitis, but cultures were negative. There was no sign of acute asphyxia. However, the patient had been admitted to another hospital for suspected appendicitis Table 1. Characteristics of pregnancy, outcome, and pregnancy complications among women with appendectomi and control group. three months earlier. Ultrasound indicated appendicitis, but the decision was taken to refrain from surgery. In the pregnant App group, there were 3 (6%) surgical complications and in the non-pregnant control group 31 (3.9%) (p ¼ .5). Intra-abdominal abscess and paralytic ileus were the dominant surgical complications (Table 2). No reoperation occurred within 30 days in the pregnant App group, but in 2 of the non-pregnant control group. Two pregnant women (4%) were readmitted within 30 days, one for contractions that needed cerclage and one with a postoperative abscess. In the non-pregnant control group, 14 (1.6%) were readmitted within 30 days (p ¼ .4). No death occurred within 30 days.
Histopathology examination of the appendix was performed in 88% of pregnant cases (n ¼ 44) and in 84.9% (n ¼ 673) in the non-pregnant control group. Of these 2.1% had an unaffected appendix, 0.6% a tumor (n ¼ 5), and "other diagnosis" in 0.6%.
Seventy-four per cent (37/50) of appendectomy cases during pregnancy were treated with low molecular weight heparin after surgery, in most cases for 7 d. No case of postoperative venous thromboembolic event (VTE) was registered.
Diagnostic laboratory test results are presented in Table 3. All six pregnant women with perforated appendicitis had a low S-Sodium ( 136 mmol/L). White blood cell count was !16 x 10 9 /L in 36% (18/ 50) of appendectomy cases. C-reactive protein (CRP) was ! 20 mg/L in 60% (30/50) of cases and < 10 mg/L in 15% (6/50). US diagnosis of appendicitis showed 100% specificity and 66% sensitivity (33/50) giving a  (Table 3). Times associated with appendectomy are presented in Table 4. There was a highly significant longer timeto-surgery in the non-pregnant control group compared to both early-and late pregnancy groups (p ¼ .001 and p .001, respectively). There were no significant differences in operation times or total timein-surgery between the groups. Total in-hospital stay was significantly longer in the late pregnancy group compared to the non-pregnant control group (p ¼ .02).

Discussion
The present study on appendectomy (both definite and suspected cases) in pregnant women at a hospital normally carrying out surgery in pregnancy, showed a low risk for pregnancy and other surgical postoperative complications. With immediate surgery (within 6 h) there was no appendix perforation in the second half of pregnancy but at the cost of a high rate of surgery for an unaffected appendix, which is in line with a prior report [10]. The low risk for preterm delivery and fetal loss seen in this study is in contrast to previously reported increased risk for fetal loss, preterm delivery, low birth weight, and fetal growth restriction when OpenApp was routine [10,11]. Indeed, we were unable to show any increase in risk beyond those normally seen in pregnancy. However, for one of the newborns in this study, we could not rule out  persistent low-grade appendicitis with hematogenous spread leading to meningitis. The risk for appendicitis is reported to be lower in pregnancy [2,12,13]. In our material, the reduced risk derives from the second half of pregnancy. In this large sample of the non-pregnant control group, the IR was 132/100 000. We found a strong age dependency for appendicitis with the maximum IR being 137/ 100 000 between 20 and 24-years-of-age, declining to 89 between 40 and 44 years. The rate of appendectomy among women giving birth in our sample was 115/100 000, i.e. 1/870 women giving birth. This is close to prior studies, one in 936 and one in 958 [12,14]. In one study 23% of early appendectomies were unaffected as compared to 4% in our material (p < .001) [12]. In late pregnancy, the percentage of negative exploration was, however, similar as in our study 36% [12].
We hypothesize that the lower rate of pregnancy complications reported in this study may be related to reduced time to surgery. The decision to operate would be further improved by better diagnostic tools to indicate whether or not appendicitis is present, to avoid perforation. Kozan et al. reported almost identical US performance with 63% sensitivity and 100% specificity as we report (66% and 100%) [15]. Magnetic resonance imaging (MRI) is excellent in diagnosing appendicitis in pregnancy and recommended in current international guidelines [16]. Thus, although we did not have access to MRI, it would presumably have improved pre-operative diagnostics and decreased the number of negative explorations in late pregnancy. Furthermore, LapApp used as the first choice during the first half of pregnancy, may have lowered the threshold for surgery as it provides diagnostic information on other pathological conditions present. Another Swedish study assessing appendectomies 1973 to 2013 with 94% OpenApp, showed a low incidence in late pregnancy appendectomies and a high rate during the peripartum period [2]. The high peripartum rate is supposedly due to a high rate of combination of Cesarean section and appendectomy close to delivery, but appendectomy en passant cannot be excluded [2].
Laboratory biomarkers also aid decision-making in the pregnant patient with signs of appendicitis. All pregnant women with perforated and half of non-perforated appendicitis in the present cohort had low Ssodium levels ( 136 mmol/L), which is in-line with prior reports [7,15]. Most pregnant women (60%) had increased CRP (> 20 mg/L), but 15% had CRP < 10 mg/L at the time of diagnosis.
The risk for a thromboembolic event is increased about 10 times during pregnancy, and a further five times after surgery. The recommendation to give thromboprophylaxis for one week was followed in 74% of cases [17,18]. No postoperative thrombotic event was seen in our cohort.

Strengths and limitations
The large material in a unit where LapApp is routine in the first half of pregnancy, adds to our knowledge. With this population-based material with prospectively gathered data, we included both appendectomies among pregnant women giving birth and not giving birth, which is not the case in register-based studies. We interpret our results in light of the inherent limitations of the retrospective design of the study. Clinically important complications are rare and a larger material may be needed to compare rare complications. However, due to the devastating consequences of late pregnancy fetal complications (preterm birth, growth restriction, etc), the present results contribute to an updated perspective on the risks and complications of appendectomy during pregnancy. Although not included in our local management guidelines, we could not exclude antibiotic treatment for appendicitis in pregnancy, especially close to delivery [19,20]. Further, routine use of MRI in cases with negative ultrasound would presumably have improved early diagnosis.

Conclusion
Appendectomy during pregnancy requires extra care to avoid complications for both mother and the unborn child. An active approach with a low threshold for surgery increases the risk of an unaffected appendix, but this is a low price for avoiding a perforated appendix and an increased risk of fetal loss and preterm delivery.