Ectopic pregnancy

An ectopic pregnancy, or eccysis, is a complication of pregnancy in which the embryo implants outside the uterine cavity. With rare exceptions, ectopic pregnancies are not viable. Furthermore, they are dangerous for the mother, since internal haemorrhage is a life threatening complication. Most ectopic pregnancies occur in the Fallopian tube (so-called tubal pregnancies), but implantation can also occur in the cervix, ovaries, and abdomen. An ectopic pregnancy is a potential medical emergency, and, if not treated properly, can lead to death.

In a normal pregnancy, the fertilized egg enters the uterus and settles into the uterine lining where it has plenty of room to divide and grow. About 1% of pregnancies are in an ectopic location with implantation not occurring inside of the womb, and of these 98% occur in the Fallopian tubes.

Detection of ectopic pregnancy in early gestation has been achieved mainly due to enhanced diagnostic capability. Despite all these notable successes in diagnostics and detection techniques ectopic pregnancy remains a source of serious maternal morbidity and mortality worldwide, especially in countries with poor prenatal care.

In a typical ectopic pregnancy, the embryo adheres to the lining of the fallopian tube and burrows into the tubal lining. Most commonly this invades vessels and will cause bleeding. This intratubal bleeding hematosalpinx expels the implantation out of the tubal end as a tubal abortion. Tubal abortion is a common type of miscarriage. There is no inflammation of the tube in ectopic pregnancy. The pain is caused by prostaglandins released at the implantation site, and by free blood in the peritoneal cavity, which is a local irritant. Sometimes the bleeding might be heavy enough to threaten the health or life of the woman. Usually this degree of bleeding is due to delay in diagnosis, but sometimes, especially if the implantation is in the proximal tube (just before it enters the uterus), it may invade into the nearby Sampson artery, causing heavy bleeding earlier than usual.

If left untreated, about half of ectopic pregnancies will resolve without treatment. These are the tubal abortions. The advent of methotrexate treatment for ectopic pregnancy has reduced the need for surgery; however, surgical intervention is still required in cases where the Fallopian tube has ruptured or is in danger of doing so. This intervention may be laparoscopic or through a larger incision, known as a laparotomy.

Tubal pregnancy
The vast majority of ectopic pregnancies implant in the Fallopian tube. Pregnancies can grow in the fimbrial end (5% of all ectopics), the ampullary section (80%), the isthmus (12%), and the cornual and interstitial part of the tube (2%). Mortality of a tubal pregnancy at the isthmus or within the uterus (interstitial pregnancy) is higher as there is increased vascularity that may result more likely in sudden major internal hemorrhage. A review published in 2010 supports the hypothesis that tubal ectopic pregnancy is caused by a combination of retention of the embryo within the fallopian tube due to impaired embryo-tubal transport and alterations in the tubal environment allowing early implantation to occur.

Nontubal ectopic pregnancy
Two percent of ectopic pregnancies occur in the ovary, cervix, or are intraabdominal. Transvaginal ultrasound examination is usually able to detect a cervical pregnancy. An ovarian pregnancy is differentiated from a tubal pregnancy by the Spiegelberg criteria.

While a fetus of ectopic pregnancy is typically not viable, very rarely, a live baby has been delivered from an abdominal pregnancy. In such a situation the placenta sits on the intraabdominal organs or the peritoneum and has found sufficient blood supply. This is generally bowel or mesentery, but other sites, such as the renal (kidney), liver or hepatic (liver) artery or even aorta have been described. Support to near viability has occasionally been described, but even in third world countries, the diagnosis is most commonly made at 16 to 20 weeks gestation. Such a fetus would have to be delivered by laparotomy. Maternal morbidity and mortality from extrauterine pregnancy are high as attempts to remove the placenta from the organs to which it is attached usually lead to uncontrollable bleeding from the attachment site. If the organ to which the placenta is attached is removable, such as a section of bowel, then the placenta should be removed together with that organ. This is such a rare occurrence that true data are unavailable and reliance must be made on anecdotal reports. However, the vast majority of abdominal pregnancies require intervention well before fetal viability because of the risk of hemorrhage.

Heterotopic pregnancy
In rare cases of ectopic pregnancy, there may be two fertilized eggs, one outside the uterus and the other inside. This is called a heterotopic pregnancy. Often the intrauterine pregnancy is discovered later than the ectopic, mainly because of the painful emergency nature of ectopic pregnancies. Since ectopic pregnancies are normally discovered and removed very early in the pregnancy, an ultrasound may not find the additional pregnancy inside the uterus. When hCG levels continue to rise after the removal of the ectopic pregnancy, there is the chance that a pregnancy inside the uterus is still viable. This is normally discovered through an ultrasound.

Although rare, heterotopic pregnancies are becoming more common, likely due to increased use of IVF. The survival rate of the uterine fetus of an ectopic pregnancy is around 70%.

Successful pregnancies have been reported from ruptured tubal pregnancy continuing by the placenta implanting on abdominal organs or on the outside of the uterus.

Persistent ectopic pregnancy
A persistent ectopic pregnancy refers to the continuation of trophoplastic growth after a surgical intervention to remove an ectopic pregnancy. After a conservative procedure that attempts to preserve the affected fallopian tube such as a salpingotomy, in about 15-20% the major portion of the ectopic growth may have been removed, but some trophoblastic tissue, perhaps deeply embedded, has escaped removal and continues to grow, generating a new rise in hCG levels. After weeks this may lead to new clinical symptoms including bleeding. For this reason hCG levels may have to be monitored after removal of an ectopic to assure their decline, also methotrexate can be given at the time of surgery prophylactically.

Signs and symptoms
Early symptoms are either absent or subtle. Clinical presentation of ectopic pregnancy occurs at a mean of 7.2 weeks after the last normal menstrual period, with a range of 5 to 8 weeks. Later presentations are more common in communities deprived of modern diagnostic ability.

Early signs include:
 * Pain in the lower abdomen, and inflammation (pain may be confused with a strong stomach pain, it may also feel like a strong cramp).
 * Pain while urinating.
 * Pain and discomfort, usually mild. A corpus luteum on the ovary in a normal pregnancy may give very similar symptoms.
 * Vaginal bleeding, usually mild. An ectopic pregnancy is usually a failing pregnancy and falling levels of progesterone from the corpus luteum on the ovary cause withdrawal bleeding. This can be indistinguishable from an early miscarriage or the 'implantation bleed' of a normal early pregnancy.
 * Pain while having a bowel movement.

Patients with a late ectopic pregnancy typically experience pain and bleeding. This bleeding will be both vaginal and internal and has two discrete pathophysiologic mechanisms:
 * External bleeding is due to the falling progesterone levels.
 * Internal bleeding (hematoperitoneum) is due to hemorrhage from the affected tube.

The differential diagnosis at this point is between miscarriage, ectopic pregnancy, and early normal pregnancy. The presence of a positive pregnancy test virtually rules out pelvic infection as it is rare indeed to find pregnancy with an active pelvic inflammatory disease (PID). The most common misdiagnosis assigned to early ectopic pregnancy is PID.

More severe internal bleeding may cause:
 * Lower back, abdominal, or pelvic pain.
 * Shoulder pain. This is caused by free blood tracking up the abdominal cavity and irritating the diaphragm, and is an ominous sign.
 * There may be cramping or even tenderness on one side of the pelvis.
 * The pain is of recent onset, meaning it must be differentiated from cyclical pelvic pain, and is often getting worse.

Ectopic pregnancy can mimic symptoms of other diseases such as appendicitis, other gastrointestinal disorder, problems of the urinary system, as well as pelvic inflammatory disease and other gynaecologic problems.

Causes
There are a number of risk factors for ectopic pregnancies. However, in as many as one third to one half of ectopic pregnancies, no risk factors can be identified. Risk factors include: pelvic inflammatory disease, infertility, use of an intrauterine device (IUD), previous exposure to DES, tubal surgery, intrauterine surgery (e.g. D&C), smoking, previous ectopic pregnancy, and tubal ligation.

Although older texts suggest an association between endometriosis and ectopic pregnancy this is not evidence based and current research suggests no association between endometriosis and ectopic pregnancy.

Cilial damage and tube occlusion
Hair-like cilia located on the internal surface of the Fallopian tubes carry the fertilized egg to the uterus. Fallopian cilia are sometimes seen in reduced numbers subsequent to an ectopic pregnancy, leading to a hypothesis that cilia damage in the Fallopian tubes is likely to lead to an ectopic pregnancy. Women with pelvic inflammatory disease (PID) have a high occurrence of ectopic pregnancy. This results from the build-up of scar tissue in the Fallopian tubes, causing damage to cilia. If however both tubes were completely blocked, so that sperm and egg were physically unable to meet, then fertilization of the egg would naturally be impossible, and neither normal pregnancy nor ectopic pregnancy could occur. Tubal surgery for damaged tubes might remove this protection and increase the risk of ectopic pregnancy. Intrauterine adhesions (IUA) present in Asherman's syndrome can cause ectopic cervical pregnancy or, if adhesions partially block access to the tubes via the ostia, ectopic tubal pregnancy. Asherman's syndrome usually occurs from intrauterine surgery, most commonly after D&C. Endometrial/pelvic/genital tuberculosis, another cause of Asherman's syndrome, can also lead to ectopic pregnancy as infection may lead to tubal adhesions in addition to intrauterine adhesions.

Tubal ligation can predispose to ectopic pregnancy. Seventy percent of pregnancies after tubal cautery are ectopic, while 70% of pregnancies after tubal clips are intrauterine. Reversal of tubal sterilization (Tubal reversal) carries a risk for ectopic pregnancy. This is higher if more destructive methods of tubal ligation (tubal cautery, partial removal of the tubes) have been used than less destructive methods (tubal clipping). A history of a tubal pregnancy increases the risk of future occurrences to about 10%. This risk is not reduced by removing the affected tube, even if the other tube appears normal. The best method for diagnosing this is to do an early ultrasound.

Other
Although some investigations have shown that patients may be at higher risk for ectopic pregnancy with advancing age, it is believed that age is a variable which could act as a surrogate for other risk factors. Also, it has been noted that smoking is associated with ectopic risk. Vaginal douching is thought by some to increase ectopic pregnancies. Women exposed to diethylstilbestrol (DES) in utero (also known as "DES daughters") also have an elevated risk of ectopic pregnancy, up to 3 times the risk of unexposed women. It has also been suggested that pathologic generation of nitric oxide through increased iNOS production may decrease tubal ciliary beats and smooth muscle contractions and thus affect embryo transport, which may consequently result in ectopic pregnancy.

Diagnosis
An ectopic pregnancy should be considered in any woman with abdominal pain or vaginal bleeding who has a positive pregnancy test. An ultrasound showing a gestational sac with fetal heart in the fallopian tube is clear evidence of ectopic pregnancy.

An abnormal rise in blood β-human chorionic gonadotropin (β-hCG) levels may indicate an ectopic pregnancy. The threshold of discrimination of intrauterine pregnancy is around 1500 IU/ml of β-hCG. A high resolution, transvaginal ultrasound showing no intrauterine pregnancy is presumptive evidence that an ectopic pregnancy is present if the threshold of discrimination for β-hCG has been reached. An empty uterus with levels higher than 1500 IU/ml may be evidence of an ectopic pregnancy, but may also be consistent with an intrauterine pregnancy which is simply too small to be seen on ultrasound. If the diagnosis is uncertain, it may be necessary to wait a few days and repeat the blood work. This can be done by measuring the β-hCG level approximately 48 hours later and repeating the ultrasound. If the β-hCG falls on repeat examination, this strongly suggests a spontaneous abortion or rupture.

A laparoscopy or laparotomy can also be performed to visually confirm an ectopic pregnancy. Often if a tubal abortion or tubal rupture has occurred, it is difficult to find the pregnancy tissue. A laparoscopy in very early ectopic pregnancy rarely shows a normal looking fallopian tube.

Culdocentesis, in which fluid is retrieved from the space separating the vagina and rectum, is a less commonly performed test that may be used to look for internal bleeding. In this test, a needle is inserted into the space at the very top of the vagina, behind the uterus and in front of the rectum. Any blood or fluid found may have been derived from a ruptured ectopic pregnancy.

Cullen's sign can indicate a ruptured ectopic pregnancy.

Medical
Early treatment of an ectopic pregnancy with methotrexate is a viable alternative to surgical treatment since at least 1993. If administered early in the pregnancy, methotrexate terminates the growth of the developing embryo; this may cause an abortion, or the tissue may then be either resorbed by the woman's body or pass with a menstrual period. Contraindications include liver, kidney, or blood disease, as well as an ectopic mass > 3.5 cm.

Surgical
If hemorrhage has already occurred, surgical intervention may be necessary. However, whether to pursue surgical intervention is an often difficult decision in a stable patient with minimal evidence of blood clot on ultrasound.

Surgeons use laparoscopy or laparotomy to gain access to the pelvis and can either incise the affected Fallopian and remove only the pregnancy (salpingostomy) or remove the affected tube with the pregnancy (salpingectomy). The first successful surgery for an ectopic pregnancy was performed by Robert Lawson Tait in 1883.

Complications
The most common complication is rupture with internal haemorrhage which may lead to hypovolaemic shock. Death from rupture is rare in women who have access to modern medical facilities.

Prognosis
The prognosis in Western countries is very good; maternal death is rare. For instance, in the UK, between 2003 and 2005 there were 32,100 ectopic pregnancies resulting in 10 maternal deaths (meaning that 1 in 3,210 women with an ectopic pregnancy died).

In the developing world, however, especially in Africa, the death rate is very high, and ectopic pregnancies are a major cause of death among women of childbearing age.

Future fertility
Fertility following ectopic pregnancy depends upon several factors, the most important of which is a prior history of infertility. The treatment choice, whether surgical or nonsurgical, also plays a role. For example, the rate of intrauterine pregnancy may be higher following methotrexate compared to surgical treatment. Rate of fertility may be better following salpingostomy than salpingectomy.

Cases with live birth
There have been cases where ectopic pregnancy lasted many months and ended in a live baby delivered by laparotomy.

In July 1999, Lori Dalton gave birth by Caesarean section in Ogden, Utah, USA, to a healthy baby girl who had developed outside of the uterus. Previous ultrasounds had not discovered the problem. "[Sage Dalton]'s delivery was slated as a routine Cesarean birth at Ogden Regional Medical Center in Utah. When Dr. Naisbitt performed Lori’s Cesarean, he was astonished to find Sage within the amniotic membrane outside the womb […]." "But what makes this case so rare is that not only did mother and baby survive — they're both in perfect health. John Dalton [(the father)] took home video inside the delivery room. Saige came out doing extremely well because even though she had been implanted outside the womb, a rich blood supply from a benign fibrous tumor along the outer uterus wall had nourished her with a rich source of blood."

On 19 April 2008 an English woman, Jayne Jones (age 37) who had an ectopic pregnancy attached to the omentum, the fatty covering of her large bowel, gave birth to her son Billy by a laparotomy at 28 weeks gestation. The surgery, the first of its kind to be performed in the UK, was successful, and both mother and baby survived.

On May 29, 2008 an Australian woman, Meera Thangarajah (age 34), who had an ectopic pregnancy in the ovary, gave birth to a healthy full term 6 pound 3 ounce (2.8 kg) baby girl, Durga, via Caesarean section. She had no problems or complications during the 38‑week pregnancy.

In September 1999 an English woman, Jane Ingram (age 32) gave birth to triplets: Olivia, Mary and Ronan, with an extrauterine fetus (Ronan) and intrauterine twins. All three survived. The intrauterine twins were taken out first.

In other animals than humans
Ectopic gestation exists in other mammals than humans.

In sheep, it can go to term, with mammary preparation to parturition, and expulsion efforts.

The fetus can be removed by caesarian section.

Pictures of caesarian section of a euthanized ewe, 5 days after parturition signs.