DEFINITIONy In this complication, fertilized ovum is implanted

and developed on other tissues of reproductive system than the uterine wall. In ectopic pregnancy, the fetus develops in the tissues of fallopian tube, cervix, ovaries, and abdomen. The ectopic pregnancies are mostly, about 98%, implanted in fallopian tube and are known as tubal pregnancies.

History of the Procedure Ectopic pregnancyy derived from the Greek word ektopos, meaning out of

place, and it refers to the implantation of a fertilized egg in a location outside of the uterine cavity, including the fallopian tubes, cervix, ovary, cornual region of the uterus, and the abdominal cavity. This abnormally implanted gestation grows and draws its blood supply from the site of abnormal implantation. As the gestation enlarges, it creates the potential for organ rupture because only the uterine cavity is designed to expand and accommodate fetal development. Ectopic pregnancy can lead to massive hemorrhage, infertility, or death

Etiologyy Pelvic inflammatory disease y Like pelvic infections, conditions such as

endometriosis, fibroid tumors y 3 Infertility One study has demonstrated that infertility patients with luteal phase defects have a statistically higher ectopic pregnancy

y Used an IUDApproximately 50% of pregnancies in

women using intrauterine devices (IUDs) will be located outside of the uterus. y Already faced ectopic pregnancy: Almost 10% of women who had already faced ectopic pregnancy have chances of going through the same in their next pregnancy. After one ectopic pregnancy

y Tubal ligation: In tubal ligation, surgery is done to

treat the damaged fallopian tubes. The procedure increases the chances of ectopic pregnancy. y Smoking habit: Women who do lot of smoking are on risky side of having this pregnancy. y Exposed to DES: Women who are in touch or exposed to diethylstilbestrol (DES) have three times more chances of having ectopic pregnanct than who are not.

y a T-shaped uterus, prior abdominal surgery, failure

with progestin-only contraception, and ruptured appendix y salpingitis isthmica nodosum y Use of fertility drugs or assisted reproductive technologyy Late pregnancy The highest rate of ectopic pregnancy

occurs in women aged 35-44 years

Major contributing factors and associated relative risks for ectopic pregnancy arey y y y y y y y y y y

Current use of intrauterine device 11.5% Use of Clomiphene citrate 10% Prior tubal surgery 5.6% Pelvic inflammatory disease 4.0% Infertility 2.9% Induced abortion 2.5% Abdominal surgery 2.3% T shaped uterus 2% Myomata 1.7% Progestin only contraceptives 1.6% Adhesions 2.4%

Pathophysiologyy Most ectopic pregnancies are located in the fallopian

tube (

Sites and frequencies of ectopic pregnancy. By Donna M. Peretin, RN. (A) Ampullary, 80%; (B) Isthmic, 12%; (C) Fimbrial, 5%; (D) Cornual/Interstitial, 2%; (E) Abdominal, 1.4%; (F) Ovarian, 0.2%; (G) Cervical

y The most common site is the ampullary portion of the

tube, where over 80% occur. The next most common sites are the isthmic segment of the tube (12%), the fimbria (5%), and the cornual and interstitial region of the tube (2%). Nontubal sites of ectopic pregnancy are a rare occurrence, with abdominal pregnancies accounting for 1.4% of ectopic pregnancies and ovarian and cervical sites accounting for 0.2% each.

Ectopic Pregnancies Symptomsy abdominal pain y vaginal bleeding. Ectopic pregnancy happening at

later stage is analyzed through external bleeding and internal bleeding. External bleeding is due to decrease in progesterone level and internal bleeding is due to hemorrhage from the affected fallopian tubes.

y the absence of menstrual periods (amenorrhea),

y Ectopic pregnancy can be confused to pelvic

inflammatory disease, hence proper diagnosis will help in finding the right complication

y that only 40-50% of patients with an ectopic

pregnancy present with vaginal bleeding, 50% have a palpable adnexal mass, and 75% may have abdominal tenderness. Approximately 20% of patients with ectopic pregnancies are hemodynamically compromised at initial presentation, which is highly suggestive of rupture. Fortunately, using modern diagnostic techniques, most ectopic pregnancies may be diagnosed prior to rupturing.

presentation. according to sitey intratubal y a-complete happy end y b-in complete bleeding cause peritubal hematocele

pelvic hematocele int he y c-missed carneusmole

y extratubal rupture y a-intraperitenial bleeding y b-intraligament pelvic hematocele y both a and b can cause advanced abd pregenancy y it may either live or die or cause lethopedian

clacification

y uterine ectopic y a-cervical abortin severe he y b-diverticular abortion y c-angular full term with abnormal presentation y d-rudmenet horn rupture intra or extra legement

How is ectopic pregnancy diagnosed?y Laproscopy or laparotomy: The presence of ectopic

pregnancy can be confirmed by performing laproscopy or laparotomy. It is essential in locating tubal abortion and tubul rupturing. Laparoscopy viewing instruments are inserted through small incisions in the abdominal wall to visualize the structures in the abdomen and pelvis, thereby revealing the site of the ectopic pregnancy.

Ectopic pregnancy. Laparoscopic picture of an unruptured right ampullary tubal pregnancy with bleeding out of the fimbriated end resulting in hemoperitoneum.

OVARIAN ECTOPIC

Imaging Studiesy Ultrasound: An ultrasound is helpful in locating a

gestational sac with fetus developed in the fallopian tube that clearly showcases the presence of ectopic pregnancy.. ultrasound can usually help to establish the diagnosis.. Transvaginal ultrasound is the most useful test to visualize an ectopic pregnancy. In this test, an ultrasound probe is inserted into the vagina,

y Transvaginal ultrasound can reveal the gestational sac

in either a normal (intrauterine) pregnancy or an ectopic pregnancy y Visualization of an intrauterine sac, with or without fetal cardiac activity, often is adequate to exclude ectopic pregnancy. The exception to this is in the case of heterotropic pregnancies, which occur from 1 in 4000 to 1 in 30,000 spontaneous pregnancies. Screening

y Transvaginal US, with its greater resolution, can be

used to visualize an intrauterine pregnancy by 24 days postovulation, or 38 days after last menstrual period, which is about 1 week earlier than transabdominal USy The gestational sac, which is a sonographic term and not an anatomic term, is the first structure that is recognizable on transvaginal US. It has a thick echogenic rim surrounding a sonolucent center corresponding to the trophoblastic decidual reaction surrounding the chorionic sac. Structures that represent a developing embryo cannot be recognized until a later time.

y A pseudosac is a collection of fluid within the

endometrial cavity created by bleeding from the decidualized endometrium often associated with an extrauterine pregnancy and should not be mistaken for a normal early intrauterine pregnancy. The true gestational sac is located eccentrically within the uterus beneath the endometrial surface, whereas the pseudosac fills the endometrial cavity.

y The yolk sac is the first visible structure within the

gestational sac, and it resembles a distinct circular structure with a bright echogenic rim and a sonolucent center. It can first be recognized 3 weeks postconception, about 5 weeks after last menstrual period. The embryo is recognized first as a thickening along the edge of the yolk sac, and embryonic cardiac motion can be observed 3.5-4 weeks postconception, about 5.5-6 weeks after the last menstrual period.

y In the absence of reliable menstrual and ovulatory

history, a discriminatory zone of bhCG levels validates the US findings. The discriminatory zone is the level of bhCG, using the Third International Standard for quantitative bhCG, at which all intrauterine pregnancies should be visible on US. With abdominal US, that level is 6000-6500 mIU/mL, but high-resolution transvaginal US has reduced this level to 1500-1800 mIU/mL. If transvaginal US does not reveal an intrauterine pregnancy when the discriminatory bhCG levels are reached, the pregnancy generally can be considered extrauterine.

y An exception to this is multiple gestations. Kadar et al

reported that patients with normal multiple gestates were found to have levels of bhCG above the discriminatory zone before any US evidence of the gestation was apparent.1 They showed multiple gestations with bhCG levels of up to 2300 mIU/mL before transvaginal US recognition. Therefore, if a multiple gestation is suspected, as in pregnancies resulting from assisted reproduction, the bhCG discriminatory zone must be used cautiously. Remember that a discriminatory zone is operator and institution dependent, and the clinician must be aware of the zone used by that institution prior to interpreting results

y The effectiveness of using US with

discriminatory zone of bhCG levels has beenwell established in the literature. y In one large study of more than 1200 patients by Barnhart et al, 78.8% of patients were diagnosed definitively at the initial visit using an algorithm that included the use of US along with serum bhCG levels above the discriminatory zone.4 According to this study, if the patient's serum bhCG level was above the established discriminatory zone at initial presentation and an intrauterine sac was not identified, an operative approach involving curettage and possible operative laparoscopy was used to diagnose ectopic pregnancy.

y If the patient's serum bhCG levels were below the discriminatory zone, serial bhCG titers were performed every 2 days. Once a patient's levels reached the discriminatory zone, US was performed. If, however, the patient's bhCG levels failed to rise appropriately (ie, at least 66% in 2 d), operative intervention was undertaken with dilatation and curettage or laparoscopy to exclude the diagnosis of ectopic pregnancy. With this protocol, Barnhart et al reported 100% sensitivity and a specificity of 99.9%.4

y The value of US is highlighted further in its ability to

demonstrate free fluid in the cul-de-sac. While free fluid could represent hemoperitoneum, it is not specific for ruptured ectopic pregnancy. Free fluid on US can represent physiological peritoneal fluid or blood from retrograde menstruation and unruptured ectopic pregnancies. Furthermore, US can be used to detect the presence of other pathological conditions that may display the signs and symptoms of ectopic pregnancy

Doppler USy Color-flow Doppler US has been demonstrated to

improve the diagnostic sensitivity and specificity of transvaginal US, especially in cases where a gestational sac is questionable or absent. A study of 304 patients at high risk for ectopic pregnancy found that the use of color-flow Doppler US, compared with transvaginal US alone, increases the diagnostic sensitivity from 71-87% for ectopic pregnancy, from 24-59% for failed intrauterine pregnancy, and from 90-99% for viable intrauterine pregnancy.

Detailed close-up of tubal pregnancy

Tubal ectopic pregnancy circled in red 4.5 mm fetal pole (between cursors) in green Pregnancy yolk sac blue

Ultrasound showing uterus and tubal pregnancy

Uterus outlined in red Uterine lining in green Tubal ectopic pregnancy yellow Fluid in uterus at blue circle is a "pseudosac" Looks like early pregnancy sac, but is not

laboratory Studiesy Patients with early normal intrauterine pregnancies

often present with signs and symptoms similar to those encountered in patients with ectopic pregnancies and other gynecological or gastrointestinal conditions. The availability of various biochemical, ultrasonographic, and surgical modalities can aid the health care provider today in establishing a definitive diagnosis and differentiating among various conditions.

y In order to reduce the morbidity and mortality associated with ectopic pregnancy, a high index of suspicion is necessary to make a prompt and early diagnosis. As mentioned earlier, neither risk factors nor signs and symptoms of ectopic pregnancy are sensitive or specific enough to establish a definitive diagnosis. Hence, screen any female patient in the reproductive years presenting with abdominal pain, cramping, or vaginal bleeding for pregnancy. In recent years, serum and urine assays for the beta subunit of human chorionic gonadotropin (bhCG) have been developed to detect a pregnancy before the first missed period. While some commercial urine test kits are able to detect bhCG in early gestation, they are associated with varying false-negative rates. In addition, the need for a quantitative value makes serum bhCG the criterion standard for biochemical testing

y1

Beta human chorionic gonadotropin

y In early healthy intrauterine pregnancies, serum levels

of bhCG double approximately every 2 days (1.4-2.1 d). Kadar et al established that the lower limit of the reference range to which serum bhCG should increase during a 2-day period is 66%.1 For example, a pregnant patient with a serum bhCG level of 100 mIU/mL should have a serum bhCG level of at least 166 mIU/mL 2 days later. An increase in bhCG of less than 66% is associated with an abnormal intrauterine pregnancy or an extrauterine pregnancy. Remember that 15% of healthy intrauterine pregnancies do not increase by 66% and that 13% of all ectopic pregnancies have normally rising bhCG levels of at least 66% in 2 days.

y Shepherd et al demonstrated that 64% of very early

ectopic pregnancies initially may have normal doubling bhCG levels.2 Barnhart et al more recently reported that the minimum rise in bhCG for a potentially viable pregnancy in women who present with vaginal bleeding or pain is 53% per 2 days (up to5,000IU/L).3 Hence, intervention when the bhCG level rises less than 66% but more than 53% should be undertaken according to other clinical and biochemical criteria.

y Furthermore, even though ectopic pregnancies have

been established to have lower mean serum bhCG levels than healthy pregnancies, no single serum bhCG level is diagnostic of an ectopic pregnancy. In short, serial serum bhCG levels are necessary to differentiate between normal and abnormal pregnancies and to monitor resolution of ectopic pregnancy once therapy has been initiated.

y The major disadvantage in relying on serial titers to

distinguish between normal and abnormal pregnancies is the potential for delay in reaching the diagnosis. Furthermore, while serial bhCG titers may be used to differentiate between a normal and an abnormal gestation, the test does little to indicate the location of the pregnancy. Hence, additional diagnostic modalities, including US and other biochemical markers, are needed.

Peak HCG level 10,000

% of ectopics 45% 21% 15% 10% 9%

Trend of hCG titers with ectopic pregnancies

Trend of HCG levels

% of cases

Falling

57%

Abnormally rising

36%

Normally rising

7%

Progesteroney

A single serum progesterone level is another tool that is useful in differentiating abnormal gestations from healthy intrauterine pregnancies. Serum progesterone levels are not gestational age dependent, they remain relatively constant during the first trimester of normal and abnormal pregnancies, they do not return to the reference range if initially abnormal, and they do not correlate with bhCG levels. However, no consensus on a single value that differentiates between a normal and an abnormal pregnancy currently exists. Several authors have proposed different cutoffs with varying sensitivity and specificity. A progesterone value of greater than 25 ng/mL excluded ectopic pregnancy with 97.4% certainty in one large study. Furthermore, levels of less than or equal to 5 ng/mL indicated a nonviable pregnancy, ectopic or intrauterine, and excluded normal pregnancy with 100% sensitivity.

y Although inexpensive, the usefulness of serum

progesterone is limited in that a significant number of results fall in the equivocal range of 5-25 ng/mL. Also, this test is unreliable in differentiating between normal and abnormal pregnancies in patients who conceive after IVF because of excessive progesterone production from multiple corpora lutea, as well as the practice of pharmacologic progesterone supplementation

Other markersy Several other serum and urine markers are currently

under investigation to help distinguish normal and abnormal pregnancies. These include serum estradiol, inhibin, pregnancy-associated plasma protein A, pregnanediol glucuronide, placental proteins, creatinine kinase, and a quadruple screen of serum progesterone, bhCG, estriol, and alfa-fetoprotein. y At present, use each of these markers only as a research tool until substantial clinical evidence proves their role in clinical medicine.

Diagnostic Proceduresy Dilatation and curettagey A simple way to rule out an ectopic pregnancy is to establish

an intrauterine pregnancy. Dilation and curettage is a rapid cost-effective method to diagnose ectopic pregnancy. Once an abnormal pregnancy is established by bhCG or progesterone levels, curettage can help differentiate between an intrauterine or ectopic pregnancy. If tissue obtained is positive for villi by floating in saline or by histological diagnosis on frozen or permanent section, then a nonviable intrauterine pregnancy has occurred. In the absence of villi, the diagnosis of ectopic pregnancy is made. Laparoscopy can be performed at that time, or the case may be followed by serial serum bhCG levels and treated medically or surgically at a later time, depending on the clinical setting.

y This method of diagnostic dilatation and curettage may only

be used, of course, in cases where continuation of a pregnancy is not desired even if it were an intrauterine gestation. y In a patient undergoing a dilatation and curettage for the diagnosis of ectopic pregnancy, obtaining consent for a diagnostic, and possibly operative, laparoscopy is also necessary in case the diagnosis of ectopic pregnancy is made; this spares the patient exposure to an additional operative procedure. y While dilatation and curettage is easy and effective, it can provide false reassurance in cases of heterotropic pregnancies where multiple gestations are present, with at least one being intrauterine and one being extrauterine.

y Culdocentesisy Culdocentesis is another rapid and inexpensive method

of evaluation for ruptured ectopic pregnancy. It is performed by inserting a needle through the posterior fornix of the vagina into the cul-de-sac and attempting to aspirate blood. When nonclotting blood is found in conjunction with a suspected ectopic pregnancy, operative intervention is indicated because the likelihood of a ruptured ectopic pregnancy is high.

y Culdocentesis is of historical interest because its use

today is rare. It is associated with a high false-negative rate (10-14%) usually reflecting blood from an unruptured ectopic pregnancy, ruptured corpus luteum, incomplete abortion, and retrograde menstruation. Furthermore, the improved technology with US and hormonal assays is far superior in sensitivity and specificity in reaching the correct

y

Ectopic Pregnancies Treatmenty Nonsurgical treatment y Nonsurgical treatments are given if the ectopic pregnancy is diagnosed at the early stage of pregnancy. In this, antimetabolite methotrexate is given to disrupt the growth of embryo to eliminate the pregnancyMedical therapy involving methotrexate may be indicated in certain patients. A number of factors must be considered. The patient must be hemodynamically stable, with no signs or symptoms of active bleeding or hemoperitoneum. Furthermore, she must be reliable, compliant, and able to return for follow-up. Another factor is size of the gestation, which should not exceed 3.5 cm at its greatest dimension on ultrasound (US) measurement. She should not have any contraindications to the use of methotrexate.

y Methotrexate is an antimetabolite chemotherapeutic agent that binds to the enzyme dihydrofolate reductase, which is involved in the synthesis of purine nucleotides. This interferes with DNA synthesis and disrupts cell multiplication. Methotrexate has long been known to be effective in the treatment of leukemias, lymphomas, and carcinomas of the head, neck, breast, ovary, and bladder. It has also been used as an immunosuppressive agent in the prevention of graft versus host disease and in the treatment of severe psoriasis and rheumatoid arthritis. Its effectiveness on trophoblastic tissue has been well established and is derived from experience gained in using methotrexate in the treatment of hydatiform moles and choriocarcinomas. Methotrexate is used in the treatment of ectopic pregnancy as single or multiple intramuscular injections.

y Adverse effects

y associated with the use of methotrexate

can be divided into drug adverse effects and treatment effects. Drug adverse effects include nausea, vomiting, stomatitis, diarrhea, gastric distress, and dizziness. Transient elevation in liver enzymes is also known to occur. Serious reactions, such as bone marrow suppression, dermatitis, pleuritis, pneumonitis, and alopecia

y Contraindications y to the use of methotrexate include documented

hypersensitivity to methotrexate; breastfeeding; immunodeficiency; alcoholism; alcoholic liver disease or any liver disease; blood dyscrasias; leukopenia; thrombocytopenia; anemia; active pulmonary disease; peptic ulcer disease; and renal, hepatic, or hematologic dysfunction. However, in each case, the risk of surgery must be weighed against any relative contraindication

Surgical treatment: Procedures:y Salpingotomy (or -ostomy): Making an incision on the

tube and removing the pregnancy. y Salpingectomy: Cutting the tube out. y Segmental resection: Cutting out the affected portion of the tube. y Fimbrial expression: "Milking" the pregnancy out the end of the tube.

. Contraindicationsy Surgical treatment in cases in which the pregnancy is

located on the cervix, ovary, or in the interstitial or the cornual portion of the tube is often associated with increased risk of hemorrhage, often resulting in hysterectomy or oophorectomy. In these cases, treatment with methotrexate is an especially attractive option. y In cases involving uncontrolled bleeding and hemodynamic instability, conservative treatment methods are avoided in favor of radical surgery.

Ectopic pregnancy. A 12-week interstitial gestation, which eventually resulted in a hysterectomy. Courtesy of Deidra Gundy, MD, Department of Obstetrics and Gynecology at MCPHU.

Ectopic pregnancy. Linear incision being made at the antimesenteric side of the ampullary portion of the fallopian tube.

Laparoscopic picture of an ampullary ectopic pregnancy protruding out after a linear salpingostomy was performed

Laparoscopyy has become the recommended approach in most cases. Laparotomy is usually reserved for patients who are hemodynamically unstable or patients with cornual ectopic pregnancies. It also is a preferred method for surgeons inexperienced in laparoscopy and in patients where laparoscopic approach is difficult (eg, secondary to the presence of multiple dense adhesions, obesity or massive hemoperitoneum). Multiple studies have demonstrated that laparoscopic treatment of ectopic pregnancy results in fewer postoperative adhesions than laparotomy. Furthermore, laparoscopy is associated with significantly less blood loss and a reduced need for analgesia. Finally, laparoscopy reduces cost, hospitalization, and convalescence period.

Linear salpingostomyy along the antimesenteric border to remove the

products of conception is the procedure of choice for unruptured ectopic pregnancies in the ampullary portion of the tube. Ectopic pregnancies in the ampulla are usually located between the lumen and the serosa and, thus, are ideal candidates for linear salpingostomy. Several studies have demonstrated no benefit of primary closure (salpingotomy) over healing by secondary intention (salpingostomy).