INTRODUCTION
Implantation of a fertilized ovum in an area other than the endometrial lining of the uterus is known as ectopic pregnancy. The incidence of ectopic pregnancy has increased from 4.5/1000 in 1970 to 19.7/1000 in 1992 in the West.1,2 Ruptured ectopic pregnancy remains an important cause of maternal death. However, due to early diagnosis and treatment after the advent of transvaginal ultrasonography (USG) and beta subunit of human chorionic gonadotropin (β-hCG) tests, the incidence of rupture and case fatality has declined.
Pregnancies in the fallopian tube are commonest accounting for 97 percent of ectopic pregnancies: 55 percent occur in ampulla, 25 percent in isthmus, 17 percent in fimbria, and 3 percent in the abdominal cavity, ovary and cervix.3 If a woman of reproductive age group presents with abdominal pain, vaginal bleeding, syncope or hypotension, ectopic pregnancy should be suspected. The clinical symptom triad of ectopic pregnancy includes amenorrhea, irregular bleeding per vaginum and lower abdominal pain. A pregnancy testing should be done and if the patient is pregnant, an ultrasound evaluation should be performed. If the results of USG are indeterminate, the serum β-hCG concentration should be measured. Serial measurement of β-hCG and progesterone concentrations may be useful when the diagnosis is in doubt. The management options for ectopic pregnancy include expectant management, medical treatment and surgery. Advances in surgical and medical treatment for ectopic pregnancy have allowed the incorporation of minimally invasive or noninvasive treatment.
- History of PID
- Previous tubal surgery
- Previous ectopic pregnancy
- History of infertility
- History of chlamydial or gonococcal cervicitis
- Documented tubal abnormality
- Tubal ligation
- Current IUD use
- In utero DES exposure
CASE SCENARIO-1
Mrs A, a 30-year-old nulliparous lady, presented with 6 weeks amenorrhea and vaginal spotting. On examination, her vitals were stable and the abdomen was soft and non tender. Per vaginum (P/V) examination revealed a bulky uterus with a tender left adnexal mass. Urine pregnancy test was positive.
Differential Diagnosis will Include
- Ruptured corpus luteal cyst or follicle
- Ovarian torsion
- Pelvic inflammatory disease
- Tubo-ovarian abscess
- Acute appendicitis
- Spontaneous or threatened abortion.
POINTS TO BE NOTED IN HISTORY
- Documentation of risk factors is an important part of history taking
- Abdominal pain—nature, duration, intensity of pain, aggravating or relieving factors and any history of syncopal episodes
- History of preceding amenorrhea—ectopic pregnancy is most common in women of reproductive age who present with approximately seven weeks after amenorrhea. However, a history of preceding amenorrhea may not be there and some patients may confuse vaginal spotting for a normal menstrual cycle
- Vaginal bleeding—duration, amount and association with passage of clots or fleshy tissue suggestive of products of conception (which may be seen in spontaneous abortion)
- History of fever—this may be present in case of pelvic inflammatory disease or tubo-ovarian abscess.
POINTS TO BE NOTED IN EXAMINATION
General Examination
General examination pallor blood pressure (BP) and respiratory rate and vitals including temperature and pulse.
Cardiovascular and Respiratory System Examination
Abdominal Examination
Abdominal tenderness, signs of intraperitoneal hemorrhage including guarding, rigidity and rebound tenderness, bowel sounds.
Pelvic Examination
Per Speculum (P/S) Examination
- Cervical os: Whether open or closed
- Bleeding: Amount and site of bleeding
- Whether any products of conception seen or not
Per Vaginum (P/V) Examination
- Cervical motion tenderness
- Uterine size and position: Uterus may be normal in size or slightly bulky in case of a tubal ectopic
- Palpable adnexal mass: Suggestive of a tubal ectopic pregnancy, tubo-ovarian mass or a corpus luteal cyst.
Diagnosis
Left unruptured tubal ectopic pregnancy
INVESTIGATIONS
Blood Investigation
Hemogram, Blood group KFT, LFT
Ultrasound Imaging
Ultrasound imaging is the diagnostic test of choice in a case of suspected ectopic pregnancy. Transvaginal ultrasound findings suggestive of ectopic pregnancy are given in Table 1.1:7
Ectopic pregnancy should be suspected when the patients β-hCG level is more than 6,500 IU/L and the transabdominal scan does not show an intrauterine gestational sac or when the transvaginal sonography does not show an intrauterine gestational sac and the β-hCG level is more than 1,500 IU/L.
β-Human Chorionic Gonadotropin Measurement
β-hCG is detectable in urine and blood as early as 1 week before an expected menstrual period. However, a single measurement of β- hCG is not very informative. In a normal viable pregnancy, the first trimester β-hCG concentration doubles about every 2 days. An increase of at least 66 percent over 48 hours has been used as a cut-off for viability.8 Ectopic pregnancy may present with rising, falling or plateau of β-hCG levels, thus requiring serial estimation. In a non-viable pregnancy, a subnormal increase in β-hCG concentration is seen. However, a doubling of serum levels over 48 hours does not rule out ectopic pregnancy. Similarly, falling levels confirm nonviability but do not rule out ectopic pregnancy.
Progesterone Measurement
Serum progesterone levels can detect pregnancy failure and patients with suspected ectopic pregnancy, but it cannot distinguish ectopic pregnancy from spontaneous abortion. Sensitivity for diagnosis of ectopic pregnancy is low (15 %), i.e. 85 percent of patients with ectopic pregnancy will have normal serum progesterone levels.7
Progesterone estimation can identify 2 subgroups of patients—stable patients with serum progesterone level above 22 ng/mL, who have a high likelihood of a viable intrauterine pregnancy and patients with levels of 5 ng/mL or less, who almost certainly have a nonviable pregnancy. Invasive testing (e.g. D&C) can be withheld till further testing in the former patients but offered to the latter group, as can the treatment with methotrexate.
Diagnostic Uterine Curettage
If chorionic villi are not detected on uterine curettage, ectopic pregnancy should be suspected. However, curettage should be only considered when β-hCG levels are falling, or when the levels are elevated and ultrasonography does not show intrauterine pregnancy. Chorionic villi are present in obtained curettage and are confirmed when the tissue floats in saline which is indicative of spontaneous abortion although it is not 100 percent accurate. It should be supported by histopathological examination and the above said β-hCG estimation.
Culdocentesis
It is a diagnostic tool for identifying intraperitoneal bleeding which involves insertion of an 18-gauge spinal needle attached to a 50 mL syringe into the cul-de-sac and aspiration of unclotted blood from the cul-de-sac. However, it does not provide information whether the blood is from an ectopic pregnancy or any other cause of intraperitoneal bleeding.
Laparoscopy
Laparoscopy remains the gold standard in detection of ectopic pregnancy and allows visualization of the pelvis and other peritoneal organs. It allows the assessment of the unaffected fallopian tube and additional information like the presence of intraperitoneal adhesions or endometriosis.
The diagnostic performance of various diagnostic tests is summarized in Table 1.2.
A patient presenting with an unruptured ectopic pregnancy can be offered expectant or medical management depending on β-hCG levels, size of ectopic mass and other criterion discussed below.
EXPECTANT MANAGEMENT
An ideal patient for expectant management is the one having β-hCG level less than 1,000 IU/L and declining, an ectopic mass less than 4 cm, no fetal heartbeat and is willing for follow-up. (grade C recommendation). Women managed expectantly should be followed twice weekly with serial hCG measurements and weekly by transvaginal sonography to ensure a rapidly decreasing β-hCG level and a reduction in the size of the mass by seven days.7
|
Thereafter, weekly β- hCG and TVS examination are advised till levels are less than 20 IU/L (Level III evidence). Expectant management is between 47 and 82 percent effective in managing ectopic pregnancy.9
MEDICAL MANAGEMENT
Methotrexate, a folic acid antagonist which inhibits DNA synthesis in actively dividing cells including trophoblasts, is the drug of choice. It is given as single dose regime or as variable dose regime (Table 1.3). Success rate in properly selected patients is up to 94 percent. Other therapeutic agents include hyperosmolar glucose, prostaglandins and mifepristone.
The criteria for starting methotrexate in treatment of ectopic pregnancy are:10
- Hemodynamic stability
- Pre-treatment β-hCG level less than 15,000 IU/L
- Absence of ultrasound evidence of fetal cardiac activity
- Gestation less than 6 weeks
- Tubal diameter of less than 3 cm with tubal serosa intact.
| |||||||||
The overall success rate is greater with multiple-dose therapy than with single-dose therapy (93% vs. 88%); however single-dose therapy is less expensive and has a lower rate of side effects. Less intensive monitoring is required and no folinic acid rescue is required with single-dose therapy. Patients who are Rh –ve require administration of Rh (D) immunoglobulin (50 µg).
Contraindications to Methotrexate
Include liver or renal disease, immunodeficiency, breastfeeding, blood dyscrasias, alcohol use, active pulmonary disease and peptic ulcer.
Medical Therapy by Local Injection
Direct injection of methotrexate, prostaglandin F2α, hyperosmolar glucose and potassium chloride into the fallopian tube or the ectopic mass have been attempted. Direct injection of methotrexate has theoretical advantage over systemic therapy, that the concentration of methotrexate at the site of implantation is much higher than in systemic administration. The use of other agents requires further larger trials to establish their safety and efficacy.
CASE SCENARIO-2
A 28 year-old-lady, G3P2L2, presented with pain abdomen for 1 day after a preceding amenorrhea of 7 weeks. On examination, she was significantly pale with pulse 110/min and BP 94/60 mm Hg. Abdominal examination revealed lower abdominal tenderness and abdominal distension with evidence of free fluid (shifting dullness). On vaginal examination, there was cervical motion tenderness and vague fullness in left fornix.
Differential Diagnosis
- Ruptured corpus luteal cyst
- Acute abdomen due to surgical causes: acute appendicitis, perforation peritonitis etc.
Diagnosis
Ruptured tubal ectopic pregnancy
Figure 1.1: USG of patient 2 showing free fluid in cul-de-sac following a ruptured tubal ectopic pregnancy and an intrauterine pseudosac
Treatment
- Vitals should be stabilized by crystalloid and colloid replacement
- Simultaneously, the patient should be prepared for emergency surgery
- Adequate blood should be arranged before commencing surgery.
SURGICAL MANAGEMENT
Surgical management of ectopic pregnancy should be reserved for patients who have contraindications to medical treatment, those in whom medical treatment has failed, those who are hemodynamically unstable or those who refuse medical treatment. Laparoscopy is preferable over laparotomy unless the patient is unstable12 (grade A recommendation). Laparoscopy is more cost-effective, has a shorter recovery time, less surgical blood loss and less anesthesia requirement. The presence of hemoperitoneum should not preclude the use of laparoscopy.
Indications for Laparotomy in a Case of Ectopic Pregnancy
- The patient is hemodynamically unstable (grade C recommendation)
- Serum β- hCG is >15,000 IU/L
- Failed conservative and medical methods
- Extensive intra-abdominal adhesions.
Conservative tubal surgery is when the tubes are salvaged, e.g. salpingostomy, salpingotomy and fimbrial expression of the ectopic pregnancy.
Radical surgery is defined by salpingectomy. In an unstable patient with hemoperitoneum, when the abdomen is opened, the uterus should be lifted up as it stretches the blood vessels and decreases the bleeding.
Salpingostomy: This procedure is used to remove a pregnancy that is usually less than 2 cm in length and located in the distal part of fallopian tube. A linear incision of nearly 10–15 mm or less is made on the anti-mesenteric border immediately over the ectopic pregnancy. The products are extruded from the incision and can be removed. The incision is left unsutured to heal by secondary intention.
Salpingotomy: It is the same as salpingostomy except that the incision is closed with a suture, usually 7-0 vicryl.
Salpingectomy: Tubal resection can be used for both ruptured and unruptured ectopic pregnancies and can be performed both via laparoscopy and laparotomy. The mesosalpinx is clamped with a 10succession of clamps as close to the tube as possible. The tube is then excised by cutting a small myometrial wedge at the uterine cornu. Suture loop or bipolar coagulation must be used before cutting the tube.
Follow-up after Conservative Tubal Surgery for Ectopic Pregnancy
There is a difference of opinion regarding follow-up with β-hCG of patients who undergo conservative tubal surgery for ectopic pregnancy:
- Most workers suggest that to avoid undiagnosed persistent ectopic pregnancies, it is necessary to estimate β-hCG prior to surgery and then repeat the measurements at intervals after surgery. A number of different regimes have been suggested to monitor the β-hCG levels.
- The simplest one is that suggested by Yao and Tulandi who recommended that levels be estimated once seven days after surgery and if the level is higher than expected, the patient should be given a single IM dose of methotrexate.13
- The other follow up protocol involves serum β-hCG estimations before and on at least one occasion within a week of therapy.
- An alternate approach suggests that the hormonal monitoring is not necessary and does not help in detecting retained products. It is suggested that such cases invariably present with abdominal pain which is a much cheaper option than monitoring β-hCG levels (grade B recommendation).
PERSISTENT TROPHOBLAST
Serum β- hCG levels following salpingostomy fall quickly and are expected to be 10 percent of preoperative values by day 12. Persistent ectopic pregnancy (PEP) complicates 5 to 20 percent of salpingostomies. Factors that increase the risk of PEP include:
- Small pregnancies, i.e. < 2cm
- Early therapy, i.e. before 42 menstrual days
- β- hCG values exceeding 3000 IU/L
- Implantation medial to salpingostomy site
In case of PEP or increasing β-hCG, additional surgical or medical treatment may be required.
HETEROTROPIC PREGNANCY
It refers to coexistence of intra- and extra-uterine pregnancies and is a rare condition (1:30,000). However, with advent of assisted reproductive techniques, the incidence is as high as 0.75 to 1.5 percent of pregnancies. The techniques and medium used for embryo transfer may also be involved.14
Abdominal pain, adnexal mass, signs of peritoneal irritation and an enlarged uterus together constitute the major clinical features associated with heterotropic pregnancy.
The majority of heterotropic pregnancies have a single tubal gestation along with an intrauterine pregnancy. The prognosis for a viable intrauterine pregnancy, however, is good, and these combined pregnancies have produced a living child in about 70 percent of cases. A high index of suspicion, repeated ultrasounds, and early intervention are mandatory to salvage the viable intrauterine pregnancy and avoid maternal mortality.13 Expectant treatment does not seem to have a role in management of a patient with a heterotropic pregnancy as the specific course of the extra-uterine component cannot be monitored with serial β-hCG estimation.
NON-TUBAL ECTOPIC PREGNANCY
Interstitial (Cornual) Pregnancy
A pregnancy developing in the interstitial portion of the oviduct is called interstitial/cornual pregnancy. The transvaginal ultrasonic criteria for interstitial pregnancy are:
- An empty uterine cavity
- A chorionic sac seen separately and >1 cm from the most lateral edge of the uterine cavity
- A thick myometrial layer surrounding the chorionic sac.
Clinical presentation: The gestational sac is better protected in the interstitium as compared to other portions of the tube, hence the symptoms of interstitial ectopic pregnancies may manifest at a more advanced gestation than tubal ectopic pregnancy. Since the interstitial area is richly vascularized, rupture usually causes profound and sudden shock.
Management: Cornual resection and repair of defect by laparotomy remains the standard conservative procedure of choice.
Ovarian Pregnancy
Rarely a pregnancy may develop in the ovary. Ovarian pregnancy accounts for less than 3% of all ectopic pregnancies. Spiegelberg criteria for diagnosis include:
- The ipsilateral tube is intact and clearly separate from the ovary
- The gestational sac definitely occupies the normal position of the ovary.
- The sac is connected to the uterus by the uteroovarian ligament.
- Ovarian tissue is definitely demonstrated in the wall of the sac.
Differential diagnosis: Hemorrhage from the corpus luteum, hemorrhagic ovarian cyst.
Clinical presentation: Clinically the condition is difficult to distinguish from tubal pregnancy.
Management: Usually involves surgical excision of the affected ovarian tissue which can be done by laparotomy or by laparoscopy. Medical management with methotrexate has also been reported.
Cervical Pregnancy
A pregnancy may get implanted in the cervical canal below the level of internal os. Rubin's criteria for diagnosis of cervical pregnancy include:
- Cervical glands must be opposite to the placental attachment.
- Placental attachment to the cervix is situated below the entrance of uterine vessels or below the peritoneal reflection on the anterior and posterior uterine surfaces.
- Fetal elements must be absent from the uterus.
Clinical presentation: Patient may present with excessive vaginal bleeding and on examination cervix may appear ballooned up and very soft.
Management: Treatment is surgical and often requires an abdominal hysterectomy. Medical therapy may also be considered for the primary treatment of cervical pregnancy or in addition to surgical therapy.
REFERENCES
- Goldner TE, Lawson HW, Xia Z, Atrash HK. Surveillance for ectopic pregnancy—United States, 1970–1989. MMWR CDC Surveill Summ 1993;42:73–85.
- Centers for Disease Control and Prevention (CDC). Ectopic pregnancy—United States, 1990–1992. MMWR Morb Mortal Wkly Rep 1995;44:46–8.
- Della-Giustina D, Denny M. Ectopic pregnancy. Emerg Med Clin North Am 2003;21:565–84.
- Ankum WM, Mol BW, van der Veen F, Bossuyt PM. Risk factors for ectopic pregnancy: a meta-analysis. Fertil Steril 1996;65:1093–9.
- Mol BW, Ankum WM, Bossuyt PM, van der Veen F. Contraception and the risk of ectopic pregnancy: a meta-analysis. Contraception 1995;52:337–41.
- BW, Van der Veen F, Bossuyt PM. Implementation of probabilistic decision rules improves the predictive values of algorithms in the diagnostic management of ectopic pregnancy. Hum Reprod 1999;14:2855–62.
- Dart RG, Mitterando J, Dart LM. Rate of change of serial beta-human chorionic gonadotropin values as a predictor of ectopic pregnancy in patients with indeterminate transvaginal ultrasound findings. Ann Emerg Med 1999;34:703–10.
- Trio D, Strobelt N, Picciolo C, Lapinski RH, Ghidini A. Prognostic factors for successful expectant management of ectopic pregnancy. Fertil Steril 1995;63:469–72.
- Lipscomb GH, McCord ML, Stovall TG, Huff G, Portera SG, Ling FW. Predictors of success of methotrexate treatment in women with tubal ectopic pregnancies. N Engl J Med 1999;341:1974–8.
- Lipscomb GH, Meyer NL, Flynn DE, Peterson M, Ling FW. Oral methotrexate for treatment of ectopic pregnancy. Am J Obstet Gynecol 2002;186:1192–5.
- Tulandi T, Saleh A. Surgical management of ectopic pregnancy. Clin Obstet Gynecol 1999;42:31–8.
- Yao M, Tulandi T. Current status of surgical and non-surgical management of ectopic pregnancy. Fertil Steril 1997;67:421–33.
- Rojansky N, Schenker JG. Heterotopic pregnancy and assisted reproduction: an update. J Assist Reprod Genet 1996;13:594.