THE RELATIONsH.JP BETWEEN PERFORATION OF THE APPENDIX AND FEMALE TUBAL INFERTILITY

David Robert Urbach

A thesis submitted in confomity with the requirements for the degree of Masters of Science

Graduate Department of Cornmunit- Health University of Toronto

S Copyright by David Robert Urbach 1999

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The Reiatiomhip Betwcen Perforation of the Appeadu and Femik Tubal Idertility

David R Urbich, Muters of Science, Cüilicd Epidemiology and H d t b Can Reseuch Program, 1999

Depvtmcnt of Community H d t b University of Toronto

A case-contmi study was perfiorrned to waiuate whether perforation of the appendix is

a risk factor for female tubal infertility. Study subjects consisied of women with documented

tubal infertility attending in vitro feitilization clinics, and pmgnant women attending routine

prenatal obstetnc visits. Demographic data and information regardïng exposure to

appendicitis, appendiceai Horation, and known risk factors for infertility were acquired

through seEsrdministered questionnaires. Wh= possible, seifkeported appendectomies and

appendiceal perforations were c o d h e d with medical records. Using prepant women as

controls for cases with primary tubal i n f ' t y , the crude risk of tubal infertility h m

perforation of the appendix was 3.5 (95% CI 0.9-13.1) and the adjusteci risk was 1.5 (95% CI

0.4-6.4). Using women with secondary idertility as controls, the crude risk of infeitilty h m

appendiceal perforation was 0.9 (95% CI 0.2-3 S) and the adj& risk was 0.6 (95% CI O. 1-

2.3). These data do not provide substantial evidence that perforafion of the appendix is an

important risk factor for fernale tubai infertility.

1 would not have been able to complete this thesis project without the invaluable

assistance of my thesis cornmittee. Rose Kung pmvided content expertise, and braine Marrett

provided methodologicd guidance. My thesis oiipervisor, Marsha Cohen, was extremely

helpful, always avaiiabley and exceptionally good at helping me adhere to a tirnetable that

dowed me ta actually complete this pmject on the.

1 am gratefiil to The Physicia~' Services Inwrporated Foundation for hding this

research project, and to the Maîerd, Inf't and Repductive Health Research Unit and the

Centre for Research in Women's Heaith for the use of their fiiciiities and expertise over the 1st

two years.

I am ais0 indebted to my f d y for theu support during my many years of clinid and

research training. 1 am especiaily gratefhl for tbe unwavering support of my wife, Stacey,

throughout aü of the üttie setbacks and smaü victoies that we have encountered dong the

way. Finallyy 1 must îhank m y daughter, Natalie, who oomehow maaaged to learn to sleep

through the night just when the time had corne for me to reaiiy get to w o k

TABLE OF CONTENTS

ABSTRACT ACKNOWLEDGEMENTS TABLE OF CONTENTS LIST OF TABLES LIST OF FIGURES LIST OF APPENDICES INTRODUCTiON 1.1 Rationale 1.2 Study question

STUDY OBJECTIVES BACKGROUND

2.1 Appendicitis 2.2 Infertility 2.3 M&g fausetion in epiderniologic d e s 2.4 Evidence LiaLing appendicitis and infettility 2.5 Recd bias in caseantrol studies 2.6 Sumxnary

METHODS 3.1 Study design 3.2 Setting 3 -3 Study subjects 3 -4 Measue of effect 3.5 Ascertainment of exposures 3.6 Data management 3 -7 Statistical adysis 3.8 Ethicai and confidentiality considerations

RESULTS 4.1 Response rates 4.2 Characteristics of the study subjects 4.3 Estimates of rislr of tubal infertility - Pregnant controls 4.4 Estirnates of Nk of tubai infertility - Controls with secondary infettility 4.5 Accuracy of seKreported appendice81 status 4.6 Attributable risk and etiologic fiaction

DISCUSSION 5.1 Summary of d t s 5 -2 Interpretation of the d t s 5.3 Limitations of the study 5.4 Importance of the study findings 5.5 Directions for fiather research 5.6 Summary

REFERENCES TABLES FIGURES

APPENDICES

LIST OF TABLES

Table 1 Table II Table III Table N Table V

Table VI Table VII Table VIII

Table IX Table X Table XI

Table XII

Table XII1

Table XIV

Table XV

Chamcîenstics of the study subjects Crude odds ratios of infettility (combined primary and secondary) Crude odds ratios of primary infertility Crude odds ratios of secondary infertility Logistic regression analysis of ri& of infertility

(combiied primary a d secondary) Logistic regression anaiysis of risk of primay infertility Logistic regression d y s i s of risk of secondary infertility Logistic regdon anaîysis of ri* of infertility

(combined primery and secondary) Logistic regression andysis of risk of primary iafertility Logistic =gression anaiysis of risk of secondary infertility Effed of confounding variables on estunates of the risic of piimary

infertility due to perfioration of the appendix Crude odQ ratios, prllmay infertility

(compared to women with sccondary infertility) Logistic regresion d y s i s of ri& of primary infértility

(compared to women with secondary infeztilty) Logistic regcesion anaiysis of risk of primary infertility

(compared to women with sewndary infertiliîy) Accuracy of recall of appendectomy data

- LIST OFFIGURES

Figure 1 Age distribution of pregnant women Figure 2 Age distribution of women with primsry infertility Figure 3 Age distribution of women with secondaty infertiiity

LIST OF APPENDICES

AppenixA Questionairies Appendix B Consent for ~elease of medical records Appendix C Ethical approval

INTRODUCTION

nie pupose of thir chapter is ro &scribe the importance of the topic, to discuss the

rationale for the presenî research, and to &#ne the SM question.

1.1 Rationale

Acirte appendicitis is the most wmmm emergency condition tmted by general

surgeons in North Amerka (Schwartz 1994). in Ontario, 27,189 patients undmuent an

appendectomy for suspected acute appendicitis in 1992 (Wen 1995). Although clinicians are

notoriousiy inaccuraîe in diagnosing acute appendicitis (Wagner 1996), early operation has

been advocated even in cases of suspected acute appendicitis, in order to avoid the morbidity

resulting fkom perforation of the eppendix (Velanovitch 1992).

'The clinical dilemma is especially ditncult in the case of young women with possible

appendicitis. The diagnostic accuracy of the clinid assessrnent of appendicitis in young

women is worse tban that of the general population because of the high prevalence of

gynecologic conditions in this age group, many of which mimic the chica l presentation of

acute appendicitis (Lewis 1975). In Ontario in 1992, the nite of hding a normal appendix

during an appendectomy (the W r positive rate" of clinid sssessment) among women aged

15-29 was 27.7% (Wen 1995). Therefore, of the 4,775 women in this age group who had an

appendectomy during that year, 1,323 had an operation that could have been avoided.

Adding to the importance of this issue is the widely held beiief of many cliniciaus that

perforation of the appendix in girls and young women is a cause of subsequent infertility- in

such cases, infertility is felt to resuit h m damage that occurs to the fdopian tubes as a

consequeme of the more severe intra-abdomid infection associateci with appendiceal

perforation. Surgeons have been encouraged to have an sggressive appmach to perforaning

surgery on girls and young women with suspcct#l ~ppendicitis to prevent the theoretical

sequela of infertility (Mueller 1986). However, lowering the threshold for appendectomy in

young women wouid translate into a signifïcaut nurnber of mecessary operatioons.

In fact, there is not a large body of highquality epidemiologic evidence linLing

perforation of the appendix with female tubal idertility (Urbach 1999). Much of the evidence

is poorquality or aoecdotai, d the ody weiidesigned epidemiofogic study on this

association (Mueller 1986) has signifiant methodological problems.

The emergence, over the last two dedes, of newer technological modalities that

improve the accuracy of diagnosis of appendicitis do not maLe this question less important, but

add to the complexity of the issue. Imaging modalities such as abdomid ultrasound (Wade

1993) and computed tomography (Cm (Ra0 1998). and invasive procedures such as diagnostic

laparoscopy (Laine 1997, Jadaüah 1994, Olsen 1993). have been proposed for the evaluation of

patients with possible appendicitis. However, the addition of diagnostic tests and procedures is

not innocuous. New technologies may hcrease health care costs, and invasive procedures pose

additional risks to patients. Therefore, it is very important to determine whether or not

pedoration of the appendix is îruly a risk k t o r for tubai infertility before recommendations

for clinical practice can be made.

1.2 Study question

In a case-control shdy of women with primary tubal infertility receiving in vitro

fertilization, as compared to pregnant controls and to controls with secondaq tubal infertility,

are appendicitis or peiforation of the appendix risk htors for the development of tubai

STUDY OBJECTIVES

Primary objectives:

1. To determine wbether sppcndicitis or peiforation of the appendix are risk f-rs

for the development of tubd infertility

Secondary objectives:

1. To detennine the accuracy of selfkpm of the statu of an appendix removed at

operation (compared to medicai records)

2. To investigate the effect of recall bias on case-conüol studies of risic f8ctors for

tubal infertiiity

3. To explore the effect of contml selection on caseantrol studies of risk factors for

tubal infertility

4. To describe risk factors for tubal infertiiity in women undergoing in vitro

fertilization at cfinics in Toronto, Ontario

BACKGROUND

The purpose of this chrrpter i s to revtevtew the background irrformüion UItderlphg the

present resemch The specijk objectives of this chpter are:

2. To review the epidrmiology, ddugnosis und treatment of qpendiciillr

2. To review the epidemiology of tubal infertili~

3. Tu di;scuss Assues regmdng c a w d inference in epidenoiogic studios

4. To strmmarùe the existing midence on the relatiomhtp ktween appendicitis d

tubal infertility

5. To diseurs the importance of recdl bias in case-control studies

2.1 Appendicitis

Fitz (1 886) first recognized the importance of the surgicd treatment of appendicitis.

Previously, physicians had been aware of a suppurative illness that occurred in the vicinity of

the cecum, tenned "perityphlitis," that was universaiiy fatal (Herrington 199 1). The diagnosis

and treatment of appendicitis have improved in modem times, and acute appendicitis is now

recognized as the most cornmon acute surgical condition of the abdomen (Schwartz 1994).

Although appendicitis can occur at any age, it is most common in the second and third

decades (Lewis 1975). The estimateci Metirne ri& of agpendicitis based on life table models is

8.6% for males and 6.7% for females, whereas the lifetime risk of an appendctomy is 12.W

for males and 23.1 % for females (Addiss 1990). Two factors account for most of the

discrepancy between the rate of appendectomy relative to appendicitis in women: (1) the

increased rate of negaiive appendectomies due to diagnostic uncertainty (Boogard 1985), and

(2) a high rate of incidentai appendectomy associated with gynecologic surgery (Wolff 1995).

Apart h m age and sex, there are no other recognized ri& f e r s for appendicitis in North

America (Addiss 1990, Luckrnann 1989).

Most cases of appendicitis are causeci by obstruction of the appendiceai lumen by a

f d t h or lymphoid hypertropby (Pieper 1982). The -dix proximal to the obstruction

rapidly becornes distended due to secretions h m the appendice81 mucosa With progressive

distention and edema, d~vascular tbrombosis Ieads to vascular engorgement Ischemia of

the mucosa may lead to necrosis, with infiltration of the waii of the appendix by colonic

bactena Although this process may reverse spontaneously (Mattei 1994), continued

distention, ischemia and bacterial invasion results in fiill-thichiess necrosis of the appendiceal

wall. Perforation rnay be localid, with formation of aii appendiceal abscess, or generalized,

resulting in periionitis (Schwartz 1994).

The clinicai features of appendicitis have k e n weîl described (Schwartz 1994),

however there are no pathognomonic feahires, and there is considerable overlap with sigus and

symptoms of o t k acute abdominal syndromes. Early symptoms of appendicitis incluàe

centriil or nght lower quadrant abdominai pain, anorexia, nausea and vomiting, and fever. Pain

may becorne pmgresively more severe with continued inflammation. The most important

physical sign is abdominal tendemess over the appendix, with signs of peritoneal infiammation

(rebound tendmess and rigidity of the abdominsil Wall musculature). Although laboratory

fïndiogs are non-specific, leukocytosis is believed to k associatecl with appendicitis (Schwartz

1994).

Plain radiographs are t y p i d y not helpnil in the diagnosis of appendicitis. Abdominal

ultrasonography has been used increasingly as a diagnostic test, with reported sensitivity

ranging h m 85% to 93%, and specificity ranging h m 84% to 94% (Rioux 1991, Wade 1993,

John 1993). A W o d computed tomography (CT) has excelient SeLISitivity and specincity,

but is more expensive than uitrasomd (Curtin 1995, Ra0 1998). Recentiyy diagnostic

laparoscopy has been widely used as a diagnostic modality in s w p t e d cases of appendicitis.

Although a g e n d anaesthetic is required, laparoscupy is safe (Jansm 1997, Bateman 1996,

Vargas 1995, Kanc 19&1), and has been shown to be effective for the diagnosis of appendicitis

in case series (Tronîn 1996, Taylor 1995, Kum 1993, Kestet 1992, Graham 1991, Whitworth

1988, Spirtos 1987, Clarke 1986) and randomized controiied triah (Laine 1997, Jadallah 1994,

OIsen 1993).

The mtjor wmplication of appendicitis is perforation, and mbsequent morbidity and

mortality are related to the incidence of perforation. The case-perforation rate is age-specific.

In young children, the perforation rate is over Wh, and declines to appmximaiely 25% in

patients aged 10-1 9 (Luclanann 1989). There is a linear increase in eo ra t ion rate aAa age

20, peaking at 75% in patients aged over 80. Braveman (1994) found that differences in

medicai insurance coverage in the United States were related to perforation rates, with

uninnired patients being 1 A6 (95% CI 1.39-1 -54) times as Iüiely to have a mptured appenduc

than patients with private capitated coverage. The implication of this finding is that access to

health care is related to carly diagwsis of appndicitis, and that timely treatment may prevent

some perforations h m occurring.

The mortality rate of uncomplicated acute appendicitis is approximately 0.05% for ali

age groups combiied The mortaiity rate of perforated appendicitis in young patients is

sirnilar, but there is an intetaction between the effects of increased age and perforation, with a

mortality rate of 4.4% for perforated appendicitis in those aged over 80 years (Lucianaun

1989).

The dinerential diaposis of appcndicitis is -ive. The rnost wmrnon aitemative

diagnoses recorded at appendectomy for presumed appendicitis are acute mesenteric adenitis,

no organic paîhologic condition, anite pelvic idammatory di-, twisted or mptured ovarian

cyst, and acute gastroenteritis (Schwartz 1994). There is bmad agreement that once a

p m p t i v e diagnosis of appendicitis is maAr., the treatment consists of appropriate

resuscitation and urgent or emergency appendectomy. Although many surgeons believe that

early diagnosis and surgery ptevents appendiceai perforation, this bas ban exûemely difiicdt

to demonstrate (Temple 1995, Pearl 1995).

2.2 Infertiiiîy

2.2.1 Definitions

InfertiIity is defineci as the absence of pregnancy after 12 or more months of regular

unprotected intercourse (Westhoff 1991). F e d i t y is dehed as the biological abity to

conceive, whereas fertiIify is defineci as the ability to deliver a liveboni ot3kpring (Gray 1993).

Pri- infertiliiy refers to the inability to become pregaant among women who have never

been pregnant. Secondmy infertilify refers to the inabiiity to become pregnant or to carry a

pregnancy to term in women who have previously been prepnant, regordless of the outcorne of

the previoza pre- (Buck 1997). Male infertiiity is a factor in 40-50.A of infertile couples,

whereas male factor infertility is the sole explanation of a couple's infertility in 2&30%

(Howards 1995).

Femaie infertility, whether primary or secondaryT may be &lassifi.ed into the

following diagnostic subtypes: (1) tubai, (2) ovuiatory, (3) tûerbe/peritoneal, (4) cervical, (5)

other factor, and (6) unexplained (Buck 1997). Tubal fàctors acmunt for 40.A of f d e

infeitility (Speroff 1994). Oftcn, muitiple factors co-exist in a single woman, and some

conditions may aflFect f m t y through a combination of factors. For example, endometriosis

may lead to infertility thtough any or aîl of: tubal occlusion, impaîred ovulation,

uterindperitoneal nictors, psychologicai fwtorsT and as an iaîmgenic resuît of the use of

hormonal therapies to treat the disease.

2.2.2 Diagnostic procedures

A multicentre study conducted by the World Health ûrganizition (1986) evaluated

three classical methods of detennining tubai patency: (1) gaseous tubal indflation, (2)

hysterosalpingopraphy (HSG), and (3) laparosçopy with dye hydrotubation. Gaseous tubal

insuf£lation (performed by monitoring intra-tubal pressure and auscultation of a bubbling

sound during C a insufflation through a tram-ce~cal cannuia) is very inaccuraie, and was felt

to be of histoncal relevance oniy for the WHO investigators.

The "gold standard" procedure for d a l . ' g tubal patency is lapamscupy and dye

hydrotubation. This p d u r e may be done under local or g e n d maesthesia, and involves

intra-vaginai injection of methylene blue or indigo carmine dye while obsming for the

presence of dye in the peritoneal cavity. Hysterosalpingography is performed by injecting

water-soluble contrast medium through a cervical annula, and waîching for spillage of

contrsst into the peritoneal cavity through a flwmscopic image intensifier (WHO 1986). HSG

is operatordependeni, wiîh a significant proportion of fa-positive (18%) and fh-negative

(9.3%) tesults compared with laparoscopy.

Newer techniques for detennining tubal patency, such as sonosaipingography,

fdoscopy and endosalpingography have not been extensively investigated (Cordino 1992).

2.23 Epidemiology

The prevalence of infertility is difficult to ascertain with pmision. Because individds

or couples will ody manifest evidence of infertility if they are trying to becorne pregnant,

reported infertility rates liLely undetestimate the tni+ prevalence of conditions causing

infertility. Estimates of "current" infertiiity among couples range h m 3.6% to 14.3% and

"lifetime" infertility range h m 12.5% to 33.6% (Schmidt 1995a). The proportion of

American women aged 1544 years who were i n f d e was 11.2% in 1965 and 7.9.A in 1988

(Buck 1997).

2.2.4 Risk Factors for Tubal Infertility

2.2.4.1 Age

Age is the most important risk k t o r for female infertility. Classic studies on the

Huttente sect in the northem United States dernomimie a pmfound decline in fertility rates

with age (Tieîze 1957). In this sect, where birth conîrol was not used and there was no iimit on

family size, 1 1% of women were infertile after age 35,33% were infertile afkr age 40, and

87% were infertile afkr age 45. In a study of ri& factors in 470 Cawiian women with

infertility lssting longer than three years, every additional year of age was associated with an

increase of 9% in the ri& of infertiÜty (Collins and Rowe 1989). This age-related declline in

fertility nite is related to a number of factors, including an increased nsk of early pregnancy

loss due to fetai chromosomal abnormalities, endocrine changes, and oocyte aging and

depletion (SperoE 1994).

Multiple epidemiologic studies have also identifieci increasing age as an independent

risk factor for tubal infertility (Mueiler 1986, Cramer 1985, Daling 1985a). The effect of age

on tubal i n f d î y persists even af€er adjustment for cornpethg risk factors, mggesting thaî it is

not simply prolonged exposure to the recognued ri& factors for tubd infertility that accounts

for the relationship with age.

2.2.4.2 Pelvic inflammatory disease

Next to age, pelvic innammatory disease (PD) is the most important ri& factor for

tubal infertility (Monif 1990). Salpingitis is usually caused by Nekseria gonorrheae,

Chlamydia trachomatir, and less typically by Mycobacteriwn tuberdosis. h@copZ~~~nta and

Ureaplasma raeal~cum are felt to be putative etiologic agents in secondary tubai infertility

due to ascending infection afbr a primary endocervical infection (Monif 1990). Westmm

(1 980) conducted a lapamscopic evaduation of 1,100 women with acute saipingitis, and found

an incidence of tubal occlusion of 1 1.4% af€er one episode, 23.1% a* two episodes, and

54.3% after thtee episodes of Pm.

Even mild or subcünicai episodes of PID c m cause hibal damage (Sweet 1995). The

pathophysiologic process leading to tubal 0ccIusion begins with ascending infection into the

fallopian tubes h m the lower genital tract, associated with an infiammatory reaction in the

upper genital tract involviag v m o n , traiMudation of piasma and migdon of

idammatory ceiis into tissue (Sweet 1995). In severe cases, progressive injury to the

endosalpinx resuits in the production of p d e n t exudaie, which may k exuded h m the

fimbriated end of the fdopian tube if it is d l patent, with subsequent pelvic peritonitis

(WoOdniflF 1987). Adjacent pelvic O-, including the ovary, omentum, sigmoid colon, smaü

bowel, broad ligament, appendix and cecum may becorne involveci in a cornplex infîanunatnry

mas. Occlusion of the hbriated end of the fdopian tube may result in acute pyosaipinx, and

involvement of the ovary in an inaammatnry m a s results in a tuboovarian abscess (Sweet

1995). Generalized perîtonitis may resuit in perihepatitis (Fitz-Hugh-Curtis syndrome). In

addition to these acute sequeiae, acute PI' may I d to chronic relapshg infection, -pic

pregnancy, and chronic pelvic pain (Sweet 1995).

The importance of Chlamydia tracho- as an etiologic agent in tubal infîertility may

be tremendously underestimsited in studies relying on patient seKreport of a history of pelvic

idammatory disease. Gump (1983) found that approximatety one-half of women with

evidence of prior chlamydial iafection did not report a diagnosis of, or treatment for, PD. As

weii, the hdings of Gump (1983) and others (Moore 1982, Jones 1982) suggest thaî some

mild cases of PID are not being diagnoseci and tmated, and that even c l i n i d y occuit

chlamydiai infection results in tubal obstruction (Sweet 1995).

2.2-4.3 Endometriosis

Endometriosis has multiple adverse effects on fertility. Severe endometriosis may

cause tubal infertility on the b i s of pelvic adhesions and distortion of the fdopian tubes

(Healy 1994). As weii, endometriosis may result in damage to the ovary, with disniption of the

process of ovulation and ovum capture. Hormonal treatment of endometriosis inhibits

reproductive fimctioa The effkct of minimal or mild endometriosis on infertiiity is not clearly

understood. Many investigators fcel that the reportcd clssociation is duc to detcction bias, since

women with infértiiity are more likely to undergo lapatoscopy and have even clinically

insimiificant deposits of endometriosis found (Thornieau 1991). Recently, lapamscopic

surgery has been shown to improve feculldity in a randornized controlied trial of infertile

women with minimrii or d d disease (Uarcoux 1997).

2.2.4.4 Intra-uterine contraceptive device

Some types of inira-uterine contraceptive dev*ces WC-) bave been asmc&ed with

tubal infertility. Daüng (1985a) reported a relative N k of primary tubal infertility of 2.6 (95%

CI 1.3-5.2) for use of any IUCD, and a relative nsk of 6.8 (95% CI 1.8-25.2) for use of the

Dalkon Shield. Use of copper WCDs was not a significant risk factor. Cramer (1985)

reported a relative risic of 2.0 (95% CI 1.5-2.6) of primary inferiilty h m use of an IUCD.

Other investigators have challenged the importance of IUCDs as ri& factors (Grimes

1992), suggestùig that because NCDs do not have the protective effect against PID that oral

contraceptives and spermicidai contraceptives do, investigators may have observed a spurious

nsk if more controis than cases used these methods of birth control. As weii, many cases of

IUCD-associated PID are related to the procedure of insertion, and may not be relaîed to the

device itself (Grimes 1992). In any case, the use of RM3Ds has diminished significantly in

recent years, largely as a resuit of public health concem over the risk of PID and infertility

(Grimes 1992).

2.2.4.5 Cigarette smoking

Cigaretîe smoking has been identifid as a signincant risk fiutor for impaired fecundity

(Hughes 1996). A large prospective study of the naaaal fecutldity of 17,032 women found a

fertility rate of 0.78 (95% CI 0.62-0.97) for smokers of > 20 cigarettes per day compared to

nonsmokers Wowe 1985). The main effects of smoking on fertility an thought to be related to

the toxic eff- of cigarette smoke on the hypothalamic-pituitary axis, ovaries aad utenis

(Mattison 1982), and on circdating estrogen levers (McMahon 1982).

Aithough the biologic efféct of smoking specindy on tirbol fertility bas not been weLl

elucidated, nicoine in cigarette smoke is a potent vasoconstrictor and is associated wiîh

decreaxd uterine blaod flow (Waish 1994). EpidemioIogic studies looling onIy at hibal

infertility have alsa demoastrated smoking to be a significant risk tàctor (Dahg 1985a).

Phipps (1987) reportad a relative ri& of 1.6 (95% CI 1.1-2.2) for primary tubai infertility in

current cigarette smokers.

2.2.4.6 Induced abortion

Daling and colieagues (1985b) investigated the effect of a past history of induced

(therapeutic) abortion on secondary infertility. They did not find a hi- of induced abortion

to be an important risk factor (RR=1.15,95% CI 0.70 - 1.89).

2.2.4.7 Oral Contraceptive use

Because oral contraceptives have a pmtective effect against PD, it has been suggested

that use of oral contraceptives may de- the ri& of subsequent tubai infertility. h a a-

control study of 283 women with primary tubal infertility and 3,833 f d e controIs, Cramer

(1987) found no effect h m the @or use of oral contraceptives (RR=1.2,95% CI 0.8 - 1.6).

2.3 Inferring causation in epidemiologic studies

Hemekens (1986) proposed a classification of epidemiologic design strategies. Studies

are cIassified as either descriptive or analytic. Analytic studies are distinguished by the explicit

inclusion of a cornparison group thaî differs h m the study gmup with respect to exposure or

disease status. Analytic studies are subdivided into intervention studies (clinid triais), and

observational studies, which consist of case-control studies, and retrospective and prospective

cohort studies.

Epidemiofogic research on the effects of potentially hsmitiil exposures is largely

limiteci to observationai studies. It is i s s t never feasible to evaluate known harmfid

exponues in clinical trials, because of ethicai considerations and p b l e m s of iosufncient

power h m smaLi sample sizes and low fkquencies of adverse outcornes (Sackett 1991).

Cohort studies identify two groups of patients who are either exposed or not exposed to a

putative risk factor, and follow them forward in time to identify individuals who develop a

disease (Levine 1994). Because individuals in cohort studies are not randomized into exposure

groups, the validity of these studies may be threatened by s e l d o n bias and by confounding

with important deteminana of outcome other than the exposure of interest, of which the

investigator may or may not be aware. in general, prospective cohort studies are less

susceptible to bias than retrospective studies (Hennekens 1986).

Although cohort studies are usualiy the most valid meam of detcnnuun . .

g causafion for

harmful exposutes, often even these investigatio~~~ are not feasible because: (1) outcome events

are very rare, (2) the time to developrnent of an outcome is very long, (3) exposure is rare, or

(4) follow-up of the exposed cohort is di5cuit (Breslow and Day 1980). In such instances, the

most usefid study design b the case~control study.

A case-control study attempts to determine whether there is an increased ri& of disease

in persons who are exposed to a certain risk factors as compareci to those who are not exposed.

This is accomplished by cornparhg individuais who have a disaise (cases), with Jimilar

individuals who do not have the diseasc (controis), in oder to ascertain the pmalence of

exposure to the diseasc's potential ri& f-rs in bot . groups. If exposure to a risk fàctor is

more prevalent among cases than controls, then that factor may be a potentiai cause of the

disease (Breslow and Day 1980). Because case subjects are seIected on the ba& of their

disease s t a t u , casecontrol studies are usually able to evaluatc many more diseased individds

than cohort studies, especially if the incidence of the disease in a population is low.

The efficiency of a case-control study makes it a very desirable method of making

causai iaferences for rare exposures. The relationship between the development of vaginal

adenocarcinoma in daughters of women who used diethylstiibestml during pregnancy was

elucidated using case-control methodology (Herbst 197 1). However, caseantrol studies are

highly susceptible to bias (Gray-Donaid and Kramer 1988). Selection b i s , wiîh resulting non-

comparabiiity of cases and controls, is the most serious thruit to the intemal validity of case-

control designs (Breslow and Day 1980). Infonmaiion b i s is also an important consideration,

of wbich the type most damaging to casecontrol studies is recall bias (Sackett 1979).

Sackett (1 991) proposed the foiiowing modified Bradford Hill criteris (Hill 1965). in

decreasing order of importance, to evaluate the strrngth of evidence for causation h m

epidemiologic research: (1) Evidence h m tnie experiments in humaas, (2) Strength of the

association, (3) Consistency of the associaiion h m study to study, (4) Correct temporal

relationship of exposute and outcome, (5) Dose-response gradient between levels exposure and

outcome, (6) Consistency of the association with epidcmiologic data, (7) Consistency of the

association with biological data, (8) Specificity of the association, and (9) Anaiogy of the

association to previously proven causal 8ssociations.

2.4 Evidence linLiag appendicitis and infertility

Pdoration of the appendix has ban assumed to k a risk factor for the development of

subsequent tubal infertility in women (Cloud 1980, Strickler 1995), although there is a lack of

good epidemiologic evidence for this reiaîioaship. The wncept that appendiceal perforation

causes tubal infertility is intuitively appeahg h m a pathophysiologic standpoint. The local

inflammatnry process and subsequent intra-abdominai infection inciteci by perforation of the

appendix is thought to resuit in the formation of peritoneal adhesions, which can cause

deformity and occlusion of the fdopian tubes. Presumaably, many opinions have been formed

by gynecologists who. while perfomhg laparoscopy for the evaluaîion of infertility,

encountered dense peritoneal adhesions under old appendectomy scars, and by the equdy

impressive p d e n t gros peritonitis that o h confronts gmeral surgeons operathg on

patients with appendiceai perfotation.

In addition to anecdotal reports that have accumulated over the years, several analytic

studies have attempted to examine the relationship between pdoraton of the appendix and

tubai infkrtiiity. Unfomiaately, these studies d e r h m methodologicai pmblans. Early

studies did not use @se definitions of outcornes and exposures, did not ascertain outcomes

in a systematic manner, and did not acc~unt for the effeds of confoumihg ri& fktors for

infertility. These methodologicai flaws can lead to bis , and weaken the strength of the

evidence provided by the reseatch.

Subsequently, welidesigned epidemiologic studies were conducted, but were also

prone to b i s . In particular, case-contiol studies of risk f8Ctors for disease are susceptible to

drawing conclusions of spurious z~ssociations due to recali bias, or differentiai exposurr

misclassification error. type of bias is especially pmblematic when investigators rely

solely on patient self-report in ascertainiag exposure s&hi~, and if case subjects behave

differently than wntrok in the way they recaü hamifiil exposures.

2.4.1 Early studies

An early comparative study (Thompson 1971) identifid a cohort of 37 girls les tban

twenty years of age who undement appendectorny for perforateci appendicitis at the Mayo

C h i c in Rochester, Minnesota. They were compared to 181 girls who had an appendectorny

for simple acute appendicitis during the same mod. When evaiuated over twenty years later,

six patients in each group were married and childless (16% vs. 3.3%)). Altéough no formal

hypothesis îesting was pedionned, the authors concluded h m their data that perforation of the

appendix could lead to infertility.

No attempt was made to rigorously define infertility in this study. Indeed, the authors

''h the interest of good taste we did not ask the patients speci£ïcaUy about infèrtility or pregnancies in general. However, in most instances patients who were married and had no children provided i n f o d o n about infertility or such information was directly obtainable h m their medical records at this clinic."

Nevertheless, the data provided in the paper do show that some of the chiidless marrieci women

with a history of perforateci appendicitis aiso had pelvic infiammatory disease, a strong risk

factor for tubal Ilifertility. This (and the methodologic shortcomings of th& study) d e n s the

study's conclusion of a causal relationship between perforation of the appendix and infertility.

A similar study (Geerdsen and Hansen 1977) cornparrd the feaility status of 39

women Who had perforateci appendicitis in childhood to 39 womm who had non@orateâ

appendicitis in childhood. The study was coiducteci in Denmadq and patients were evaluated

five to fifteen years after their appendectomies. Twenty six percent of women with perforation

reported 6'inv~luntary i n f i compared to 14% of women with imcompticated

appendicitis, a difference that was not statisticaiiy signifiant. However, the age-adjusted rate

of infertility among women with a history of appendiceai pedoration was higher îhan that

expected in the general population. Therefore, the authors mncluded that a causal effect of

perforated appendicitis could not be excIuded.

A study conducted in Norway (Wiig 1979) cornparcd a case senes of 64 women who

had perforated appendicitis to 58 women who had simple acute appendicitis. AAcr a minimum

of fourteen years of follow-up, 22% of the perforateci group had infértility, compared to 12% in

the non-perforated group. This difference was not statistically signifiant In the nibgroup of

women wbo had developed pe1vic abscesses as a result of their appendiceal perforation, 3 1%

were infertile. The authors agreed with the conclusions of previous studies that pedoration of

the appendix is associated with infertilitty.

A retmspective study h m Sweden (Forsell and Pieper 1986) foiIowed up a cohort of

4 1 women operated on for perforated appendicitis and compareci them to 41 population-baseci

controls, matched by age, race and sociocconomic stanis. The rate of "involuntary infertility"

in study women four to fourteen ycars foiiowing appendiceai perforation was 25% cornparcd to

4% among controls (RR=6.25), a ciifference thai was not stathticaiiy significant.

These four studies are best charsctenIed as retrospective cohort studies. They

determine the incidence of an outcome ( i i i t y ) in a ahort of patients dehed by the

presence or absence of an exposure (appendicitis and perforation). Al1 of the studies suggest

that there is an increased rate of infettility in women with a history of appendiceal @oration,

but formal hypothesis testing did not demonseatc merences that were dsticaily sigdicant.

This is primarily due to the d sample sizes, and relative inbquency of outcornes of interest

in these M e s . These studies arc aiso hweâ by the absence of a unitorm definition of

infertifity, and by the lack of a sysîematic rnanner of ascertauua . . g outcornes. A quantitative

meta-analysis of these studies would not provide a more vaiid estimate of the effect of

perforation of the appendix on infertility, since their methodologid flaws, and the

heterogeneity of exposwes and outcome measures, do not permit meaninsfiii pooling of the

redts.

Other investigators have taken different approaches in examining the iink between

appendiceal @oration and infertüïty. Trimbos-Kemper (1 982) conducted a cross-sectional

analysis of women with infertility. She and her colleagues perfonned diagnostic laparoscopy

on 820 infertile women who had been previously interview4 regarding risk factors for tubal

infertiiity. On the basis of laparoscopie findings, tbey classified the women into two groups,

depending on whether they saw tubai abnormalities severe enough to account for the infertiiity.

Risk factors that were more strongiy associateci with tubal abnormalities than normal tubes

were judged to be etiologic fmtors for the development of tubal iafertility.

Tubal paîhology judged to be severe enough to explain the patient's infertility was

identifiai in 474 women. Complicated appendicitis was associateci with an in& incidence

of tubal pathology, as was salpingitis, endometritis, and gyneco10gic surgery. Uncbmplicated

appendicitis was not associaîed with an i n c d ri& of tubai pathology. The auhors

concluded that perforaîion of the appendix is a cause of tubal infertility whereas rmcbmplicated

appendicitis is not, and wged an -ive approech to appendectomy in yomg women with

SUSPeCfed appendicitis.

A retmspective cohort saidy done in Dubün, Ireland concludeci that perforation of the

appendix was not an impotant risk fbctor for infèrtility. Piiri and colleagues (1989)

administered questionriliiies to 181 of 276 women who had undergone appendectomy for

perforated appendicitis as girls. niey attempted to ascerhh the burden of inferLility in this

cohort afkr £Xeen or more Yeats of foUow-up by determining the fertility status of di childless

married women. Since none of these women had tubal i n f d t y attributable to the sequelae of

appendiceal perforation, the authors concluded that perforation of the appendix did not appear

to be an important cause of infertility in theu population.

2.4.2 Case-control studies

The principai study supporting an association between perforation of the appendix and

femaie tubal Uifertiiity was reported by Mueller and colieagues (1986). Their case contml

study is the only weii-designeci epiderniologic analysis of this re1ationship. The study was not

designeci specificaily to investigate the effcct of appendiceal disease, but was conducted as pazt

of a larger investigation of f-rs associatecl with female infertility.

Women aged 20-39 who were evaluaîed for i n f d t y in King Co*, Washington,

were matched by age, race, socioecommic staîus and gravidity to control women who had

given birth during the calendar year a f k the matched case first kgan trying to conceive.

Information on exposures was gathered by stnictured interview. ùifertility was dehed to be

due to tubal fmrs iftbere had been evidence of occlusion of the fhilopian tubes at

laparotomy, laparoscopy or hysterosaipingography. Aithough medical records were reviewed

to acquire details of the infertility evaluation of case women, the investigators did not confkn

with medical records reported exposures to appendicitis or paforation.. Women who reported

incidental appendectomy were excluded h m m e r anaiysis.

The resuits were anaiyzed using a logistic r e m i o n mode1 that adjusted for the effects

of hown rïsk factors for i n f d t y , including demographic data, a history of intra uterine

contraceptive device (IUCD) use, a history of pelvic idammatory disease (PD), and cigarette

smoking stahis. The investigators e h e d case women with primary unà secondary

infertility, and presented the d t s separateiy for each p u p . One hundred and fiffy eight

cases with prïmary infertility were wmpared to 501 controis, and 121 cases with secondary

infertility were compared to 453 controis.

The adjusted odds ratio for primary tubal infertility was 0.8 (95% CI 0.3-2.4) if a

patient had a history of an appendectomy, and 4.8 (95% CI 1.5-14.9) for a history of

perforation of the appendix. nie adjusted odds ratio for secondary infertility was 1.7 (95% CI

0.8-3.8) for an appendectomy, and 3.2 (95% CI 1.1-9.6) for perforation.

Although Mueller's case-wntrol study appears to support a ûue relationship betwem

perforation of the appendix and tubal inferfility, a cntical examhiion of the resuits reveak an

interesting phenomenoa Analysis of the group of women with secondmy infertility (defined

as women who had at le& one pregnancy) reveals that of the six case women with secondary

infertility who rrported a history of appendiceai Woration, five (83%) of the six perforations

occmed @or to a pregnancy. This observation should weaken the evidence for a cause-effect

relationship beîween perforation and tubal infertility, shce mod of the women with

appendiceal perforation were, in fact, able to achieve a pregmncy at lest once afkr the

presumptive cause of theù infertile state. Mueller discusses this phenornenon in her paper, but

suggests thaî it does not preclude a causal relationship, arguing that appendiceal perforation

may incite a primary lesion that causes progxessive tubal dysfimction over tirne.

There is another e x p l d o n why Muelier's case-contml sndy may have fouud a causal

relationship between perforation and infertility. Because the investigators relied only on

patient self-report to asccitalli exposure to appendicitis and appendiceal paforation, it is

possible that error in this measurement wuld have led to a b i d remît. For example, if

control women under perforation by reporrthg that they had an appendectomy for

acute appendicitis instead of perforated appendicitis, while case women accurately recall their

expsiire, the d t s would be biased towards over-estimatiag the effect of perforation on

infertility. Altedvely, if case women over-esfimated their exposurr to perforation W e

control women reported their exposure accurafely, a simiiar bias in effect would be observeci.

This phenomenon will be d i s c d in more depth in the next five sections.

2.5 Recall bias in case-control studies

A large body of literature examinhg the accuracy of recaii of health-related

information has accumulated over the past two decades. Many studies compare patient recall

(evaluated by postal surveys, questionnaires and interviews) to information h m medical

records. In general, these d e s show that patient recall varies h m extremely accurate to

wholiy inaccurate dependhg on a number of f ~ r s , such as the specifk type of health-related

information being assessed, the age of the subject, the duration of the recaU pend, and the

method of determinin8 exposue (Coughlin 1990).

Although the medical record might appear to represent the gold standard of "üuîhn in

medical information, medical records can k notoriously inaccurate (Hewson and Bennett

1987). Unless the records under consideration are those dealhg specindy with the events of

interest, they may not provide the necasary information For example, miiewing medicai

records of a patient's appendectomy shouid be an excelient way of aJcerrsining that the

appendectomy ha4 in facf occiarrd However, in the chari of a patient admitted to hospitai

for treatment of pneumonia, historicd âata on prîor appndectomy may be omitted because the

patient was not asked, did not remember, or the medical interviewer did not document the

information.

2.5.1 S tatistical rnethods of q~811tifLing the accuracy of d

Various meas- of quantifjing accuracy of d of dichotomous data have been

use& such as percentage agreement, analysis of matched pairs, the intraclas comlation

coefficient and the kappa staîistic (Portney 1993). Of the statistical test. of agreement between

patient recaii and medical records, the kappa statistic is the prefemd method since it measutes

agreement in excess of that expected by chance done. Estimating the accuracy of recall of

exposures with a very high or very low pievalence using percenage agreement (or mother

measure that does not correct for chance agreement) will d t in biased estimates (Fleiss

198 1). in general, kappa vaiues between 0.80 and 1 .O represent new-perfect agreement,

values between 0.60 and 0.80 represent substantiai agreement, values between 0.40 and 0.60

represent moderate agreement, and vaiues less tban 0.40 indicate poor agreement (Fleiss 198 1).

2.5.2 Accuracy of recall of health information

Harlow and Linet (1989) reviewed the literature on the accuracy of recaii for a range of

health-related informafion. They found that there was wide variability in the accuracy of

recall, with good agreement between s ~ ~ r e p o r t and medicai records for information on

hormonal meàications, hospitaiidon, and pregnancy-related events. Recall of diagnostic x-

rays and specific chronic diseases correlated pooriy with medicai records.

Several stuàies have looked specifically at d of heaith information about previous

swgery. In generd, there is good recd of generai information, such as m e r or not a

patient ever had a given procedure. The accuracy of recail of ever having had an

appendectomy was evaluated in a c8seconîrol study of chronic lymphocytic leukemia that

assessed surgicd excision of lymphoid tissue (Linet 1989). The percentage agreement between

strucnued interview and medicai records for ever having had an appendectomy was 88%, with

a kappa of 0.67 (95% confidence interval: 0.564.78). Recall was better for seE-respondents

than for surrogates. Paganini-Hill and Ross (1982) examhed agreement between stnichired

interviews and medical records for a history of hystetectomy and oophorectomy, as part of a

larger case-contml study of postmenopausai estmgen therapy and breast cancer. They found

that patient recall wrrelated weii with medical records, and that recall of hysterectomy (percent

agreement 98%, kappa 0.96) was better than thpt of oophorectomy (percent agreement 93%,

kappa 0.78).

However, the accrwEy of d for specific details of surgical procedures is not as

good as that for general i n f o d o n . To detcrmw the accuracy of recaii of the date of a

previous operation, Couiter (1 985) compareci the responses on a postal questionnaire of 198

patients h m one general practice to their medical chart regardhg their surgical histones.

There was 93% agreement on ever having had an operation, but ody 82% agreement on the

exact date of the o p d o n

As part of a iarger casecontrol study on oral contraceptive use and the risk of breast

cancer, Irwin (1990) compared seif-reported data on previous gynecologic surgery with

medical records for 550 case women with breast caucer and 496 controls. Orily women who

undenvent ovarian surgery for a benign indication, whose medical records were available, and

who had a hown number of rernaining ovm*es accordhg to seEreport and medicai records

were evaluated. The agreement between seKreported da!a and medical records was good, and

was marginaiiy better for cases than controls. nie accutacy of recall for the presence or

absence of ovaries (agreement for cases 92.6%, controls 90.3%; kappa for cases 0.85. controls

0.8 1) was better than that for the exact number of rernaining ovaries (agrrement for cases

87.1 %, controis 84.1%- kappa for cases 0.80, wntrols 0.73).

Although patient seif-report can be an accurate of health-record information

regarding the surgical history, there is signincant variability in the extent of this accuracy.

Specifk idonnation, such as the exact date of an operation or the operative hdings, xuay not

be recalled as accurately as simply wnaber or not a surgical procedure has been performed.

2.5.2.1 Pilot study - Accuracy of r d of appcndectomy data

To investigate the accuracy of d of a history of appendicitis and appendiceal

perforation, we conducted a maiied questionnaire survey of patients who undenvent a primacy

appendectomy at Women's College Hospital in Toronto h m 1995 to 1997. Patients were

asked whether thek appendix was nomial, infi- or perforated. Q u e s t i o h responses

were correlated with operative and paîhologic reports in the inpatient medical record. Specinc

criteria for the casedefinition of appendicitis and appendiceai perforation in medical rewrd

reports were developed prospectively and w m applied systematidy.

Of 63 questionnaires mailed to patients with a known address, 29 were completed and

returned (46%)). The o v d accurecy of recail was 82%, end the weighted lrappa was 0.66

(95% CI 0.39-0.92). AU paîients who had an inflamed appendix accordhg to medicai records

accurately recaUed an infiamed appendix. However, thme of five patients with a n o d

appendix recaNed an inflamed appendk ( 8 c ~ u t 8 c ~ û ? / i ) , and two of sÎx patients with a

perforated appendix u n d m the seventy of their ihess by recdlhg only an inflamed

appendix (accuracy==7%).

These findings demonsttated thai disagreement between self-report and medical records

with respect to the ststus of an appendix m o v e d at surgery is possible, with a bias towards

recalling an inflamed appendix, even if the appendix was actually normal or perforated. The

subjects who participated in tbis survey were aii paîients who had an appendectomy during the

study period, and not necessarily those who had complications, chronic illnesses, or health

conditions aitributable to appendicitis. As such, they would be expected to refïect the r e d

behaviour of CCcuntrois" in a case-contml study. This suggests that if self-report is used to

assess exposure in a case-control study, wntrols may under-edxmk (but not over --imam

exposure to appendiceal perforation.

2.5.3 The problem of differential and non-diff'erential exposure misclassification

Since misclassincation of exposure status will occur in at least some caseantrol

studies, it is important to appmiate the possible efféct of this bïas on the conclusions that are

drawn h m these analyses (Correa 1994). Misclassikation of exposurc statu in case-control

studies of rïsk factors may be subdivided into differential and non-differential

misclassifkaîion N o n d ~ ~ e r e ~ a I misclassification aror mil occur when maisurement of

exposure is hprecise (such that the true exposure is either over- or und-), and the

degree and direction of misclassScaîion in cases is similar to controls. DiJ2renîiaZ

misclassification d t s when e m r in cietenninaton of exposure statuts is different in cases

compared to controls.

In many epidcmiologic studies of risic futors for disease, cases (who have the disease

of interest) will over-estimate the presence or level of exponire to potentially ha-

exposures. In contcast, controls ( d o are fiee of the disease of interest) might underestimate

exposure to harmful exposures. For example, a case-control study spuriously atîributed an

increased risk of breast cancer to a history of induced abortion, entirely on the basis of under-

reporting of induceci abortion by (heaithy) controls (Rooinis and van Leeuwen 1996).

In g e n d , non-diffmential exposure misclassincation behaves iike other fonns of

measurement error, and will decrease statistical power, biasing the results of case-control

studies towards the "nuli" hypothesis of no efféct (Armstrong 1992). This may not hold true

for the special case of studies that analyze dose-response relationships of trend datsi, in which

noa-differentid exposure misclassification of risk f ~ r s with varying levels of exposure

might change the direction of a true association, or result in spurious associations (Dosemeci

1990, Birkett 1992).

DiEerential misclassification of exposure, on the other han& can in-, decrease or

reverse the direction of an association between the exposure and disetse, or may lead to the

finding of a spurious association when in fsct no true relationship exists. in g e n d , estimates

of the odds ratio will tend to be biased away h m 1 .O (the "nulln hypothesis of no effkct). 'Ibis

phenornenon has drawn d c i s m to many studies on so-caüed 'kisk factor" epidemiology

(Taubes 1995).

2.5.3.1 Meaouring the effect of exposure misclassification in epidemiologic shidies

Detecting the presence of Mêrentid eexposure misclassifiaiion is relatively

straightforward in caseumtrol studies of risk fators that have multiple levels of exposure

(Levois and S w i t m 1998). If an observai dose-response r c I a î i o ~ p between a risk f ~ r

and a disease is solely the d t of diffkrential recaii, it is either because cases differentiaily

recall higher levels of exposure, or because controls differentially mali lower leveb of

exposure. Such a process is easiiy identifid by examining the estimate of risic of the lowest

level of exposure. I f recall bias is operating, then this estimate will be aprotective effect (i.e.,

an odds ratio 4 .O) at the lowest level of exposme, with harmful effects at higher levels of

exposure. The only other possible explanations for such an observation are random error, and

hormesis (a protective effect of low levels of an exposure that is harmful at higher levels). If

hormesis is not plausible, then a test of the presence of differential exposrae misclassincaiion

is the test of signüïcance of the odds ratio for the lowest exposure class (Le., the 95% CI

exclude 1 .O) (Levois and Switzer 1998).

This test may be appiied to d e s loolcing at the effèct of appendicitis and appendiceal

perforation. If perforation appears to be a sipificent ri& factor while simple appendicitis (the

lowest exposure level) appears to be pmtcaive, then r d bias may be siispe*cd. In fkt,

Mueller (1 986) obtained an adjusted point estimate of infertility ri& for nonperfotaied

appendicitis of 0.8 in h a study on tubal infertility. However the 95% CI (0.3-2.4) around the

estimate include 1.0, so one cannot infer statistically signifïmt evidence of recail bias.

It is difficult to demonstrate the presence of differential exposure misclassification for

exposures that are binary ( m d as either present or absent). However, Drews and

Greenland (1 990) and Barry (19%) have pmposed models to estimate the effêcts of varying

levels of differential exposure erra on estimates of ri& obtained in case-control studies. If

differential exposure misclassification is possible, then the resuits of casccontrol studies

should be accepteci as valid only if they are robust to assumptions of modest degrees of

exposure measurement error.

2.5.3.2 Straîegies for reducing the effect of difEerential exposure misclassifidon

Many methods have been proposeci to elhinate, minimize, or control for the effects of

recall bias. The availabiiity of unbiased records of exposures would viraially eiiminate the

effect of this bias, but such records are seldom avdable (Raphael 1987). Cognitive

psychologists and survey researchers have developed a number of methods of improving

information retrieval such as thinlc-aloud intcniews, paraghrasing, probes and personal tirne

h e construction (Friedemeich 1994). Although such maneuvers would not be expected to

reduce over-fecall of exposures by cases, they migbt improve recalI of exposures by controls.

Conadhg the hypothesis of ri& factor studies h m study participants, or -g

by and controiiing for subjects' knowledge of the hypothesis have been pmposed as bias-

reducing strategies (Weiss 1994). Studies showing an effect of the exponm under

consideration but not other exposutes unrelated to the study hypothesis have i n c d

credibility. For example, a case-control study on pyloric stenosis in infants of mothers who

used Bendectin during pregnancy showed a signifiant odds ratio for Bendectin but not other

medications, thereby reducing the possibility of recaii bias as an exphmation of the association

(Eskenzi and Bracken 1982). Rapbeel(l987) suggesîed c o h g a validity scde for

reportai exposures by obtaining information on "decoy" exposures (howwn to be unrelated to

the disease of interest) in addition to information on the -sures of interest. Since a

respondent's score on such a validity sale wouId be a fùnction of the extent of their personal

recall bias, this saxe could be kluded in a multivariate mode1 to adjust for the effects of this

b i s .

2.5.4 The '%vishW bias

The effect of differential exposure misclassincation in retrospective studies of hamfûl

exposures appears to depend on case subjects7 perceptions of whether the potentially hamiful

exposure is within or beyond their control. ifthey believe their disease is caused by personal

behaviours, patients will tend to those behaviors. For example, smokers with

lung cancer or heart disease will tend to underestimate their smoking, patients with alcoholic

liver disease tend to underestimate their alcohol coasumption (Liu 1996), and drivers wiil

under-report trafic violations that occurred while they were intoxicated (Chang 1996).

In contrast, paîients with diseases that they b e h e to be caused by environmentai

exposures beyond their control tend to ove restimate the presence or degree of putative

exposures. nius mothers of children bom with congenital malformations WU recali more

exponires to dnigs duriug pregnancy than mothers of healthy babies, even îhough there may

have been no difference in true exposme (WerIer 1989). Nonsrnokm who develop lung

cancer might report more exposuh to environmental tobacco smoke than wntrols with similar

levels of exposure (Levois and Switzer 1998), and parents of chiidren with Ieukemia might

recall greater exposure to power lines (Campion 1997). This phenornenon has been tenned the

"wish" bias by Wynder (1 990). Patients may "wish" that their distase were c a d by an

enviro~~rnental exposure rather than by theu personal behaviours for reasons such as absolution

of personal responsibiility for their condition, or for financiai p r d t h m medical litigation.

Infêxtiiïty is a good example of a condition likely to be sffeîted by a "wish" bias in

case-conttoi studies. Infertility fiequenly exacts a high cmotiod and financiai burden on

affected individuals (Stolberg 1997). Women with tubal inf'ertility typically undergo an

extensive batiery of investrCgatio~ duriag which they may be rrpeatedly questioned about

possible risk factors for infertility. Since many physicians klieve that perforation of the

appendix is a risk factor for tubal infertility, women with a history of appendicitis would be

fiequenly asked whether their appcnâix was pedorateâ or not It is possible that Moration of

the appendix may be nilsely implicated as a ri& factor in case-cuntml studies as a result of this

phenornenon

2.6 Summary

Although perforation of the appendix has been historically implicated as a cause of

tubai infertility, good epidemiologic evidence of this association is lacking. Detemünin . . g

whether or not perforation reaüy is a risk f;lftor for infertility is extremely important

Knowledge of the natiaal history of a pedorated appendix will help surgeons with decision-

making when faced with the dilemma of whether or not to perfonn surgery on a girl or young

woman with suspecteci appendicitis. Understanding the consequences of appendiceal

perforation will also guide the ratiomi use of new diagnostic modalitia that bave been

proposed to irnprove the accuracy of phys ich ' diagnosis of appendicitis.

The most appropriate type of shidy to investigate the relationship between appendiceai

perforation and tubal infertility is a case-~ontrol design. However, the validity of case-control

snidies may be keaîened by a number of biases, the most imporîant of which are selection

bias and recail bias (differentiai cxposure misc1assification). There is evidence that sewreport

of a history of a pgforated appendix may not be as 8ccraate as medical record data. Therefore,

a weU-desimed case-control study shouid achieve accurate m e n t of exposure by

validating a history of appendicitis or prrfolaton with medical records. A b , the presence of

other risk fictors for tubai infertiüty must be taken into acwunt, since they might act as

confounding factors of the relationship between appendiceal perforation and tubal infértility.

METHODS

The purpose of this chapter t to &smCtlk the met- used in cortducting th& resemch

The specijic objectives are:

1. To &scribe t k s t d ) design sening d subjects

2. To dWws rhe prkri,Zes of contrai seiection in case-control research

3. To describe the methodr of ascerfaimet of expowes

4. To describe &a wtaraagement and ana&sis

S. To dilsms ethical issues regarding this research

3.1 Study design

A case-control study design was used. Case-control studies are the most efficient

m e m of investigating relationships between potential ri& factors and diseases, when both the

risk faftor and disease aze relatively rare (Breslow and Day 1980, Wacholder 1992~). A

common conceptualization of a case-control study is that of an extremely efficient

retrosgective cohort study, where ail of the individuals belonging to a theoretical inception

cohort who develop the outcome of interest are identifieci, and a representative portion of

individuals who did not develop the outcome are sumpled (Schlesselman 1985).

Miettinen (1985) disagrees with the characteruation of case-control studies as a

counterpart of cohort studies. He describes the caseconml methodology as a census of a

study base with respect to outcome, foiiowed by a census of the cases and a sample of the

study base to obtain informaiion about the potential deteminants of disase. Irrespective o f

the debate concexning the nomenclature samounding case-conîrol methodology (Spitzer 1985,

Feinstein 1985, Axelson 1985). there is universal agreement thaî investigators must k

extremely vigilant to avoid the biases that are essociated wïth this approach.

3.2 Setting

The study was conducted in several c l in id centres in Toronto. Women with tubal

infêrtility were recruited fimm The Toronto Hospital Reproductive Biology Unit, The LEE

Program at the Toronto Easî General Hospital, IVF Caaada (a private in vitro fertilization

clinic), and fkm the practice of a repductive endocrinologist at the Markham-Stouffiriue

Hospital. Pregnant women were recruited h m obstetric cIinics and obstetricians' offices at

Women's Coliege Hospital and St. Michsel's Hospital. The study was based at the Maternai,

Infant and Reproductive Health Research Unit at the Centre for Research in Women's Heaith,

a research facility dEliated with Women's Coiiege Hospital and the University of Toronto.

3.3 Study subjects

Subjects were eligible for inclusion in the study if they aîtended any of the in vitro

fertiiization centres, or obstetric clinics or physician offices, thai partkipated in the snidy.

Patients were recruited between 1 Juiy 1398 and 3 1 January 1999. The foiiowing inclusion

cnteria were applied:

(1) fernale (2) age 20 -44 (3) residence in the Greater Toronto Area

Women with tubai tofertility were defïned, for the prirposc of this study, as women

seeking in vitro fertilization treaünent at participating clinics in Toronto, Ontario, who had

evidence of tubal occlusion either on hysterosaipingogram, laparoscopy, or bth. Specinc

records of hysterosaipingography and lagaroscopy were not reviewed. We klieved these to be

recordeci acc~rafely by the clinics, since insurancc for assisted-reproduction technology

seMces in Ontario is dependent on the specifïc etiology of the infertility (Ministry of Health

1998). As weli, different techniques of asskted-reproduction technology are used for different

etiologies of i n f d t y , and accurate diagnosis is crucial for rational m e n t planning.

If women with tubal infertility rrported any history ofprior pregnancy achieved

without the use of in vitro f m o n , regardles of pregnsncy outcorne, then their infertility

statu was denned as secomby.

Fertile adrols, for the purpose of this study, wae denaed as women attending a

participating obstetnc clinic or physician's office, who became pregnant without the use of in

vitro fedlization. Pregnancy was defïned as evidence of an intraoterine gestation on

abdominal uitrasonography, a d o r auscultation of the faal heartbeat. Diagmsis of pregnancy

was made by participating ohtetricians, and was not wnfirmed by the study investigators.

The following excluion criteria were applied to women with tubal SertiIity:

(1) pnor tubal ligaîion

The following exclusion criteria were applied to pregnant women:

(1) pregnancy achieved by in vitro fertilization.

3 -3.1 Selection of controIs

The validity of case-control d i e s is dependent on the appropriate selection of cases

and controls (Lasky and Stoliey 1994). The most important characteristic of case and control

subjects is that they should be compmobe. Comparability between cornparison groups

minimizes the effect of selection bias. Wacholder (1 992a) describeci three principles of

comparability: the sîud) base principle, the deconfoMding principle, and the comparable

accwacy principle.

3.3.1.1 The Study Base Principle

The concept of the study base was p p o s e d by Miettinen (1985), and implies tbat cases

and controls shouid be "qmsentative of the Jame base expaience," de- in temis of

individuals or person-time. Ifcases and controls are drawn h m the same study base, then

controls, had they developed the disease of interest, would potentiaüy have becurne cases. The

study base is defïned as aprin>my base if it can be weIk6PRctcrizod a pori in tgms of

geography and time, and the cases identified reptesent the totality of cases arising h m the

study base (Le., the cases are identified secortrtan'iy to the base) (Miettinen 1985). Cases may

be drawn h m a primary base in population-based case-control studies. A shuiy base is

defined as secondhy if the cases are defïned apriori, and characterhtion of the study base is

secondary to the identification of the cases.

3.3.1.1.1 Control selection with incomplete case ascertainment

A special case of a problem with control selection from a secondary base that is highly

relevant to this research question is that of incomplete case ascertainmeet. In terms of

diagnostic test characteristics, incomplete case ascertainment is most problcmatic when there is

perfect specificity of disease classincation (there are no false positives), but there is l e s than

perfect seasitivity (there are some fâlse negatives).

Savitz and Pearce (1988) presented a comprehensive discussion of this problem. Case

under-ascertainment may be a source of bias if the disease definition can ody be fiilfilleci if a

study abject arbitiarily undergoes specifk diagnostic tests or procedures. For example, the

cases in this study of tubal infertility arc not simply those women with tubai infertility

demonstrated on hystemsalpingography or laparoscopy. Rather, they are women with

documentai tubal disease who have elected tu d r g o investigation for infertility and who are

having in viîmfZrtiZlirrrrion becawe they want IO becorne prepmt. Clearly, this is a subset of

the p a t e r population of womm with tubal infertility, and may differ h m o k women with

tubal infertilitty with respect to a number of chamcteristics, some of which may affect the

likelihood of exposw (or rcporting of exposure) to perforation of the appendix (Schmidt

1995a).

Savia and Pearce (1988) propose a method for dcaling with the problem of incomplete

case ascertainment. Essentially, they suggest treating the determinants of case m e n t

as cmnfounders of the relaîionship between the disease and the exposure of interest, and

adjusting for their effats as for other confounders (i-e., by restriction, matching or modeling,

see below).

For example, if the willingness to have a chiid in the presence of infertility (described

by Savitz and Pearce as "child-seeking" in a hypotheticai mdy of alcohol use and maieef8ctor

infertility) is a characteristic of the cases, then one should atiempt to obtain controls that are

comparable to cases with respect to this characteristic. (in this context, "child-seeking"

involves a number of characteristics including sca?ls to appropriate health-tare facîlities, and

the wiilingness to undergo uncornfortable procedures and expensive treatment modalities in

order to achieve a pregnancy.) Tàis might be accomplished by restrifting study subjects to

"child-seekew" by matchhg cases and contmls on the bask of uchild-seeking," or by adjusting

for "child-seeking" in a multivariate analysis.

In practice, it is diff?cuit to identifi. "chiid-seeking." ûne cannot even assume that

pregnant women are similar to women with infertility with respect ta "chüd-seehg," since

they have not faced the same type of decision to bave a child as the case women. Clearly, not

ail pregnant women wanted to become pregnant initialiy, and it would be extremely difncult to

obtain an unbiased accuunt of how "desired" a pregnancy was h m a pregnant contml.

Adjusting for surrogate variables (such as residence by census tract, socioeconomic status or

education) would not be expected to capture the subtle detemiinants of "child-seeking" that, in

practice, lead women with i n f î d t y to pursue an o h diffiicuit and expensive course of

treatment. Therefore, it is not possible to correct for the CC~hiId-seeking" variable by matcbing

on it or bypost hoc adjustment in a logistic regression model.

However,it is possible to restrict the study population to "child-seekers." This may be

accomplished by limiting cases and conîrols to women who have documenteci tubd IlifixWty

and who are naiving in vitro f a o n . To investigate the effécts of childhood appendiceal

perforation on tubal infertility in a case~control study, an appropriate control group for women

with primary tubd infertifity is women with seconhy tubal idertility (i-e., women who have

had a prior pregoancy without in vitro fertilization and subsequently developed problems with

fertility). This method is valid only if one considers exposure to be a perforation of the

appendix that o c c d p p i o r to the initial pregnancy. Women with secondary tubal infertility

may be conceptualized as contmls with respect to primary tubd infertility, since they were able

to become pregnant (and therefore had patent tubes) after the at-risic period for the exposure of

interest (perforation of the appendix).

We therefore conducteci a separate analysis using women with secondary tubal

infertility as controts. This aaalysis used the tbept ion that a causal linL ktween perforation

of the appendix and tubal occlusion is ody valid if tubal occlusion occurs immediately afkt

the exposure, since appendicitis is an acute, limited event that does not persist over many

years. Inference of a causai association is less tenable if tubal occlusion occurs a - a discrete

time subsequent to the exposure event, as would be evidenced by one or more conventional

pregnancies occurring between the time of the exposure and the onset of infertility.

In fact, women with secondary infertiiity d t e d h m in vitro f-on clinics

undergo a diagnostic worhip and treatment pottoc01 identical to that of women with primary

infettility. Therefore, they should k as similar as possible to cases with respect to the possible

determinants of case under-aaxrhhnent. Restricting the aaalysis to cases with primary tubai

infertility, to controls with secondary tubal infettility, and limiting exposutes to pedorations

that occurred prior to the adult reproductive period, provides a p u p of subjects that are fke

fiom bias redting h m incornpletc case m e n t , However, restricting the anaiysis in

this way will unde rrnimate the effkct of perforation if in fact perforation pria to an index

pregnancy is related to subsequent (secondary) infertility.

Therefore, in this snidy, two difEerent wntrol groups were used: (1) pregnant coatrols,

and (2) controls with secondary infertility. For cornparisons with the control group with

secundary idertiiity, only exposures to appendicitis that occurred in childhood (@or to age

18) were acceptai as valid exposures for the analysis.

3.3.1.2 The Deconfounding Principle

The deconfounding principIe addresses the problem that occurs &en risk f w r s other

than the exposure of interest are also associated with the disease (Wacholder 1992a).

Confounding can bias the d t s of any study. Ensuring that confounding does mt b i s a

study's r e d t is accomplshed by minimizing (or eliminïatingl the vmiobility in the confounding

factor with respect to the disease of interest (Wacholder 1992a).

Confounders may be mea9iaed or unmeasured. Variability in measured confounders

(those that the investigator is aware of) can be dealt with by restriction, matchhg, orposr hoc

adjustment in the anaiysis (Wacholder 1992~). Variability in unmeasured confounders is

addresseci indirectiy, by ensuring that cases and contmls are homogeneous with respect to

variables that might be detetminants of unmeasured wnfomders, such as sociocconomic

status, residence or ethnicity.

Risk factors are confounders of an sssociation between an exposure and di- ifthey

satisfy three properties: (1) they are associaieà with the disease amoag unexposed individuals,

(2) they are correlated with exposure in the study base, and (3) they are not intermediate steps

of the causal pathway between the exposure and disease under investigation (Grrenland and

Robins 1985). Of course, the procise characteristics of the W y base snd the distribution of

risk factors in unexposed individuals are usuaiiy not available h m case-contrd data

Therefore, in caseantroI d e s , bias may result even h m "con.ound.hg" by variables that

do not fùEU the above criteria for confounding.

For example, if a variable is a risk factor for disease but is not associateci with an

exposure in the study base, then it wodd not be considered to be a confounder 8ccording to the

dennition given above. However, if the variable differezltially influences selection wifh respect

to expostae, then it may act as aficnctio~i confomder in caoe-control studies, since it wiii

impact on an individuai's probability of reporthg that exposure depending on case-control

status @ay 1980).

With respect to the scenario of appendiceai perforation and infertility, P D is a risk

factor for infertility. If reporting a history of PID is essociated with appendiceai perforation

with respect to case selection (for example, ifboth a perforated appendix and the diagnosis of

42

P D are associated with access to health care, and access to heaith care facilities affects the

iikelihod of undergoing in vitro fertilization for fertility dBcdties) then a history of PID

might still act as a wnfounder with respect to appendiceal jm5oration and infertility.

Contmiling for such variables may reâuce bias, even though they me not c o n f o ~ r s

according to the classical definition. A similar argument may be made for variables that are

correlated with exposure in the study base, are not ri* factors for disease per se, but influence

selection dinérentialIy with respect to disease status (Mietîinen and Cook 1981).

The essential point is that causal inference in case-contml studies is highly sensitive to

biases that affect the pmbability of an exposeci individuai's becoming a "casen or of an affecteci

individual's reporthg an uexposure.n AdjuStment for variables related to exposure or disease

may still duce bias, even ifthey do not f i U l the classical criteria for confounders

(Greenland and Robins 1985, Bresiow and Day 1980).

3.3.1.3 The Comparable Accuracy Principle

The principle of comparable accuracy recognizes that whereas some degree of

measurement error is inevitable in epidemiologic research, this ermr shouid be nondifferentiai

with respect to cases and controls (Wacholdet 1992a). The implications of nondifferential

exposure misclassification on this research have been discussed in Chapta 2 (Background).

3.4 Measure of effect

The risic of tubal infertility d t i n g fiam appendiceal dora t ion can be e x p d

either as (1) a risk esiimate for appendiceai pedoration relative to never having had an

appendectomy, or (2) an estimate of the effect of Woration on infettility compared to an

uacomplicated appendectomy. A meastue of effed quantifving the n s k of i n f i t y h m

perforateci relative to non-perforated appendicitis is more appeatiag h m the standpoint of

clinical relevance, since it wodd quant- the "excessn risk attributable to perforation beyond

that of simple appendicitis. Since alterations in treabnent can only possibly affect the case-

perforation rate (and not the incidence of appendicitis itseif), this is the meapure that would be

most usefùl in fomuiating guidehes for clinid practice. However, to derive this value

experimentally wouid necessitate compariag only those cases and controis who had a bistory of

appendicitis. The d t h g number of individuals would be so low as to preclude the

performance of any m d g f i i l adjusiment for other variables. Therefore, the measure of

effect used in this study is the odds ratio of infertility given exposure to perforation of the

appendix (or uncomplicated appendicitis), compared to never having had appendicitis.

3.5 Ascertainment of expomres

Self-administered queSfionnaiFeS were used to obtain demographic data and information

on exposures h m study participants. Development of questionnaires was eonducted in

consultation with an expert in survey design, and items were modeled aftet the instrument used

for the National Population Health S w e y (Statistics Canada 1998). Preliminary evaluation of

the questionnaires was done using a pilot test of twenty study subjects.

Questionnaires w m either completed within the clinic setîing, or were mailed to study

subjects dong with staxnped retum envelopes. A sample questionriaire is reprinteà in

Appendix A.

Based on our d e w of the literature of risk &tors for infertility, questionnaire items

included seEreported exposure to cigarette smoking, PD, pnor abdomiinil or pelvic surgery,

prior pregnancy, therapeutic aborîion, pregnancy loss, ectopic pregnancy, endometriosis, and

use of oral contraceptives or an RTCD. Exposure to appendectomy was ascatahed through a

combination of seKreport and medical record search, Subjects who reported an appendectomy

were asked whether th& -dix was normai, inflamed or ruptureâ, and whether they had an

incidental appendectomy (done at the time of another procedure).

Patients who reported an 8ppendectomy were asked to sign a witnessed consent form

(Appendix B) for the release of the pertinent medical records. When approprhte, the health

records departments of source hospitais wcn contactexi via telephone and a request for copies

of operative and pathologic reports was mded dong with the original copy of the study

participant's consent form. When records werc available, the medical record was used as the

measure of true exposure if there was disagreement with ~e~repor t . Incidental

appendectomies were not considered to be exposures to appendiceai disease for the purpose of

this study.

Appendicitis 8ccording to medical records was defined by the use of any of the terms

"appendicitis," "acute idammation," or any variations or combination of terms to describe the

state of the appendix in the operaiive report, the pathologic report, or both Perforaîion was

defined by the use of the terms "perforation," "rupture," or any variant on either the operative

or pathologic report, or by use of the tams "gross peritonitisn or "genaalizsd peritonitis" on

the operative report. Ifthere was disagreement between operative and pathologic reports, the

status of the appendix was defined according to the more severe description among the two

sources.

W e attempted to minimin bias due to Merential exposure misclassification for the

exposm of primary interest (appendicitis). However, there may k b i i relateci to differential

exposure misclassiEication for other exposures. in pracfice, it is proh'bitively dif]Eicult to

confirm multiple exposures. In order to optimize efficiency M e simultaneously maximiPng

our ability to preciseIy esthate the main effect of interest, wc only validaîed self-qmrted

e x p o m to appendiceal clkase. Validation of exposure would not be expected to improve

the problem of under-reporting of exposure by controls, which is di a potential source of bias

in this analysis.

3.6 Data snanagement

Questionnaites thaî were missing data on the cxposure of interest (appendectomy) were

not included. Data h m an individual m o n n a i r e was used as long as fewer than t h

questions were left unanswered. Items for which no response was given were handieci by

interpolation of the modal value for that item.

Daîa h m questionnaires were entered onto an e1ectron.i~ dahbase (Microsoft Access

970, Microsoft Corporation) that was specifidy programmeed for this study. Data tables

were converteci into SAS (SAS Institute, Cary NC) data files for subquent statistical analysis.

The accuracy of data entry was checked by cornparison with the originai questionnaire records.

3.7 Statistid analysis

3.7.1 Sample size consideratiolis

ui case-control studies, the number of cases required depends on the dcsired

signincance level statisticai power, the prevalence of exposure among controls, and the

stcength of the relationship that the investigators fa1 would be important to exclude

(Schlesseiman 1974). Based on data reporteci by Mueller (1986) we used a sample size with

dEcient power to detect an oMs ratio of 4.0 or pater for perforation of the appendix.

Increasing the ratio of controis to cases can improve precision if cases are limited, but the

marginal bewfit aiminisbes et contro1:case ratios p a t e r than 4: 1 (Wacholder 1992~).

From a synthesis of the literanire, we assumed a caseperforaiion rate of 25%, and used

the foilowing mode1 to estimate the lifetime prevalence of appendicitis for the relevant age

groups:

where P,, is the cumulative probability of having appendicitis af€er k years, and pi is the

annual rate of developing appendicitis durhg the P year. Using data h m Naylor (1996) on

annual positive primary appendectomy rates for Ontario women, the probabiity of developing

appendicitis would be 3.8% by age 35 and 4.6% by age 50 using 1989-90 data, and 3.2% by

age 35 and 4.0% by age 50 using 1995-96 data Assuming a case-perforation rate of 25%, the

cumulative prevalence of appendiceal perforation by age 50 is 1.2% using 1989-90 data and

1 .O% using 1 995-96 data.

For a sigdcance level of 0.05 and power of 800/0, and a a:controI ratio of 1 :2,

detecting an odds ratio of 4.0 or pater requires 159 cases and 3 18 controls if the prevalence

among controls is 0.02.

3 -7.2 Explanatory variables

The explanatory variables of greatest interest for this aaalysis were exposurr to

appendectomy and to pedoraton of the appendix. Thme biaary variables were used to

represent appendectomy exposures (with value 1 if exposed and O ifnot exposed): (1) any

appendectomy (excluding incidental appcndectomy), (2) appendcctomy without perforation,

and (3) appendectomy with perforation Appendectomies for a normai appendix and for

simple appendicitis were combinai into one exposure category in order to avoid obtainiag

unstable estimates of risk for variables with extmnely low tkpnc i e s .

In addition to exposure to appendectamy, the foliowing variables were analyzeü to

determine their effects on tubat i n f d t y : (1) agc, (2) annual income, (3) level of e d d o n (4)

smoking statu0 (mcluding ever smoking and current smoking), (5) PD, ((6 endometriosis, (7)

oral contraceptive use, and (8) IüCD use. in e stimahg the ri& of secondaqr infertility, the

foiiowing additional variables were analyzed: (1) therapeutic abortion, (2) pregnancy los, and

(3) ectopic pregnancy.

Age, a ~ u a l household income (stratified into 430,000, $3O,ûûû-$d0,000 and

>$60,000), and level of educstion (stratifieci into less than a high school diplorna, more than

high school but less than a university d e p . and a university degree) were used as

classincation variables. Age was stratified into three groups (20-29,30-34,3544) for the

crude andysis and into five 5-year age classes for the muitivariate analysis. The remaining

variables were dichotomous (binary), taking the value 1 if expoaure to that variable was

reporteci by an individual, and O if it was not.

3.7.3 Choice of control groups

Two sepivate sets of analyses w m peifomied, one using a control group consisting of

p r e v t women, and one using a control group of women with secondary infertility. The use

of pregnant women as controis pennitted esthaîion of the ri& of primary or secondary tubal

uifertility for aii of the exposures of interest. However, the inclusion of this control p u p

might produce biased estimates of risk for some exposures, due to the pmblan (discussed

earlier) of incomplete case ascertainment.

In order to control for the effkct of incomplete case -en& a second analysis of

the risk of al1 the exponirrs was conducfed uskg a wntrol p u p mnsisting of women with

secondary infertility, and using cases consisting of womcn with primery Mertiliity. This

wntrast of case and control p u p s is expedcd to provide estimates of ri& of perforation of the

appendix that are not affected by seIection bias.

3 -7.4 Estimation of crude ri* of infertility

Crude odds ratios of infertility and 95% confidence intervals wexe estimated using

logistic regression for each of the exposure variables. lüsk estimates were calculated

separately for (1) combiaed primary ond secondary tubai infertility, (2) primary tubai

infertrlity, and (3) secondary tubal infertility. For each of these analyses, pregnant women

were used as controls.

An additional set of estimates of ri& for primary nibal infertility was derived using

women with kondary tubal infertility as controls. For this set of cornparisors, exposures

other than appendicitis and perforation would not be expected to agpear as signifiant

detednants of risk, since they are aII risk fators for both plimary und secondaxy infertility.

Furthexmore, they are al1 risk &tors that are characterized by chronicity (such as

endometriosis and smoking), or by the opportunity for multiple recumnt -sure (such as

pelvic inflammatory disease). In con- perforation of the .ppcndix is an acute event that

exerts its effect over a finite period of time, afkr which the outcorne (tubai occlusion) is either

present or absent.

3.7.5 Estimation of adj& ri& of infettility

To adjust for the effécts of coafounding variables on esbates of risk of infertility for

appendicitis and appendiceal pedorston, odds ratios were also derived using a muitivariate

logistic regession modeL AU explanatory variables that were signincant ri& factors in the

crude analyses were forced into the model. As for the d e aaalysis, several multivariate

analyses were perfomed. Adjusted estimaies of risic were obtained d g a wntrol group

consisting of pregnant women for. (1) combined primary and secondary tubal infertility, (2)

primary tubal infertility, and (3) secondary tubal infertility. Subsequently, adjusted estimates

of risk for primary tubal infertility were also obtained using a control group wnsisting of

women with secondary tubal infertility.

3.7.5.1 General definition of the lagistic mode1

The logistic fiindon takes the general fom:

K logit pr (y = 1 1 x) = log

1 - p r & = l ( x )

where the logit is the logarithm of the odds of an event occurring; y is the response

("dependent") variable, assuming the value y=l whea an outcorne event is present and y=O

when it is absent; a is the interapt of the hctioo; and j?i is the parameter estimate of the dope

of the hct ion for each explanaîory ("independent") variable xi with respect to the log odds of

y=l.

The SAS procedure LOGISTIC wos ured for the multivariate analyses (SAS Institute

Inc. 1989). This command perfîorms multiple logistic regression using the method of

maximum l ikel ihd esthatioû, With the LOGISTIC procedure, variables are treated as

continuous by defâult, unless their possible values are limited to O and 1, in which case they are

handled as binary data. Therefore. sets of dimimy variables were wastnrted to represent

grouped data classifieci into more than two categories. For each classification variable thus

defined, the parameter estimate for each dummy -able is a vaIid estimate of risk relative to

the referent category (defineâ by the class for which ai l dummy variables in the set have the

value zero). as long as all the dummy variables sufncient to describe a classification variable

are included in the model.

3.7.5.2 Interaction terms

Interaction between explanatory variables occurs when the effect of one explanatory

variable on the response variable varies at d i n i t levels of another explanatory variable

(Breslow and Day 1980). Detecting interaction is more diffïcult than detecting main effects.

typically rquiring sample sizes four times as large in order to d e out the presence of

interaction (Breslow and Day 1980). Because we did not consider interaction among

explanatory variables tci be biologidy plausible or important, we did not evaluate the

significance of interaction effects for pairs of variables beyond that of a simple multiplicative

model.

Including highiy correlated ocplanatory variables in a single multiple regrcssion model

may result in unstable parameter edhmtes, a problem that is termed multicoIlineafity (Kahn

and Sempos 1989). We avoided this pmblem opriori by not including in the same model

variab1es that are known or highly suspccted to bc coIlinear (such as ever smoking and cunent

smoking, appendicitis and perforation of the appendix, or income and level of e d d o n ) .

Pairs of variables tbat mi& be r e k d (such as PID and rUCD use, age and WCD use, and

smoking and PD) wete tested for association using the chi squared test and the Spearman nink

correlation coefficient (SAS Iastitute Inc. 1989). If tbe Spearman correlation coefficient was

greater than 0.5, the variable associateci with lower risk of tubal infettility was dropped h m

the model.

3.7.5.4 Mode1 calibraiion and discrimination

The important indices of performance of logistic tegression models are model

discrimimtion and mode1 calibration. Mode1 discriminati . . 'on refers to the abiüty of a model to

predict the occurrence of an event in subjects who actually experience the event. It may be

quantifid using the c-statistic, whicb is equivaient to the area under a receiver operating

characteristic (ROC) curve. A model that predicts an event perfectly has a c-statistic of 1 .O

(A& and Shwartz 1994). Calibration is the extent to which the values predicted by a model

match the a d values, and is a measure of the goodness of fit of a model to a data set

Calibration may be evaluated using the Hosmer and Lemeshow GOOdIless-of-Fit statistic, a chi-

square test of similarity between average and predicted values within subgmups at different

predicted risk of experiencing aa outcome (Lemeshow and Hosmer 1982). A model is well

caiibrated to a data set if the p value for the chi-square test is large (Ash and Shwartz 1994).

3.7.6 Agreement between self-report and medid rtcords

Agreement between ~ e ~ r e p o r t and medicai records for appendectomy status ( n o d ,

infiameci or perforated) was expressed using percent agreement, Speaman rank correlation

coefficient and the kappa d s t i c (SAS Institute Inc. 1989). For measures with more than two

possible values, a weighted kappa vaiue was calculated using quaciratic weighting of non-

wrrelated dues.

3 -7.7 Meas\aes of attributable risk

The attributabIe risk (AR) of exposme (appendice81 perforation) for exposed subjects

(Le., the excess risk of tubal infertility among subjects who had appendiceal Moration, due to

their appendiceai perforation) was calculated using the expression:

where RR is the relative risk of tubai infertility f b m exposure to appendiceai perforation.

The etiologic fraction (EF), also d e d thepopuIation attributable ris& is a measure of

the proportion of disuise (tubal infertility) occuning withi. the entire population thaî can be

attributed to a risk h r Woration of the appendix). It was calcdated using the expression:

where p is the proportion o f individuais in the population exposed îo the ri& fwtor, and RR is

the relative risk (Breslow and Day 1980, Bruzzi 1985).

3.8 Ethical and confidentiality considerations

Approval for this research was obtained h m the University of Toronto Human Subject

Review Commïttee. Institutionai appmval was also obtained by the research ethics boards of

Women's Coilege Hospital, The Toronto Hospital, and the Toronto East General Hospital

(Appendix C).

AU data were kept at a secure facility (the Centre for Research in Women's Heaith).

Completion of questionnaires was entirely voluntary, and study participants were informeci that

there would be no adverse comequences as a result of non-participation, No attempt was made

to contact any study participant by mail, telephone or in person after return of the

questionnaire. Where medical records relating to a previous appendectomy were sought, study

participants were asked to complete and sign a witnesseâ consent form authorking the re1ease

of their medical records h m source hospitais.

RESULTS

The pvrpose of th13 chapter is tu disms thejîndings O* resemch deseribed in the

previous chapter. The pczj'ic objecîives of this chpter me:

1. Tu describe the response rates of stt& subjects, and to review excluded

pmfr-s

2. To &scribe the characteristics of the shbyprticipants

3. Tu discuss the risA of tubal infertility orisingfiom vanous enposures

4. To review the ucauacy of serf-reported qpendectomy dolo

5. To pumtîî the btuden of disease (inlertility-) mrybutable ?O exposaue to perforution

of the appendrx

4.1 Response rates

QuestionaaKes were distributed to pregnant women in the setting of a hospitai obstetric

clinic or physician's office. Of 650 questionnaires made available to pregnant women, 503

were completed and retumed, with d!iIcient data to permit inclusion in the analysis (response

rate 77.4%). Thirteen questionnaires were excluded: twelve because the respondents were

aged l e s than 20 or over 44 years, and one because the respondent's pregnancy was achieved

through in viîro fertilization.

Of 560 mailed questionnaires sent to women with tubal infertility, 261 were returned

sufnciently complete to permit Malysis (overail response rate 46.6%). The response rates for

infertility patients did not vary significantly between centres. The rcsponse rate was 55.0%

(66/120) at The Toronto Hospitai, 51.7% (31/6û) at Maricham-Stouffiille Hospital, 50.W

(95/190) at The LIFE Program at the Toronto East Genexai Hospital, and 36.3% (6911 90) at

NF Caoada. Twelve respondents were absequentiy excluded: six because the respondents

were aged over 44 (2 with primary infertility and 4 with secondary infertifity), and 7 because of

incidental appendectomy (5 with primary infertility and 2 with secondary infertility).

4.2 Characteristics ofthe study subjects

The characteristics of the study abjects are described in Table 1. The age distributions

of pregnant women and women with infertility were cüfferent. Pregnant women were typically

younger (mean and standard deviation for age: 33I4.8 years for pgnant women versus

3 5 . 5 s .9 years for primary infeRility and 36.9i4.5 yeas for secondary infertility). As weu,

the pattern of distribution diff'ered, with the age distribution of pregnant women following an

approximaîely nomial distribution (Figure l), the age distribution of women with primary

infertility skew to the right (Figure 2), and the age distribution of women with secondary

infertility bimodal and skew to the left (Figure 3).

Marital status was g e n d y similar: 87.1 % of pregnant women and 85.5% of women

with infertility were marrieci. However, 6.1% of pregnant women ~ported their marital status

as single (versus 1.6% of infertile womea), and only 4.9% of pregnant women reported living

common law compared to 9.6% of infertile women.

Differences were morc süiking with respect to education and annual household incorne.

Pregnant women were far morc lïkely than were womm with infertility ta have less than a high

school education (1 1.0% versus 4.4%). As weli, pregnant womm were more Iürely to be in the

lowest income class, with 29.6% reporting annual household incorne 430,000 in 1997

compared to 11 2% of women with infertility.

There was a large difference in the number of women who had undergone previous

surgery: 20.4% of pregnant women rrported pnor abdomiruil or pelvic q e r y compared to

70.7% of infertile women. Most ofthe operations in pregnaut women were cesarean secti011~.

whereas most of the procedures in the gmup of infèrtile women w m infertility-related, and

included lapan,scopy, surgery for ectopic pgnancy, tuboplasty, ovariau cystectomy and

uterine myomectomy. Many women with Uifertility had multiple procedures.

4.3 Estimates of nsk of tubai infertility - Pregnant controls

4.3.1 Crudeesthaksofrislc

The ri& of tubal infertility resulting h m exposures to various risk factors was first

determined by calculating cmde (unadjusteci) odds ratios (OR) and 95% confidence intemals

(CI) for each exposure using logistic regmion. Estimates of the OR are sbtisticaüy

significant at the @.OS level if the 95% CI exclude 1.0, the magnitude of risk associatecl with

no effect Since these estimates of risk were performed as an exploratory anaiysis of the data,

no correction was made for multiple comparisons. The cnde ORS and 95% CI are presented in

Tables II-IV.

Ri& estimates were dcdated for d i B i n t case groups. Table II compares ail women

with infertility (primary and seconàary combined) to pregaent women, and the estimates of

risk for each exponm may be interpreted as the ri& of any type of tubal infertility. Tables III

and N kt estimates of nsk for (rrspectively) primary and secondary tubal infertility compared

to pregnant controls.

All of the exposures analyzed were risk f-rs for any (primary or secondary) tubal

infertility (Table II). Increased age had a striking dose-response relationslip: relative to the

lowest age class (20-29). the ri& of infertiiity assaciat#l with age 30-34 was 3.6 (95% CI 2.2-

6.2), and the risk essociated with the highest age class (35-44) was 6.2 (95% CI 3.7-10.5).

Women with any type of infertiiity were aIso more likely to have a "middle" Ievel of educaîion

(greater than high school but no imiversity) than pregnant women (OR 3.3,95% CI 1.76.6).

Higher muai howhold incorne was 8ssociaîexi with tubal i n f d t y : beiig in the middle

incorne class was associated with a risk of 3.1 (95% CI 1.949). and being in the highest

income class was associated with an inmase in the risk of tubal infertility of 3.5 (95% CI 2.2-

5.6).

Both ever- and climnt smoking were significant risk factors for either type of

infertility, with evidence of a dose-ne~pdnse relationship with extent of smoking. The

magnitude of ri& associated with smoking was large: current smoking i n d the ri& of

tubal idertility by 4.5 (95% CI 2.7-7.6), and ever smoking increased this risL by 3.4 (95% CI

2.5-4.7).

A history of pelvic Mammatory disease was a strong risk factor. PID was associateci

with an OR of 8.6 (95% CI 5.413.7). Endometriosis was aiso a strong predictor of tubal

infertility, increasing the risk by 6.2 (95% CI 3.4-1 1.5). Both ever use of oral

contraceptives (OR 2.4,95% CI 1.7-3.4) and IUCD (OR 3.0,95% CI 1.7-5.1) were associated

with increase in ri&.

Any appendectomy was aosociated with a smali but signiscant increase in crude risk

(OR 2.1,95% CI 1.1-3.8). whereas the risk h m pcrforation of the appendix sppeared ta be

more marked, with an unadjusteci oâds ratio of 3.6 (95% CI, 1.2-1 1 .O).

Cnide estimates of ri& of primay tubai infertility are given in Table III. The findings

are generally similar to those for primary or seçondary infertility given above, 4 t h some

notable exceptions. The d a t i o n with i n d age was less prominent, with a crude odds

ratio of 4.7 (95% CI 2.3-9.3) for the highest age class. PID had a weaker relationship to

primary tubal infertility (OR 62,95% CI 3 .Cl 1 .O) and endometriosis had a stronger

relationship to primary tubal infertility (OR 7.8,95% CI 3 . M 5.6) than to any type of tubal

infertility. Appendicitis and appendiceai perforation were a s o c i d with sWar de- of

risk.

Cnide estimates of risk of secondary tubal infertility are given in Table IV. The most

StCÜMg ciifferences in risk for this group compareci to the previous two were the m e r effeçt

of increased age (OR for being in the highest age class 8.1,95% CI 3.9-16.8), PID (OR 1 1 .O,

95% CI 6.51 8S), and IUCD use (OR 4.1,95% CI 2.2-7.5).

For women with secondary infertility, additional exposurrs were examineci:

history of thetapeutic abortion, other pregnancy loss (miscaniage), and ectopic pregnancy.

Both therapeutic abortion (OR 3.1,95% CI 2.04.8) and pregnancy loss (OR 2.9,95% CI 2.0-

4.4) were moderaîe risk fators. A bistory of ectopic pregnancy was highly correlated with

secondary infertility, with an OR of 107.5 (95% CI 32.8-352.4).

4.3.2 Adjusted estimates of risk

In order to control for the effects of wnfounding exposures on the relationship between

appendiceal disease and tubal idertility, logistic regression models were developed to derive

adjusted estimates of the risk of infertility from any appendectomy, nonperforaîed appendicitis,

and appendiceal perforaton The results of tbe multivsriate logistic regrasion analyses ushg

pregnant controls are summarized in Tables V-W. The data in the tables include estimates of

crude and adjusted odds ratios with their 95% codidence intervals, as well as the measures of

diScfiLnination end calibraiion of the model, and the p values for the parameter estimates Up,) of

the explanatory (exposure) variables for each model.

Table V Summarues the adysis for combined primary and secondary infertility.

Separate logistic regression models were developed for each of the following rrspoase

variables (relative to never having had an qpmkîorny): (1) any appendectomy, (2)

appendectomy without perforation, and (3) appendectomy with perforation. Each model

included the foiiowing avariates: age, annuai income, smoking sta!us, Pm, endometriosis,

oral contraceptive use, and IUCD use. h l of education was not included because of

signiscant correlation with annual income (Spearman d . 5 2 , pi0.001). There was no

evidence of sipifiant comîations between any otha paiff of variables that were examined.

All of the models had excellent discriminati . . 'on (c-statistic=û.83) and masonable dbration U,

values for Hosmer and Lemeshow Goodness+f-Fit Test 0.15 to 0.54).

nie adjustecl increase in the risk of infertility was 1.6 (95% CI 0.û-3.4) for any

appendectomy, 1.2 (95% CI 0.5-3-2) for appendectomy without perforation, and 2.4 (95% CI

0.7-8.1) for perforation.. None of the parameter eshates were significant nt the @.OS level,

as represented by the p values for the Wald 2 test of the n d hypthesis of BpO (An alternative

test of the signiscance of the ri& estimates at the p4.05 levd is the detemination of whether

the 95% CIs exclude 1.0).

Table VI nimmarizes the resuits of the logistic regression models consiructed to

estimate the adjusted risk of primary tubal infertility h m exposure to diffetent types of

appendectomy. The modeis included the same covariates as those developed for the analyses

in Table V, and demomtmteâ good diocrimination (c-staîid~O.80) and d i ra t ion (Hosmer

and Lemeshow p 0.47 to 0.94). Thc adjusted ri& of primary tuba1 i n f d t y was 1.8 (95% CI

O.W.2) h m any appendectomy, 1.9 (95% CI 0.7-5.4) h m appendectomy without

perforation, and 1.5 (95% CI 0.4-6.4) fbm perforation.

Table W s u . the atialysis of adjusted ri& of secondary tubal infkdity. The

moàels used the same covariates as for the previous two adyses, in addition to the

explanaiory variables: therapeutic abortion, miscarriage, d -pic pregnancy. Ail regression

models had excellent discrhïmïon (c-staîistic=0.91 to 0.92) and dbration to the data

(Hosmer and Lemeshow p values 0.55 to 0.84). Once again, none of the parameter estimates

for the exponin variables was compatible with a stMistically significant eEect size. The

adjusted risk of secondaty tubal infertility was 0.6 (95% CI 02-2.3) h m any appendectomy,

0.2 (95% CI O. 1-1 -4) h m appendectomy without perforation, and 1.8 (95% CI 0.3-1 0.7) h m

perforation.

Adjusted risk estimates for aii exponne variables (including variables other than

appendiceal disease) are s w m d z d in Tables VIII-X Each table Lists crude and adjusted

odds ratios for d the important risk f e r s for tubal infertility? using perforation of the

appendix as the variable for appendiceai diseruse. Adjustecl ri& estimates for cornbined

primary and secondary infertility are iisted in Table VIII. A h adjustment for dl other

variables, oral contraceptive use, IUCD use, a ~ u a l inwme pater than $6û,000, and

perforation of the appendix are not significant risk fkctors. Age, smoking statu, pelvic

idammatory h a s e aad endometriosis remain stmng ri& fiaciors for tubal infertility. Table

Ix Iists adjusted odds ratios for primary tubal infertjlity, and Table X üsts adjusted odds ratios

for secondary tubal idiercility. The effects of simultaneous adjustment for all infertility ri&

factors are simiiar to those observeci in Table VIII.

The effcfts of individual confouuding variables on cstimstes of risk h m perforation of

the appendix are describeci in Table XL This table presents the d t s of a series of r e g s o n

models developeà to determine the effccts of the most iduential confomâers of the

relationslip between perforation of the appendix and primary aibal infertility. Sequentid

models retain the confounding exposurc variable that results in the largest change in effî size

(odds ratio of idertiiity h m pdoration of the agpendix). Conttolling for age aione decreases

the crude odds ratio h m 3.5 (95% CI 0.9 - 13.1) to 2.1 (95% CI 0.5 - 8.4). Including

exposure to pelvic infiammatory disease in addition to age fiirther reduces the odds ratio to 1.8

(95% CI 0.4 - 7.4). Adjustment for age, pelvic inflammstnry di- and smoking status

results in an odds ratio of 1.6 (95% CI 0.4 - 7.0). Inclusion of additional exposure variables

does not have a large impact on estimates of risk.

4.4 Estimates of risk of hibal infertility - Controls with secondary infertility

4.4.1 Unadjusted estimates of risk

Table XII Summarizes the d j u s t e d risk estimates for exposures using women with

primary infertility as the case group and women with mndary infertility as the control group.

For this set of comparisons, aLl subjects who had an appendectomy after age 18 w m excluded,

in order to be reasonably certain thai all controls with secondary infertility who had a bistory of

appendicitis did not have tubal occlusion immediately a h this exposure. Therefore, ali

control women with an exposurr to appendicitis had patent failopian tubes for a period of the

prior to developing tubai occlusion, as evidenced by the ability to btcome pregnant by

conventional means before seeking treatment for tubal infértiiity. Estimates of risk deriveci

h m this analysis can be interpreted as the risk of &veIoping tubal occlusion as an immediate

consequence of exposwe to chiIrOrood clppendectomy.

The characteristics of the subjects in the two groups were very simüar with respect to

their demographic variables. There was a slight ciifferaice in age distribution. The p u p of

women with secondary i n f d t y had a slightly higher mean age (36.9 vs. 35.5, p-0.01), but a

large proportion (28.6%) of this group w m in tbe highest age c las (40-44). The riskr of hibal

infertility associated with increased age, smoking, PD, endometriosis, oral contraceptive use

and IUCD use were all non-signifiant, in contrast to the crude analyses using pregnant

controls. This is expected, since these exposures are aU risk factors thaî are etiologically

related to both primary and seconâary tubai infertility.

For this contrast of case and conîrol groups, the crude risks of appendicitis and

appendiceal perforation were s d a than those obtained using pregnant controls. The ri& of

tubal infedity was 1.3 (95% CI 0 . 5 3 -3) for any appendectorny, 1.8 (95% CI 0.56.4) for

appendectomy without perforation, and 0.9 (95% CI 0.2-3.5) for perforation of the appendix.

4.4.2 Adjusted esîkmks of ri&

Table Xm describes the resuits of the multiple logistic regression anaiysis of the nsk of

primary tubal infertility, using women with secondary tubal infertility as controls. Three

different models were developed to estimate aâjusted risks h m Miren t types of

appendectomy. AU models included covariates to adjust for the effects of age, annuai incorne,

smoking status, PID, endometriosis, oral contraceptive use, and IUCD use. The c-stetistics for

the models mged h m 0.65 to 0.66, and the p valws for the Hosrner and Lemeshow staîidics

ranged h m 0.51 to 0.89, indicaîing reasonably good discrimination and calibraîioa The

effect sizes wem miall and not statisticaiiy signifiant The adj& estimates of the risk of

primary tubal infertility w m 1.1 (95% CI 0.4-3.0) for sny appendectomy, 2.1 (95% CI 0.5-

8.8) for appendectomy without perforaiion, and 0.6 (95% CI 0.1-2.3) for Horation of the

appendix. Table XIV describes the adjustcd e f f i of aii other infertility ri& b r s ,

including perforation of the appcndix as the variable for appendiceal disaise. No signifiant

differences were observeà between crude and adjusîed esfba&s of risk for any of the other

exposure variables,

4.5 Accuracy of self-reportecl appendiceai status

Of 42 women who reporteci a non-incidental appendectomy, we were able to rrtneve

medical records for 13 (3 1 .OO/o). Most records were not retrievable because: (1) respondents

did not satisfactorily complete the consent for release of meâical records (n=7), (2) information

provided by respondents did not allow identification of the hospital where the appendectomy

was reportedly pediormed (n=2), (3) appendectomies were penormed outside Canada and the

United States (n=14), or (4) appendectomies wae perfiormeù in the remote past and records

were no longer king held (n=7). Medicai records were available for seven of the 14

respondents Who reporteci appendiceal perforation (50%)).

Seven records were h m women with infertility and six were h m pregnant women.

Patient self-report comlateâ extrrmely well with medicai rrcords w l e XV). In fa& review

of medical records did not lead to a change of category for appendix s t a t u in any subject The

single discrepancy was for a study participant with primary infertility who nported her

appendix as inflmed, wtrereps review of her medicai records sbowed that h a appendix was

normal. Be- this exposure was st i i i categorized 'appendectomy, not for perforation of the

appendix,' the exposure category remained unchangeci.

The indices of agreement for this srnail sample were quite good The c d e agreement

was 923%, the Spearman correlation coefficient was 0.97, and the weighted kappa was 0.87

(95% CI 0.61-1 .O).

4.6 Attribuîable risk and etiologic M o n

Measures of the attributable risk and the ''burden of iilness" due to exposure to a risk

factor are usefiil because they put into perspective the effect of that risk factor on a population

of individuals a . risk. Estimates of risk used in caicuiathg these masures were taken h m

Table Vm, which sumrnarizcs the adjusted risk of various risk factors for any type of tubai

infertiiity. The adjusted odds ratio for perforation of the appendix was 2.4. The value for the

proportion of individuais in the population exposed to perforation of the appendix was derived

from the population-basxi mode1 described in Chapter 3 (Methods, 3.7.1.1 Modeling the

cumulative probability of appendicitis) which was 1 .W.

The attrriutable ri& (AR) of exposure in exposed subjects for an odds ratio of 2.4 is

58.3%. Therefore, assuming a moderate risk of infertility as a result of perforation, even in

wornen who have a perforated appendix fuliy 41.7% of the exces risk of infertility will be due

to factors other than perforation under the present assumptions.

The etiologic fiaction (EF) orpopulation attributable risk, is 1.4% when the proportion

of women with a perforated appendix is 1.00/a, and the relative ri& of tubal infertility is 2.4.

Therefore, even if perforation of the appendix is a moderate risk factor for iafertility, it

accounts for approximateIy 1.4% of ali tubal infertility. in contrast, using the cstimate of the

odàs ratio for tubai infertility h m PID of 6.4 h m Table VIII, the etiologic fiaction of tubal

infertility due to P D is 33.2% (ushg chlamydia1 semlogy pmalence data reporteci by Gaydos

(1 998)). This value is liicely to be an underestimate since the Wetime prevaleme of P D may

be even higher.

DISCUSSION

The prapose of th& chapter i$ to d h m s the strengths and limitations of the research

reviewed in the prmow chapters, and to desmcnbe the inrpIicaîions of the flndings. The

spectjlc objectives of th& chapter me:

1. To summarùe the shrtiyfindings

2- Tu intepret the findings in the context of previow resemch in this ama

3. To discuss the Iiwaitutionr of the stu& & s i ,

4. To discuss the inipwance of the snuIj, r e d t s

5. To suggest directionsforj%rther research

5.1 Summary of d t s

This study did not provide evidence of a substantial increase in the risk of female tubal

infertility as a d t of perforation of the appendix. Using a wntrol gmup of pregnant women,

the adjusted ri& of primary tubai infertility h m appendiceal perforation was 1.5 (95% CI 0.4-

6.4). Using a wntrol group consisting of women with secondary infertility, the adjusted risk of

tubal infèrtility h m appendiceal perforation was 0.6 (95% CI 0.1-2.3). DBerent eEect sizes

were observed with diffmnt analyses, demonstrathg that cstimPtes of the risk of infertility

derived from case-control research are sensitive to the choice of the control p u p . Self-report

of status of the appendix was extremely accurate compared to medical records.

5.2 Interpretation of the resuits

Eshmtes of risk derived fiom the analysis of casecontrol studies must be interpreted

with caution. Since wen the most rigorous study designs are prone to bias, causal inference

h m casecontrol data mut not be iimited to a simple inkqmtation of an odds ratio and its

confidence intervals. Critical appraisal of îjndings h m case-contn,l research nquirrs an

assessment of the interna1 validity of the study's methodoIogy in addition to an assessment of

the size of the effect.

An important observation arisïng h m the resuits of this study is that the esthate of

nsk derived nom the analysis of case-control data can Vary depending on the choice of a

control group. For example, when women with primary infertility were used as a case series

for cornparison with pregnant controls, the crude OR for tubal infertility was 3.5 (95% CI 0.9-

13. l), and the adjusteü OR was 1.5 (95% CI 0.44.4). Although neither estimate of the OR

indicates a statisticaiiy simiificant efféct, the data used to derive both estimates are ceriainly

consistent with the possibility of an effkct, including a large efféct, as indicated by the values

for the upper limits of the 95% CI of 13.1 and 6.4.

The effect size markedly diminished after adjustment for a number of important

confounding variables, including age, smoking, Pm, incorne level and endometriosis.

Therefore, much of the effect of perforation suggested by the d e d y s i s was related to the

eEects of the confounding variables, and it diminished a h controllhg for these effects. The

confounders with the largest impact on adjusted ri& estimates were age, bistory of PID and

smoking stanis. Of these variables, age was the most infïuential, reducing the aude OR of

primary tubal infertility due to Horation of the appendix h m 3.5 (95% CI 0.9 - 13.1) to 2.1

(0.5 - 8.4). Clearly, pregnant women (sampled h m prenatal office visits) do not have

substantial comparability to women with tubai infertility (sampled h m in vitro fertilhtion

clinics) with respect to important determhmts of infertility. When non-comparablity of cases

and controls exkts, then se1ection bias must be considered as a threat ta the internai validity of

the study.

When women with secondary infertiiity were used as the control p u p , the effkct of

perforation of the appendix diminish . . . ed finzher- The crude OR was 0 9 (95% CI 0.2-3.5), and

the adjusted OR was 0.6 (95% CI 0.1-2.3)- Again the estimates of effect size are not

statisticaiîy signincant at the @.OS Ievel and the magnitude of the point estimate is close to

1 .o.

With respect to the important determinants of tubai infertiiity, women with secondary

infertility are very similar to women with primary infertiiity. Clearly, this holds tnre because

most of the nsk factors for primay tubal Mertility are also ri& factors for secondary tubai

infertility. Furthemore, virtually aU of these risk factors are exposures thai extend over

prolonged periods of time (such as smoking, endometriosis, oral contraceptive or IUCD use),

or have a recurring course (such as endometriosis and pelvic inflammntory discase).

Perforation of the appendix, however, is an acute, finite exposure, and any motbidity

attributable to a perforatecl appendix s W d becorne manifést shody a f k the actuai event.

For analyses using women with secondary tubal infértility as controls, we assumed that if a

period of fertility folIows the event of a perforateci appendix, then subsequent tubal occlusion

should not be attributed to the paforation. Therefore, if exposure to perforation of the

appendix is limited to those expoutes that occur prior to the reprcxiucfive period (defineci for

the purpose of this study as age 18 y-), then women with secondary infertility represent a

valid control group for women with primary infertiiity, since they had evidence of fertility ut-er

the at risk period for the exposure. The fact that no important risk of perforation of the

appendix was observed when this control group was used suggests thaî some of the e f f i

observed in the earlier anaiysis may be ascribed to seledon bias.

As d i d pmiously, Mueiier and colleagues (1986) had identifiecl appendiceal

perforation as a risk firtor for tubal infertility (adjusteci OR 4.8,95% CI 1.5-14.9). However,

these investigaiors found that perforation was a ri& factor for secondary infèrtility as well

(adjusteci OR 3.2,95% CI 1.1-9.6). If women with sewndary infertility had been used as a

control group for Mueiïer's cases w i i primay tubai infertility, the effect of perforation woufd

have disappeared. Mueiier and her coileagues observed that ail but one of the perforations

among women with secondary infedty occuind prior to an earlier pregnancy, but felt that

these peiforations couid stili be interpreted as causai, since they may have led to tubd

dysfimction that graduaily progressed over the (Muelier 1986).

There is no highquality literature on the biological or clhical behaviour of peritoneal

adhesions. There have been a number of clinical studies published in the Gynecology and

Idertility literaîure that suggest that peritubal adhesions can indeed becorne more severe over

time (DeCherney and Mezer 1984, Operative Laparoscopy Study ûmup 199 1). These d e s

examined the operative findings at ~sccond-look" laparoscopy (lapamscopy @O&

following a previous lapamtomy or lapamscopy to evaluate stnictures in the abdomen and

pelvis) following tuboplasty or lysis of pelvic adhesions. However, the evaluation of adhesions

is a subjective measmement, and b therefore subject to bias. As weii, patients who undergo

tuboplasty for peritubaî adhesions have extensive surgery involving the fdopian tubes, and

many &O have chronic pelvic inflammaîory di- or endometriosis, which can lead to

progressive tubal adhesions due to ongoing disease d v i t y .

It ïs not clear that these findings wouid be generalizsble to the case of adhesions caused

by an exposure to appendicitis. Following a limiteci inûammaîory p m , peritoneal

adhesions initially fonn as infiammatory, vascular "fibrinous" adhesions, and mature over tirne

into fine %brousn adhesions (Eih 1982). The majority of non-infertility relaîeâ complications

of peritoneal adhesions due to appendicitis, suçh as sdhcave intestinai obsiruction, tend to

occur shortly after the appendectomy (Ahlberg 1997).

Ifindeed the historicai reIationship between pcrforati0on of the appendix and tubai

infertility has been due to the effects of bias or confounding, the foiiowing question arises:

which factors are fiinctioning as confoders or soutces of bias? The ody known risk factors

for appendicitis and appendiceal perforation am age and sen Sex cannot be a confounder in

this study, and we controlled for the effects of age by adjustment in the multivariaîe analysis.

The variables that are cesponsible for residuat bias and wnfounding are liLely the

unmeasured (or unmeasurab1e) determinants of oeelring various types of health seNices, and of

reporting various health-relaîed exposames. We found thai the p u p of women who seek

treatment for tubal infertility has distinctive characteristics. In our analysis, these subjects

tended to be older, better educated, and wealthier than pregnant women. These observations

have k e n corroborated in reports of cross-sectional sweys of the use of infertility services

(Schmidt 1995% Hïrsch and M o s b 1987). It is an interesthg observation that cigarette

smoking was more wmmon among women with tuM infertility, even though they had higher

average incornes and levels of ducation. In most d e s on the epidemiology of cigarette

smoking, there is an inverse relationship with detenninants of higher socioeconomic status

(Townsend 1994). This serves as a M e r indication of the non-representativeness of women

receiving treatment for tubal infertility.

It is possible that some of these determinana affect access to heaith services, or the

accuracy of reporting expo- to adverse h d t h events. Women who receiveû treaûnent for

appendicitis may k more likely to seek infertility trtatment, based on increased access to

services and contact with the health care system. As welî, they might m a exgosure to

perforateci appendicitis more accumtely than other individuais. Both of these possibilities

would bias a study towaràs finding an association.

There are other ways thet the rehtionship between Snfertility-related variables and

perforation of the appendix may interact in a complex manner- For example, a surgeon treating

a woman with amte abdominal pain mi@ k less likely to suspect appendicitis if she had a

history of endometriosis, pelnf inflammatory disease, or chronic pelvic pain, and might be less

Wely to proceed with an immcdiate appendectorny. ifpatients with a history of PID or

endometriosis are obse~ed in hospital without undergoing surgery for longer periods of time

than women without a history of thse conditions, then it is possible that a larger proportion

wiii end up with an appendiceal perforation. However, because PID and endometriosis are

independently relateti to tubai inf i î ty , they would act as confounding variables in such an

association

The two approaches we used to evaluate the relationship between perforation of the

appendix and tubal idertility may k viewed as complementary. There was a trade-off

between avoidiag confounding by exposure at the ri& of increasing selection bias @y using

pregnant controls), and avoiding selcction bias at the expense of possibly d o u n d i n g by

detemimnts of disease (by using controls with secondary tubal inferti1ity)- The fact that a

substantial risk of tubal infertility h m appendiceal perforation was not observed using either

approach suggests that not detecâing an association was not a conse~uence of only selection

bias or confounding.

5.3 Limitations of the study

As with di observational this study has Iimitations that must be c o n s i d d

when interpreting our fïndings. Even though we aîtempted to identify and reduce possiile

biasps and contro1 for confounding, therc are potentiai -les that we were u n a m of that

may affect the validity of the results.

As discussed earlier, selection bias is a significant problem in casecontrol studies. The

valid selection of controls for cases was hampered by incomplete case ascertainment. We

attempted to explore the effect of diffmnces ktween cases and controls with respect to the

u n m d determinana of infertility tteatment-seeking by repeathg the anaiysis using

controls with secondary infertility, who arc similar to cases with respect to these detenninants.

However, this approach may aloo pose problems, because if perforation of the appendix is a

bona fide determinant of risk for secondary tubal infertility, then the effect on primary tubal

infertility wiil be uuderestimated. This problem is analogous to overmatching (Breslow and

Day 1980): if cases and controls are inadvertently YmatchedW on a variable stmngly issociated

with the disease, then the observed eff- wiU be biased towards the nuii hypothesis.

Whenever a study fails to mject the nul1 hypothesis of no effect, one must consider

whether the study had enough statisticai power to d e out effkcts of interest if they existeci.

For some of the analyses that did not detect a sipifkant cffkt, thm was limited powa to d e

out moderate effects, evidenced by the wide 95% confidence intervals. The cornparison of

women with primary tubal infertiiity with pregnant controis, which found an OR for

appendiceai perforation of 1.5 (95% CI 0.444). had 57.6% power to d e out an OR of 4.0.

The cornparison of cases with primary tubal infertility and controis with secondary tubal

infertility, which found an a d j d ri& h m pedoration of 0.6 (0.1-23). had 75.7% power to

d e out an OR of 4.0, and 51.3% power to rule out an OR of 3.0. Therefore, there is a

significatlt chance that this study's negative conclusion is a Type II error, or an erroneous

failure to reject the null hypothesis.

A possible source of bias is the differentiai responsc rates in m g questionnaires

between pregnant women and women with infertility. Ssbjects who complete and r e m

n w e y questionnaires may be systematidy different h m those who do not. The mode of

administration of the questioxmaires to infertile women and to pregnant women was different

Pregnant women wen asked to complete and retum questionnaires at an office or clinic setting.

This method was used to try to d u c e study costs, and ta improve response rates. However,

this method was ineffective in d t i n g enough study abjects with tubai i n f d t y , because

of the limited number of women who could be sarnpled prospectively in a clinic setîïng. W e

therefore maileci questionnaires to women who had been treated for tubai infertility over the

previous two years, in order to increase the number of study participants.

If infertile women who had a history of appendiceai paforation w m less Ucely to

retum questionnaires than were other women, then the d t i n g bias would weaken the

strength of the association. Although unükely, such a phenornenon could explain the lack of

an effect between dora t ion of the -dix and tubal infertijity obsetved here.

Another source of bias could arise through d i f f i c e in ascertainment of exposures

between cases and controls. The comparable accuracy principle (Wacholder 1992a) requires

that exposure measmernent ern,r be non-differential between cases and controis. W e

attempted to vaiïdaîe ail reportcd exposures to appendicitis, but it was impossible to validate

non-reporthg of exposures. Ifcontrols under-teport exposure to appendicitis compared to

cases, a study would be biased towards fincihg a spurious association. We did not valiâate

exposurts to other important detenninants of tubai infertility, and there may have been

important d i f f m c e s in the accuracy of seKreport for these exposaneS. I n f d e women may

better r e d previous conditions that are risk fàctors for infertility, such as endometnosis and

pelvic inflammatnry disease, since t k y may have been adcd aboui these wnditions as pert of

their idertility waiuation. Because women with idertiiity are extremely likely to have had a

diagnostic laparoscopy as part of the infertility evaluation, they rnay also be more likely to

receive a diagnosis of asymptomatic endometriosis or PID due to "detedon" or "workup"

b i s . Better recd of these confounding variables by infertile women compand to pregnant

women would Iead to smailer adjusted eshates of ri& for infertiiity h m appendiceai

perforation.

Importantly, Merential emr in m e n t of exposures is a much bigger problem

in comparisons involving pregnant women and infertile womea For cornparisons iimited to

women with primary and secondary tubal infertility, 8cctsracy would be expected to be

comparable with respect to m e n t of exposures.

5.4 Importance of the study kdings

The conclusions of this study have implications for a number of areas. However,

because of the nature of observationai research, one can never rule out bias or confounding as

sources of error in a study's finciinp. Therefore, any conclusions ârawn must be conservative,

and modifications in clinid practice or hdth care poiicy shodd never be msde on the b i s

of a single observational stuây* Each additional piece of observatiod research on associations

shouid be viewed as an addition to the larger body of evidence.

We did not find evidence for a mbstantial causal relationship between pedoration of

the appendix and tubal infertility. If appendiceal Woration does nut signin:cantly increase the

risk of tubal infertility, then cihicians should not be overly influenad by considerations of

fuhae fertility when deciding whether or not to pcrform an appendectomy on a young wornan

with suspected appendicitis. As WU, young women who have had surgezy for a perforated

appendix can be given accurate prognostic information. If they do not have other risk factors

for Ilifertility, their pmbability of developing tubai i n f d t y solely on the b i s of a perforateci

appendix is low. In fat , the relationship between perforation and secondary tubal infertility is

just as strong as thaî for primary tubal infertility. Therefore, of women who might develop

idertility because of appendiceal perforation, they are just as likely as not to have a period of

fertiiity before the development of tubal occlusion. If a causal relationship between pcdoration

and secondary tubal infertility is believed, then young women who have a pefiorated appendix

and who are planning to have a f d y might k advised not to postpone childbearing, in order

to avoid the potentiai problem of delayed tubai infertility.

Another implication of these findings is in the area of medical-legal wnsiderations.

Even in women with tubal infertility who have had a perforateci appendix, the excess ri&

attributable to the perforation is 58% (the attributable ri&) if the odds ratio is 2.4 ( h m Table

vm). There is a substantial possibüity that the developnent of infertility in such cases rnight

have ken the result of other ri& factors* Perforaîion of the appendix caused by undue delay in

the treatment of appendicitis m o t necessarily be implicaîed as the cause of subsequent

infertility.

Perhaps the most important ramification of our fïndings is a better understanding of the

relative importance ofthe risks associaîeà wîth the différent detenninaots of tubal infertility.

The degree of ri& of an exposure must be considercd in the contact of the prevalence of that

risk factor compared to the prevaience of otba risk factors for a condition of interest. There

are a number of risk factors for tubal infertility. Some of these risk factors, such as increased

age, P D and endometriosis, are very much stronger ri& fstors than perforation of the

appendix. As well, these rïsk factors arc more prevaient than appendiceai pe15oraton.

Therefore, of the "universe" of tubal infértility that exists, comparatively M e c m be explaineci

by perforation of the eppendix. This is evidenced by the etiologic fraction of 1.4%. Even if

major alterations in clinid practice are able to greatly reduce the case-perforation rate of acute

appendicitis, it is unlitely that any effat on the pmvalence of aibal infertiiity wodd be

observed.

5.5 Directionsforfùrtherresearch

Our study highlights many of the challenges of perfonniag epidemiologic research to

evduate risk factors. Typically, the adverse events or expo-s evaluated with observational

methods are rame. In studying rare cvents, very large sample sizes are tequired in order to have

sutaicient power to truiy mie out effects, even though a study may not dernonstrate evidence of

an efEect that is staîisticaliy significant For an exposure as rare as perloratïon of the appendix

in non-infertile controls, good s&tistical power to d e out small risks would muire a sample

size at least three times larger than ours. Any fûturc study should &ive to achieve a larger

sample size.

Another challenge we encountered was validation of reporteci exposures using medical

records. Although we did not detect evidence of signifïcant e m r in seEreport, we were only

able to retrieve rewrds for a minority of exposed patients. The difncuity in fïnding medical

records for appendectomies is compounded by the fhct that many events occurred in non-

English spealirig countria or many yeam in the pst, and hospital health records departments

do not hold records indefbitely. As well, we did not validate exposure to risk factors other

than perforation of the appendix, cven though theh might have been signiiicant inaccuracy in

sesreport for exposures such as pelvic infiammatory disease and endometriosis. Future

studies should attempt to vaiidate cxposures for which differential enor might be a source of

bias, although this would be methodologically challenging.

We found that age, smoking status, and a history of PID were important confounders of

the relationship between perforation of the appendix and tubai infertility. Adjusmient for these

variables resuIted in a large change fiom the cnide odds ratio for perforation of the appendix,

indicating large variabiiity in these characteristics between cases and controis. It is unlikely

that a wntrol group that is similar to cases with tubal infertiiîty with respect to a hisbry of P D

could be assembled, if the control group consists of women without tubal idertility. However,

further studies codd improve the efficiency of the analysis of ri& by mufching subjects by age

(and possibly smoking status). This will m . the variabiiity between cornparison groups

with respect to these variables, and shodd d t in crude esbates of risk that are closet to

their adjusted values.

A method that muid be used to fi3Ither study the relationsbip between perforation of the

appendix and tubal infertility is linkage of medicai records h m admm&&~ 0 . 've &abases.

Such a study could foiiow young women haviag a pedorated appendix and a cornparison p u p

of women who did not have an appendectomy, and eva1mt-e the proportion of women in each

p u p who have a delivay or investigation for infertility. This approach would have the

advantage of a large, population-based sarnple. However, sigiüncaot aror is possible in

coding for perforation of the appendix. As well, it might k difficult to capture records for

women with tubai infertility using sdministrati . . 've and data on women with tubal

infertiliîy identifieci through procedure or semice claims would be abject to the same types of

seledon bias that we encounteted. I n f o d o n on confounding variables would not be

available. Finally, women who haâ an appendectomy in other coutries or during a period of

time that linkzge of records is not available, would not appear as exposed individuals in a study

using information h m existing &tabases. A prospective cohort study using conventional

follow-up methods would be even more resource-intensive and methodologicaily difncult

Finally, a challenge that is ubiquitous in case-control research is that of fïnding a

control group that is similar to the cases with respect to important deteminana of disease risk,

but is not "over-matched" to the case group because of codiounding by exposute to

unmeasured determinants of disease. Research on risk factors for tuba infertility poses

especidly difncult obstacles, due to the problems of incornplete case ascertainment, and the

identification of controls who do not have infertility and are sampled in a mamer that is similar

to the cases.

5.6 Summary

We did not f h d evidence for a substantial effect of perforation of the appendix on

femaie tubal iafertility. However, an effect canoot be ruled out with d t y because of

iimited statisticai power, and because of the possible cffea~ of b i s and confounding.

ObservaîionaI research on risk factors for tubal infertility is pl+ by the potential

problems of incomplete m e n t of cases (and subsequent bias h m selection of

controis), and dinerential miscldcation of recalled exposures (and subsecpent recali bias).

The effect of incomplete case m e n t was explod by using différent groups of

controls, and the e&ct of dinerential exposure misciassification was atplored by evaluafing

the 8ccuracy self-report& appendectomy exposiaes.

The use of different control groups led to mirent estimata of the effkct of

appendiceai perforation, suggesting that selection bias might be a source of error in case-

cuntrol studies of this association. Although th- was no evidence of ovcr-rcpor&ing of

appendiceal Moration, under-reponing by pregnaat women remains a possible source of bias.

Although m>y efféct of appendiceal perforation on subsequent tubai infertility caunot be

d e d out with certainty, the size of any plausible effcct is unWrely to be large. T h in the

context of other risk factors for tubal infertiiity, variations in the case-pdoration rate of

appendicitis are unükely to have a large effect on the prevalence of tubal infertility.

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TABLES

Table 1

Charrrcteristics of the Study Subjeets

Prtgnaat Infertile womcn women All 1'Infii.ality 2.Infcitility

Characteristic N49û N=249 N416 N=133

Age - no. (%) 20-24 25-29 30-34 35-39 40-44

p value (vs. prepnant women)'

Marital status - no. (%) Mamed Cornmon-law Living with a parber Single WiQwed separated Divorced

p value (vs. prtgnant women)t

Education - no. (96) Less than high school High school dipIoma Trade or vocational Community coilege, nursiag University undergraduate University graduate, professional

p value (vs. pngnaut women)*

Annuai household k m e - no. (96) Less thaa S30,OOO $30,000 to S60,oOO Over Sd0,OOO

p value (vs. ptepant women)'

Prior surgay - no. (%)

Table II

Cnide Oddr Ratios of Idertiiity (Combineà Prima y and Sceonday)

Variable ('k) ('A) N-249 N 4 W OR 95% CI

Ase 20-29 20 (8.0) 143 (29.2) 1 .O - 30-34 1 03 (4 1.4) 202 (4 12) 3.6 22-62 3544 126 (50.6) 145 (29.6) 62 3.7 - 105

Highest level of bducation < high school diploma 1 1 (4.4) 56 (1 1.4) 1 .O - High ~cbool, ~ ~ U c g c 160 (643) 244 (49.8) 33 1.7 - 6.6 h y \miver~ity 78 (313) 190 (38.8) 2.1 1.0 - 4 2

Annual incorne < S30,oOO 28 (1 1.2) 14s (29.6) 1 .O - S30,000-S60,000 94 (37.8) 159 (32.4) 3.1 1.9 -4.9 > S60,OOO 127 (51.0) 1 86 (3 8.0) 3.5 2.2 - 5.6

Smoking status Never smoked 1 16 (46.6) 366 (74.7) 1 .O - Ever smolrcr 133 (53.4) 124 (253) 3 -4 2.5 - 4.7 Curreat s m ~ k 47 (18.9) 24 (4.9) 4.5 2.7 - 7.6

Pelvic infiammatory disase Never 166 (66.7) 463 (945) 1 .O - Evcr 83 (33.3) 27 (5.5) 8.6 5.4 - 13.7

Endornetriosis No 208 (833) 475 (96.9) 1 .O - Y= 41 (16.5) 15 (3.1) 6 2 3.4 - 115

Oral contraceptive use Never 56 (225) 20 1 (4 1 .O) 1 .O - Ever 193 ( 7 7 3 289 (59.0) 2.4 1.7 - 3.4

IUCD use Never 2 16 (86.7) 466 (95.1) 1 .O - Ever 33 (133) 24 (4.9) 3.0 1.7 -5.1

Appendicitis Never 228 (9 1.6) 469 (95.7) 1 .O - A ~ Y ~ P F - ~ Y 21 (8.4) 21 (43) 2- 1 1.1 -3.8

N o n p e r f i 12 (4.8) 16 (33) 1.5 0.7 - 3 2 Perforateci 9 (3-6) S (1.0) 3.6 12 - 11.0

Table ï ï I

Infertile wowm R e g ~ i t womn (W (W

Variable N-116 N49û OR %?4 CI Age

20129 11 (9-9 143 Q9.2) 1 .O - 30-34 53 (45.7) 202 (412) 3.4 1.7 - 6.8 35-44 52 (44.8) 145 (29.6) 4.7 2.3 - 9 3

Highest level of educaîion < high school diplocna 5 (43) 56 (1 1.4) 1 .O - Hi& ~ c h d , ~ ~ I k g t 70 (60.3) 244 (49.8) 3 2 12-8.3 University 41 (353) 190 (38.8) 2.4 0.9 - 6.4

Annual incorne < $30,000 14 (12.1) 145 (29.6) 1 .O - S30,ooO1S60,ooO 50 (43.1) 159 (32.4) 3 3 1.7 -6.1 > S40mO 52 (44.8) 186 (38.0) 2.9 1 5 -5.4

Smoking status Never smokcd 64 (552) 366 (74.7) 1 .O - Ever smokcr 52 (44.8) 124 (253) 2.4 1.6 - 3.6 CIJnent ~ m o k 21 (18.1) 24 (4.9) 4 3 2 3 - 8.0

Pelvic innammatny d.kasc Never 85 (733) 463 (94.3 1 .O - Evet 3 1 (26.7) 27 (5.5) 6 2 3.6 - 11.0

Endometriosis No 93 (80.2) 475 (96.9) 1 .O - YS 23 (19.8) 15 (3.1) 7.8 3.9 - 15.6

Oral contraceptive use Never 29 (25.0) 201 (4 1 .O) 1 .O - Ever 87 (75.0) 289 (59.0) 2.1 1 3 - 3 3

IUCD use Never 106 (91.4) 466 (95.1) 1 .O - Ever 10 (8.6) 24 (4.9) 1 .8 0.9 - 3.9

Appendicitis Ncver IO5 (905) 469 (95.7) 1 .O - A ~ Y ap~end-Om~ 11 (9-5) 21 (4.3) 2.3 1.1 -5.0

No~pcrforated 7 (6.0) 16 (33) 1.9 0.8 - 4.7 Perforateci 4 ( 3 3 5 (1.0) 3 3 0.9 - 13.1

Table IV

Crude Od& Ratios of Sccondiry Infertility

Infertik womei Pregnait womei ('W

Variable N-133 N49û OR 95% CI Age

2û-29 30-34 35-44

Highest level of aducatiou < higb scbool dipiorna High s c h l coUege University

Annuai income < S30,000 S30,oOO-S60,ûûû > s60,oOO

Smoking status Nevcr smoked Ever smokcr Cuntnt s m o k

Pelvic inihmatq discase Never Ever

Therapeutic abortion Nevcr Ever

preeiruicy Never Ever

Ectopic pregnancy Never Ever

Endometriosis No Yes

Oral contraceptive use Never Ever

WCD use Never Ever

Appendicitis Never A ~ Y appendcctomy

Nonperforateci

Table V

Logistic Regmssion Anaiysis of Risk of Inlertiïity (Combineà Primary and Sccondary) NI739

Rbk Estimatcr Rcprcrrki Diagnostics Hùtory of Cmde Adjrutd* Parameter Modd Appendectomy OR %%CI OR 9S0rCCI ~ > W l l d ~ e3trtbtie H-L?

* Adjusted forage, annual incorne, smoking status, pelvic inflPmmstory disase, endomctriosis. oral contmc@vc use and intra-uterine contraceptive &vice use t p value for Hosmer and Lcmcshow Goodness-oGFit Test

Table VI

Logistic Regrusion Andyris of Risk of Primary ïdertility

Rhk Estimates Regrcssion Diignorticr History of Cmde Adjusttd* Plirmeîer Mode1 Appendcctomy OR %./.CI OR %%CI ~ , W d d 2 ortrtbtk H-L'

Never 1 .O - 1 .O - A ~ Y 23 1.1-5.0 1.8 0.8 -4.2 0.18 0.80 0.47

Nonperforated 1.9 0.8 - 4.7 1.9 0.7 - 5.4 0.22 0.80 0.97 Perforateci 3 0.9-13.1 1.5 0.4 - 6.4 0.58 0.80 0.94

Adjusted for age, annual incorne, smoking status, pclvic in5mmtmy discase, endometriosis, ocai contraceptive use and intra-utcrine cootraceptive device use

p value for Hosmcr and Lemeshow Godncswf-Fit Test

Table VLI

RWkEstimatcs Anaiysis of Parameter Cmdt Adjwtedt Estimates

Variable OR 95% CI OR 95YeCI wald 2 p > ~ a l d 3

20-29 30-34 3 5-44

Annual iucome 430,000 $30,0001$60,000 >560,000

Smoking status Never Ever

Pelvic inflzimmatory Disease Never Ever

Endometriosis No Yes

Oral Contraceptive use Never Ever

IUCD use Never Ever

Perforatecl Appendix No YS 3.6 1 2 - 11.0 2.4 0.7 - 8.1 1.94 O. 16

estatistic for model: 0.83 p value for Hosmer aad Lemeshow GOOdlKSS-of-Fit Test for model: 0.15

t Adjusted for agt, mual incomc, smoking status, pelvic dhuc, cadomctriosis, oral conûaceptivc use, intm-utcrint contraceptive &vice use and hi* of perfontod rppendix

Table IX

RiskEstilmm Analysis of Panuneter Cnde Adjustadt

Variable OR 95Y0 CI OR 9S%CI ~ a l d 2 p>wald$

Annual income 630,000 $30,000-S60.000 >S60,000

Smoking stanis Never Ever

Pelvic I n f l m Discase Never Ever

Endometriosis No Yes

Oral Contraceptive use Never Ever

IUCD use Never Ever

Perforated Appendix No Y ~ s 3.5 0.9 - 13.1 1.5 0.4 - 6.4 030 0.58

c-statistic for model: 0.80 p valut for Hosmer and Lemeshow GooQess4'Fit Test for model: 0.94

t Adjusted for age, annual income, smoking srpais, pcivic disease, endomet"osis, oral contraceptive use, intra-uterine contraceptive device use and hisbry of PCrfOcatcd appcndix

Table X

RiskEstimrrtes Mysis of Parawtcr Crude Adjusteci?

Variable OR 95% CI OR 95%CI Wald 2 PWald 2 Age

20-29 30-34 3 5-44

Annual incorne <$30,ûûû $30,000-S60,000 ~$60,000

Smoking status Never Ever

Pelvic idammatory Discase Never Ever

Endometriosis No Yes

Oral Conüaceptive use Never Ever

WCD use Never Ever

Perforaîed Appendix No Y ~ s 3.8 1.1 - 133 1.8 0 3 - 10.7 0.44 0.5 1

c-statistic for model: 0.92 p value for Hosmer and Lemeshow GooQess-oGF& Test fot modcl: 0.89 Adjusted for age, annual incorne, smoking sÉatus, pclvic discase, endometriosis, oral contraccptive use, intra-uterinc contraceptive &vice use a d history of PerfOCBtCd appcndix

Table XI

Effect of Confounding Vuhblea on Estimatu of the Risk of Primaq Inlertility due to Pdoratioi of the Appendix

N= 606

Od& Ratio Covariatm inchdeà in mode1 (Perforation) 95% CI

Age PID* Incorne Smoking oct use Endometriosis WcD# use

Age+ P D Age+ Smoking Age + OCuse Age+ h o m e Age + Endometriosis Age + ILJCDuse

Age+ PID+ Smoking Age + P D + OC use Age+ P D + Lncome Age + P D + Endodosis Age + P D + IUCD use

Age+ P D + Smoking+ WCDuse 1.6 0.4 - 6.8 Age + P D + Smoking+ OC use 1.6 0.4 - 6.8 Age+ P D + Smoking+ Iacome 1.6 0.4 - 6.6 ~ g e + P D + Smoking+ Endometriosis 1.6 0.4 - 6.7

Table XII

Cmde Odds Ratios, Primry Inftrtüity (Compad to Women with Sceondr y InlcdIity)*

~ r i m a y Inrwuity SU!OII&V ~irtrtüity

Variable (W (W

N-1 15 N-132 OR 95% CI Age

20-29 30-34 35-44

Highest level of ducatkm <bigil school diplorna High school, coilege University

Annuai incorne < S30,oOO $30,000-S60,oOO > Sd0,ooo

Smoking status Never smoked Evcr smokcr Currcnt smokcr

Pelvic discase Never Ever

Endometriosis No Yes

Oral contraceptive use Never Ever

ruCD use Never Ever

Appendicitis Never A ~ Y appe-my

Non~orPtcd

*Excluding one womrra with ptimrvy infèdity rnd oae wompn with secoaduy -rtility with appcndcctomy after age 1 8 years

Table XlII

LogMc Regremion Aiidpis of Risk of Primriy InfertiIity (Cornpucd to Women with Seeondug Iiircrtility)*

Ne47

Rbk Estimatea Regressioa Diagnostics History of Criide ~djwstcd' hmmeîer Mode1 Appendcctomy OR %./.CI OR %%CI P W d d 2 H-L~

~Excluding one woman with Pnmary infertility and one woman with ~ecobdary infertility who had an appendectomy aftcr agc 18 years t Adjusted for age, a n n d incarne, smoking staûs, pclvic mflammatory disease, endometriosis, oral contraceptive use and inminerine wnîmqtivc &vice use $ p value for Hosmcr and Lenicshow G-CFit Test

Table XIV

Logistic Regre!ssion Andyst of RLk of Primiy Iafertility* (Cornpimi to Women with Sccondary Infertiiiây)

N=247

Cndc: Adjusîedt Variable OR 95% CI OR 9596CI Wald 2 p> Wald 2

Annual incorne 430,000 $30,000-S60,000 >$60,000

Smoking stahis Never Ever

Pelvic M m Disease Never Ever

Endometriosis No Yes

Oral Contraceptive use Never Ever

KJCD use Never Ever

Perforated Appendix No YS 0.9 0.2 - 3.5 0.6 0.1-2.3 0.66 0.4 1

Excluding one woman with primary inftrtüity and one woman with secondary infertility w b had an appendectomy aAer age 18 y- oscatistic for modeI: 0.66 p value for Hosmer and Lcxneshow Goodnes~e~Fit Test for modcl: 0.86

t Adjusted for age, annuai incane, smoking status, pelvic idamm&q diserse, endometriosis, oral contrafcptive use, intra-utcrine contreceptive &vice use md history of pcrforrted lppcndix

Table XV

Accuracy of R d of Appcndcetomy Data (N=13)

MediCril Recorda Seif- Report N o d Iaaamed Perforated

Normal O L* O fnfIamed O 5' O P e r f o d O O 7'

* one respondent with primary infertility 7 four pregnant women and one woman with primary infatilty $ two pregnant women, two wornen with primary i n f ' t y and three women with secondary infiertility

FIGURES

F i 1

Age Distribution of Regnant Women

N= 490

AGE

r i 2

Age Distribution of Women nith P h a y Inlcrtiiity

N = l l 6

Figrire 3

Age Distribution of Women with Sceonduy Infeitility

N = 133

2 1 24 27 30 33 Y 39 42 45

AGE

APPENDICES

Appendix A

Qucstiomlires

Infertility Risk Factors Questionnaire

Questionnaire for women with infertility

Information for Participants:

Piease be assurcd tbat your respoases WU be completely wnfjdential and that your name will never be placed on the questionnaire. Ali questionmk wiU be dcstroyed once the study is coacluded.

If you havt any qwsths, plcase fa1 h c to contact Dr. M d Urbach, MD

(416) 351-3772 Fm: (416) 351-3771

Please mark the box beside the best answer to the foilowing questions. Please answer a i i questions that apply.

If you do not wish to anmer any specific question, then p1ease proceed to the next question.

1. Wha t is your age:

2. What is your date of birth?

Year: Monk Day :

3. What is your cument marital status:

4. Whicb of the foiïowing choices best describes your binhest level of ducation (check one):

0 less than high school diploma

P high school P trade, technical or diploma vocational school

diplorna or d c a t e

nursing school or undergraduate degree or certificate de-

doctorate or professional degree

5. Which of the fouowing choiccs bat describes yoar hoasehold incornt in 1997:

6. Do yoa smoke cigaretîes? @lme mark ONE only)

7. Have you wer b e n t rutd for pelvic Uin.iamato y dis#st (PIID; infection of the uterus, ovaries md/or fillopian tub; Gonorrha, Chiamydi.)?

8. Have you ever had surgery in your abdomen or peivïs (other than nmovd of the appendix)?

9. If you answered "Yes" to the above, pl- write the nunes of the operations below:

11. Have you wer had a thcnpc~tic abortion?

12. Have you cvcr had a dscadage?

13. Have you ever had an ectopic (tubil) pregniacy?

0 Yes 0 No

14. Do yoa have endometriosis?

yes 0 NO O Not sure

15. Have you mer used the following formr of contraception:

Oral Contraceptives (Birth Control PU) P Yes O No P ~ o t NC

16. Have you ever had your appendb removcd?

If you answered "Ycr" to the above question, please anrncr the foiiowing two questions, and please read and sign the attacheü consent form. IF YOU ANSWERED "NO" TO THE ABOVE QUESTION, YOU DO NOT NEED TO SIGN THE CONSENT FORM OR ANSWER TEE FOLCOWING TWO QUESTIONS.

17. At the tirne of nmovd were you told yorv appendir wu:

0 nomai P infiameu P binstl O dont iafected but know not mptured

18. W.s your appendu removeà at the urne time u other surgey?

InfertiLity Risk Factors Questionnaire

Questionnaire for pregnant women

Information for Participants:

This study is king coaductcd to evaluatc WI~OI~S *factors foraibal-factor infcrtility

If you have any questioos, plcase feel k to contact m. mvid urbocb MD

(416) 351-3772 FW (416) 351-3771

Please mark the box b i d e the best answer to the foilowing questions. Please anmer al1 questions that apply.

If you do not wish to answer any specinc question, then please proceed to the next question.

2. What is your date of birth?

Year: Mon& Day :

3. What W your currcnt marital statiis:

0 widowed ' L = t e d P divorced

4. Which of the fouowing choices best describes your hi~hest level of education (check one):

0 community coiiege or 0 University bachelor's 0 University master's, nursing school or undergraduate doctorate or degree or certifiate de- professional degree

5. Which of the foUowing choiees b a t describes your hoiuehold income in 1997:

0 under $30,000 0 $3O,OOO - $60,000 0 above $60,000

6. Do you smoke cigarettes? (~ICISC mark ONE oniy)

0 never smoked 0 previous smoker 0 -nt smoker

7. Have you ever been trtrteü for peMc inflrmmato y dkase (Pm; W d o n of the rrteras, ovaries rnd/or fdopian tubes; Gononhea, Chiamydia)?

8. Have you ever had surge y in your abdomen or pivis (other than removal of the appendix)?

cl Yes

9. If you answered "Yes" $0 the above, pltase write the namw of the operations below:

10. Did you conceive this pregnancy rsing in vitro fertilizrtion (IVF)?

0 Yes 0 No 0 NO^ sure

11. Have you mer been pregnmt th& pregniny?

12. If you have been pregnant befom how many ümes bave yoa beea prrgiant (oot hc1ud.g Ikis pregnanq):

13. Have yoa ever had r thcrapeutic rbortion?

O Yes

14. Have you ever Lad a miscamhge?

15. Have you mer had an ectopie (tubil) pregnany?

O ~ o t sure

0 ~ o t sure

16. Do you have endometriosis?

17. Have you ever iwed the followiag for- of contraception:

Oral Contraceptives (Birth Control Piil) O yes P NO O ~ o t sure

18. Have you ever had your appendù icmovd?

If you rinswered "Ycr" to the above quation, p h anmer the foUowing two questions, and pl- read and rign the attacheâ consent formi. IF YOU ANSWERED "NO" TO THE ABOVE QUESTION, YOU DO NOT NEED TO SIGN THE CONSENT FORM OR ANSWER THE FOLLOWING 'IWO QUESTIONS.

19. At the time of rcmovd were you told your appcnir was:

20. Was yout rppendis removcd at the aame time u other srugeq?

AppendU B

Consent for Releast of Medicai Records

CONSENT FOR RELEASE OF HEALTH RECORDS INFORMATION

1 am voluntarily pdcipatiag in a study hvestigating risk &tors for infertility- 1 have completed a questionnaire asLing about various aspects of my medicai and supical history. Completion of the shdy requires tbat sow detaiis of m y surgical history, documented in rny medical records, be reviewed by the stuây investigaiors.

M y signature on this fonn mpresents my consent for the hospital named below to release the following medicai records h m m y file: (1) Opcrative report, (2) Surgicai pathology report, and (3) Discharge ~ummary~ These records s h d oniy be r e l e d for the hospital admission of whifh the most responsible admitting diagnosis was agpendicitis.

1 understand that copies of the aforementioned records will k sent via mail or Fax to the centrai &y facility? in the Mittema& Iafant and Reproductive Health Research Unit (MIRU). Once the records have k e n reviewed, any personal identifiers (name? date of birth, etc.) wili be removed h m aii files and aii copies of my confidentid health records WU be destmyed-

Study participant: Please complete the following information, which atso will indicate your permission for the named hospital to release the specific medicai records Listed above:

Name of Participant (at the tirne that appendù was removed, if dinerent):

Your date of birth: DAY: MONTH: YEAR:

Signature of Participant:

Name of hospital (where appendix was removed):

Approximate year that appendix was removed:

Today 's Date: Witness:

Appendu C

Ethicd Appmv.1