Ectopic Pregnancy

INTRODUCTION
An ectopic pregnancy is a pregnancy implanted in an abnormal location (outside of the uterus).  During the past 40 years its incidence has been steadily increasing concomitant with increased STD rates and associated salpingitis (inflammation of the Fallopian tubes).  Such abnormalities of the tubes prevent normal transport of the fertilized egg to the uterus.

The most common site of ectopic implantation is the Fallopian tube.  Other sites such as the abdomen, ovary, or cervix are far less common but are associated with higher mortality.  This higher mortality is due to greater detection difficulty and to massive bleeding that can result if rupture occurs at these sites.

EPIDEMIOLOGY

How many women suffer from an ectopic pregnancy?
Ectopic pregnancy occurs at a rate of about 1-2% of pregnancies and can occur in any sexually active woman of reproductive age. The increase in incidence in the past few decades is thought to be due to two factors:

• increased incidence of salpingitis (infection of the Fallopian tube, usually due to a sexually transmitted disease (STD), such as Chlamydia or gonorrhea), and
• improved ability to detect ectopic pregnancies.

There is a marked increase in ectopic pregnancy rate with increasing age from 6.6 per 1000 pregnancies in women aged 15 to 24, to 21.5 per 1000 pregnancies in women aged 35 to 44.

Most ectopic pregnancies occur in women who have had more than one pregnancy. Only 10% to 15% of ectopic pregnancies occur in women who have never been pregnant before.

In the United States, the rates are higher for non-white (about 30 in 1000, or 3 in 100, pregnancies) than for white women.

SUMMARY
Summary: About 1-2% of pregnancies are ectopic.

• Ectopic pregnancy can occur in any sexually active woman of reproductive age.
• More are being seen because (1) more salpingitis and (2) better ability to detect ectopic pregnancies. 
• Rates of ectopic pregnancy are higher in women who (1) are older, (2) have had multiple pregnancies and/or (3) are non-white. 

How many women die of ectopic pregnancies?
Ectopic pregnancy is the most common cause of pregnancy-related deaths in the first trimester of pregnancy. There are more than 40 deaths per year in the United States. It accounts for about 10% of all pregnancy-related deaths. However, the number of deaths per ectopic pregnancy is decreasing dramatically because of earlier diagnosis and treatment. This death-to-case rate is 4 times higher in non-white women. Because the incidence of ectopic pregnancy is also higher in black Americans, a pregnant black woman is 5 times more likely to die of ectopic pregnancy than a white woman. It causes about 20% of pregnancy-related deaths among black women.

Blood loss is the major cause (about 85%) of death in ectopic pregnancy. Misdiagnosis leading to delayed treatment contributed to about half of the deaths.

SUMMARY

• In the first trimester, ectopic pregnancy is the most common cause of pregnancy-related deaths (causes 10% of such deaths). 
• Earlier diagnosis and treatment is dramatically decreasing the number of deaths. 
• A black American woman is 5 times more likely to die of an ectopic pregnancy because it happens more often and is more dangerous. 
• Most deaths (85%) are due to blood loss. Half of these deaths were due to delayed treatment because of misdiagnosis.

ETIOLOGY

What causes ectopic pregnancy?

The major cause of ectopic pregnancy is salpingitis, accounting for about half of first time ectopic pregnancies.

In most of the remaining first time ectopic pregnancies (accounting for about 40%), the cause is undetermined. One theory is that in some women the fertilized egg travels in the Fallopian tube slower, so that at time of implantation (7 days after fertilization) the embryo is still in the Fallopian tube. Instead of implanting in the uterus as is normal, it implants in the Fallopian tube. A possible cause for this slowing down of travel is a hormonal imbalance. Increased amount of estrogen or progesterone can change the contractions of the tube (contractions are required to help move or propel the embryo along the tube). Increased levels of progesterone can be found with the use of a progesterone-releasing IUD (intrauterine device, for contraception) or the use of progestin-only oral contraceptives (one type of "the pill"). Increased levels of both estrogen and progesterone can occur after hormonal treatment for the purpose of in-vitro fertilization ("test tube baby").

Animation of Fertilization Process (will open in a new window)

Another theory is that an abnormality of the embryo, such as an incorrect number of chromosomes (normally every cell has 23 pairs of chromosomes, and 1 X and 1 Y chromosome; these chromosomes carries the person's complete genetic material, which should be the same in each cell), would interfere with its ability for normal transport in the Fallopian tube. Many studies have indicated that cigarette smoking increases the risk of ectopic pregnancy. The greater the number of cigarettes smoked per day, the greater the risk. Smoking 30 or more cigarettes per day increases a woman's risk 4 times.

7% of women with ectopic pregnancy have had an ectopic pregnancy before. After one ectopic pregnancy, about 12% of subsequent pregnancies are ectopic pregnancies.

SUMMARY

• The common cause of ectopic pregnancy is salpingitis (causes 50% of first time ectopic pregnancies). 
• 40% have no known cause. One hypothesis is that there is slowing of transport through the Fallopian tube of the fertilized egg. This transport slowly could possibly be due to hormonal imbalance (such as due to progesterone releasing IUD, progestin-only oral contraceptive or in-vitro fertilization treatment) or possibly an abnormality (e.g. chromosomal) of the embryo. 
• Cigarette smoking significantly increases a woman's risk. 
• Previous ectopic pregnancy increases the risk for another. 

How does salpingitis cause ectopic pregnancy?
Salpingitis can fuse together the folds in the Fallopian tube. These folds are naturally found lining the inside of the tube. This narrows the inside of the tube such that sperms can travel normally through it, but the embryo cannot.

Secondly, the embryo can be trapped in blind pockets formed by adhesions inside the tube (adhesions are abnormal joining between organ parts, which usually form after damage to organs). 


SUMMARY

• Salpingitis can prevent normal transport of the embryo by (1) narrowing the Fallopian tube by fusing together folds inside the tube, and/or (2) trapping the embryo in blind pockets formed by adhesions inside the tube. 

How about other abnormalities to the tubes?
Besides salpingitis from infection, previous surgery is another cause of adhesions. About one quarter of women with ectopic pregnancy had previously had surgery in the abdomen.

Another abnormality that can be found is diverticulum of the Fallopian tube, which is small out-pouchings of the tube.


SUMMARY

• About 25% of women with an ectopic pregnancy had previous surgery in the abdomen. 
  

Can "tying the tubes" cause ectopic pregnancies?

It can occur, but rarely. The chance of unexpectedly getting pregnant after tubal sterilization (failure of sterilization) is about 2%. Of these pregnancies, 40% are ectopic.

In sterilization done by electrocoagulation ("melting and solidification" of tissue with electricity) a passage can occasionally be created for sperms to exit the uterus into the pelvic cavity through the site of coagulation. The sperm can then travel to the fimbrial end of the Fallopian tube to fertilize an ovulated egg (see diagram below) and cause an ectopic pregnancy. Women sterilized with metal clips or silicone rings are also at risk.

If a woman who has undergone tubal sterilization misses an expected menses (period), a pregnancy test should be done immediately. If pregnant, it is necessary to determine if it is ectopic.

SUMMARY

• Failure of tubal sterilization resulting in an ectopic pregnancy rarely occurs (less than 1%). 
• This can be due to exit of the sperm into the pelvic cavity and subsequent entry of the Fallopian tube through the fimbrial end to fertilize an egg. 
• If a woman who has undergone tubal sterilization misses an expected menses, a pregnancy test should be done immediately. 

PATHOLOGY

What happens in ectopic pregnancy?

An ectopic pregnancy is a pregnancy that implants and develops outside the endometrial lining of the uterus. 97% of ectopic pregnancies occur in the Fallopian tube. 80% of these occur in the ampulla region of the tube. About 10% occur in the isthmus region and about 5% in the infundibulum region.

Only about 3% occur in the interstitial portion of the Fallopian tube. Rarely do ectopic pregnancies occur in the ovary, in the cervix, or in the abdomen. Although these non-tubal and interstitial ectopic pregnancies are rare, they represent nearly 20% of deaths due to ectopic pregnancies. This high danger to life at these locations likely results from massive bleeding when these pregnancies rupture (These abnormal pregnancy locations, unlike the uterus, cannot expand enough to fit the growing embryo; thus these structures can eventually rupture, causing bleeding. The woman can lose enough blood that her life is threatened.)

Most cervical pregnancies occur after a sharp uterine curettage. More than half of the women with a cervical pregnancy need treatment by hysterectomy. Even if hysterectomy is not performed, the prognosis for future fertility is poor.

Most abdominal pregnancies occur after the embryo first implants in the Fallopian tube, after which it is expelled from the fimbrial opening of the tube and then implants in the abdomen. An unusual type of abdominal pregnancy may implant in the spleen or liver, which causes massive lethal bleeding in the abdomen.

Uncommonly, an ectopic and a uterine (normal) pregnancy may both occur at the same time. This is termed heterotopic pregnancy. Such a circumstance might be more common after drug induced ovulation (such as for in-vitro fertilization) because multiple ovulations can be more likely to occur. Heterotopic pregnancy occurs in 1% to 3% of pregnancies occurring after in-vitro fertilization. The incidence increases with the number of embryos transferred into the uterus.

SUMMARY

• 97% of ectopic pregnancies occur in the Fallopian tube, with 80% in the ampulla, 10% in the isthmus, 5% in the infundibulum and 3% in the portion.
• The ovaries, cervix and abdomen are rare site.
• Though rare, these non-tubal and interstitial sites cause 20% of ectopic pregnancy deaths because of massive bleeding upon rupture.
• Most cervical pregnancies occur after a sharp uterine curettage, most require a hysterectomy, and prognosis for future fertility is poor.
• Most abdominal pregnancies occur after tubal abortion.
• Heterotopic pregnancies are rare, but can occur in 1 to 3% of in-vitro fertilization induced pregnancies, with the incidence increasing with the number of embryos transferred.

SYMPTOMS

What symptoms can a woman experience with ectopic pregnancy?
For women in whom it is suspected that they are in danger of ectopic pregnancy, with the use of testing and imaging it is now often possible to determine a diagnosis of ectopic pregnancy before symptoms develop.

It is important to be aware of the symptoms of ectopic pregnancy because it can occur in any sexually active woman whether or not she is using contraceptives or has undergone tubal sterilization ("tying the tubes").

Symptoms occur as the embryo grows and as bleeding occurs from expelling of blood through the fimbrial opening of the Fallopian tube or from rupture of the tube. Mild bleeding can occur without causing symptoms.

The most common symptoms that a woman presents to a doctor are abdominal pain (90-100% of women), absence of menses ("not getting your period") (75-90%) and unexpected bleeding through the vagina (50-80%).

Before rupture occurs, there might be just a vague soreness or spastic (colic) pain in the abdomen.

Abdominal pain can be generally everywhere, or it can be in a specific spot (localized) in one side or both sides. About one quarter of women also have pain in the shoulder because of diaphragmatic (broad muscle under the lungs and heart that separates the chest from the abdomen and helps move the lungs during normal breathing) irritation from blood in the abdomen. During rupture, the pain usually becomes intense.

Other symptoms also occur less commonly. Dizziness and fainting occur in about one third of women with symptoms. Pregnancy symptoms also occur in about 20% of women with symptoms. 10% of the time, there can be an urge to have bowel movement (defecate).

SUMMARY

• It is important to be aware of the symptoms because an ectopic pregnancy can occur whether or not a woman is on oral contraceptives or has undergone tubal sterilization.
• The most common symptoms are (1) abdominal pain (usually caused by blood), (2) absence of expected menses and (3) unexpected bleeding through the vagina.
• Other less common symptoms include (1) referred shoulder pain, (2) dizziness and fainting, (3) pregnancy symptoms and (4) defecation urgency.

What findings can a doctor find upon physical examination of a woman with an ectopic pregnancy?
The most common finding is tenderness in the abdomen and pelvis. Half the time, a mass is felt on the sides of the uterus (adnexal mass). In about one third of women, an enlarged uterus is found which is smaller than would be found in a normal pregnancy, except when an interstitial pregnancy is present. Accelerated heart rate (tachycardia) and low blood pressure (hypotension) can be found if there has been profuse blood loss. However, in most early ectopic pregnancies no abnormal findings can be found.

SUMMARY

• Most common sign is abdominal and pelvic pain.
• Adnexal mass (50%)
• Smaller enlargement of uterus than would be expected in a normal pregnancy (33%).
• Tachycardia and hypotension can be found with profuse blood loss.
• However, in most early ectopic pregnancies, no abnormal findings can be found.

What other disorders can be confused with ectopic pregnancy?
Before rupture the symptoms and physical examination findings are non-specific and can occur with other gynecological disorders, such as salpingitis, impending or incomplete abortion, ruptured corpus luteum, appendicitis, dysfunctional uterine bleeding, adnexal torsion, degenerative uterine leiomyoma ("fibroids") and endometriosis.

SUMMARY

• Differential diagnosis (especially unruptured ectopic pregnancy) includes numerous other gynecological disorders (see above).

DIAGNOSIS

DIAGNOSIS FLOW CHART (will open in a new window)

TREATMENT

How is ectopic pregnancy treated?
Medical Therapy:

Methotrexate (a single dose) has demonstrated high success rates (86 to 94%) that are not skill-dependent and has become a standard medical treatment in appropriate patients. Methotrexate is an anti-cancer drug that has been used for a variety of conditions, such as hydatiform mole, leukemia, and psoriasis. The occurrence of miscarriages or malformed fetuses does not increase after its use. The best candidates for methotrexate therapy for ectopic pregnancy are those who are not suffering symptoms, have a blood level of -hCG of less than 5000 mIU/mL, tubal size of less than 3cm, no fetal cardiac activity on ultrasonography, and will come in to be followed closely.

If there is a heterotopic pregnancy (most common after in-vitro fertilization), methotrexate cannot be used and surgery is done. Measures are taken to preserve the normal pregnancy, but the presence of an "abnormal" pregnancy might still cause a miscarriage.

As with all medical treatment, there are risks and side effects. Despite observing low and declining -hCG levels in the blood, tubal rupture still can occur. With severe pelvic pain, monitoring of vital signs (heart rate, blood pressure, respiratory rate, temperature) and hematocrit (proportion of red blood cells in blood) can help differentiate between tubal abortion (usually 3-7 days after therapy and lasting less than 12 hours) and tubal rupture.

The side effects are usually mild and spontaneously resolve. The most common are stomatitis (ulcers in the mouth) and conjunctivitis (inflammation of the eye whites). Mild abdominal pain lasting only 1 to 2 days is not unusual. Rare side effects include dermatitis (skin rash) and pleuritis (irritation of the lung surface lining). It is important to regularly see your doctor to make sure the treatment is progressing properly. Thus, for those women who cannot be followed closely or who live far from a medical institution, surgery might be a better treatment option.

If there are no serious symptoms (such as severe abdominal pain), -hCG measurements and transvaginal ultrasonography are performed twice in the first week and then once every week.

Surgical Treatment

Surgery is done only if transvaginal ultrasonography shows an ectopic pregnancy in the Fallopian tube or a mass about the ovary suggestive of an ectopic pregnancy. If nothing is seen on ultrasonography, it is not likely to be seen at surgery either, so continuous close follow-up or medical treatment can be done.

Laparoscopic surgery (involving small incisions for the entry into the abdomen of a viewing camera and other surgical instruments) has been found to be superior to laparotomy (a large incision is made to open the abdomen for surgery). Most ectopic pregnancies can be treated by laparoscopic approach, even in the presence of a hemoperitoneum (blood collected in the abdomen) or a heterotopic pregnancy (simultaneous ectopic and normal pregnancies).

Persistent Ectopic Pregnancy

Persistent ectopic pregnancy is seen in 8.3% of women treated by laparoscopic salpingostomy and in 3.9% of these treated by laparotomy. However, this also depends on the expertise of the laparoscopic surgeon. In our institution, this is rarely encountered. Persistent ectopic pregnancy refers to the continued growth of trophoblastic tissue (part of the ectopic pregnancy still remaining after the surgery) after surgery. This tissue is often found in the proximal (closer to the uterus) portion of the tube; thus greater attention should be given this area. Piecemeal removal of the ectopic pregnancy with forceps is not recommended because trophoblastic tissue is more likely to be retained. It is better to flush the ectopic pregnancy out of the tube with suction irrigation under pressure.

Persistent ectopic pregnancy is detected by observing -hCG levels that do not decline after surgery and/or pelvic pain. Thus, a -hCG measurement is usually done a week after surgery. If the level remains high, a single dose of methotrexate can be given.

Expectant Management

Expectant management is done when an ectopic pregnancy is suspected, but fails to show an ectopic pregnancy. In expectant management, no treatment is given and the patient is followed closely with weekly transvaginal ultrasonography and weekly blood measurements of -hCG until the level is less than 10 mIU/mL.

Rh (rhesus) factor

All pregnant (including ectopic pregnancies) women who are Rh-negative (determined by a blood test) should receive Rh immunoglobulin (antibodies directed against the Rh).

The reason this is important is to ensure that the woman's own immune system does not develop memory cells for producing antibodies directed against Rh factor (which can be found on the red blood cells of individuals who are Rh-positive). This can happen if the embryo is Rh-positive and its blood comes into contact (termed "Rh sensitization") with the woman's (Rh-negative) immune system. This is dangerous because if the woman becomes capable of producing antibodies against Rh factor and she becomes pregnant again, her antibodies can attack the red blood cells of her fetus (if it is Rh-positive), lethally damaging the fetus. Thus, to prevent her from producing such antibodies, antibodies are injected that destroy any Rh-factor before her immune system can come into contact with Rh-factor.

This is not a concern for Rh-positive women because they will not be able to produce antibodies against Rh factor (otherwise she would attack her own red blood cells!).

SUMMARY

• Single dose methotrexate is best used for those are asymptomatic, whose -hCG is < 5000 mIU/mL, have tubal size < < 3 cm, have no fetal cardiac activity on ultrasonography, and will come in to be followed closely. It cannot be used if there is a heterotopic pregnancy.
• Despite low and declining -hCG levels, tubal rupture can still occur with methotrexate treatment. With severe pelvic pain, monitoring of vital signs and hematocrit can help differentiate between tubal abortion and tubal rupture.
• Most common side effects of methotrexate are (1) stomatitis, (2) conjunctivitis, (3) mild abdominal pain of short duration. Rare side effects include dermatitis and pleuritis.
• Surgery is done only if transvaginal ultrasonography shows an ectopic pregnancy.
• Laparoscopic surgery has been found to be superior to laparotomy and can treat most patients.
• Persistent ectopic pregnancy refers to the continued growth of trophoblastic tissue after surgery. Special attention should be given the proximal portion during surgery and the ectopic pregnancy should be flushed out with suction irrigation.
• Expectant management is done when ectopic pregnancy is suspected, but transvaginal ultrasonography does not show an ectopic pregnancy. The patient is followed with weekly ultrasonography and weekly -hCG measurements until the level is < 10 mIU/mL.
• All pregnant women who are Rh-negative should receive Rh immunoglobulin.

PROGNOSIS

How is my future fertility changed after an ectopic pregnancy?
The fertility outcome following an ectopic pregnancy is improved by several factors, such as younger age (<30) and greater number of previous births (>3). Subsequent pregnancy rate is lower in women who have a history of infertility, previous salpingitis, a rupture of an ectopic pregnancy, and adhesions about the Fallopian tube.

Most studies to date indicate that conservative treatment (medical or linear salpingostomy) provides comparable or higher rates of future normal pregnancies than radical surgery (salpingectomy), but the rate of recurrent ectopic pregnancies may be higher with conservative treatment.

SUMMARY

• The fertility outcome following an ectopic pregnancy is improved by several factors such as younger age (<30) and greater number of previous births (>3).
• It is worse with a (1) history of infertility, (2) pervious salpingitis, (3) rupture of an ectopic pregnancy, and (4) adhesions about the Fallopian tube.
• Most studies to date indicate that rates of future normal pregnancies are as good or better with conservative treatment than radical surgery, but the rate of recurrent ectopic pregnancies may be higher.

What are my risks for another ectopic pregnancy?
The average rate of repeat ectopic pregnancies after one ectopic pregnancy is 12%.

In women with indications of significant damage to a Fallopian tube, if surgery is to be performed, it might be preferred to remove that tube (salpingectomy) to decrease the risk of another ectopic pregnancy.

If a woman has had two ectopic pregnancies, it might be better to perform in-vitro fertilization for conception to reduce the risk of having a third ectopic pregnancy.

SUMMARY

• The average rate of recurrence is 12%.
• Significant tubal damage may indicate salpingectomy, if surgery is to be performed, to decrease the recurrence risk.
• History of two ectopic pregnancies may indicate the use of in-vitro fertilization to reduce the recurrence risk.

References:

References

Copyright Molson Medical Informatics Project at McGill University - 2000

Reprinted with permission from Molson Medical Informatics Project at McGill University

Note: All laparoscopic pictures reproduced with permission from "Atlas of Laparoscopic and Hysterectomy Techniques"

(Ed. T.Tulandi), W.B.Saunders, London, 1999.