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\begin{document}

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



\author[1]{Pelle G. Lindqvist}%
\author[1]{Lennart Boström}%
\author[1]{Hans Pettersson}%
\author[1]{Gabriel Sandblom}%
\author[1]{Martin Dahlberg}%
\affil[1]{Department of Clinical Sciences and Education, Karolinska Institutet}%


\vspace{-1em}



  
  \date{May 17, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Objective: To assess the outcome of pregnancy after appendectomy, the
mode of surgery used, appendectomy rates and complications. Design: A
prospective cohort study of pregnant women undergoing appendectomy.
Setting: All appendectomies at South Stockholm General Hospital,
December 2015 to February 2021. Population: Pregnant women undergoing
appendectomy. Methods: 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. Results: During the study period, 50 pregnant
women underwent appendectomy of 38 199 women giving birth. During the
same period 793 non-pregnant women underwent appendectomy and served as
controls. No differences in preterm delivery (4.5\% vs. 5.6\%),
small-for-gestational age (2.3\% vs. 6.2\%), or mode of delivery
(cesarean delivery 18.2\% vs. 20.4\%) were observed between pregnant
women with or without appendectomy. There were no cases of perforated
appendix in the second half of pregnancy. However, women with
gestational age \textgreater{} 20 weeks more frequently had an innocent
appendix compared to those operated \textless{} 20 gestational weeks
(4/11 vs. 2/39, p = 0.005). Laparoscopic surgery was used in 92\% of
appendectomies \textless{} 20 weeks gestation. The appendectomy rate was
three times lower during the second half of pregnancy. Conclusion:
Appendicitis in pregnancy is not a threat as long as surgery is
conducted as soon as possible. Although a low threshold for surgery may
increase the risk of finding an innocent appendix, this is outweighed by
the lower risk for perforation and serious adverse events such as fetal
loss or preterm delivery.%
\end{abstract}%



\sloppy


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

PG Lindqvist,\textsuperscript{a,b} H Pettersson,\textsuperscript{b} M
Dahlberg, \textsuperscript{b,c} G Sandblom,\textsuperscript{b,c} L
Bostr\selectlanguage{ngerman}öm, \textsuperscript{b,c}

\textsuperscript{a}Department of Gynecology and
Obstetrics,\textsuperscript{b}Department of Clinical Science and
Education\textsuperscript{c}Department of Surgery, Department of
Clinical Science and Education, South General Hospital (Södersjukhuset),
Karolinska Institute, Stockholm, Sweden

Correspondence

Lennart Boström,

Department of Surgery,

South Stockholm General Hospital (Södersjukhuset),

Clinical Science and Education, Karolinska Institute,

SE-11883 Stockholm, Sweden.

E-mail: Lennart.bostrom@regionstockholm.se

\textbf{Abstract} 250 words

\textbf{Paper} 2547 words

\textbf{Key words:} Pregnancy, rate, complications, appendectomy,
appendicitis

Abstract

\textbf{Objective:} To assess the outcome of pregnancy after
appendectomy, the mode of surgery used, appendectomy rates and
complications.

\textbf{Design:} A prospective cohort study of pregnant women undergoing
appendectomy.

\textbf{Setting:} All appendectomies at South Stockholm General
Hospital, December 2015 to February 2021.

\textbf{Population:} Pregnant women undergoing appendectomy.

\textbf{Methods} : 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.

\textbf{Results:} During the study period, 50 pregnant women underwent
appendectomy of 38 199 women giving birth. During the same period 793
non-pregnant women underwent appendectomy and served as controls. No
differences in preterm delivery (4.5\% vs. 5.6\%), small-for-gestational
age (2.3\% vs. 6.2\%), or mode of delivery (cesarean delivery 18.2\% vs.
20.4\%) were observed between pregnant women with or without
appendectomy. There were no cases of perforated appendix in the second
half of pregnancy. However, women with gestational age \textgreater{} 20
weeks more frequently had an innocent appendix compared to those
operated \emph{\textless{}} 20 gestational weeks (4/11 vs. 2/39,\emph{p}
= 0.005). Laparoscopic surgery was used in 92\% of appendectomies
\emph{\textless{}} 20 weeks gestation. The appendectomy rate was three
times lower during the second half of pregnancy.

\textbf{Conclusion:} Appendicitis in pregnancy is not a threat as long
as surgery is conducted as soon as possible. Although a low threshold
for surgery may increase the risk of finding an innocent appendix, this
is outweighed by the lower risk for perforation and serious adverse
events such as fetal loss or preterm delivery.



\textbf{1 \textbar{} 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,
anaesthetist, 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 foetus 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 is a negative
predictive factor in appendicitis in children {[}7{]}. A Swedish
population-based study suggested that pregnancy is protective against
appendicitis, with 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
appendectomy, mode of surgery, appendectomy rates, and complications
associated with appendectomy during pregnancy.

\textbf{2 \textbar{} METHODS}

\textbf{2:1 \textbar{} Data source}

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
Gynaecology and Obstetrics has approximately 7000 deliveries every year.
Data on preoperative imaging, surgical approach, intraoperative
findings, microscopic findings, hospital stay, and 30-day complications
are recorded prospectively in an appendectomy register. Pregnant women
with suspected appendicitis are routinely given priority for surgery
(within 6 hours after decision to operate) compared to 24 hours for
non-pregnant women without suspicion of peritonitis.

\textbf{2:2 \textbar{} Patient population}

We identified all pregnant women who underwent appendectomy at South
Stockholm General Hospital between December 2015 and February 2021. As a
reference group to be able to compare pregnancy outcome, we identified
women giving birth without appendectomy giving birth during the same
time-period. 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.

\textbf{2:3 \textbar{} Routines and complications}

There are standard routines for antibiotic administration at South
Stockholm General Hospital, and these 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 iv is given, and for gangrenous appendix, 3
doses of Piperacillin Tazobactam iv are given. In cases of perforated
appendix, Piperacillin Tazobactam i.v. 3 times daily is given until
bowel function is restored, and thereafter Ciprofloxacin 500 mg x 2 and
metronidazole 400 mg x3 by mouth.

At South Stockholm General Hospital, it is standard for pregnant women
to be operated within 6 hours and non-pregnant within 24 hours after
appendicitis has been diagnosed or is suspected. 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, CRP, white blood cell count, and ultrasound were
investigated for their possible predictive value in the diagnosis of
appendicitis during pregnancy.

\textbf{2:4 Statistical analysis}

We present results as number (percentages), mean (±standard deviation)
or median (interquartile range). We used Fischer-Freeman-Halton exact
test to compare proportions and Mann Whitney U test to compare means and
medians between the groups. 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 \emph{p} -value \textless{} 0.05
was considered as a significant difference.

\textbf{3 \textbar{} Results}

During the study period 50 pregnant women were appendectomized and 38
155 who gave birth without appendectomy. During the same period 793
non-pregnant fertile women underwent appendectomy for suspected acute
appendicitis (control group). Of the pregnant women, 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
\emph{+}5-years-of-age, and the non-pregnant control group 31 \emph{+} 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 (4\textsuperscript{th} gestational week), and
two cases with abortus imminens (foetal death before surgery). One woman
was a tourist in Sweden and was delivered in her home country. 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 pregnant and non-pregnant women with
appendectomy. LapApp was used in 39 of 50 (78\%) pregnant women and in
770 of 793 (97\%) non-pregnant women (p \textless{} 0.001). OpenApp was
used in 11 pregnant women (8 of these \textgreater{} 20 weeks of
gestation), and in 7 non-pregnant women. Twelve per cent (n = 6) of
pregnant women operated had an innocent appendix, 4 (36\%)
\textgreater{} 20 weeks gestation and 2 (4\%) \textless{} 20 weeks). The
corresponding figure in the non-pregnant control group was 2.1\%
(\emph{p} = 0.03).

In pregnant women, 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\% (\emph{p} = 0.03). Three
pregnancy complications were noted: one case of early foetal loss
(4\textsuperscript{th} week), one case of contractions, and one newborn
with flaccid moderate hypoxic ischaemic encephalopathy (HIE = 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 3 months
earlier. Ultrasound indicated appendicitis, but the decision was taken
to refrain from surgery.

In the pregnant appendectomy group, there were 3 (6\%) surgical
complications and in the non-pregnant control group 31 (3.9\%)
(\emph{p}= 0.001). Intra-abdominal abscess and paralytic ileus were the
dominant surgical complications (Table 2). No reoperation occurred
within 30 days in the pregnant women group, but in 2 of the non-pregnant
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 group, 14 (1.6 \%) were readmitted within 30 days
(\emph{p} = 0.4). No death occurred within 30 days.

Histopathology examination of the appendix was performed in 88 \% of
pregnant cases (n = 44) and in 84.9 \% (n = 673) in the non-pregnant
control group. Of these 2.1 \% had an innocent appendix, 0.6 \% a tumour
(n = 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 days. No case of postoperative venous thromboembolic event
(VTE) was registered.

Diagnostic laboratory test results are presented in Table 3. All 6
pregnant women with perforated appendicitis had a low S-Na
(\emph{\textless{}} 136 mmol/L). White blood cell count
was\emph{\textgreater{}} 16 x 10\textsuperscript{9}/L in 36\% (18/50) of
appendectomy cases. CRP was \emph{\textgreater{}} 20 mg/L in 60\%
(30/50) of cases and \textless{} 10 mg/L in 15\% (6/50). Ultrasound
diagnosis of appendicitis showed 100\% specificity and 66\% sensitivity
(33/50) giving a high positive predictive value (PPV = 100\%), while the
negative predictive value was lower.

Times associated with appendectomy are presented in Table 4. There was a
highly significant longer time-to-surgery in the non-pregnant control
group compared to both early- and late pregnancy groups (\emph{p} =
0.001 and \emph{p} = \textless{}0.001, respectively). There were no
significant differences in operation times or total time-in-surgery
between the groups. Total in-hospital stay was significantly longer in
the late pregnancy group compared to the non-pregnant control group
(\emph{p} = 0.02).

The mean annual incidence rate (IR) of appendectomy in Stockholm County
for females ages 20 to 44 years was 132/100,000 women/year (95\% CI
123\selectlanguage{english}-141), decreasing from IR = 137 (95\% CI 115\selectlanguage{english}-164) for women aged 20
to 24 to IR = 89 (95\% CI 73\selectlanguage{english}-107) for those aged 40 to 44. The rate of
appendectomy among delivering women was 115/100 000 (1/870) and the rate
of appendicitis 99.6/100 000 (1/1004). Of these 33/44 (75\%) occurred in
early pregnancy (\emph{\textless{}} 20 weeks) and 11/44 (25\%) after 20
weeks of gestation. Thus, the odds of late pregnancy appendectomy were 3
times less in late pregnancy. Since, 7/11 late appendectomies had
appendicitis, the true odds of appendicitis were even lower in late
pregnancy.

\textbf{4 \textbar{} DISCUSSION}

\textbf{Main Findings}

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. Immediate surgery (within 6 hours) seems to significantly
reduce the risk for appendix perforation, but at the cost of a high rate
of surgery for an innocent appendix, as reported in a previous paper
{[}10{]}. The low risk for preterm delivery and foetal loss seen in this
study is in contrast to previously reported increased risk for fetal
loss, preterm delivery, low birth weight, and foetal growth restriction
{[}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 rule out persistent low-grade
appendicitis with haematogenous spread leading to meningitis.

The risk for appendicitis is reported to be lower in pregnancy
{[}2,12,13{]}. In this large sample of non-pregnant control women 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 was 115/100 000, i.e., 1/870 women giving birth. This
is close to a prior large (n = 778) Swedish study during 1973 to 1981,
one in 936 {[}12{]}. In that study 23\% of early appendectomies were
innocent as compared to 4\% in our material (p \textless{} 0.001)
{[}19{]}. In late pregnancy the percentage of innocent appendix was,
however, similar as the present 36\% {[}12{]}.

Clearly, a lower time to surgery in pregnancy will lower the risk of
outcome regarding perforated appendicitis with its complications. The
decision to operate would be further improved by better diagnostic tools
to indicate whether or not appendicitis is present, to avoid
perforation. When positive, ultrasound gave correct diagnosis in 2/3 of
the cases. MRI is excellent in diagnosing appendicitis in pregnancy and
recommended in current international guidelines {[}14{]}. Thus, although
we did not have access to MRI, it would presumably have improved
pre-operative diagnostics and decrease the number of innocent appendices
in late pregnancy. Furthermore, LapApp used as 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 5.8\% LapApp, showed a low incidence in late pregnancy
appendectomies and a high rate during peripartum period {[}2{]}. The
high peripartum rate is supposedly due to a high rate of combination
Cesarean section and appendectomy close to delivery, but
appendectomy\emph{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 plasma
sodium levels (\emph{\textless{}} 136 mmol/L), which is in-line with
prior reports {[}7,15{]}. Most pregnant women (60\%) had increased CRP
(\textgreater{} 20 mg/L), but 15\% had CRP \textless{} 10 mg/L at the
time of diagnosis.

The risk for a thromboembolic event is increased about 10 times during
pregnancy, and a further 5 times after surgery. The recommendation to
give thromboprophylaxis for one week was followed in 74\% of cases
{[}16,17{]}. No postoperative thrombotic event was seen in our cohort.

\textbf{Strengths and limitations}

We interpret our results in the light of the inherent limitations of the
retrospective design of the study, but comparisons have been made with
comparable cohorts both with respect to pregnant women without
appendicitis and non-pregnant women with appendicitis. The IR are
subject to substantial fluctuations, and clinically important
complications are rare. However, due to the devastating consequences of
late pregnancy foetal complications, 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 non-operative antibiotic treatment for
appendicitis in pregnancy, especially close to delivery {[}15,18{]}.

In 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 negative
findings, but this a low price for avoiding a perforated appendix and an
increased risk of fetal loss and preterm delivery.

\textbf{Acknowledgements}

We thank all surgeons, and secretary Lisbeth Iljin for her assistance in
collecting data. We are also grateful to Fredrik Ros at SLL who supplied
data on the catchment area from Statistics Sweden.

\textbf{Funding}

None.

\textbf{Disclosure of interests}

The authors declare no conflict of interest.

\textbf{Contributions to Authorship}

LB, GS, HP, and PL contributed to study design, data analysis, data
interpretation and manuscript. MD contributed to manuscript and critical
manuscript revision. All authors approve the final version

\textbf{Ethics approval}

This study was approved by the Regional Ethics Committee, Uppsala
University Dnr 2019-05976 and Dnr 2020-03849. Use of registers was
approved by the South Stockholm General Hospital Ethics Board.

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