Ectopic pregnancy

Blood in Morrison's pouch between the liver and kidney due to a ruptured ectopic pregnancy

The most common complication is rupture with internal bleeding which may lead to hypovolemic shock. Damage to the fallopian tubes can lead to difficulty becoming pregnant in the future. The woman's other fallopian tube may function sufficiently for pregnancy. After the removal of one damaged fallopian tube, pregnancy remains possible in the future. If both are removed, in-vitro fertilization remains an option for women hoping to become pregnant.[10][11][12]

Left fallopian tube with an ectopic pregnancy in a 25-year-old woman after a salpingectomy

Tubal pregnancy is when the egg is implanted in the fallopian tubes. 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.[22] Women who smoke have a higher chance of an ectopic pregnancy in the fallopian tubes. Smoking leads to risk factors of damaging and destroying cilia.[22] As cilia degenerate, the amount of time it takes for the fertilized egg to reach the uterus will increase. The fertilized egg, if it does not reach the uterus in time, will hatch from the non-adhesive zona pellucida and implant itself inside the fallopian tube, thus causing the ectopic pregnancy.

Women with pelvic inflammatory disease (PID) have a high occurrence of ectopic pregnancy.[23] This results from the build-up of scar tissue in the fallopian tubes, causing damage to cilia.[24] However, if 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. 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.[25][26][27] Asherman's syndrome usually occurs from intrauterine surgery, most commonly after D&C.[25] 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.[28]

Tubal ligation can predispose to ectopic pregnancy. 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%.[24] 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.

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. Vaginal douching is thought by some to increase ectopic pregnancies.[24] Women exposed to DES in utero (also known as "DES daughters") also have an elevated risk of ectopic pregnancy.[29] However, DES has not been used since 1971 in the United States.[29] 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.[30] The low socioeconomic status may be risk factors for ectopic pregnancy.[31]

An ultrasound showing a gestational sac with fetal heart in the fallopian tube has a very high specificity of ectopic pregnancy. It involves a long, thin transducer, covered with the conducting gel and a plastic/latex sheath and inserted into the vagina.[32] Transvaginal ultrasonography has a sensitivity of at least 90% for ectopic pregnancy.[5] The diagnostic ultrasonographic finding in ectopic pregnancy is an adnexal mass that moves separately from the ovary. In around 60% of cases, it is an inhomogeneous or a noncystic adnexal mass sometimes known as the "blob sign". It is generally spherical, but a more tubular appearance may be seen in case of hematosalpinx. This sign has been estimated to have a sensitivity of 84% and specificity of 99% in diagnosing ectopic pregnancy.[5] In the study estimating these values, the blob sign had a positive predictive value of 96% and a negative predictive value of 95%.[5] The visualization of an empty extrauterine gestational sac is sometimes known as the "bagel sign", and is present in around 20% of cases.[5] In another 20% of cases, there is visualization of a gestational sac containing a yolk sac or an embryo.[5] Ectopic pregnancies where there is visualization of cardiac activity are sometimes termed "viable ectopic".[5]

• 
  Transvaginal ultrasonography of an ectopic pregnancy, showing the field of view in the following image
• 
  A "blob sign", which consists of the ectopic pregnancy. The ovary is distinguished from it by having follicles, whereof one is visible in the field. This patient had an intrauterine device (IUD) with progestogen, whose cross-section is visible in the field, leaving an ultrasound shadow distally to it.
• 
  Ultrasound image showing an ectopic pregnancy where a gestational sac and fetus has been formed

A pregnancy not in the uterus[33]

The combination of a positive pregnancy test and the presence of what appears to be a normal intrauterine pregnancy does not exclude an ectopic pregnancy, since there may be either a heterotopic pregnancy or a "pseudosac", which is a collection of within the endometrial cavity that may be seen in up to 20% of women.[5]

A small amount of anechogenic-free fluid in the recto-uterine pouch is commonly found in both intrauterine and ectopic pregnancies.[5] The presence of echogenic fluid is estimated at between 28 and 56% of women with an ectopic pregnancy, and strongly indicates the presence of hemoperitoneum.[5] However, it does not necessarily result from tubal rupture but is commonly a result from leakage from the distal tubal opening.[5] As a rule of thumb, the finding of free fluid is significant if it reaches the fundus or is present in the vesico-uterine pouch.[5] A further marker of serious intra-abdominal bleeding is the presence of fluid in the hepatorenal recess of the subhepatic space.[5]

Currently, Doppler ultrasonography is not considered to significantly contribute to the diagnosis of ectopic pregnancy.[5]

A common misdiagnosis is of a normal intrauterine pregnancy is where the pregnancy is implanted laterally in an arcuate uterus, potentially being misdiagnosed as an interstitial pregnancy.[5]

Algorithm of the management of a pregnancy of unknown location, that is, a positive pregnancy test but no pregnancy is found on transvaginal ultrasonography.[5] If serum hCG at 0 hours is more than 1000 IU/L and there is no history suggestive of complete miscarriage, the ultrasonography should be repeated as soon as possible.[5]

Where no intrauterine pregnancy (IUP) is seen on ultrasound, measuring β-human chorionic gonadotropin (β-hCG) levels may aid in the diagnosis. The rationale is that a low β-hCG level may indicate that the pregnancy is intrauterine but yet too small to be visible on ultrasonography. While some physicians consider that the threshold where an intrauterine pregnancy should be visible on transvaginal ultrasound is around 1500 mIU/mL of β-hCG, a review in the JAMA Rational Clinical Examination Series showed that there is no single threshold for the β-human chorionic gonadotropin that confirms an ectopic pregnancy. Instead, the best test in a pregnant woman is a high resolution transvaginal ultrasound.[1] The presence of an adnexal mass in the absence of an intrauterine pregnancy on transvaginal sonography increases the likelihood of an ectopic pregnancy 100-fold (LR+ 111). When there are no adnexal abnormalities on transvaginal sonography, the likelihood of an ectopic pregnancy decreases (LR- 0.12). An empty uterus with levels higher than 1500 mIU/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. The serum hCG ratios and logistic regression models appear to be better than absolute single serum hCG level.[34] If the β-hCG falls on repeat examination, this strongly suggests a spontaneous abortion or rupture. The fall in serum hCG over 48 hours may be measured as the hCG ratio, which is calculated as:[5] ${\displaystyle hCG~ratio={\frac {hCG~at~48h}{hCG~at~0h}}}$

An hCG ratio of 0.87, that is, a decrease in hCG of 13% over 48 hours, has a sensitivity of 93% and specificity of 97% for predicting a failing pregnancy of unknown location (PUL).[5] The majority of cases of ectopic pregnancy will have serial serum hCG levels that increase more slowly than would be expected with an IUP (that is, a suboptimal rise), or decrease more slowly than would be expected with a failing PUL. However, up to 20% of cases of ectopic pregnancy have serum hCG doubling times similar to that of an IUP, and around 10% of EP cases have hCG patterns similar to a failing PUL.[5]

A laparoscopy or laparotomy can also be performed to visually confirm an ectopic pregnancy. This is generally reserved for women presenting with signs of an acute abdomen and hypovolemic shock.[5] 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.

Progesterone levels of less than 20 nmol/L have a high predictive value for failing pregnancies, whilst levels over 25 nmol/L are likely to predict viable pregnancies, and levels over 60 nmol/L are strongly so. This may help in identifying failing PUL that are at low risk and thereby needing less follow-up.[5] Inhibin A may also be useful for predicting spontaneous resolution of PUL, but is not as good as progesterone for this purpose.[5]

There are various mathematical models, such as logistic regression models and Bayesian networks, for the prediction of PUL outcome based on multiple parameters.[5] Mathematical models also aim to identify PULs that are low risk, that is, failing PULs and IUPs.[5]

Dilation and curettage (D&C) is sometimes used to diagnose pregnancy location with the aim of differentiating between an EP and a non-viable IUP in situations where a viable IUP can be ruled out. Specific indications for this procedure include either of the following:[5]

• No visible IUP on transvaginal ultrasonography with a serum hCG of more than 2000 mIU/mL.
• An abnormal rise in hCG level. A rise of 35% over 48 hours is proposed as the minimal rise consistent with a viable intrauterine pregnancy.
• An abnormal fall in hCG level, such as defined as one of less than 20% in two days.

The vast majority of ectopic pregnancies implant in the fallopian tube. Pregnancies can grow in the fimbrial end (5% of all ectopic pregnancies), the ampullary section (80%), the isthmus (12%), and the cornual and interstitial part of the tube (2%).[24] 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 bleeding. 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.[35]

Two percent of ectopic pregnancies occur in the ovary, cervix, or are intra-abdominal. Transvaginal ultrasound examination is usually able to detect a cervical pregnancy. An ovarian pregnancy is differentiated from a tubal pregnancy by the Spiegelberg criteria.[36]

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 intra-abdominal 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 is unavailable and reliance must be made on anecdotal reports.[37][38][39] However, the vast majority of abdominal pregnancies require intervention well before fetal viability because of the risk of bleeding.

With the increase in Cesarean sections performed worldwide,[40][41] Cesarean section ectopic pregnancies (CSP) are rare, but becoming more common. The incidence of CSP is not well known, however there have been estimates based on different populations of 1:1800–1:2216.[42][43] CSP are characterized by abnormal implantation into the scar from a previous cesarean section,[44] and allowed to continue can cause serious complications such as uterine rupture and hemorrhage.[43] Patients with CSP generally present without symptoms, however symptoms can include vaginal bleeding that may or may not be associated with pain.[45][46] The diagnosis of CSP is made by ultrasound and four characteristics are noted: (1) Empty uterine cavity with bright hyperechoic endometrial stripe (2) Empty cervical canal (3) Intrauterine mass in the anterior part of the uterine isthmus, and (4) Absence of the anterior uterine muscle layer, and/or absence or thinning between the bladder and gestational sac, measuring less than 5 mm.[44][47][48] Given the rarity of the diagnosis, treatment options tend to be described in case reports and series, ranging from medical with methotrexate or KCl[49] to surgical with dilation and curettage,[50] uterine wedge resection, or hysterectomy.[46] A double-balloon catheter technique has also been described,[51] allowing for uterine preservation. Recurrence risk for CSP is unknown, and early ultrasound in the next pregnancy is recommended.[44]

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.[1] 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 a heterotopic pregnancy is around 70%.[52]

A pregnancy in a rudimentary horn refers to a rare and life-threatening condition that occurs when a fertilized egg implants inside the small rudimentary horn of a unicornuate uterus, which is a type of congenital uterine abnormality caused by the incomplete development of one of the Müllerian ducts. This type of ectopic pregnancy is often results in rupture of the rudimentary horn between 10 and 15 weeks of gestation, leading to a high risk of morbidity and mortality.[53]

A persistent ectopic pregnancy refers to the continuation of trophoblastic 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.[54] 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 pregnancy to assure their decline, also methotrexate can be given at the time of surgery prophylactically.

Pregnancy of unknown location (PUL) is the term used for a pregnancy where there is a positive pregnancy test but no pregnancy has been visualized using transvaginal ultrasonography.[5] Specialized early pregnancy departments have estimated that between 8% and 10% of women attending for an ultrasound assessment in early pregnancy will be classified as having a PUL.[5] The true nature of the pregnancy can be an ongoing viable intrauterine pregnancy, a failed pregnancy, an ectopic pregnancy or rarely a persisting PUL.[5]

Because of frequent ambiguity on ultrasonography examinations, the following classification is proposed:[5]

In women with a pregnancy of unknown location, between 6% and 20% have an ectopic pregnancy.[5] In cases of pregnancy of unknown location and a history of heavy bleeding, it has been estimated that approximately 6% have an underlying ectopic pregnancy.[5] Between 30% and 47% of women with pregnancy of unknown location are ultimately diagnosed with an ongoing intrauterine pregnancy, whereof the majority (50–70%) will be found to have failing pregnancies where the location is never confirmed.[5]

Chorionic villus on histopathological examination of a tubal pregnancy

Persisting PUL is where the hCG level does not spontaneously decline and no intrauterine or ectopic pregnancy is identified on follow-up transvaginal ultrasonography.[5] A persisting PUL is likely either a small ectopic pregnancy that has not been visualized, or a retained trophoblast in the endometrial cavity.[5] Treatment should only be considered when a potentially viable intrauterine pregnancy has been definitively excluded.[5] A treated persistent PUL is defined as one managed medically (generally with methotrexate) without confirmation of the location of the pregnancy such as by ultrasound, laparoscopy or uterine evacuation.[5] A resolved persistent PUL is defined as serum hCG reaching a non-pregnant value (generally less than 5 IU/L) after expectant management, or after uterine evacuation without evidence of chorionic villi on histopathological examination.[5] In contrast, a relatively low and unresolving level of serum hCG indicates the possibility of an hCG-secreting tumour.[5]

Other conditions that cause similar symptoms include: miscarriage, ovarian torsion, and acute appendicitis, ruptured ovarian cyst, kidney stone, and pelvic inflammatory disease, among others.[1]

Most women with a PUL are followed up with serum hCG measurements and repeat TVS examinations until a final diagnosis is confirmed.[5] Low-risk cases of PUL that appear to be failing pregnancies may be followed up with a urinary pregnancy test after two weeks and get subsequent telephone advice.[5] Low-risk cases of PUL that are likely intrauterine pregnancies may have another TVS in two weeks to access viability.[5] High-risk cases of PUL require further assessment, either with a TVS within 48 h or additional hCG measurement.[5]

Early treatment of an ectopic pregnancy with methotrexate is a viable alternative to surgical treatment[55] which was developed in the 1980s.[56] If administered early in the pregnancy, methotrexate terminates the growth of the developing embryo; this may cause an abortion, or the developing embryo 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 embryonic mass > 3.5 cm.

Also, it may lead to the inadvertent termination of an undetected intrauterine pregnancy, or severe abnormality in any surviving pregnancy.[5] Therefore, it is recommended that methotrexate should only be administered when hCG has been serially monitored with a rise less than 35% over 48 hours, which practically excludes a viable intrauterine pregnancy.[5]

For nontubal ectopic pregnancy, evidence from randomised clinical trials in women with CSP is uncertain regarding treatment success, complications and side effects of methotrexate compared with surgery (uterine arterial embolization or uterine arterial chemoembolization).[57]

The United States uses a multi dose protocol of methotrexate (MTX) which involves four doses of intramuscular along with an intramuscular injection of folinic acid to protect cells from the effects of the drugs and to reduce side effects. In France, the single dose protocol is followed, but a single dose has a greater chance of failure.[58]

Surgical treatment: Laparoscopic view of an ectopic pregnancy located in the left fallopian tube, hematosalpinx is present on the left, the right tube is of normal appearance

The left fallopian tube containing the ectopic pregnancy has been removed (salpingectomy).

If bleeding 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 tube 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.[59] It is estimated that an acceptable rate of PULs that eventually undergo surgery is between 0.5 and 11%.[5] People that undergo salpingectomy and salpingostomy have a similar recurrent ectopic pregnancy rate of 5% and 8% respectively. Additionally, their intrauterine pregnancy rates are also similar, 56% and 61%.[60]

Autotransfusion of a woman's own blood as drained during surgery may be useful in those who have a lot of bleeding into their abdomen.[61]

Published reports that a re-implanted embryo survived to birth were debunked as false.[62]

Fertility following ectopic pregnancy depends upon several factors, the most important of which is a prior history of infertility.[65] The treatment choice does not play a major role; a randomized study in 2013 concluded that the rates of intrauterine pregnancy two years after treatment of ectopic pregnancy are approximately 64% with radical surgery, 67% with medication, and 70% with conservative surgery.[66] In comparison, the cumulative pregnancy rate of women under 40 years of age in the general population over two years is over 90%.[67]

Methotrexate does not affect future fertility treatments. The number of oocytes that were retrieved before and after treatment with methotrexate does not change.[68]

In case of ovarian ectopic pregnancy, the risk of subsequent ectopic pregnancy or infertility is low.[69]

There is no evidence that massage improves fertility after ectopic pregnancy.[70]