FERTILITY AND STERILITY Vol. 53, No.

1, January 1990
Copyright© 1990 The American Fertility Society Printed on acid-free paper in U.S.A.

Nine cases of heterotopic pregnancies in 4 years

of in vitro fertilization

Essam S. Dimitry, M.R.C.O.G.* Raul Margara, M.D.

Robert Subak-Sharpe, M.R.C.O.G. Robert Winston, F.R.C.O.G.
Martin Mills, M.R.C.O.G.

Institute of Obstetrics and Gynaecology, Hammersmith Hospital, The Royal Postgraduate

Medical School, London, United Kingdom

The incidence of simultaneous intrauterine and extrauterine pregnancy increased after

wider use of ovulation induction and the advent of techniques of assisted reproduction.
Nine cases of heterotopic pregnancies are reported after in vitro fertilization (IVF) and
embryo transfer (ET) between September 1984 and November 1988. The incidence of
heterotopic pregnancies in clinical IVF pregnancies was 9 of 312 (2.9% ). Superovulation
and IVF-ET appear to predispose to heterotopic pregnancy, particularly after tubal
disease. Fertil Steril53:107, 1990

Until recently the incidence of heterotopic preg-
nancy was estimated at between 1:30,0001 and
1:15,000. 2 The incidence has risen after wider use
of ovulation induction and the advent of tech-
niques of assisted reproduction. The rising inci-
dence presents a serious problem as the diagnosis
of this potentially fatal condition is often missed.
We report nine cases of heterotopic pregnancy
and record its incidence after in vitro fertilization
(IVF). Methods for early diagnosis are discussed.
MATERIALS AND METHODS
During September 1984 to October 1988, 1996
IVF treatment cycles were performed. Three hun-
dred fifteen clinical pregnancies resulted and in 9
cases, the pregnancy was heterotopic.
Case Reports
The patients were superovulated with one of the
following regimes: (1) clomiphene citrate (CC)/
Received April 5, 1989; revised and accepted September 14,
1989.
*Reprints requests: Essam S. Dimitry, M.R.C.O.G., Insti-
tute of Obstetrics and Gynaecology, Hammersmith Hospital,
The Royal Postgraduate Medical School, London, United
Kingdom.
human menopausal gonadotrophin (hMG)/human
chorionic gonadotropin (hCG); (2) hMG/hCG; and
(3) buserelin (Suprefact, Hoechst, Paris, France)/
hMG/hCG.
The number of oocytes retrieved ranged from 3
to 12. With the exception of one patient who had
two embryos transferred, all the others had three
or four.
CaseNo.l
Patient 1, a 31-year old primigravid patient, pre-
sented 28 days after embryo transfer (ET) with
lower abdominal pain, brown vaginal loss, and diz-
ziness. Previous ultrasound scan showed an intra-
uterine gestation sac with bilateral adnexal cysts.
Abdominal tenderness, uterine enlargement, and
adnexal fullness were found. After admission, vagi-
nal ultrasound showed a nonviable intrauterine
gestation with bilateral adnexal swellings. The
symptoms settled and she was discharged after 11
days. Three days later, on the day repeat sonogra-
phy was planned, the patient was admitted to her
local hospital with a clinical picture of ruptured ec-
topic pregnancy. Laparotomy revealed a ruptured
left ampullarypregnancy with 500 mL of intraperi-
toneal blood. Two units of blood were transfused.
The intrauterine pregnancy ended as a missed
abortion.

Vol. 53, No.1, January 1990 Dimitry et al. Heterotopic pregnancies 107
Case No.2
Patient 2, a 24-year old primigravida, presented
29 days after ET with abdominal pain and vaginal
bleeding. Abdominal ultrasound scan showed an
echogenic left adnexal structure but no clear intra-
uterine sac. The uterus was clinically enlarged.
Five days after admission, an intrauterine preg-
nancy was demonstrated. Human chorionic gonad-
otrophins levels increased satisfactorily. Twenty-
one days after admission, ultrasound scan showed
a nonviable intrauterine pregnancy, whereas the
left adnexal swelling continued to enlarge. Twenty-
eight days after admission, laparoscopy revealed an
unruptured left ampullary pregnancy. A left salpin-
gectomy was performed with suction evacuation of
the uterus.
Case No.3
Patient 3, a 34-year old patient, para 0-0-2-0,
presented 17 days after ET to her local hospital as
an acute abdominal emergency. At laparotomy, a
ruptured left infundibular pregnancy was found
and the fallopian tube was excised. Two litres of
blood were removed from the peritoneal cavity and
four units transfused. Subsequent ultrasound ex-
amination showed an intrauterine gestation. Spon-
taneous vaginal delivery occurred at term.
Case No.4
Patient 4, a 33-year old patient, para 0-0-3-0,
presented 26 days after ET complaining of lower
abdominal pain. She appeared pale and distressed,
with a blood pressure of 140/90 mmHg and a tachy-
cardia of 105 beats/min. Abdominal rebound
tenderness, uterine enlargement, and left adnexal
tenderness were the main clinical findings. An ul-
trasound scan showed a single intrauterine preg-
nancy, but initial hCG levels were consistent with
twins. A heterotopic pregnancy was suspected.
Laparoscopy proceeded to laparotomy. A ruptured
left tubal pregnancy was removed. Estimated blood
loss was 300 mL. The intrauterine pregnancy pro-
gressed to term when a healthy infant was deliv-
ered vaginally.
Case No.5
Thirty-five days after ET, patient 5, a 29-year
old, para 0-0-2-0, presented with constant lower
abdominal ache. Her vital signs were stable. Ultra-
sound scan revealed intrauterine and right tubal
gestational sacs both with fetal pole and heart pul-
108 Dimitry et al. Heterotopic pregnancies
sation. Laparotomy showed an unruptured right
ampullary pregnancy. Salpingectomy was per-
formed. The intrauterine pregnancy progressed to
term. Caesarean section was carried out for fetal
distress, but the infant succumbed to multiple con-
genital abnormalities.
Case No.6
Thirty-seven days after ET, patient 6, a 38-year
old para 0-0-1-0, presented with severe lower ab-
dominal pain and heavy vaginal loss. She was
distressed but haemodynamically stable. Abdomi-
nal tenderness was elicited. Initial hCG levels
suggested multiple pregnancy. Ultrasound scan
showed a viable intrauterine gestation with a non-
viable right tubal pregnancy. Laparotomy revealed
a ruptured right ampullary pregnancy and salpin-
gectomy was carried out. The intrauterine preg-
nancy continues.
Case No.7
Patient 7, 37 -year-old, para 0-0-1-0, presented 37
days after ET with severe lower abdominal pain.
She was distressed, pale, and her blood pressure
was 90/60 mmHg, pulse 90 beats/min. Abdominal
examination showed rigidity and rebound tender-
ness. Initial hCG levels had suggested multiple
pregnancy and previous ultrasound scan had
shown only one intrauterine sac. Heterotopic preg-
nancy was suspected. Laparoscopy and subsequent
laparotomy revealed a ruptured left ampullary
pregnancy with 1100 mL free blood. Salpingectomy
was carried out. Ultrasonography later demon-
strated a second fetal heartbeat, and the twin preg-
nancy continues.
Case No.8
Patient 8, 29-year-old primigravida, presented at
54 days after ET with lower abdominal pain and
vaginal bleeding. Two weeks previously, ultra-
sound had shown a viable intrauterine gestation.
Her vital signs were stable. Ultrasound scan re-
vealed missed abortion in utero and a large viable
right tubal gestation. Laparotomy confirmed an
unruptured right ampullary pregnancy. Salpingec-
tomy and suction evacuation of the uterus were
performed.
Case No.9
Patient 9, a 28-year-old primigravida, presented
34 days after ET complaining of lower abdominal
Fertility and Sterility
pain and no vaginal bleeding. She was not dis-
tressed, but abdominal and adnexal tenderness
were elicited. Ultrasound showed viable twin gesta-
tion with free fluid in the pouch of Douglas. Lapa-
roscopy and subsequent laparotomy showed a rup-
tured left ampullary pregnancy. Salpingectomy
was carried out. The twin pregnancy is still on-
going.
All of the patients gave a history of tubal disease
and tubal surgery. Four had had an appendicec-
tomy, four pelvic inflammatory disease. Two pa-
tients had previously had one ectopic pregnancy
and a further two had a history of two ectopic preg-
nancies. In four cases one tube was patent, but in
the remaining five tubal blockage was bilateral, ac-
cording to laparoscopy and hysterosalpingography.
DISCUSSION
Heterotopic pregnancy is an unusual but poten-
tially deadly condition. This report would appear
to be the largest collected series from one unit.
The factors that predispose to ectopic pregnancy
are well known. These factors could also lead to
heterotopic pregnancy especially after ovulation
induction, when the risk of multiple pregnancy is
increased to levels as high as 12% after CC 3 and
40% after gonadotropin therapy. 4 Heterotopic
pregnancy has been reported after the use of both
of these drugs. 5
In vitro fertilization mostly involves deliberate
superovulation and multiple embryo transfer. This
presents an opportunity for simultaneous intra-
uterine and extrauterine implantations to occur.
The earliest published report of heterotopic preg-
nancy after IVF was by Y ovich et al. 6 and after ga-
mete intrafallopian transfer by Abdalla et al. 7
The direct insertion of the embryos into the
uterotubal orifice has been previously suggested as
one explanation. 6 Another theory is migration of
embryos from the uterus into the tube. 6 This mi-
gration may be mediated by the female genital tract
itself. 8 Carbon particles can be identified in the fal-
lopian tube shortly after their deposition in the va-
gina. This finding also suggests an inherent retro-
grade mechanism for transfer of nonmotile parti-
cles.9 Lastly, it is just possible that ectopic
pregnancy could result from spontaneous fertiliza-
tion of an unrecovered oocyte, if coitus occurs.
However, coitus was unlikely in these patients as it
has been our policy until recently to instruct pa-
tients to avoid intercourse.
Since the emergence of IVF-ET, more patients
Vol. 53, No.1, January 1990
with tubal damage have conceived. Not surpris-
ingly, this is probably the most important reason
why ectopic pregnancy is so common after IVF-ET.
Cohen et al. 10 quote an incidence of 5% in a large
collaborative study.
The incidence of heterotopic pregnancy in Co-
lumbus, Ohio was estimated to be 1/2600. 11 Since
then, the following series were reported, 1 in 7963
from New York/ 2 1 in 6778 from Israel,l 3 and 1 in
4112 from Belgium.H
The incidence of heterotopic pregnancy in IVF
clinical pregnancies in our series is 2.9%. This inci-
dence is probably higher than in other IVF centers
because of Hammersmith's active tubal microsur-
gery unit. Tubal disease diagnosed by laparoscopy
was the main cause of infertility in all the nine
cases of heterotopic pregnancies in this series.
Tubal disease is classically believed to be the
major cause of ectopic pregnancy. Ectopic preg-
nancy from tubal damage occurs after pelvic in-
flammatory disease (PID)/ 5 tubal surgery/6 and
appendicectomy. 17 Previous ectopic pregnancy 18 is
also a recognized risk factor.
In this study, a history of symptomatic PID was
found in only 4 out of 9 cases. Brunham et al. 19
showed that a history of PID being elicited less fre-
quently than the histological evidence could well be
explained by the observation of chlamydia! tubal
infection leading to ectopic pregnancy being com-
monly subclinical.
Apart from PID, appendicectomy and previous
ectopic pregnancy were found in the history of four
of nine patients in this study. Ectopic pregnancy
after IVF-ET has previously been reported to be
three times more common when there is unilateral
tubal patency than bilateral patency or blockage. 10
In this series, four of the nine patients had unilat-
eral tubal patency.
We found that the following criteria may aid the
diagnosis, in cases of heterotopic pregnancy: (1)
When the uterine size is compatible with dates in
a patient believed to have an ectopic pregnancy; (2)
When there are symptoms of pregnancy after exci-
sion of an ectopic pregnancy; and (3) When signs
of hemoperitoneum occur after evacuation of the
uterus.
It should also be remembered that if ovarian
superovulation is used, the sonographic presence of
an intrauterine gestational sac does not exclude an
ectopic pregnancy.
Raised levels of serum hCG levels 12, 14, and 16
days after egg collection may indicate the presence
of a multiple gestation. However, if ultrasound
Dimitry et al. Heterotopic pregnancies 109
 scan shows only one intrauterine gestation (case
nos. 4, 6, and 7), heterotopic pregnancy must be
considered.
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