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<< Complications In Pregnancy Part I: Early Pregnancy

Treatment

The Complications of Early Pregnancy Clinical Pathway on page 16 presents a general management algorithm for the pregnant patient presenting to the ED in the first trimester with vaginal bleeding or abdominal pain. In rare cases where the patient cannot be stabilized, an immediate laparotomy may be indicated. However, the majority of patients who seek treatment can be systematically evaluated with management based on diagnostic findings.

In stable patients, the goal is to exclude ectopic pregnancy in a timely fashion. In stable patients suspected of having an ectopic pregnancy, two general outpatient approaches have been described, using either sonography or β-hCG as the initial screening tool.72,73 Both of these are equally sensitive, but when TVS is performed first, fewer normal pregnancies were terminated in the evaluation of   resenting symptoms. Data from two or more ancillary studies can be used together to evaluate the odds of ectopic  pregnancy. Cost, availability, and convenience willdrive the ordering of ancillary studies in different institutions. In all cases, if the patient is discharged, give careful instructions for symptoms that would require return to the ED, see Table 7.


An alternative strategy using β-hCG determination prior to ultrasound has been used.41 However, waiting times for the serum assay can increase length of stay in the ED. In addition, sonography can be diagnostic of ectopic pregnancy even if the β-hCG level is less than 1000 mIU/mL.30 Finally, the diagnosis may be missed in those patients with a β-hCG lower than the discriminatory threshold who are not assessed with sonography.30

A subset of patients has indeterminate ultrasonographic results and β-hCG levels less than 1500 mIU/mL. When the β-hCG levels never rise to the discriminatory zone, the differential diagnosis includes intrauterine fetal demise and ectopic pregnancy. Early D & C with identification of POCs can be useful to the patient with flat β-hCG levels to detect chorionic villi and confirm a failed IUP.74 Alternatively, expectant management may be utilized to follow β-hCG levels until they reach zero, particularly if initial levels are low. Expectant management is not recommended in patients who have received infertility treatment because the risk of heterotopic pregnancy is so high.75

All patients who are at risk for a fetomaternal transfusion in early pregnancy (pregnancy with vaginal bleeding, miscarriage, significant trauma, or an ectopic pregnancy) require assessment of their Rh antigen. Although the classically described Kleihauer-Bethke test has been purported as the standard of care for identifying fetomaternal hemorrhage, some studies have found it to be unreliable. In any patient at risk for fetomaternal hemorrhage, anti-D immune globulin (RhoGam®) should be administered if the patient is Rh-negative (unless the father is also Rh-negative) regardless of the results of the Kleihauer-Bethke test. A 50 μg dose is used during the first trimester and a full 300 μg dose after the  first trimester.13,76 Although it has never been prospectively studied, retrospective analysis shows that anti-D immune globulin prevents the alloimmunization of Rh-negative.77,78

Miscarriage Management

In the stable patient with a threatened miscarriage, as long as ectopic pregnancy has been excluded, observation over time may be sufficient to determine when intervention is needed. Serial quantitative β-hCG levels may be used to assess the health of the fetus if ultrasonography is indeterminate or if the gestational age is less than six to seven weeks. The sonographic “discriminatory zone” occurs when the quantitative β-hCG level is high enough to indicate that a normally developing IUP should be seen. This has been set at 1500-2000 mIU/mL for transvaginal sonography, and 6500 mIU/mL for transabdominal sonography.13,23,793000 mIU/mL should be used as the upper limit of the “discriminatory zone” for TVS, the level at which normal intrauterine pregnancies should always be visualized.80 Sonography should be performed or repeated when β-hCG levels rise to 3000 mIU/mL. If β-hCG levels are flat or decline or if sonographic criteria for fetal demise are demonstrated, refer the patient to a specialist for follow-up. Patients with such findings must be followed closely. When β-hCG levels are falling, a D & C may be performed, especially if β-hCG levels are less than 250 mIU/mL. The tissue removed should be examined for chorionic villi. Chorionic villi will be identified after D & C in approximately 70% of patients with indeterminate sonography.74 If chorionic villi are not found, the risk of ectopic pregnancy increases.74

After assessment of hemodynamic status and management of blood loss, a patient with a threatened miscarriage requires very little specific medical treatment. Ectopic pregnancy should always be considered and sonography performed if risk factors for ectopic pregnancy are present or if the patient has pain. Although ectopic pregnancy can be associated with painless bleeding,81 this occurs less frequently. Sonography can be scheduled more routinely at a later time as long as the patient is aware that the potential for ectopic pregnancy still exists. In the patient who is planning pregnancy termination, prompt referral should be encouraged and chorionic villi confirmed at the time of uterine evacuation.

Fifty percent or more of women with threatened miscarriage who are seen in ED’s ultimately miscarry.82 Treatment to “prevent” miscarriage is not useful because most fetuses can be shown to be nonviable one to two weeks before actual symptoms occur.17 In the vast majority of cases, spontaneous miscarriage is the body’s natural method of expelling an abnormal or undeveloped (blighted) pregnancy. Thus a major goal of ED management should be patient education and support. Patients should be advised that moderate daily activities will not affect the pregnancy. Tampons, intercourse, and other activities that might induce uterine infection should be avoided as long as the patient is bleeding, and she should return immediately for fever, abdominal pain, or a significant increase in bleeding. If tissue is passed by the patient, it should be brought for analysis for the presence of products of conception, because differentiation of fetal parts from decidual slough (decidual cast) is difficult.

Treatment of the patient with inevitable miscarriage includes dilation and evacuation (D & E) or D & C to remove the remaining intrauterine contents. When the os is open, the uterus is unable to contract adequately to limit bleeding from the implantation site, and simple removal of tissue from the cervix usually allows contraction to occur. Bleeding may be brisk, and gentle removal of fetal tissue from the cervical os with ring forceps often slows bleeding considerably.

Management of patients with presumed completed spontaneous miscarriage is more complicated. If the patient brings tissue with her, this should be preliminarily inspected in the ED and then sent to the pathology department for evaluation. Recent studies have shown that, in women with a history consistent with miscarriage who have minimal remaining intrauterine tissue as determined by sonography, expectant management is safe if ectopic pregnancy can be excluded.83 If endometrial tissue is not seen with ultrasonography, bleeding is mild, and gestational age is less than eight weeks, curettage is frequently unnecessary and the patient may be safely followed-up by a gynecologist for serial hormonal assays.84 In contrast, in women with significant remaining intrauterine tissue, the risk of complications may be decreased by uterine curettage.83 Consultation with a specialist is advised and, if D & C is not performed, the patient should be instructed to return if increased bleeding, cramping, fever, or tissue passage occurs. Follow-up is required in one to two weeks to assure that the miscarriage is complete.

After miscarriage, the patient should be advised that fetal loss is associated with significant psychological stress, even during the first trimester. Followup  in one to two weeks with a gynecologist should be provided.85 Some physicians prescribe antibiotics after D & C (usually doxycycline or metronidazole), particularly in patient populations at high risk for genital tract infections. Ergonovine or methylergonovine (0.2 mg PO twice daily) may also be used to stimulate uterine involution. The patient should receive careful advice to return if signs of infection (fever or uterine tenderness) occur, if bleeding resumes, or if further tissue is passed. As noted in the previous section, anti-D immune globulin may also be indicated.

Ectopic

The primary goal of accurate and early identification of ectopic pregnancy is to limit morbidity and eliminate mortality resulting from this condition. If diagnosed early, the patient is potentially a candidate for either minimally invasive surgery or medical therapy. In early stages, these therapies have been foundto be just as effective as the traditional laparotomy with salpingectomy. However, newer therapies have the advantage of salvaging the fallopian tube. In unstable patients with a high suspicion of tubal rupture, the choice of treatment is still laparotomy.

Medical Therapy - Methotrexate

Non-operative management has become standard care for the stable patient with an ectopic pregnancy.43,77 Methotrexate is the most commonly used drug and belongs to a class of drugs called folic acid antagonists.86 It works by inhibiting the enzyme dihydrofolate reductase, leading to a depletion of the cofactors required for DNA synthesis. Initially, methotrexate was used to treat leukemia but gained wide acceptance in the treatment of choriocarcinoma. In pregnancy, methotrexate causes destruction of rapidly dividing fetal cells and involution of the pregnancy.87 Methotrexate may be given orally, intramuscularly, or by continuous infusion. For the treatment of ectopic pregnancy, the intramuscular route is currently preferred.87 However, success has been reported with the oral route alone in a few studies.87 Stovall et al performed the largest study of methotrexate, which involved 100 patients, 96 of whom responded successfully.91 Several smaller studies had success rates ranging from 3-100%.86-90 With the exception of the study by Stovall et al, ectopic pregnancies with cardiac activity were excluded from methotrexate treatment.

Methotrexate may be given with citrovorum (Leucovorin®) rescue as a therapy for ectopic pregnancy. Citrovorum, which is a reduced form of folate, blocks the effects of methotrexate. Given after administration of methotrexate, it appears to rescue cells from additional adverse effects of the drug.

The use of methotrexate is associated with several complications, the most common of which is lower abdominal pain.92-96,98 The pathophysiology of the abdominal pain is unclear, though it is probably related to bleeding and/or expulsion of the ectopic resulting in peritoneal irritation. These patients ca be managed conservatively if they have a stable hemoglobin and no evidence of significant free fluid in the cul-de-sac by ultrasound. Twenty percent of patients in the study by Stovall et al had an increase in abdominal pain managed as an outpatient, and an additional 4% were subsequently hospitalized for observation.91

Other complications included transient elevation of transaminase levels, mild stomatitis, dermatitis, pleuritis, and nausea.86-91,97 These side effects appear to be dose-related, occurring with higher doses of methotrexate received, without significant morbidity or mortality.

The most serious complication of the methotrexate regimen is tubal rupture, the pathophysiology of which is unclear, see Table 8. In six studies reviewed, there were seven ruptures among 275 treated patients.92,96,99In addition, there was one case report of tubal rupture despite falling β-hCG levels.100 The possibility of rupture exists until complete resolution of the ectopic is documented (β-hCG less than 10-20 mIU/mL). There is no correlation between β-hCG levels and risk of rupture that can aid the clinician. Due to the extended time until resolution of the ectopic pregnancy, the symptoms of tubal rupture need to be monitored on a continuous basis.86-91


All patients presenting with worsening abdominal pain after receiving methotrexate should be carefully evaluated for tubal rupture. When a patient presents with abdominal pain after methotrexate administration, she should be evaluated with a repeat hemoglobin, an ultrasound to detect free fluid, and consultation with an obstetrician. Patients with increased abdominal pain who are hemodynamically stable with no fluid in the cul-de-sac and a stable hemoglobin may be managed as outpatients. Admission for continued observation despite negative studies may be required if her pain is not controlled or her vital signs are abnormal.

The success of higher dose methotrexate protocols with citrovorum rescue led to trials of lower single dose intramuscular (IM) methotrexate without citrovorum rescue. Success rates with this protocol have ranged from 85 to 100%.83-86 In the largest study, which treated 120 patients, there was a 94% rate of ectopic termination (defined as a β-hCG of 10-20 mIU/ml).87 Ectopic termination and resolution times range in various studies from a mean of 23.1+2.9 days to 38.4+6.4 days.83-87Low dose treatment is reported to result in longer resolution times, but higher initial β-hCG levels where found in these studies. It is unclear why initial levels where higher, but it could represent a selection bias in these studies. 87,13,15 Predictors for success of methotrexate treatment are listed in Table 9. 92 Of these markers, a low β-hCG level has proven to be most predictive. In a retrospective study of 60 patients, Tawfiq et al found that failure occurred in 65% of the cases where the β- hCG level was greater than 4000 mIU/mL.102 In a review of 350 ectopic pregnancy patients, the methotrexate failure rate rose to greater than 13% when the pretreatment β-hCG level was greater than 5000 mIU/mL.103 However, despite these studies, there is not an accepted absolute β-hCG level where use of methotrexate is contraindicated.104,105



In addition to the primary treatment of ectopic pregnancy, methotrexate is also indicated for the treatment of persistent ectopic after salpingostomy, prophylaxis for suspected persistent products of conception after conservative surgery, and in cases of unusual ectopic pregnancy, such as abdominally implanted pregnancies.104 Absolute contraindications can be seen in Table 10. Relative contraindications include a gestational sac of greater than 3.5 cm and embryonic cardiac activity. In addition, any patient who receives methotrexate must be compliant, understand the importance of follow-up, and be able to return for surveillance and possibly further care.105 Any patient receiving methotrexate should be screened with a complete blood count, liver function tests, and an electrolyte panel with a serum creatinine. 96 In addition, if the patient has a history of pulmonary disease, a baseline chest x-ray must be obtained due to the risk of interstitial pneumonitis.



The ability to conceive after the use of methotrexate for ectopic pregnancy has been addressed in several studies. One weakness in these studies is that the tubal patency rates were not established prior to methotrexate use, possibly leading to lower percentage of patency than expected. Of the patients attempting to conceive after methotrexate therapy, a success rate of about 80% has been reported. 96,106The recurrent ectopic pregnancy rate is about 10% in patients treated with intramuscular methotrexate versus 13% in patients treated with linear salpingostomy, but this is not a statistically significant difference.96,106

Methotrexate Dosing Regimens

Traditionally, multi-dose IM methotrexate has been the treatment of choice, but single dose ethotrexate is becoming more popular, see Table 11. These two regimens have never been directly compared, but a recent meta-analysis was conducted to compare efficacies.119 In qualifying cases, the overall success rate for IM methotrexate was 89%. The success rate for multi-dose IM methotrexate was 92.7% while the success rate for the single dose regimen was only 88.1%. This was found to be statistically significant. When controlling for β-hCG levels, the failure rate with single dose therapy was almost five times greater than the multi-dose regimen. The success rates found in this meta-analysis mirrors what other studies have found regarding successful treatment rates in single dose and multi-dose regimens. A new two dose IM methotrexate protocol has been developed which attempts to balance efficacy as well as convenience, see Table 12. A dose of methotrexate is given on day one and day four without leucovorin rescue, and the prior single dose follow- up protocol is then followed. Due to the risk of failure with increasing β-hCG levels, some have advocated the use of the two dose protocol with β- hCG levels greater than 1000 mIU/mL, but this has not been prospectively studied to date.104




Operative Care

Historically, laparotomy was the treatment of choice for ectopic pregnancy. With the advent of methotrexate therapy and laparoscopy, laparotomy has become significantly less frequent. Laparotomy still has a role in patients who are unstable and unable to be emergently resuscitated as well as those with evidence of extensive intraperitoneal bleeding. In addition, in hemodynamically unstable patients with an open cervical os, D & C may be useful to obtain tissue that will either confirm an IUP or show a decidual cast suggestive of ectopic pregnancy.

For hemodynamically stable patients, those with peritoneal signs, or those who cannot receive methotrexate, use laparoscopy.71,72 It is associated with decreased blood loss, fewer analgesic requirements, and shorter hospital stays. It has also been found to be cost effective when compared to the traditional approach of laparotomy.

Traditionally, salpingectomy was the surgical procedure of choice, but with the newer laparoscopic techniques, tubal salvage procedures in hemodynamically stable patients are commonly used. Although the rate of persistent ectopic is 5-20% higher in the salpingostomy group, the use of methotrexate has abated most concerns. In general, it is thought that the risk of future ectopic pregnancy is increased by the use of salpingostomy, but this is balanced by an increased rate of future fertility.107-110 Salpingostomy is preferred to salpingectomy if the patient is stable and the procedure is technically feasible.72