Frank W. Ling

Single-dose methotrexate: An expanded clinical trial

OBJECTIVE Our purpose was to report an expanded clinical trial with a nonlaparoscopic approach to ectopic pregnancy diagnosis combined with single-dose intramuscular methotrexate treatment. STUDY DESIGN A prospective cohort of 120 women with an ectopic pregnancy < or = 3.5 cm in greatest dimension was enrolled. RESULTS Patients had a mean age of 26.1 +/- 6.2 years, a mean gravidity of 3.2 +/- 1.6, and a mean parity of 0.97 +/- 1.0. The mean human chorionic gonadotropin titer before treatment initiation was 3950 +/- 1193 mIU/ml. Transvaginal ultrasonography visualized cardiac activity in 14 (11.7%) patients, with an ectopic mass visualized in 113 (94.2%). The mean time to resolution in the 113 (94.2%) subjects successfully treated was 35.5 +/- 11.8 days. Four (3.3%) patients required a second methotrexate dose on day 7. No biochemical or clinical side effects occurred. Posttreatment hysterosalpingograms demonstrated tubal patency on the ipsilateral side in 51 of 62 (82.3%) patients. Of those attempting pregnancy, 79.6% were pregnant, 87.2% intrauterine and 12.8% ectopic. The mean time to achieve pregnancy was 3.2 +/- 1.1 months. CONCLUSIONS This regimen requires minimal laboratory follow-up and eliminates leukovorin recovery, making it the regimen of choice for medical treatment of unruptured ectopic pregnancy.

Predictors of Success of Methotrexate Treatment in Women with Tubal Ectopic Pregnancies

BACKGROUND The use of methotrexate for the treatment of women with tubal ectopic pregnancies is now common practice. However, the clinical and hormonal determinants of the success of this treatment are not known. METHODS We studied 350 women with tubal ectopic pregnancies who were treated with methotrexate intramuscularly according to a single-dose protocol. Pretreatment serum concentrations of human chorionic gonadotropin and progesterone, the size and volume of the gestational mass, fetal cardiac activity, and the presence of fluid (presumably blood) in the peritoneal cavity were correlated with the efficacy of therapy, as defined by resolution of the ectopic pregnancy without the need for surgical intervention. RESULTS There was no relation between the womens age or parity, the size or volume of the conceptus, or the presence of fluid in the peritoneal cavity and the efficacy of treatment. Among the 320 women in whom treatment was successful (91 percent), the mean (+/-SD) serum chorionic gonadotropin and progesterone concentrations were 4019+/-6362 mIU per milliliter and 6.9+/-6.7 ng per milliliter (21.9+/-21.3 nmol per liter), respectively, as compared with 13,420+/-16,590 mIU per milliliter and 10.2+/-5.5 ng per milliliter (32.4+/-17.5 nmol per liter) (P<0.001 and P=0.02) in the 30 women in whom treatment was not successful. Fetal cardiac activity was present in 12 percent of the successfully treated cases and 30 percent of those in which treatment was not successful (P=0.01). Regression analysis revealed the pretreatment serum chorionic gonadotropin concentration to be the only factor that contributed to the failure rate. CONCLUSIONS Among women with tubal ectopic pregnancies, a high serum chorionic gonadotropin concentration is the most important factor associated with failure of treatment with a single-dose methotrexate protocol.

Randomized controlled trial of Depot leuprolide in patients with chronic pelvic pain and clinically suspected endometriosis

Objective: To evaluate and compare the safety and efficacy of leuprolide versus placebo in managing chronic pelvic pain in women with clinically suspected endometriosis. Methods: Women 18–45 years of age with moderate to severe pelvic pain of at least 6 months’ duration underwent extensive, noninvasive diagnostic testing and laboratory evaluation, including pelvic ultrasound, complete blood count, determination of erythrocyte sedimentation rate, and endocervical cultures. Those with clinically suspected endometriosis were randomized to double-blind treatment for 3 months with depot leuprolide (3.75 mg/mo) or placebo. The accuracy of the clinical diagnosis of endometriosis was evaluated by posttreatment laparoscopy. Results: Of 100 women randomized, 95 completed the study: 49 in the leuprolide group and 46 in the placebo group. Women in the leuprolide group had clinically and statistically significant (P ≤ .001) mean improvements from baseline after 12 weeks of therapy in all pain measures. These mean improvements were significantly greater (P ≤ .001) than those in the placebo group. At 12 weeks, mean decreases in physician-rated scores for dysmenorrhea, pelvic pain, and pelvic tenderness were 1.7, 1.0, and 0.8 points greater, respectively, in the leuprolide group than in the placebo group (on a four-point scale). Thirty-eight (78%) of 49 and 40 (87%) of 46 patients in the leuprolide and placebo groups, respectively, had laparoscopically confirmed endometriosis after 12 weeks of treatment. No women withdrew from the study because of adverse events. Conclusion: Depot leuprolide was effective and safe for treating patients with chronic pelvic pain and clinically suspected endometriosis, confirming the potential of its empiric use in these patients.

Outpatient chemotherapy of unruptured ectopic pregnancy

This report describes an individualized, reduced dose, methotrexate (MTX) and citrovorum factor (CF) treatment regimen for outpatient management of unruptured ectopic pregnancy (EP). One hundred sixteen laparoscopically documented EPs, the majority (90%) of whom were symptomatic, were diagnosed from an Emergency Department population. Eighty of 116 (69%) were unruptured, 37 (46.3%) of whom were eligible for MTX-CF chemotherapy. One patient refused chemotherapy. Thirty-four of the 36 (94.4%) patients treated with MTX-CF had complete resolution of their ectopics, whereas 2 experienced rupture after chemotherapy, 1 of them 23 days after MTX initiation. While there were no major chemotherapy-related side effects, 3 of the 36 (8.3%) patients experienced minor side effects. The authors conclude that: (1) individualized dosing of outpatient MTX-CF chemotherapy for symptomatic EP can be safely managed, even in an indigent population; (2) rupture can occur up to 23 days after chemotherapy initiation; (3) fetal cardiac activity is an absolute contraindication to chemotherapy; (4) chemotherapy in patients with symptoms is of limited value because the disease is too far advanced; therefore, it is essential that the diagnosis of EP be established before symptom onset; and (5) chemotherapy offers no significant immediate advantages to outpatient laparoscopic surgery. However, increasingly reliable nonlaparoscopic diagnosis will soon give wider application to this approach.

Analysis of three hundred fifteen ectopic pregnancies treated with single-dose methotrexate☆☆☆★

OBJECTIVES The objective of this study was to review the largest single series of ectopic pregnancies treated with single-dose methotrexate reported to date. STUDY DESIGN A review of 315 patients with unruptured ectopic pregnancies treated with single-dose methotrexate 50 mg/m2 from March 21, 1990, to March 1, 1997, was performed. RESULTS Overall 287 patients were successfully treated with methotrexate for a success rate of 90.1%. Six patients electively withdrew and requested surgery within 1 week of starting therapy. Excluding withdrawals the overall success rate was 92.9%. Ten patients with an ectopic pregnancy > 3.5 cm but < or = 4 cm in size were treated for a 90% success rate. Forty-four patients with positive ectopic cardiac activity were treated with an 87.5% success rate. CONCLUSIONS This large series indicates that single-dose intramuscular methotrexate for treatment of ectopic pregnancy is associated with an excellent overall success rate.

Emergency department diagnosis of ectopic pregnancy

STUDY OBJECTIVES To assess the accuracy of the history and physical examination as compared to the addition of serum progesterone screening for ectopic pregnancy in women presenting to the emergency department. DESIGN Prospective, consecutive case series, N = 2,157. SETTING ED of the Regional Medical Center at Memphis, a publicly subsidized, 450-bed acute care hospital staffed by residents and faculty of the University of Tennessee, Memphis. TYPE OF PARTICIPANTS All ED patients with a positive urine pregnancy test treated between January 1 and December 31, 1988. INTERVENTIONS Screening history, physical examination, and serum progesterone (P) and quantitative human chorionic gonadotropin (hCG) titer. MEASUREMENTS All discharged patients were given follow-up appointments within two weeks; those found to have a P less than 25 ng/mL were called to return for repeat hCG and transvaginal ultrasound. MAIN RESULTS One hundred sixty-one of 2,157 patients (7.5%) with a positive urine pregnancy test were found to have an ectopic pregnancy. All but five had a P of less than 25 ng/mL (sensitivity, 97%); four of these were admitted for immediate surgery because of symptoms. Overall, the ED physician detected 89 of 161 ectopics (55.3%) on initial presentation, 53 (60%) of which were ruptured at the time of surgery. Seventy-two patients (44.7%) who were discharged but later found to have an ectopic pregnancy had benign clinical presentations, including 41 with vaginal bleeding. There were no statistically significant differences in the presenting symptoms of patients with unruptured ectopics compared with normal intrauterine pregnancies. All but one of the 72 discharged patients were noted the following day to have a progesterone of less than 25 ng/mL and contacted to return. Eight of these were found to have a ruptured ectopic at the time of surgery. Only 91 of 161 patients (56.5%) with ectopic pregnancy acknowledged one or more clinical risk factors on follow-up questioning. CONCLUSION The standard history and physical examination, including those performed by gynecologic specialists, are insufficiently sensitive for early detection of unruptured ectopic pregnancy. EDs with a high incidence of ectopic pregnancy should strongly consider implementation of a universal progesterone screening program to decrease unnecessary patient morbidity and the risk of mortality from undiagnosed ectopic pregnancy.

Nonsurgical diagnosis and treatment of tubal pregnancy

These data suggest that EP can be diagnosed and safely treated medically with MTX using the scheme outlined with no laparoscopy. Laparoscopic removal can be reserved for those patients with large unruptured EP (greater than 3.0 cm; cardiac activity) or the individual who requires laparoscopy for diagnosis.

Reproductive performance after methotrexate treatment of ectopic pregnancy

The purpose of this study was to examine return of reproductive potential, hysterosalpingographic findings, and time to conception in patients treated with methotrexate and citrovorum factor for unruptured ectopic pregnancy. Fifty-seven patients with unruptured ectopic pregnancies less than 3.0 cm in greatest dimension were treated with methotrexate and citrovorum factor. The mean time from resolution of the ectopic pregnancy to return of menses was 26.0 (0 to 157) days. Forty-four patients were available for follow-up (2 to 15 months). Nineteen of 23 patients who had hysterosalpingograms demonstrated patency in the ipsilateral tube. Fourteen patients desired pregnancy; 11 of 14 (78.6%) were successful, with 10 of 11 (90.9%) having an intrauterine pregnancy, whereas one of 14 (9.1%) were extrauterine gestations. The mean time from first attempt to achieving pregnancy was 2.3 (1 to 4) months. We conclude that methotrexate and citrovorum factor treatment of unruptured ectopic pregnancy is associated with subsequent tubal patency and does not impair return of menses. Most importantly, the pregnancy rates after this form of therapy appear to be better than those achieved by traditional surgical methods, and are comparable to results after laparoscopic salpingostomy.

Preventing ruptured ectopic pregnancy with a single serum progesterone

Retrospective data on patients with documented ectopic pregnancies have demonstrated the potential usefulness of serum progesterone in decreasing the time to diagnosis. We report a prospective trial utilizing serum progesterone in the emergency department of a large city-county hospital. Sixty-seven ectopic pregnancies were document in the 582 patients screened; 54 (80.6%) had a progesterone level less than 15 ng/ml. Only one (1.5%) ruptured ectopic pregnancy was associated with a progesterone level greater than 25 ng/ml. There were 387 documented or presumed normal intrauterine pregnancies, 41 (10.6%) had progesterone concentrations of less than 15 ng/ml and 236 (61%) had a progesterone level greater than 25 ng/ml. We decreased minimum time of diagnosis from 48 to 72 hours to less than 24 hours by use of a progesterone screening protocol. During this time the percentage of ruptured ectopic pregnancies decreased from 79.2% to 38.8% (p less than 0.05). Because of its simple interpretation and 24-hour maximum delay, we conclude that the determination of serum progesterone should be used for ectopic pregnancy screening in all patients at risk for ectopic pregnancy, or at any time when the diagnosis is in question.

Reproductive animal researchAdhesion prevention by solutions of sodium carboxymethylcellulose in the rat. I.

Solutions of sodium carboxymethylcellulose (SCMC) were studied in rats to determine their longevity within the peritoneal cavity and their potential for prevention of postoperative intraperitoneal adhesions. In 18 rats, test solutions of SCMC and 10% dextran 40 were instilled at laparotomy. At 48 hours copious amounts of SCMC remained, whereas no 10% dextran 40 could be detected. In addition, standardized surgical injury was produced on the ceca of 100 rats at laparotomy. All control animals had significant adhesions at 2 weeks. Eighty-two percent of the 10% dextran 40 group had significant adhesions, while only 16% of the 0.9 wt% SCMC and 17% of the 1.0 wt% SCMC groups had significant adhesions. Solutions of SCMC were significantly more effective than 10% dextran 40 in the prevention of adhesions (P less than 0.001). Properties of SCMC and a possible mechanism for its striking effectiveness in adhesion prevention in this study are discussed.