Apendicectomía en embarazadas

1. ORIGINAL ARTICLE
Appendicectomy is Associated With Increased Pregnancy Rate
A Cohort Study
Li Wei, PhD,∗ Thomas M. MacDonald, MD,∗ and Sami M. Shimi, MD†
There is controversy surrounding the association between
Objective: This study was carried out to determine whether pregnancy rate is
appendicectomy, appendicitis, and subsequent fertility. Appendici-
reduced after appendicitis or appendicectomy.
tis complicated by perforation, peritonitis, or pelvic abscess has
Background: The association between appendicectomy, appendicitis, and
been associated with normal fertility,4–10 or substantially reduced
subsequent fertility is controversial.
fertility.11–15 Similarly appendicectomy with or without proven ap-
Methods: A cohort study was carried out in the Medicines Monitoring
pendix inflammation has also been associated with both normal
database. The cohort of women who underwent appendicectomy and appropri-
fertility16–18 and reduced fertility.19,20 One epidemiological study
ate comparators were followed up until first pregnancy after appendicectomy
found increased fertility after removal of a normal appendix in
date. Pathology of the appendix was verified manually. The association be-
childhood.10 However, many of these studies have had methodologi-
tween appendicectomy, appendicitis, and pregnancy was determined by Cox
cal deficiencies that limit their reliability.21
regression models.
We have used a large, validated database to study whether
Results: The age and social deprivation score–matched analyses included
female appendicectomy or appendicitis is associated with reduced
2935 patients who had appendicectomy with 5870 comparators. There were
subsequent fertility.
1277 (43.5%) pregnancies in the appendicectomy cohort and 2319 (39.5%) in
the comparator cohort during a mean follow-up of 12.4 (standard deviation:
7.3) years. The adjusted hazard ratios (HRs) for pregnancy rates were 1.20 METHODS
(95% confidence interval [CI]: 1.10–1.31). In an unmatched cohort analysis
(3009 in the appendicectomy cohort and 122,912 in the comparator cohort), the
Study Design
adjusted HRs for pregnancy rates were 1.65 (95% CI: 1.55–1.75). Within the A population-based cohort study was carried out within the
histologically proven appendicitis subset, the adjusted HR was 1.21 (95% CI: Medicines Monitoring unit record-linkage database.22
1.08–1.37) in comparison with the matched comparator cohort. In comparison
with the group of participants who had appendicectomy for a normal appendix, Medicines Monitoring Database
the HRs were 0.98 (95% CI: 0.83–1.15) for mucosal and catarrhal appendicitis, Medicines Monitoring is a University-based organization that
0.72 (95% CI: 0.64–0.82) for suppurative appendicitis, and 0.64 (95% CI: works closely with the National Health Service to record-link health
0.50–0.80) for gangrenous appendicitis. care data sets for the purposes of carrying out research. The Medicines
Conclusions: Appendicectomy and early appendicitis were associated with Monitoring database covers a population that is geographically com-
increased pregnancy rates. Young women with early appendicitis had better pact and serves about 400,000 National Health Service patients in
pregnancy rates than those with advanced appendicitis. Early referral for Scotland, 97% of whom are of white ethnic origin. The National
laparoscopy and appendicectomy is advocated. Health Service is tax-funded, free at the point of consumption, and
Keywords: appendicitis, appendicectomy, fertility, pregnancy rate it covers the entire population. In Tayside, there is almost no health
care delivered without the National Health Service and there is a low
(Ann Surg 2012;256: 1039–1044) rate of patient migration (<3% of patients aged ≥60 years left the
Tayside region over a 5-year period from 2004–2008). In short, the
database contains several data sets including all dispensed community
D espite a recent decline in appendicectomy rates,1–3 appendicec-
tomy remains one of the most common surgical operations per-
formed worldwide. Both the acute inflammatory condition of ap-
prescriptions, acute hospital discharge data (the Scottish Morbidity
Record 1), maternity inpatient and day case episodes (Scottish Mor-
bidity Record 2), General Registrar Office mortality data, laboratory
pendicitis and/or the trauma of the surgical operation to remove the data, and other data that are linked by a unique patient identifier, the
appendix might promote adhesion formation particularly around the community health index number.
fallopian tubes, which could lead to tubal dysfunction and possible
subfertility in women of childbearing age.
Study Cohorts
Appendicectomy Cohort
From the ∗ Medicines Monitoring Unit, School of Medicine, Division of Medi- The cohort consisted of all female subjects who underwent
cal Sciences; and †Department of Surgery and Molecular Oncology, Centre
for Academic Clinical Practice, Division of Clinical and Population Sciences
an appendicectomy and who were younger than 45 years at the time
and Education, University of Dundee, Ninewells Hospital & Medical School, of operation in Tayside between January 1980 and September 2002.
Dundee Scotland. They entered the study at the date of the appendicectomy and were
Disclosure: All authors have completed the Unified Competing Interest form at followed up until December 2008.
www.icmje.org/coi disclosure.pdf (available on request from the correspond-
ing author) and declare no conflicts of interest.
Caldicott Guardian (the UK legal entity that determines
Reprints: Sami M. Shimi, MD, Department of Surgery and Molecular Oncology, whether access to personal health care data is in the public inter-
Centre for Academic Clinical Practice, Division of Clinical and Population est) permission was given to link the paper records of the histology
Sciences and Education, University of Dundee, Ninewells Hospital and Medical reports of the removed appendixes into the research data set before
School, Dundee DD1 9SY, Scotland. E-mail: s.m.shimi@dundee.ac.uk.
Copyright C 2012 by Lippincott Williams & Wilkins
anonymization. The pathological appearances were classified as nor-
ISSN: 0003-4932/12/25606-1039 mal, mucosal appendicitis, catarrhal (intramural) appendicitis, suppu-
DOI: 10.1097/SLA.0b013e3182766250 rative (phlegmonous) appendicitis, or gangrenous appendicitis. Other
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Copyright © 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

2. Wei et al Annals of Surgery r Volume 256, Number 6, December 2012
pathological descriptions including paraappendicitis, carcinoid of the were adjusted for before cohort study entry (baseline). Previous hos-
appendix, or Crohn disease of the appendix were also ascertained. pitalizations were measured for 5 years before study entry for all
subjects. A sensitivity analysis was carried out to exclude patients
Comparator Cohorts who may have been pregnant before and during the appendicectomy
Matched comparator cohort. This was a 1:2 exact age, and episode. Another sensitivity analysis was done, which included co-
social deprivation score–matched cohort (within ±0.5) from the Tay- variates that occurred both before and after study entry in the matched
side female population who did not have an appendicectomy during cohort.
the same period. Controls entered the study on the same date as their All statistical analyses were carried out using SAS (version
matched case. 9.2; SAS Institute Inc, Cary, NC).
Unmatched comparator cohort. This was the rest of the Tayside
female population who did not have an appendicectomy during the RESULTS
same period. A random date of entry to the study was generated for
each member of the comparator cohort using a frequency-matched Matched Analysis
calendar year generated from the dates of entry to the study in the The age and social deprivation score–matched analysis in-
appendicectomy cohort. cluded 8805 patients (2935 in the appendicectomy cohort and 5870
Subjects were censored during the follow-up if they experi- in the comparator cohort). Table 1 shows the characteristics of the 2
enced a pregnancy, reached the age of 53 years, were younger than 12 cohorts. There were no differences in previous pregnancy and oral
years at the end of the study, had a sterilization or hysterectomy, died, contraception use. The difference in comorbidities improved slightly
or at the end of follow-up. Subjects were excluded from the study if in the matched analysis compared with the unmatched cohort anal-
they had less than 30 days of follow-up available. ysis. There were 1276 pregnancies (43.5%) after appendicectomy in
the appendicectomy cohort and 2319 (39.5%) in the comparator co-
Ethical Approval hort during a mean follow-up time of 12.4 (standard deviation, 7.3)
Ethical approval was obtained for the Medicines Monitoring years. The adjusted HR was 1.20 (95% CI: 1.10–1.31) (Table 2).
study from the Tayside Committee on Medical Research Ethics. The Kaplan-Meier plots of the pregnancy outcomes between the age-
and social deprivation score–matched appendicectomy and compara-
Study Outcome tor cohorts are shown in Figure 1. A sensitivity analysis excluded
The study outcome was the first pregnancy after appendicec- women who were pregnant before and during the appendicectomy
tomy date including live birth, recorded miscarriage, or termination episode. The adjusted HR was 1.29 (95% CI: 1.18–1.40). Within
during the follow-up period. These were ascertained from the ma- the appendicectomy cohort, histology results showed that 33% of the
ternity admission data (Scottish Morbidity Record 2) and the acute removed appendices were normal, 44% showed suppurative (phleg-
hospital admission data (Scottish Morbidity Record 1) coded by pri- monous) appendicitis, 14% showed mucosal appendicitis, and the rest
mary International Classification of Diseases, Ninth Revision codes showed other diseases of the appendix. Within this cohort, appen-
(630–676) and International Classification of Diseases, Tenth Revi- dicectomy for pathological appendicitis in comparison with a normal
sion codes (O00–O99 and Z34–Z39). appendix had a decreased pregnancy rate (adjusted HR [95% CI]:
0.98 [0.83–1.15] for mucosal appendicitis and catarrhal appendicitis,
Definition of Covariates 0.72 [0.64–0.82] for suppurative appendicitis, and 0.64 [0.50–0.80]
for gangrenous appendicitis). However, within the overall appendici-
Age at entry to the study was a covariate as was parity. Other
tis subset (including all women who had pathological appendicitis),
covariates included the use of oral contraceptives, the number of
the adjusted HR (95% CI) was 1.21 (1.08–1.37) compared with the
previous hospitalizations, inflammatory bowel disease (International
comparator cohort.
Classification of Diseases, Ninth Revision codes 555, 556, 557, 558
and International Classification of Diseases, Tenth Revision codes
K50, K51, K52), pelvic inflammatory disease (International Classi- Unmatched Analysis
fication of Diseases, Ninth Revision codes 614, 615 and International There were 3009 patients in the appendicectomy cohort and
Classification of Diseases, Tenth Revision codes N70, N71, N73, 122,912 patients in the comparator cohort. There were significant dif-
N74), other abdominal surgery (defined by Office of Population Cen- ferences in age, comorbidity, and oral contraceptive use between the
sus and Surveys, fourth revision codes), and social deprivation score 2 cohorts. Patients in the appendicectomy cohort were significantly
(the Carstairs’ score derived from the patients’ postcode and census younger, they had more comorbidities, and more of them had previ-
data comprised of social class, overcrowding, male unemployment, ous pregnancies and had used oral contraceptives than patients in the
and car ownership23 ). comparator cohort.
Compared with the comparator cohort, patients in the appen-
Statistical Analysis dicectomy cohort had an increased pregnancy rate (adjusted [HR
Data were presented as mean (standard deviation) for continu- (95% CI]: 1.65 [1.55–1.75]) (Table 2). The Kaplan-Meier plots of the
ous variables and as numbers (%) for categorical variables. Pregnancy pregnancy outcomes between the appendicectomy and unmatched
events were plotted by Kaplan-Meier curves and Cox proportional comparator cohorts are shown in Figure 2.
hazards regression models with a time-dependent variable of oral We have also done an analysis by including confounding vari-
contraceptives used to determine the association between the study ables both before study entry and during the follow-up and we found
and comparator groups taking into account the fact that parity is a similar results (adjusted HR [95% CI]: 1.55 [1.43–1.69]) for the
discontinuous covariate. Univariate and multivariate analyses were matched analysis. A further sensitivity analysis was carried out mea-
carried out. In the multivariate models, the hazard ratios were ad- suring hospitalizations over an equal period of time for all subjects
justed for all covariates between the study and control groups. The at 1-year, 2-year, 3-year, 5-year, 10-year, and 15-year follow-up. The
results were expressed as hazard ratios (95% confidence intervals) number of hospitalizations at different follow-up times was associ-
[HRs (95% CIs)]. A ratio larger than 1 implied a greater probability ated with a reduced rate of pregnancy for all time periods. At 2-year
of a pregnancy earlier than in the comparator group. All covariates follow-up, the adjusted HR (95% CI) was 0.84 (0.82–0.87).
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3. Annals of Surgery r Volume 256, Number 6, December 2012 Appendicectomy Does Not Impair Fertility
TABLE 1. Characteristics of Subjects in the Appendicectomy Cohort and Comparator Cohorts
Age and Social Deprivation
Score–Matched Cohort Unmatched Cohort
Appendicectomy Comparator Appendicectomy Comparator
Cohort (n = 2935) Cohort (n = 5870) P Cohort (n = 3009) Cohort (n = 122,912) P
Age, mean (standard deviation) 20.9 (9.9) 20.9 (9.9) — 20.9 (9.9) 24.1 (13.2) <0.01
Social derivation category
1 (most affluent) 159 (5.4) 318 (5.4) — 159 (5.4) 8053 (6.7)
2 528 (18.0) 1056 (18.0) 528 (18.0) 21467 (18.0)
3 840 (28.6) 1680 (28.6) 840 (28.6) 32753 (27.4)
4 268 (9.1) 536 (9.1) 267 (9.1) 11787 (9.9)
5 478 (16.3) 956 (16.3) 478 (16.3) 17165 (14.4)
6 428 (14.6) 856 (14.6) 428 (14.6) 18563 (15.5)
7 234 (8.0) 468 (8.0) 234 (8.0) 9635 (8.1)
Histology∗
Normal 918 (33.1) — 939 (33.0) —
Mucosal appendicitis 395 (14.2) — 407 (14.3) —
Catarrhal appendicitis 19 (0.7) — 19 (0.7) —
Suppurative appendicitis 1219 (43.9) — 1253 (44.0) —
Gangrenous appendicitis 154 (5.6) — 155 (5.4) —
Periappendicitis 72 (2.6) — 74 (2.6) —
Previous pregnancy 578 (19.2) 1148 (19.6) 0.88 578 (19.2) 19953 (16.2) <0.01
Concurrent use of oral contraceptive 725 (24.1) 1361 (23.2) 0.11 725 (24.1) 15926 (13.0) <0.01
Previous disease history
Inflammatory bowel disease 9 (0.3) 4 (0.1) <0.01 9 (0.3) 183 (0.2) 0.04
Pelvic inflammatory disease 26 (0.9) 8 (0.1) <0.01 26 (0.9) 73 (0.1) <0.01
Other abdominal surgery 54 (1.8) 39 (0.7) <0.01 54 (1.8) 634 (0.5) <0.01
No. hospitalizations
0 2258 (76.9) 5025 (85.6) <0.01 2332 (77.5) 106702 (86.8) <0.01
1 438 (14.9) 596 (10.2) 438 (14.6) 11590 (9.4)
2 157 (5.4) 161 (2.7) 157 (5.4) 3056 (2.5)
3 51 (1.7) 55 (0.9) 51 (1.7) 910 (0.7)
4 19 (0.7) 20 (0.3) 19 (0.7) 335 (0.3)
5+ 12 (0.4) 13 (0.2) 12 (0.4) 319 (0.3)
Data are numbers (%) of subjects unless otherwise stated. ∗ Excluding missing data.
nancy rates in comparison with the comparator cohort. Patients with
TABLE 2. Impact of Appendicectomy on Pregnancy
advanced appendicitis had a less pronounced increase in pregnancy
Outcome
rate.
Unadjusted Adjusted∗ The association between appendicectomy and increased preg-
HR (95% CI) HR (95% CI) P nancy rate was statistically significant, the lower bound of the 95% CI
Matched analysis being 55% and 10% increased for the unmatched and matched anal-
Comparator 1.00 1.00 yses, respectively. To ensure that our study results were robust, we
Appendicectomy 1.21 (1.12–1.30) 1.20 (1.10–1.31) <0.01 have done a confirmatory analysis in the General Practice Research
Unmatched analysis Database.24,25 This found similar results (data to be published sepa-
Comparator 1.00 1.00 rately) but in summary, 228,079 subjects were matched for age and
Appendicectomy 1.81 (1.71–1.91) 1.65 (1.55–1.75) <0.01 practice (76,130 patients in the appendicectomy cohort and 151,949
∗
Adjusted for age, social deprivation score, previous pregnancy, use of oral in the comparator cohort). The pregnancy events were more frequent
contraceptives, inflammatory bowel disease, pelvic inflammatory disease, other in the appendicectomy cohort than in the comparator cohort (HR
abdominal surgery, and the number of hospitalizations before study entry. [95% CI]: 1.58 [1.56–1.61]). These data led us to suggest that at the
very least, appendicectomy does not appear to be associated with
reduced fertility.
One plausible explanation for the association between appen-
DISCUSSION dicectomy and increased pregnancy rate is that the presentation with
In the matched analysis, we found significantly increased preg- right iliac fossa pain necessitating exploration and appendicectomy
nancy rates after appendicectomy and early appendicitis in com- was due to ovulation pain acting as a surrogate marker of increased
parison with comparators. Within the appendicectomy cohort, the fertility. An alternative explanation for higher pregnancy rates associ-
subgroup with suppurative or gangrenous appendicitis had reduced ated with appendicectomy might be explained by gonadal hormones,
pregnancy rates in comparison with the group who had appendicec- which fluctuate throughout the menstrual cycle. These hormones pro-
tomy for a pathologically normal appendix but similar pregnancy duce far-reaching effects on inflammation and on the peripheral and
rates to the comparator cohort. In the unmatched analysis, the in- central nervous systems to modulate pain.26–28 These hormonal fac-
creased pregnancy rate after appendicectomy was maintained and tors in combination influence both fertility and admission for surgical
all the subgroups within the appendicitis cohort had increased preg- exploration whether the pain is caused by appendicitis or not. Thus,
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4. Wei et al Annals of Surgery r Volume 256, Number 6, December 2012
FIGURE 1. A, Kaplan-Meier plot of pregnancy outcome in FIGURE 2. A, Kaplan-Meier plot of pregnancy outcome in the
the appendicectomy cohort and an age and social depriva- appendicectomy cohort and an unmatched cohort. B, Kaplan-
tion score–matched cohort. B, Kaplan-Meier plot of pregnancy Meier plot of pregnancy outcome for the subgroups within the
outcome for the subgroups within the appendicectomy cohort appendicectomy cohort and an unmatched cohort.
and an age and social deprivation score–matched cohort.
The advent of laparoscopy in the early 1990s and its routine use
has undoubtedly reduced the rates of “negative” appendicectomy.29
the “symptoms” of appendicitis might be increased in more fertile Although there is evidence of reduced adhesion formation after la-
women. paroscopic tubal surgery, this did not affect tubal patency.30 The
The relationship between histologically determined appendici- benefits of laparoscopic surgery have been repeatedly demonstrated
tis and fertility is more complex and less certain. Intra-abdominal for a variety of procedures. Although surgical practice is moving to-
sepsis might reasonably be causally related to infertility because ward increasing the adoption of laparoscopic appendicectomy with
the association between appendicitis and tubal dysfunction is bio- emphasis on fertile women,31 there is little evidence that this will
logically plausible on the basis of inflammatory adhesions. Other have a profound effect on fertility in young women. Although there is
intra-abdominal inflammatory processes, such as pelvic inflammatory a recent trend toward more conservative management of appendicitis
disease, are strongly related to infertility.13,19,20 In addition, dense with intravenous antibiotics in recent years,32 it is unknown what the
peritubal adhesions have been shown under the appendicectomy scar impact of this will be on future fertility.
when laparoscopy is carried out to investigate infertility.13,17 How- We conducted 2 analyses for this study. One matched cohort
ever, there is no increase in the rate of right-sided ectopic pregnancies analysis (matched for age and social deprivation score) in 8805 sub-
in patients with a history of appendicectomy.16,19 jects with an adjusted HR of 1.20 and another multivariate analysis
The association between appendicectomy and fertility was con- using the entire cohort of subjects (n = 125,921) with an adjusted HR
sistent in 2 large UK population representative samples (Medicines of 1.65. Although matching improves efficiency, there were 74 cases
Monitoring database and the General Practice Research Database). It in this study that were not matched with controls and thus the matched
is also consistent with the only large well-designed published study.10 controls may not accurately represent the general population in terms
However, it is not consistent with other much smaller studies that of confounding factors. This may explain some of the difference in
have been published (see Table 3). This is mainly because many of the HRs for the methods used to control for confounding effects in this
studies were descriptive case series with limited numbers and without study.
an appropriate comparison group.4–6,11–13,16,17 Other studies looked
specifically at the relationship between appendicectomy and tubal STRENGTHS AND LIMITATIONS
infertility13,15,17,18 or examined appendicectomy as a risk factor for The strengths of this study include the large number of patients
ectopic pregnancy.8,16,19,20 There were other methodological flaws in studied using a well-validated database. We have also demonstrated
some of these studies21 including the study population,8,15,19,20 com- consistency by repeating this study in a different data set with similar
parability of the groups,15 unreliability of data,19 recall bias,8,15 and results. The use of first pregnancy after exposure as an outcome; the
determination of exposure.20 verification and stratification of appendix histology in the Medicines
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5. Annals of Surgery r Volume 256, Number 6, December 2012 Appendicectomy Does Not Impair Fertility
TABLE 3. Published Studies on the Association Between Appendicitis or Appendicectomy and Infertility
Authors Type of Study Sample Size Outcome Exposure Effect on Fertility
Urbach et al9 Case/Control 122/490 Tubal Infertility ANPA No effect
APA No effect
Andersson et al10 Cohort, Case/Control 9840 / 49200 Pregnancy rate NA Sig fert
ANPA Sig fert
APA No effect
Michalas et al20 Case/ Control 361/ 420 Ectopic pregnancy Appendicectomy Sig infert
Coste et al8 Case/ Control 279/ 279 Ectopic pregnancy ANPA Sig infert
APA No effect
Nordenskjold and Ahlgren, 199119 Case/ Control 119/ 357 Ectopic pregnancy Appendicectomy Sig infert
Lalos18 Case/ Control 71/126 Tubal infertility Appendicectomy No effect
Mueller et al15 Case /Control 158 / 504 Tubal infertility ANPA No effect
APA Sig infert
Forsell and Pieper7 Case/ control 41/41 Pregnancy rate APA No effect
Wiig et al14 Case/ Control 64/ 58 Pregnancy rate ANPA No effect
APA Sig infert
Lehmann et al17 Retrospective cohort 1743 Tubal infertility Appendicectomy No effect
Puri et al6 Retrospective cohort 389 Pregnancy rate APA No effect
Puri et al5 Retrospective cohort 134 Pregnancy rate APA No effect
Trimbos-Kimber et al13 Retrospective cohort 820 Tubal infertility ANPA No effect
APA Sig infert
Cromartie and Kovalcik16 Retrospective cohort 109 Ectopic pregnancy Appendicectomy No effect
Geerdsen and Hansen12 Retrospective cohort 78 Pregnancy rate ANPA No effect
APA Sig infert
Thompson and Lynn4 Retrospective cohort 37 Pregnancy rate APA No effect
Powley11 Retrospective cohort 32 Pregnancy rate APA with abscess Sig infert
APA indicates acute perforated appendicitis; ANPA, acute nonperforated appendicitis; NA, normal appendix removed; Sig fert, significantly more fertile, Sig infert, significantly
less fertile.
Monitoring cohort; and the control for several potential confounders tive or gangrenous appendicitis had reduced fertility when compared
of the relationship between appendicectomy, appendicitis, and first with those who had a histologically normal appendix but similar preg-
pregnancy are also strengths. However, the study has some limita- nancy rate to the comparator cohort. To prevent other adverse events
tions. First, the Medicines Monitoring database did not have infor- related to progression to complicated appendicitis, early referral for
mation on certain risk factors such as lifestyle, that is, body mass laparoscopy and appendicectomy is advocated.
index, smoking, alcohol, and exercise. Second, the current study (and
the subsequent General Practice Research Database study) was ob- ACKNOWLEDGMENTS
servational and confounding factors could not be fully controlled, The authors thank Sabrina Garbarino and Philip Thompson
which is a limitation of all observational studies. Approximately 33% for help with data assembly. Contributions of the authors were as
of the appendicectomy cohort had a normal appendix. This is a re- follows: The study was conceived by S.M.S. and T.M.MacD. and both
flection of historical surgical practice before the laparoscopic era. It took part in the design of the initial study protocol. L.W. took part
is acknowledged that not all women would seek health care for an in the design of the supplementary study protocol for the General
early abortion and subsequent registration. This may bias the results Practice Research Database and performed the data analysis. S.M.S.
in both the appendicectomy and comparator cohorts. completed the literature search. S.M.S. and L.W. prepared the initial
manuscript. All authors were involved in revisions of the manuscript.
CLINICAL IMPLICATIONS All authors had full access to all of the data (including statistical
On the basis of the results of this study, we believe that clini- reports and tables) in the study and can take responsibility for the
cians can take comfort that appendicectomy per se does not appear to integrity of the data and the accuracy of the data analysis. All authors
have adverse consequences on fertility. The natural history of acute commented on the final manuscript before submission.
appendicitis follows a sequential progression from simple to compli-
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