Cases & Commentaries

Ruptured Heterotopic Pregnancy

Commentary By Marcelle I. Cedars, MD

The Case

A 43-year-old woman, gravida 3 para 2, presented
at 16 weeks' gestational age with abdominal pain. Her current
pregnancy was the result of in vitro fertilization (IVF) with a
donor egg. An outpatient ultrasound at 14 weeks was reportedly
normal. On the day of presentation, she had experienced a sudden
onset of severe lower abdominal pain followed by nausea and
vomiting. Responding paramedics documented transient loss of
consciousness and difficulty recording blood pressures en route to
the emergency department (ED). In the ED, she was hypotensive and
tachycardic with an initial spun hematocrit of 28. The ED physician
performed an ultrasound, which showed an intrauterine pregnancy and
free fluid in the peritoneal cavity. The ED physicians were
concerned about a ruptured appendix.

After surgery and obstetrics were informed of the
patient, she was given IV fluids and sent to the CT scanner. The
patient was seen in the CT scanner by the obstetrics resident, who
after reviewing the history and noting the patient's appearance
(hypothermic, tachycardic, and hypotensive), felt the patient was
at high risk for a ruptured heterotopic pregnancy (a pregnancy in
which one embryo implants inside the uterus and another is outside
the uterus [Figure]). The patient was pulled out of the scanner and
taken emergently to the operating room, where an exploratory
laparotomy found a 12-week fetus in the right fallopian tube along
with 4 liters of peritoneal blood.

The Commentary

Heterotopic pregnancies occur in approximately
1/5,000-1/10,000 pregnancies (1,2),
and more than half are diagnosed in the operating room.(3) The
heterotopic pregnancy rate in cycles utilizing assisted
reproductive technologies (ART) (IVF and ovulation induction) is
increased more than 100-fold, to 1%-3% (4,5), largely due to the presence of multiple embryos in
a given cycle and the increased risk for tubal damage in an
infertile population. Although the increasingly common practice of
removing damaged tubes prior to ART has decreased this rate, the
diagnosis of a heterotopic pregnancy should always be considered in
this population.

While the index of suspicion may be raised in
pregnancies resulting from ART, the common tools for diagnosis of
ectopic gestations are of limited use. Diagnostic algorithms for
ectopic pregnancies utilize ß-hCG levels, progesterone
levels, and ultrasound to document an empty uterus.
On the other hand, diagnostic testing in a patient with a
heterotopic pregnancy will demonstrate the presence of a viable
intrauterine pregnancy on ultrasound, increased ß-hCG levels,
and progesterone levels within the normal range for pregnancy.

Clinicians caring for women who undergo ART
should be familiar with the normal ranges for ß-hCG in their
laboratory for a singleton gestation in early pregnancy (14-17 days
after retrieval). An extremely high initial level or a more than
typical doubling should heighten the suspicion for a multiple
gestation and hence, a heterotopic pregnancy. Unfortunately,
ß-hCG levels alone are not diagnostic as they may fall and
rise in some situations, such as a "vanishing twin" (spontaneous
resorption of one twin). The high risk of an ectopic pregnancy with
ART (3%-5%) mandates early ultrasound (4 weeks post-transfer),
performed by an experienced obstetrician or radiologist, to confirm
the presence of an intrauterine pregnancy.(6)

Once an intrauterine pregnancy is identified, the
adnexa should be carefully examined. The ovaries are frequently
enlarged from ovarian hyperstimulation and may contain blood from a
transvaginal retrieval. This common finding complicates the early
identification of a heterotopic pregnancy, even with the best
ultrasound skills and a high index of suspicion. Even in the
absence of ART, an adnexal mass is not found in the presence of an
ectopic pregnancy 15%-35% of the time.(6) Therefore, follow-up ultrasounds are critical and
should be performed 2 weeks following the initial ultrasound. As
the size of the pregnancy increases and the size of the ovaries
decreases, the extra-uterine pregnancy may become more visible.
However, 50% of heterotopic pregnancies are missed on
ultrasound.(3)
Non-specific symptoms may be attributed to the pregnancy itself
and/or ovarian enlargement and may be thought to be self-limited,
which could impede an early diagnosis even with a high index of
suspicion.

In this case, the heterotopic was not "diagnosed"
until 16 weeks' gestation. At this time, the patient's ovaries are
generally small enough and the pregnancy large enough to reliably
visualize the heterotopic when the adnexa are carefully examined.
The absence of visualization of an extra-uterine gestational sac
earlier in the pregnancy may have falsely reassured her outpatient
physicians. However, upon presentation—with the history of
loss of consciousness and symptoms to suggest hemodynamic
instability—the presence of peritoneal fluid should have
prompted a more detailed evaluation of the pelvis by
ultrasonography. Obstetric residents receive early pregnancy
ultrasound training and have heightened awareness of ectopic
gestations as a result of regularly following and caring for these
pregnancies. If emergency department physicians are to be the first
line of defense in recognizing ectopic pregnancies, they should be
trained in early pregnancy scans and be aware of the increased risk
in patients utilizing ART. Even following ART, diagnosis of a
heterotopic pregnancy will still be occasionally missed until
rupture is evident.

This heterotopic pregnancy was diagnosed late,
which may have further complicated its course in the ED. More than
85% of heterotopic pregnancies are tubal (3), and tubal pregnancies very rarely go into the second
trimester without rupture.(6)
That the pregnancy was reportedly at 16 weeks’ gestation may
have falsely reassured the ED physician regarding an ectopic
gestation.

In this case, the biggest concern is the transfer
of an unstable patient to the CT scanner. In the presence of
hemodynamic instability and free fluid in the pelvis, this patient
should have been resuscitated with IV fluids and blood products and
sent directly to the operating room for exploratory laparotomy. No
further testing would have added to the clinical picture.

Diagnosing a heterotopic pregnancy is not easy,
and delayed diagnoses will continue to occur. However, the current
rate of missed diagnosis is too high. While treatment is
complicated given the presence of a coexistent intrauterine
pregnancy, earlier diagnosis would allow for less invasive
procedures and potentially eliminate the need for blood products.
The most important factor in preventing cases like this one is
early diagnosis of the heterotopic pregnancy.

Take-Home Points

  • In patients undergoing infertility
    treatments, there should be a high index of suspicion for both
    ectopic and heterotopic pregnancies.
  • The presence of ovulation induction,
    with multiple resultant mature ova, with or without IVF, should
    increase the suspicion for a heterotopic pregnancy.
  • The initial level of ß-hCG and its
    early pattern of rise may further raise the index of suspicion and
    be helpful if clinicians are familiar with expected levels.
  • Following embryo transfer, initial
    ultrasound should be performed no later than 4 weeks. Even in the
    presence of an intrauterine pregnancy, the adnexa should be
    examined. Follow-up examination should be performed 2-3 weeks
    later, when the ovaries should be decreasing in size.
  • Earlier evaluation should be performed
    for abdominal pain and/or non-specific GI complaints. Emergency
    physicians should have added training in early pregnancy
    ultrasound.
  • Following ART, if a pregnant patient is
    hemodynamically unstable, she should be considered to have a
    ruptured extrauterine pregnancy and taken for exploratory
    laparotomy.

Marcelle I. Cedars,
MD
Director, Division of Reproductive Endocrinology and
Infertility
Director, Embryology Laboratory
University of California San Francisco

References

1. Dumesic DA, Damario MA, Session DR.
Interstitial heterotopic pregnancy in a woman conceiving by in
vitro fertilization after bilateral salpingectomy. Mayo Clin Proc.
2001;76:90-2.[ go to PubMed ]

2. Lau S, Tulandi T. Conservative medical and
surgical management of interstitial ectopic pregnancy. Fertil
Steril. 1999;72:207-15.[ go to PubMed ]

3. Heard MJ, Buster JE. Ectopic pregnancy. In
Scott JR, Gibbs RS, Karlan BY, Haney AF, eds. Obstetrics and
gynecology. Philadelphia, PA: Lippincott, Williams and Wilkins;
2003.

4. Dor J, Seidman DS, Levran D, Ben-Rafael Z,
Ben-Shlomo I, Mashiach S. The incidence of combined intrauterine
and extrauterine pregnancy after in vitro fertilization and embryo
transfer. Fertil Steril. 1991;55:833-4.[ go to PubMed ]

5. Ikeda S, Sumiyoshi M, Nakae M, Tanaka S,
Ijyuin H. Heterotopic pregnancy after in vitro fertilization and
embryo transfer. Acta Obstet Gynecol Scand. 1998;77:463-4.[ go to PubMed ]

6. Ankum WM, Van der Veen F, Hamerlynck JV,
Lammes FB. Transvaginal sonography and human chorionic
gonadotrophin measurements in suspected ectopic pregnancy: a
detailed analysis of a diagnostic approach. Hum Reprod.
1993;8:1307-11.[ go to PubMed ]

Figure

Figure. Ultrasound Image of Heterotopic
Pregnancy.