Suspected Ectopic Pregnancy Obstetrics & Gynecology vol. 107, No2 part 1, February, 2006 OBGY R2 BYUN JUNG MI
Suspected Ectopic Pregnancy • Abstract • Incidence • Risk factors • Diagnostic Approach • Therapeutic Approach • Follow-up
Abstract • Women who present with pain and bleeding in the first trimester are at risk for ectopicpregnancy, a life-threatening condition. • Predisposal condition : damaged fallopian tubes from prior tubal surgery or previous pelvic infection, smoking, conception using assisted reproduction. • Many women without risk factors can develop an ectopicpregnancy. • A diagnostic algorithm : use of • transvaginal ultrasonography, • human chorionic gonadotropin (hCG) concentrations • sometimes, uterine curettage
Abstract • When the initial hCG value is low, serial hCG values can be used to determine whether a gestation is potentially viable or spontaneously resolving. • The minimal rise in hCG for a viable pregnancy : 53% in 2 days. • The minimal decline of a spontaneous abortion : 21–35% in 2 days, depending on the initial level. • A rise or fall in serial hCG values that is slower than this is suggestive of an ectopicpregnancy.
Abstract • Treatment - medical management with methotrexate (for unruptured ectopic pregnancy ) : used to safely treat an ectopicpregnancy with success rates, tubal patency rates, and future fertility that are similar to those obtained with conservative surgery. : Success rates using methotrexate - inversely rated to baseline hCG values - higher using "multidose" compared with "single-dose“ regimens. - Surgical treatment : may be conservative or definitive and should be attempted in most cases via laparoscopy.
Ectopic pregnancy • Definition : The implantation of a fertilized ovum outside the endometrial cavity, continues to be a major cause of morbidity and mortality in reproductive- age women. • Prevalence : 2% of pregnancies in the United State • If undiagnosed and/or untreated : accounting for about 9% of maternal pregnancy-related deaths in U.S. (result in rupture of the fallopian tube and massive intraperitoneal hemorrhage )
Incidence • Between 1970 and 1992, a 6-fold increase was seen in the number of ectopic pregnancies diagnosed in the U.S. • earlier, more accurate diagnosis of pregnancies. • increased incidence of sexually transmitted infections • earlier diagnosis of pelvic inflammatory disease resulting in tubal damage but not complete blockage • rise in the number of ectopic pregnancies resulting from assisted reproductive technologies(ART) → may account for the overall increase.
Incidence • Incidence of tubal pregnancy after oocyte retrieval / embryo transfer may be as high as 4.5% (by Maymon and Shulman) • Incidence of heterotopic pregnancy : about 1:4000 in the general population 1:100 in in vitro fertilization (IVF) pregnancies (much higher than the originally described prevalencies of 1:30,000 in the late 1940s’) -> Due to the increasing use of ovulation induction agents that increase the chance of twinning and may cause hormonal fluctuations affecting tubal motility, and also due to the invasive nature of ART.
Risk Factors • Impede the migration of the fertilized ovum to the uterus • Damage to the fallopian tube from prior pelvic inflammatory disease • History of ectopic pregnancy and previous tubal surgery, including previous tubal ligation Cigarette smoking (thought to affect tubal motility) • Increasing age more than one lifetime sexual partner weakly linked to an increased risk of ectopic pregnancy. • No clear association has been documented between ectopic pregnancy and oral contraceptive use, previous elective pregnancy termination, spontaneous miscarriage, or cesarean delivery.
Fig.1. Possible anatomic sites in ectopic pregnancies. Illustration :John Yanson.Seeber. Suspected Ectopic Pregnancy. Obstet Gynecol 2006.
Diagnostic Approach • Symptoms : abdominal or pelvic pain and vaginal bleeding in the first trimester of pregnancy (m/c) * Nonspecific : spontaneous miscarriage, cervical irritation or trauma, and infection • Physical examination • hypotension and tachycardia with rebound tenderness and guarding → tubal rupture with immediate need for surgical intervention • ß-hCG • USG (transvaginal sonography) • Evacuation of Uterine contents • Progesterone
Diagnostic Approach-Steps to Diagnosis - • Transvaginal ultrasound examination • Gestations >51/2 weeks should identify an intrauterine pregnancy with near 100% accuracy. • Geataional sac (‘double decidual sign’ at 41/2~5weeks after the LMP) • Yolk sac (at 5 weeks) • Fetal pole with later cardiac motion (at 51/2~6weeks)
Diagnostic Approach- Discriminatory Cutoff- • Definition : level of ß-hCG at which a normal intrauterine pregnancy can be visualized by ultrasonography with sensitivity approaching 100% • above the discriminatory cutoff of 1,500~2,500 IU/L, using transvaginal ultrasonography, a normal intrauterine pregnancy should always be visualized.
Diagnostic Approach- Discriminatory Cutoff- Varying the discirminatory cutoff will affect the sensitivity and specificity for diagnosis In our view, it is better to set the discriminatory cutoff high, especially in a population of stable patients who maintain close medical follow-up.
Diagnostic Approach(Fig. 2. Diagnostic algorithm for ectopic pregnancy. ) Early Pregnancy with pain / bleeding Expectant management Intrauterine pregnancy Treat ectopic pregnancy Ultrasound Ectopic pregnancy Abnormal intrauterine pregnancy Non-diagnostic Expectant management vs D&C vs intravaginal misoprostol ß-hCG >discrminatory zone (no intrauterine pregnancy) < discriminatory zone No treatment Abnormal rise or fall Evaluation of uterine contents Serial ß-hCG Normal fall No chorionic villi Chorionic villi (Dx: Abnormal intrauterine pregnancy) Normal rise ⁂ Uttrasound when ß-hCG > discriminatory zone (back to top) Treat ectopic pregnancy
Diagnostic Approach- Human Chorionic Gonadotropin Above Discriminatory Cutoff- • Diagnosing an ectopic pregnancy based solely on serial ß-hCG levels that are declining abnormally below the discriminatory zone is inaccurate in up to 31% of cases. if pathological examination : not available →ß-hCG may be checked approximately 12-24hrs later if the level does not drop significantly on the day after uterine evacuation, → an extrauterine gestation is diagnosed. • We use a drop of 15% as the minimal needed but normally see a much steeper drop if the pregnancy tissue has been successfully removed. • To definitively confirm resolution of the pregnancy in the absence of tissue diagnosis, ß-hCG values should be followed at least weekly until undetectable, a process that may take up to several weeks.
Diagnostic Approach- Human Chorionic Gonadotropin Below Discriminatory Cutoff- • initial ß-hCG < the discriminatory zone → serial ß-hCG measurements are needed to document a growing (potentially viable) or a nonviable pregnancy. • The minimum rise for a potentially viable pregnancy that presents with pain and/or vaginal bleeding is 53%, based on the 99th percentile confidence interval(CI) around the mean of the curve of ß-hCG rise over time → followed with serial ß-hCG levels until an intrauterine pregnancy was confirmed.
Diagnostic Approach- Human Chorionic Gonadotropin Below Discriminatory Cutoff- • Intervention for a ß-hCG rise of less than 66% over 2days, a practice supported by previous data, would potentially result in the interruption of many viable pregnancies. • If the ß-hCG does not rise appropriately, or declines, a nonviable pregnancy has been diagnosed. • A rapid decline in ß-hCG value is consistent with a miscarriage that may resolve spontaneously. • If the ß-hCG does not fall 21~35% in 2days (depending on the initial value), → suspected ectopic pregnancy. @
Diagnostic Approach-Definitive Diagnosis- More than 70% of women who have an ectopic pregnancy will have - a rise in hCG that is slower than the minimal rise for a viable pregnancy or - a decline that is slower than the minimal rate of fall in a spontaneous abortion hCG rises like an IUP in 21% of EP hCG falls like an SAB in 8% of EP
Diagnostic Approach-Progesterone- • Debated. • Progesterone levels are higher in intrauterine pregnancies : no well-established upper cutoff to use to discriminate
Diagnostic Approach-Novel Diagnostic Methods- • develop a serum-based test that relies on placental or pregnancy-specific markers* elevated levels of vascular endothelial growth factor (VEGF) have been noted 11days after embryo transfer during IVF cycles in ectopic gestations, but with rather low predictive values. • Pregnancy-associated plasma protein A (PAPP-A) • Pregnancy-specific B1-glycoprotein • human placental lactogen (hPL) • hCG • anonplacental markers - glycodelin, VEGF and progesterone
Diagnostic Approach-Novel Diagnostic Methods- • One study : VEGF + PAPP-A + progesterone →discriminate ectopic pregnancy from intrauterine pregnancy : sensitivity : 97.7% / specificity : 92.4% (although this discriminative power was lower for early gestations. ) • Other markers- not appear useful in the clinical setting at this point- : creatinine kinase, fetal fibronectin, leukemia inhibitory factor, smooth muscle heavy-chain myosin and CA125.
Therapeutic Approach • minimally invasive surgery or medical therapy →These treatment modalities have been shown to have success rates comparable to the gold-standard treatment of laparotomy with salpingectomy, but with the potential benefit of fallopian tube conservation. • Laparotomy : therapy for hemodynamically unstable patients with high suspicion of tubal rupture.
Therapeutic Approach-Methotrexate- • Class of drugs called folic acid antagonists • History • Initially used for treating leukemia, it gained wide use in gynecology for the treatment and cure of choriocarcinoma • First introduced as a novel therapy for ectopic pregnancy in 1982. • Action mechanism ; by inactivating the enzyme dihydrofolate reductase (DHFR), leading to depletion of the cofactors required for DNA and RNA synthesis. • Goal of medical management with MTX : to selectively kill the cytotrophoblasts, the rapidly dividing cells at the fallopian tube implantation site. → The body will then spontaneously resorb the remaining products of conception and blood clot that constitute the ectopic pregnancy.
Therapeutic Approach-Methotrexate- • Leucovorin( folic acid ) : used as a “rescue” medication - allows for higher MTX dose administration by preventing some of the otherwise prohibitive adverse effects. • Administration : oral, intramuscular, intrathecal, or by continuous infusion • In ectopic pregnancy : IM is preferred, although there have been reports of success with the oral route. • It may be used as primary treatment of (Indication) • persistent ectopic pregnanacy after salpingostomy • prophylaxis for suspected persistent products of conception after conservative surgery • in cases of unusually located ectopic pregnancies.
Therapeutic Approach-Methotrexate Dosing Regimens- <Protocol > Multidose regimen - MTX : 1mg/kg per day, IM, on days 1,3,5, and 7 - leucovorin : 0.1mg/kg , IM, on days 2,4,6 and 8 * Surveillance : ß-hCG should be checked every 7days until ß-hCG,<5
Therapeutic Approach-Methotrexate Dosing Regimens- <Protocol > Multidose regimen • Patients are given up to 4 doses (1MTX, 1leucovorin) until the ß-hCG decreases by at least 15% on 2 consecutive days • 2nd course after one week may be given if there is an increase or plateau in 2 consecutive ß-hCG values
Therapeutic Approach-Methotrexate Dosing Regimens- <Protocol > Single-dose regimen - MTX : 50mg/m2 , IM , not use leucovorin rescue. Surveillance : ß-hCG should be checked every 7days until ß-hCG <5 • 2nd dose may be administered after 1week if ß-hCG values do not decline by • at least 15% between days 4 and 7 after treatment • Using the “single-dose” protocol, approximately 20% of women require more • than one treatment cycle.
Therapeutic Approach-Methotrexate Dosing Regimens- • Regardless of the MTX regimen used, patients need to be followed weekly with surveillance ß-hCG after their treatment until ß-hCG is undetectable in serum. → only way to confirm complete resolution of the ectopic pregnancy → It is important to be aware that ectopic pregnancies may cause tubal rupture even when the ß-hCG levels are on their way down. • Specifically, in situations where the ß-hCG increased at least 66% over 48 hours before MTX administration →the tubal rupture risk : as high as 20%.
Therapeutic Approach-Effectiveness of Methotrexate- • based on 12 studies with at least 20 patients each, the authors concluded that MTX treatment has been shown to be successful in 78~96% of selected patients, → posttreatment hysterosalpingogram-documented tubal patency : 78%, 65% : subsequent pregnancy succeeded 13% : incidence of recurrent ectopic pregnancy. - Reviewed by Pisarska et al
Therapeutic Approach-Single Dose Versus Multidose- • Recent meta-analysis : Barnhart et al (data from 26 articles that met their search criteria, reviewing 1.327 cases of women diagnosed with ectopic pregnancy who were treated with MTX) - overall success rate for the use of methotrexate : 89% - considering each regimen separately, • the success rate of “multidose” therapy : 92.7%with a 95 CI of 89~96% • for “single-dose” : 88.1%with a 95% of 86~90%, a statistically significant difference. • Importantly, when the frequency of failure was compared, controlling for initial hCG value and the presence of embryonic cardiac activity, the failure rate with single-dose therapy was almost 5 times greater (95%CI)
Therapeutic Approach-Single Dose Versus Multidose- • New protocol • 2 doses of MTX (on day 1 and day 4) without leucovorin rescue • using the follow-up of the single-dose protocol may more optimally balance convenience and efficacy.
Therapeutic Approach-Single Dose Versus Multidose- Absolute Contraindications to Medical Therapy With Methotrexate • Breastfeeding • Overt or laboratory evidence of immunodeficiency • Alcoholism, alcoholic liver disease, or other chronic liver disease • Preexisting blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia • Known sensitivity to methotrexate • Active pulmonary disease • Peptic ulcer disease • Hepatic, renal, or hematologic dysfunction Relative contraindications • Gestational sac 3.5cm or greater • Embryonic cardiac motion Adapted from American Colleage of Obstetricians and Gynecologists Medical Management of Tubla Pregnancy. ACOG Practice Bulletin 3. Washington, DC ; ACOG ; 1998.
Therapeutic Approach-Single Dose Versus Multidose- • Premedicational preparation • CBC, LFT, and S/E especially Scr • Chest X-ray : if, Hx of pulmonary disease(+) • discontinue folic acid supplements and prenatal vitamins. ★ When using the multidose protocol, the above laboratory studies should be repeated 1 weekafter the last dose of MTX.
Therapeutic Approach-Predictors of Success- • Initial serum ß-hCG level (most predictive) • progesterone level, • size and volume of the gestational mass, • presence or absence of cardiac activity, • presence or absence of free peritoneal blood
Therapeutic Approach-Predictors of Success- • Treatment failure • 65% of cases : ß-hCG level > 4,000 IU/L • 7.5% : ß-hCG < 4.000 IU/L. -Tawfiq et al • Median pretreatment serum ß-hCG level was lower in women in whom treatment was successful compared with women with treatment failures (773 vs 3.802 mIU/mL) –Potter et al • Recent review of 350 women treated with single-dose MTX for ectopic pregnancy found that the only factor that contributed significantly to the failure rate was ß-hCG level before treatment * >5,000 mIU/mL: the failure rate rose to about 13% - No absolute level at which medical management is contraindicated. • We currently use the multidose protocol or the new “2-dose protocol” to treat women with a hCG above 1,000mIU/mL
Therapeutic Approach-Post-Methotrexate Follow-up- • abdominal pain6-7 days after receiving the medication (33% ~ 60% of patients ) • result from tubal abortion or hematoma formation with distention of the fallopian tube. • can be treated conservatively with pain medications and close follow-up and do not require surgical intervention. • if there is evidence of tubal rupture with bleeding, as evidenced by declining hemoglobin levels or ultrasound visualization. → Surgery • the ß-hCG level may plateau, or even rise, before it begins to fall. → explained by the fact that, although MTX arrests mitosis in the cytotrophoblasts, the syncytiotrophoblast continues to increase and produces hormone.
Therapeutic Approach-Post-Methotrexate Follow-up- • ultrasound examination : may show an increase in the ectopic size and possibly an increase in vascularity before resolution. • increases in ectopic size were not associated with failure of treatment. -Atri et al →not necessary to follow patients with serial ultrasound examinations once they have received MTX treatment → ultrasound findings would not alter management unless a new tubal rupture is seen.
Therapeutic Approach-Post-Methotrexate Follow-up- Signs of Treatment Failure and/or Tubal Rupture • Significantly worsening abdominal pain, regardless of change in ß-hCG level • Hemodynamic instability • Levels of ß-hCG that do not decline by at least 15% between day 4 and day 7 postinjection • Increasing or plateauing ß-hCG levels after the first week of treatment Adapted from American Colleage of Obstetricians and Gynecologists Medical Management of Tubla Pregnancy. ACOG Practice Bulletin 3. Washington, DC ; ACOG ; 1998.
Therapeutic Approach-Methotrexate for Extratubal Ectopics- • Used for ectopic pregnancies located outside the fallopian tube (cervical, interstitial, ovarian, or abdominal gestations) : first-line treatment d/t the difficulty and risk of surgical resection • MTX use for cervical ectopic : one review included 36 women treated with systemic MTX, local injection of MTX or potassium chloride(KCl) or a combination of these therapies → 80~90% success rate. • Interstitial pregnancy : 83%
Therapeutic Approach-Complications of Methotrexate- • Folic acid analogue : affects rapidly dividing cells ( esp. those of the gastrointestinal tract and the bone marrow ) • Major adverse effects impaired liver function stomatitis gastritis-enteritis bone marrow suppression
Therapeutic Approach-Complications of Methotrexate- • Multidose regimen(100) : sotmatits(2), elevated liver transaminases (3) - spontaneously resolved --reported by Stovall et al • Single-dose regimen(120) : nausea and vomiting (1) -- reported by Barnhart et al • Prevalence of adverse effects of about 30~40% using the “single-dose” and “multidose” regimens finding no difference between the two once they adjusted for ß-hCG values (table3.) their meta-analysis Adapted from Barnhart KT, Gosman G, Ashby R, Sammel M. the medical management of ectopic pregnancy ; a meta-analysis comparing “single dose’ and ‘multidose’ regimens. Obstet Gynecol 2003;101:778-84
Therapeutic Approach-Complications of Methotrexate- Adverse Effects associated with Methotrexate Treatment • Drug Adverse Effects • Nausea • Vomiting • Stomatitis • Gastric Distress • Dizziness • Severe neutropena (rare) • Reversible alopecia(rare) • Pneuminitis • Treatment Effect • Increase in abdominal pain • Increase in ß-hCG levels during • first 1-3days of treatment • Vaginal bleeding or spotting Adapted from Amnerican College of Obstetricians and Gynecologists. Medical Management of Tubal Pregnancy. ACOG Practice Bulletin 3. Washington, DC;ACOG;1998.
Therapeutic Approach-Surgical Resection- • Laparotomy : reserved for cases of extensive intraperitoneal bleeding with intravascular compromise due to active bleeding, where hypovolemic shock must be prevented. • Open surgical approach : may be preferable include - extensive pelvic adhesions : adequate visualization of the ectopic is impossible - extra-tubal, intra-abdominal ectopic gestations where risk of injury to other pelvic structures is high.
Therapeutic Approach-Surgical Resection- • Laparoscopic approach • decreased surgical blood loss, a decrease in the amount of analgesic used, and shorter postoperative hospital stay. (compared with laparotomy) • safe, effective and less costly
Therapeutic Approach-salpingostomy versus salpingectomy- • Removal of the ectopic pregnancy can be accomplished • by resection of the involved fallopian tube with the implanted trophoblastic tissue (salpingectomy) • by dissection and removal of only the ectopic pregnancy with tubal conservation (salpingostomy)
Therapeutic Approach-salpingostomy versus salpingectomy- <Reproductive outcomes after salpingostomy and salpngectomy> • Yao and Tulandi reviewed the data from 9 studies • The follow-up period in these studies ranged from 3months to15years. • subsequent intrauterine pregnancy rate was similar in patients who had been treated with salpingostomy and those treated with salpingectomy : 50% • the rate of a subsequent ectopic : higher in the salpingostomy group (15% vs 10%)
Therapeutic Approach-salpingostomy versus salpingectomy- • Other studies • a higher intrauterine pregnancy rate in women after salpngostomy (almost doublethat of salpingectomy), • a 2-fold risk of recurrent ectopic after 3years of follow-up (after salpngostomy) • Another recent study • a high rate of successful pregnancy after salpingostomy(88%) compared with salpingectomy (66%) • with an equal recurrent ectopic rate of about 16% after at least 18months of follow-up and, in some cases, up to 8years posttreatment .
Therapeutic Approach-salpingostomy versus salpingectomy- • The concern with conservative treatment via salpingostomy is that of the persistence of trophoblast tissue due to incomplete removal from the fallopian tube. →complicating about 5~20% of cases treated with tubal conservation, • It has been reported as being higher in those patients treated with laparoscopy than with laparotomy. → very important to document a complete resolution of the ectopic pregnancy by monitoring the ß-hCG values until they return to zero. • Levels that fail to drop, or ones that plateau, indicate a likely persistent ectopic pregnancy that should be treated. • Very early gestations, ectopic pregnancies less than 2cm in size, and those with high starting ß-hCG levels are at increased risk of persistence.
Therapeutic Approach-salpingostomy versus salpingectomy- • In cases of tubal conservation is not indicated • if tubal bleeding is encountered that reqiures extensive coagulation to achieve hemostasis, then future tubal function would likely be compromised, and salpingectomy may be the appropriate intervention. • Recurrent ectopic pregnancy in a previously incised tube should also be treated with salpingectomy.