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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. References

Objective To assess the effectiveness of systemic treatment with methotrexate in combination with local injection for unruptured tubal pregnancy, and to evaluate reproductive function following treatment.

Design Prospective, open clinical study.

Setting University clinic.

Population Sixty-seven women with unruptured tubal pregnancy.

Methods Systemic methotrexate (intramuscular methotrexate 0.5 mg/kg for up to five days) in combination with local application of 12.5 mg methotrexate via laparoscopy.

Main outcome measures The subsequent surgical intervention required and future fertility.

Results In 89.6% of women no further surgical intervention was required and 47 women (81%) experienced subsequently an intrauterine pregnancy. In 39 of 40 women who underwent hysterosalpingo-graphy following treatment, patency of the affected tube was observed.

Conclusions Combined local and systemic methotrexate treatment for unruptured tubal pregnancy seems to be more effective than each therapeutic modality alone.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. References

The incidence of extrauterine pregnancy has increased in the last two decades, and it remains the leading cause of pregnancy related death in the first trimester. Yet, early awareness coupled with increased sensitivity of serum β-hCG (β-human chorionic gonadotrophin) immunoassay and improved quality of transvaginal ultrasonography allowing early detection of extrauterine pregnancy, have changed the goal of management from a life-saving intervention to tubal and fertility preservation.

Early detection of unruptured tubal pregnancy has led to less invasive and nonsurgical methods of treatment, which have almost eliminated the need for laparatomy, and in many cases the need for laparoscopy. Prostaglandins, RU-486, potassium chloride and actinomycin-D have all been employed as medical treatment modalities1–4. Methotrexate emerged as the drug of choice for this purpose5–7. In the late 1980s we described a combined methotrexate protocol of local methotrexate injection into the gestational sac, followed by a course of intramuscular methotrexate and folinic acid for five days5.

As there is little information about the fertility outcome of women treated conservatively by either methotrexate or salpingostomy8–16, we present here the subsequent reproductive performance in women treated according to our methotrexate based protocol.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. References

Between May 1987 and December 1993, 291 women were admitted with the diagnosis of extrauterine pregnancy. Sixty-seven fulfilled the inclusion criteria of the present study: 1. intact gestational sac located within the fallopian of less than 4 cm in diameter; 2. no evidence of intrauterine pregnancy by ultrasonography; 3. haemo-dynamical stability; 4. no evidence of intra-abdominal bleeding; 5. constant or rising β-hCG levels; and 6. the woman's desire to retain her fertility.

The remaining 224 women, who either did not conform to the inclusion criteria of the study or could not be recruited due to night admission (73%), underwent various interventions such as salpingectomy (n= 201), salpingostomy (n= 14), milking (n= 2), and suction and irrigation for tubal abortion (n= 7). No information was available as for the interest of these patients in future fertility.

Sixty-seven women with unruptured tubal pregnancy were treated with methotrexate at the Department of Obstetrics and Gynaecology at the Edith Wolfson Medical Center. Before enrolment in the study protocol, informed written consent was obtained from all women. In a previous publication we reported on 10 of these 67 women5. The management protocol included: 1. laparoscopic identification of extrauterine pregnancy and injection of 12.5 mg methotrexate into the gestational sac; 2. administration of 0.5 mg/kg methotrexate intramuscular daily up to five days; or 3. concomitant administration of 0.1 mg/kg folinic acid 12 hours after each methotrexate injection up to five days.

Each woman was carefully observed for changes in pulse, blood pressure and other vital signs for the first 24 hours. Tests for haemoglobin concentration, white blood cell count, platelets count, liver enzymes, kidney function and β-hCG levels were performed on every alternate day. The women were discharged from the hospital when β-hCG level decreased to at least 10% of the basic level, and were followed at the outpatient clinic until β-hCG level dropped below 10 mIU/mL. Forty women agreed to a hysterosalpingography 2–3 months after resolution of β-hCG levels.

Data on fertility outcome were obtained at periodic visits, by telephone survey or by letters, until an additional pregnancy occurred, or fertility became irrelevant. We referred to ‘time to conception’ as the time from treatment onwards, since intention to conceive was expressed by all women immediately and was part of the inclusion criteria. Given this set up, the time frames ‘treatment—to—conception’ and ‘intention—to—conception’ were congruent in this series.

Statistical analysis

Results are presented as average (SD)[range] and percentages. Distribution of β-hCG levels was stabilised using the natural log transformation. Due to small numbers and deviations from normality, nonparametric statistics were used (Mann-Whitney U test and Spearman correlation).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. References

The total number of deliveries during the study period was 18,885 for a prevalence of 1:55 at this institution. Since in Israel patients may choose freely a hospital for delivery or for the treatment of complication of pregnancy, such as extrauterine pregnancy, this prevalence does not necessarily reflect the prevalence rate nor an incidence rate for Israel. Since the number of known pregnancies or the number of fertile women during the study period is not available, a calculation based on these denominators cannot be presented.

The average age of the women was 28.8 years (4.8). Average gravidity was 2.7 (1.5)[1–8], and average parity was 1.3 (1.2)[0–4]. Twenty-three of the women (34%) were nulliparous. Almost two-thirds (63%) of ectopic pregnancies occurred in the left tube, and the average gestational age at diagnosis was 7.0 weeks (0.8). β-hCG levels on admission ranged between 147 and 47,600 mIU/mL. The duration of hospital stay averaged 7.5 days (2.2)[4–15].

On laparoscopy, additional pelvic pathology was found in nine women. There were ipsilateral peritubal adhesions in three women, all of which conceived subsequently with an intrauterine pregnancy. In three patients bilateral adhesions were observed. In one of these, methotrexate treatment failed and salpingectomy was performed. She eventually had an intact intrauterine pregnancy. A second patient did not conceive and in the third woman an ipsilateral tubal pregnancy occurred necessitating salpingectomy.

Seven of 67 women (11.6%) failed to respond to methotrexate treatment and needed further surgical intervention (salpingectomy). Failure of treatment was significantly associated with higher β-hCG levels. (one tailed Mann-Whitney test = 0.0465 (Fig. 1)). The failure rate among women with initial β-hCG level ≥ 5000 mIU/mL was 21.4% (3/14), compared with a failure rate of 7.5% (4/53) among those with β-hCG levels < 5000 mIU/mL. Probably due to the small numbers of cases the difference did not reach statistical significance. The time of resolution of β-hCG levels was also longer in women with higher β-hCG levels (Fig. 2).

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Figure 1. Comparison of initial β-hCG levels in successful and failed methotrexate treatment.

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Figure 2. Correlation between initial β-hCG levels and resolution time.

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In the remaining 60 women, the resolution time of serum β-hCG was 21 days (11.5) on average, and the median time was 18 days. Except for stomatitis, which developed in four women (6%), no other complications from methotrexate treatment, were observed.

Forty women agreed to undergo a hysterosalpingography following treatment. In all but one, hysterosalpingography confirmed patency of the treated fallopian tube (success rate of 97.5%). Two women were lost to follow up and therefore calculations were based on 58 women. These were followed for 27 months (17) [10–76]. Five women did not have additional pregnancies due to hysterectomy (n= 1), tubal sterilisation (n= 1), intrauterine device use (n= 1) and pelvic adhesions (failure of in vitro fertilisation treatment) (n= 2).

Forty-seven women (81%) experienced an intrauterine pregnancy within 27 months (17). Of these, nine women aborted spontaneously (15.5%) and the remaining 38 gave birth at term. No malformations were noted among the neonates.

Six women (10.5%) had a repeated extrauterine pregnancy within 17 months (28). In five women the extrauterine pregnancy occurred on the opposite side, and in one in the same tube. Three of these women had subsequent intrauterine pregnancies, and one woman experienced again a recurrent (third) extrauterine pregnancy. In nulliparous women the conception rate following an extrauterine pregnancy was 100%.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. References

Traditionally, ectopic pregnancies have been treated surgically with subsequent impaired fertility prognosis17–19. With the development of the laparoscopic approach, fertility prospects have significantly improved (Table 1).

Table 1.  Outcome of laparoscopic salpingostomy treatment for extrauterine pregnancies (EUP). Values are given as n or n (%). IUP = intrauterine pregnancy; HSG = hysterosalpingography.
      pregenancy outcome
AutherNo. of patientsNo. of successful casesNo. of HSGPatient tubesPatients trying to concetivePregnanciesIUPEUP
Paulson et al.8125116(92.8)7165 (91.5)4838 (79.2)26 (68.4)12(31.6)
Vermesh et al.93028 (93.3)2016 (80.0)1914 (73.7)13 (92.9)1(7.1)
Shale v et al.115551 (92.7)2312 (52.2)2319 (82.6)14 (73.7)5 (26.3)
Hajenius et al.184935 (71.4)3523 (66.0)    
TOTAL259202 (80.0)149116(77.8)9071 (78.9)53 (74.6)18 (25.4)

Further advance has been made by the introduction of medical treatment for unruptured extrauterine pregnancy.

One problem with either systemic or local medical treatment remains persistent extrauterine pregnancy requiring additional surgery. In our study seven women (10.4%) required salpingectomy following medical treatment, a rate that is similar to the reported 9% for systemic methotrexate treatment, and better than the reported 24% for local methotrexate treatment (Table 2). Women who underwent salpingostomy had failure rates between 9% and 29% (Table 1).

Table 2.  Outcome of methotrexate (MTX) treatment for extrauterine pregnancies (EUP). Values are given as n or n (%). (%). IUP = intrauterine pregnancy; HSG = hysterosalpingography; TVS = transvaginal sonography.
      pregenancy outcome
AutherNo. of patientsNo. of successful casesNo. of HSGPatient tubesPatients trying to concetivePregnanciesIUPEUP
Local MTX        
Injection by laparoscopy        
Panski et al.127761 (79.0)2119 (90.7)3128 (90.3)24 (85.7)4(14.3)
Shalev et al.104427 (61.4)1913 (68.4)1915 (78.9)12 (80.0)3(20)
Injection by TVS        
Femandez et al.132019 (95.0)1715 (88.0)106 (60.0)6 (100.0)0
TOTAL141107(75.8)5747 (82.5)6049(81.7)42(85.7)7(14.3)
Systemic MTX        
Ichinoe et al.142322 (95.7)1910 (52.6)    
Stovall et al.15120113(94.0)6251 (82.3)4939 (79.6)34 (87.2)5(12.8)
Hajenius et al.115142 (82.0)3723 (62.0)    
TOTAL194177 (91.2)11884(71.2)4939 (79.6)34 (87.2)5(12.8)
TOTAL overall335284 (85.0)175131(74.9)10988 (80.7)76 (86.4)12(13.6)
Present study6760 (89.5)4039 (97.5)5553 (96.3)47 (88.7)6(10.9)

The only parameter that could be correlated to the failure of our methotrexate protocol was the initial level of β-hCG. The failure rate of methotrexate treatment was significantly higher when initial β-hCG level was above 5000 mIU/mL (21.4%vs 7.5%), although not reaching statistical significance. We do not have an explanation for the exceptionally high conception rate (100%) among the nulliparous women.

Methotrexate has been widely used for extrauterine pregnancy during the last decade and offers an alternative to the surgical approach. Some groups have treated extrauterine pregnancy by local methotrexate injection into the gestational sac either by the laparoscopic route or guided by transvaginal ultrasonography. Others have administered methotrexate systemically (Table 2). We have established a protocol, which constitutes a combination of both modalities. Sixty-seven women were included in this prospective study, of which the vast majority (89.6%) did not require subsequent surgery. These results are comparable with those reported by others (Table 2). Following our treatment protocol tubal patency was observed at hysterosalpingography in 39 women out of 40 (97.5%). These figures are significantly higher (77.8%) than those reported following salpingostomy (Table 1) or following local and systemic methotrexate treatment (74.9%)(Table 2).

Typically, patients after laparoscopy are discharged on the following day. The reason for the prolonged hospital stay in our patients was the local regulation, which permits the use of methotrexate only for inpatients.

All three treatment modalities (i.e. salpingostomy, systemic methotrexate use and local injection of methotrexate) seem to yield similar results in terms of subsequent pregnancies (Tables 1 and 2). Yet our combination protocol appears to produce better results compared with each of above treatment schemes in terms of both intrauterine pregnancy rate (88.7%) and low rate of recurrent extrauterine pregnancy (11.3%). Today, we do not consider this treatment protocol as first line therapy. Operative laparoscopy, which has rapidly gained popularity in recent years, is applied in our department, as in many others, as first line therapy aimed at performing direct surgery on the fallopian tube (salpingostomy/salpingectomy). Yet, in instances where either the attending physician or the patient prefers to refrain from tubal surgery, methotrexate treatment is a valid option. Based on our data we rely on our protocol, as presented here, for these cases.

CONCLUSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. References

We believe that methotrexate treatment of unruptured extrauterine pregnancy as proposed in our combined protocol is very efficient while requiring only limited laparoscopic experience of the surgeon. While the failure rate of our protocol was similar to other treatment modalities, subsequent tubal patency and reproductive performance were felt to be better than that of surgical treatment or that of various protocols of methotrexate treatment previously reported. Human chorionic gonadotrophin level measurements on admission may be helpful to identify women in whom a primary surgical approach may be warranted, due to a relatively high failure rate of medical treatment in women with high β-hCG levels. In women with high initial β-hCG levels the treating physician may want to consider a primary surgical approach. In the presence of intermediate or low β-hCG levels, and taking into account the patient's preference and the physician's preference and surgical skills, our combined protocol offers satisfactory results.

References

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. References
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