Eur. J. Obstet. Gynecol. Reprod. Biol.

, 23 (1986) 321-331 321

Elsevier

ET0 00401

Background factors of ectopic pregnancy.

I. Frequency distribution in a case-control study

Jane Thorburn, Christina Berntsson, Marianne Philipson and Bo Lindblom

Depurtment of Obstetrics and Gynecology, Universrty of Giitehorg, Giiteborg Sweden

Accepted for publication 27 August 1986

Summary

Two hundred and five patients with ectopic pregnancy in a well-defined Swedish
population were interviewed with respect to prior disease and pregnancy histories as
well as various constitutional and socioeconomic factors. The results were compared
with those of two control groups, i.e. 110 early pregnant women intending to
continue the gestation to term as well as 101 women seeking voluntary interruption
of pregnancy. The results provide evidence that several factors may be involved in
the etiology of ectopic pregnancy, including abdominal (or pelvic) surgery, previous
ectopic pregnancy and pelvic inflammatory disease. Furthermore, a history of
infertility is strongly correlated to ectopic pregnancy. On the other hand, there is no
evidence that uncomplicated spontaneous or induced abortion, parity or marital
status are important factors.

Ectopic pregnancy; Infertility; Controlled study; Etiology

Introduction

An increasing incidence of ectopic pregnancy (EP) has been reported from many
countries. In Sweden (Uppsala county) the overall incidence rate of EP has risen
from 0.3% of notified pregnancies to 1.0% during the last two decades [13]. The ratio
of ectopic to intra-uterine pregnancies has changed from 1: 177 to 1: 90 during the
same period [22]. In the United States a similar increase has recently been described
[15,17].

Correspondence: J. Thorbum, M.D., Department of Obstetrics and Gynecology, University of Gateborg,

GBteborg, Sweden.

0028-2243/86/$03.50 0 1986 Elsevier Science Publishers B.V. (Biomedical Division)

322

Since EP involves a considerable threat to a young woman’s health and in most

cases results in impairment of future fertility, interest has been directed towards
identifying predisposing factors [3,6,7]. However, the main etiological factors of EP
are still uncertain and the cause of the increased rate remains a matter of con-
troversy.
In order to analyze further the relationship between EP and various possible
background determinants, we conducted a case-control study in a well-defined
Swedish population during the years 1981-1982. Since more than 25% of intra-
uterine pregnancies in Sweden terminate as induced abortions, a special control
group including such cases was collected. Frequency rates of the analyzed factors in
the different groups were determined and compared statistically.

Material and methods

The study included 416 women of reproductive age (16-45 years).

Cases

Two hundred and five women were treated for ectopic pregnancy at the three
Departments of Obstetrics and Gynecology in the Gothenburg area from January 1,
1981, to June 30, 1982. For one of the departments (East Hospital) only cases
occurring later than July, 1981, were included (n = 54). From SahIgren’s Hospital a
total of 81 patients entered the study, and 70 cases of EP were eullgcted at the
Central Hospital of Mtihdal (Table I).
In each case, the operative diagnosis was confirmed by histopathologic examina-
tion of the removed specimens. All subjects were interviewed at the hospital 2-4
days following surgery. The interviews were performed by one of the authors using a
standardized questionnaire specifying 24 items. Each interview took approximately
20 min. Special attention was paid to avoid concentrating the responder’s attention
towards the possible relationship of a particular background factor to EP.

Controls

Two kinds of denominators were chosen. The first control group consisted of
women with an intrauterine gestation who intended to continue their pregnancy to

TABLE I
Patient material related to hospitals
I, Sahlgrenska Hospital; II, East Hospital; III, MBndal Hospital

I II III No. in Total in

studv the area
Cases Ectopic pregnancies 81 54 70 205 247

Controls Deliveries 30 11 69 110 11337

Legal abortions 56 18 27 101 4605
 323

term. These subjects were randomly collected at the corresponding antenatal clinics,
i.e. ‘deliveries’ (n = 110). The second control group consisted of women undergoing
voluntary interruption of pregnancy in the first trimester, i.e. ‘legal abortions’
(n = 101). Similar interviews to those described above were performed at the end of
the first trimester during the corresponding period of time (Table I).
The comparisons between the groups were performed by Fisher’s permutation
test [2], two-sided.
A p value of -C0.05 was considered significant (*), p < 0.01 = **, p < 0.001
= ***
Three women had a second EP during the course of the study. These cases,
however, only entered the study on the first occasion.

Results

Social and constitutional factors

The mean age of cases with ectopic pregnancy was 29.3 years, which was slightly
higher than in the control groups (Fig. 1). Of the EP cases 89.8% were married or
lived in a stable partnership, which did not differ from the delivery group. However,
in the legal abortion group nearly half of the women were singles. No difference
with regard to nationality, race or occupation was observed.
There was no difference in the patient’s body length or weight between the
groups (Table II).

Reproductive factors

Infertility. 36.6% of the EP cases reported a history of involuntary infertility

(one year or more), whereas the corresponding figure for the delivery group was
18.2% and for the abortion group 3.0%. One-fourth of the EP cases had 2 3 years of
infertility compared to 10.0% in the delivery group and 1.0% in the abortion group.
With regard to infertility all three groups were significantly different from each
other (Fig. 2).

EP DEL LA

Fig. 1. Mean age of patients: EP = ectopic pregnancies, DEL = deliveries, LA = legal abortions.
324

TABLE II
Mean body length and weight of patier& (n = 128)

Length (cm) Weight (kg)

Cases Ectopic pregnancies 162.8 51.1

Controls Deliveries 167.5 59.4

Legal abortions 166.2 59.0
(ns.) (n.s.)

Desire for pregnancy. 60.0% percent of women with EP reported a desire to

become pregnant. In the delivery group the figure was 88.2% and in the abortion
group 4.0%. These significant differences should be considered in relation to the use
of contraceptive methods (see below).
Contraceptive methods. In the EP group 151 of 205 women (73.7%) did not use
any contraceptive method at the time of conception. Of the remaining EP cases, 37
subjects (18.1%) used a copper IUD, whereas 2.0% used ‘mini-pills’. Thus, of EP
cases using contraceptives, more than two-thirds had a Cu IUD. Two percent used
combined contraceptive pills and 3.4% used barrier methods (Fig. 3). Among the
delivery cases 96.4% were without contraceptives. In the abortion group, almost half
of the women had not used any protection. Of the remaining cases, 12.9% used a
copper IUD whereas one-third used barrier methods (Fig. 3).
Irregular periods, endometriosis. About 20% of each group reported bleeding
irregularities (n.s.). A history of endometriosis was present in five EP cases, in one
case in the delivery group and none in the abortion group (n.s.).
Deliveries. 46.3% of the EP cases were nulliparas, compared to 45.5% in the
delivery group and 55.5% in the abortion group (n.s.).
Spontaneous abortions. 18.1% of women with EP had a history of one or more
spontaneous abortions, as compared to 19.1% in the delivery group and 10.9% in the
abortion group (n.s.).

Infertility

5oI

0
EP DEL LA

Fig. 2. Incidence and duration of infertility among cases and controls: EP = ectopic pregnancies,
DEL = deliveries, LA = legal abortions.
 325

Use of I.U.D.s,Mini-pills, Oral Contraceptive pills

and Barrier Methods

IUD
IZ Mini-pills
53 P-pills
0 Bonier
0
EP DEL LA

Fig. 3. Distribution of contraceptive methods in the various groups: EP = ectopic pregnancies, DEL =
deliveries, LA = legal abortions. IUD = copper intrauterine devices, Mini-pills = progestagen-only oral
contraceptives, P-pills = combined oral contraceptives, Barrier = diaphragms or other mechanical meth-
OdS.

Legal abortions. 22.9% of EP cases reported one or more legal abortions

compared to 11.8% in the delivery group and 32.7% in the abortion group (Fig. 4).
Abortion was thus significantly more common in the EP group than in the delivery
group (p < 0.05) and significantly less common compared to the abortion group
( p < 0.05).
Ectopic pregnancy. In our material, thus, 30 cases out of 205 had repeat ectopic
pregnancies. 14.6% of the EP cases had a history of a previous EP. This was
significantly less common in the comparison groups (p < O.OOl), i.e. 1.8% in the
delivery group and none in the LA group (Fig. 5).
Curettage and hysterosalpingography. In the EP group 27.8% had undergone
uterine curettage (at least once) under non-pregnant conditions, which differed
significantly ( p < 0.01) from the corresponding figures for the control groups, which
were 10.9% and 12.9% respectively (Fig. 6).

Legal abortions

0
Eb DEL Lh

Fig. 4. Incidence of previous legal abortion among cases and controls. EP = ectopic pregnancies.
DEL = deliveries, LA = legal abortions.
326

Ectopic pregnancy

EP DEL LA

Fig. 5. Incidence of previous ectopic pregnancy among cases and controls. EP = ectopic pregnancies,
DEL = deliveries, LA = legal abortions.

Curettage

EP DEL LA

Fig. 6. Incidence of previous curettage and/or hysterosalpingography among cases and controls.
EP = ectopic pregnancies, DEL = deliveries, LA = legal abortions.

Abdominal surgery

EP DEL LA

Fig. 7. Incidence of previous abdominal surgery among cases and controls. EP = ectopic pregnancies,
DEL = deliveries, LA = legal abortions.
 321

PID

Fig. 8. Incidence of previous pelvic inflammatory disease among cases and controls. EP = ectopic
pregnancies, DEL = deliveries, LA = legal abortions.

Abdominal surgery. Ninety women (43.9%) in the EP group had a history of

abdominal surgery, i.e. laparotomy. In the delivery group the proportion was 17.3%
and in the abortion group 17.8% (Fig. 7). This difference in rate between EP cases
and controls was highly significant (p < 0.001). Sixty-two women in the EP group
had had only one earlier laparotomy. Of these cases, most frequent operations were
appendicectomy (n = 25), and surgery for ectopic pregnancy (n = 13).
Pelvic inflammatory disease. A history of PID was found in 33.7% of the EP
group, in 20.9% of the delivery group and in 14.9% of the abortion group. The rate
for the EP group was not significantly different as compared to the delivery group,
but was significantly higher than in the legal abortion group (p < O.Ol), (Fig. 8).
Miscellaneous. Nineteen percent of EP cases used some kind of medication
regularly. This was slightly more common than for the control subjects (8.2% for the
delivery group and 15.8% for the abortion group, n.s.).
Almost one out of five EP cases reported a history of temporary illness or
marked psychological stress at the time of conception, which was significantly more
common than in the two control groups (Table III). Examples of such events,
regarded by the patient as a considerable personal burden, were: influenza, urinary
tract infection, change in diurnal rhythm, family crises.
Cigarrete smoking - defined as a daily consumption of more than 5 cigarettes
was reported by 42% of EP cases, and by 48.5% in the abortion group. This

TABLE III

Temporary illness Intercurrent disease

(%) (5%)
Cases Ectopic pregnancies 19.5 13.7

Controls Deliveries 4.6 (*** vs. EP) 15.5

Legal abortions 8.9 (* vs. EP) 13.8
(n.s.)
328

TABLE IV

Cigarette smoking Regular alcohol intake

6) (W
Cases Ectopic pregnancies 42.0 20.0

Controls Deliveries 26.4 (** vs. EP) 12.8

Legal abortions 48.5 (n.s. vs. EP) 13.9
(n.s.)

difference was not significant. (However, the delivery group differed from both
these groups (Table IV.)
Although the rate for the delivery group was significantly lower (26.4%) there was
no significant difference as compared to the EP cases when the controls were pooled
(Table IV).
There was no difference in alcohol use in the three groups (Table IV).

Discussion

The present investigation was designed as a case-control study. The control group
was aimed to reflect a female population which, in contrast to the cases under study,
had normal intra-uterine pregnancies. However, intra-uterine pregnancies may
terminate differently, i.e. some will proceed to term while others may lead to
spontaneous abortion in various stages of pregnancy. In still another group preg-
nancy is interrupted by legal abortion. While the real rate of miscarriage seems
impossible to measure [1,9], the figures for deliveries and legal abortions in the
population under study can be determined with great accuracy (Table I).
In order to obtain a representative control group of intra-uterine pregnancies we
choose to use a control group consisting of two subgroups, i.e.: (1) women with
pregnancies planned to continue to term and (2) pregnancies deliberately inter-
rupted. We thus excluded the third possible group of intra-uterine gestation, i.e.
spontaneous abortion, since this group includes pathological pregnancies.
Among the various determinants analyzed in this study, pelvic inflammatory
disease (PID) has long been considered as the main causative factor for EP [8,21,22].
In the present material, a history of previous PID was present in one-third of the
cases. The frequency of PID .in the case group is thus in agreement with earlier
reports [3,8]. However, the unexpected high rate of pelvic infections among the
control subjects raises doubts as to whether a history of PID actually is the
quantitatively dominant etiological factor of EP. As demonstrated by Westrom [22],
a verified salpingitis considerably increases the risk that a subsequent pregnancy
will be ectopic. However, the definition and criteria of PID are a matter of
controversy and, according to many authors, both underestimation and overestima-
tion occur.
The rate of prior spontaneous abortion in the case.group did not significantly
differ from that of the control groups. This finding agrees with that of Levin et al.
[lo], although their rates for both cases and controls were higher. In our study, the
 329

proportion of patients having more than one spontaneous abortion was not higher
among the EP cases. It thus seems unlikely that spontaneous abortion per se is a
causative factor for EP.
Earlier investigations suggest that a history of one previous induced abortion
does not increase the risk of a subsequent EP [4,10], but if the abortion is
complicated by infection or retained products of conception, there seems to be a
markedly elevated risk. It has also been demonstrated that the risk is increased with
the number of legal abortions undergone [lo]. In our material, the EP group had a
legal abortion rate (one or more) in between that of the delivery group and the LA
group. If the control groups were pooled, however, there was no significant
difference between cases and controls. It therefore seems unlikely that legal abortion
is a major etiological factor for EP in Sweden.
About one-half of our cases had at least one previous delivery, which was not
significantly higher than in the control group. It therefore seems unlikely that parity
as such should have an impact on the EP rate. When primigravidas were excluded
there was still no difference between EP cases and the delivery group.
Of the EP cases approximately 15% had a history of one or more previous EP.
For the pooled control group this rate of EP was 1.2% (Fig. 5). These figures
illustrate the marked tendency of recurrence of the condition, which is in agreement
with other reports [3,16].
A history of previous abdominal surgery (i.e. all types of laparotomy) was found
in nearly 50% of the women with ectopic pregnancy. For the pooled control group,
this proportion was 17.5%. When excluding patients operated upon for a previous
EP, the rate of abdominal surgery was 36.0%, which is still significantly higher than
for the controls. Similar figures have been reported in a variety of studies, although
no control groups were used for comparison (for review see Chavkin [5]). The
three-fold higher frequency of previous abdominal surgery among women with
ectopic pregnancy as compared to the rate in the control subjects suggests that
abdominal surgery is an important causative factor for the development of ectopic
pregnancy.
It is interesting to note that one-third of the earlier laparotomies in the EP group
were appendectomies, i.e. 34 out of a total of 205 EPs. Twenty of these 34 cases had
an ectopic gestation located in the right oviduct, whereas 14 ectopics were left-sided.
These figures are congruent with the well-known higher frequency of right-sided
EPs [8]. This also suggests that right-sided ectopics are not over-represented after
appendectomy. In the control groups, the corresponding figures for appendectomies
were ll/llO and 12/101, respectively.
The higher proportion among EP cases of previous involuntary infertility (one
year or more) is consistent with clinical experience that an ectopic pregnancy is
often preceded by a long period of childlessness. Infertility was three times more
common in the EP group as compared to the pooled control group. The reason for
the low figure in the abortion group is obvious.
The rate of previous D & C and/or hysterosalpingography was more than twice
as high among EP cases than in the control groups. This difference may be
explained by the high rate of infertility problems in the EP group, increasing the
probability that these women may undergo such interventions.
330

The question as to whether certain contraceptive methods increase the risk of an

ectopic pregnancy has long been a matter of dispute. Special attention has been paid
to examining any interrelation between copper IUDs and EP. According to Tietze
[20] a copper IUD reduces intrauterine implantation by 99.5% and tubal implanta-
tion by only 95%. Tatum et al. [18] described a ten-fold increase in risk that a
pregnancy associated with a Cu IUD in situ would be ectopic. In spite of this, it has
long been accepted that only combined hormonal contraceptives provide better
protection against EP than the Cu IUD [11,14]. However, Meirik and Nygren [12]
have proposed that the risk of EP for IUD users may have been underestimated due
to bias factors in the choice of contraceptive methods. In our study, the proportion
of EP cases having a Cu IUD in situ at the time of conception was 18.1%, which is
in agreement with most other recent investigations. However, our data do not
permit a conclusion concerning the risk for ectopic pregnancy in IUD users. For
this purpose lifetable analysis should be a more correct approach. We suggest that
the observed difference in IUD use between the two control groups is a reflection of
the tendency to choose a legal abortion due to the highly increased risk of
miscarriage among such pregnancies [19].
It is evident that the probability of the occurrence of many of the recorded events
(e.g. spontaneous and legal abortion) increases with age, and the slightly higher age
in the EP group might imply a somewhat higher frequency of such factors as
compared to the controls. However, the difference in mean age (1.8 years) between
EP cases and the pooled control group cannot per se explain the great differences
registered.
In conclusion, the present case-control study provides evidence that several
factors may be involved in the etiology of ectopic pregnancy. Such background
factors include previous ectopic pregnancy, abdominal surgery, infertility, and
pelvic inflammatory disease. On the other hand, nationality, marital status, profes-
sion, parity, uncomplicated legal or spontaneous abortions, endometriosis, bleeding
abnormalities, intercurrent disease, physical constitution, cigarette smoking and
alcohol consumption seem unlikely to be predisposing factors. Psychological stress
at the time of conception might play some role in this context, but for obvious
reasons such information is connected with great uncertainty and it seems hazardous
to draw conclusions from this study.
To provide more detailed information concerning the validity of the possible risk
factors and to assess confounding factors and interaction by various variables in the
present material, multivariate analysis or logistic models seem appropriate. An
elaboration of this material utilizing such methods is presently under way.

Acknowledgements

This investigation was supported by the Goteborg Medical Society and the
Swedish Medical Research Council.

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