Abstract
Introduction
Approximately 1/100 pregnancies are ectopic, with the conceptus usually implanting in the fallopian tube. Some ectopic pregnancies resolve spontaneously, but others continue to grow and lead to rupture of the tube. Risks are higher in women with damage to the fallopian tubes due to pelvic infections, surgery, or previous ectopic pregnancy.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What treatments improve outcomes in women with unruptured tubal ectopic pregnancy? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2011 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations, such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). The authors also separately searched Medline and Pubmed up to July 2011 in addition to the Clinical Evidence systematic search to support the comments and clinical guide sections.
Results
We found 19 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: salpingotomy, salpingectomy, methotrexate, methotrexate following salpingotomy, methotrexate plus mifepristone, and expectant management.
Key Points
Approximately 1/100 pregnancies are ectopic, with the conceptus usually implanting in the fallopian tube. Some tubal ectopic pregnancies resolve spontaneously, but others continue to grow and lead to rupture of the tube.
Risks for ectopic pregnancy are higher in women with damage to the fallopian tubes because of pelvic infections, pelvic surgery, or previous ectopic pregnancy, and in smokers.
The IUD does not increase the absolute risk of ectopic pregnancy, but pregnancy that does occur with IUD use is more likely to be ectopic than intrauterine.
Primary treatment success and reduced risk of future pregnancy (intrauterine and/or ectopic) are prioritised outcomes for women with ectopic pregnancy not desiring future fertility. However, treatment success and repeat intrauterine pregnancy are the prioritised outcomes for women with ectopic pregnancy desiring future fertility. Given these individualised outcome preferences, even though data from RCTs are absent, the most effective treatment for ectopic pregnancy in women not desiring future fertility is salpingectomy.
Salpingotomy, salpingectomy, or methotrexate show similar rates of primary treatment success in women with ectopic pregnancy desiring future pregnancy; however, there is uncertainty over which treatment option is superior given the individualised outcome preference for this group of women and the absence of data from RCTs.
Salpingotomy by laparoscopy may lead to fewer complications and shorter recovery times compared with laparotomy, but may also be less likely to remove all the trophoblast.
Single- or multiple-dose methotrexate seems as likely as salpingotomy to eliminate trophoblast material and leave a patent fallopian tube in women with non-invasively diagnosed small ectopic pregnancies with no tubal rupture or bleeding, no sign of fetal cardiac activity, and low beta hCG levels.
About 15% to 40% of ectopic pregnancies may be suitable for such non-surgical management.
Adding mifepristone to systemic methotrexate seems unlikely to increase treatment success compared with methotrexate alone, other than in women with higher progesterone levels.
Expectant management of unruptured ectopic pregnancies may lead to similar subsequent intrauterine pregnancy rates compared with surgery, but few studies have been done.
A single prophylactic dose of methotrexate after salpingotomy is more effective at reducing persistent trophoblast compared with salpingotomy alone.
Clinical context
About this condition
Definition
Ectopic pregnancy is defined as a conceptus implanting outside the uterine endometrium. The most common implantation site is within the fallopian tube (95.5%), followed by ovarian (3.2%), and abdominal (1.3%) sites. The sites of tubal implantation in descending order of frequency are ampulla (73.3%), isthmus (12.5%), fimbrial (11.6%), and interstitial (2.6%). Population: In this systematic review, we consider haemodynamically stable women with unruptured tubal ectopic pregnancy, diagnosed by either non-invasive or invasive techniques.
Incidence/ Prevalence
About 10,000 ectopic pregnancies are diagnosed annually in the UK. The incidence of ectopic pregnancy in the UK is 11.1/1000 pregnancies. Differing rates are reported in other countries such as Norway (14.9/1000), Australia (16.2/1000), and the USA (6.4/1000). Since 1994, the overall rates of ectopic pregnancy and resulting mortality (0.35/1000 ectopic pregnancies in 2003–2005) have been static in the UK. Until recently, most epidemiological studies failed to distinguish between ectopic pregnancies occurring in women who did not use contraception (reproductive failure) and women who used contraception (contraceptive failure). A French population study undertaken from 1992 to 2002 found that, over the duration of the study, the rate of reproductive-failure ectopic pregnancies increased by 17%, whereas the rate of contraceptive-failure ectopic pregnancies decreased by 29%. Increasing rates of chlamydia infection, smoking, and assisted reproductive technology use may have contributed to the disproportionate increase in the reproductive-failure ectopic pregnancies. Widespread use of dedicated early pregnancy-assessment units and non-invasive diagnostic algorithms are likely to have contributed to increasing rates of ectopic pregnancy diagnosis.
Aetiology/ Risk factors
The aetiology of ectopic pregnancy is unclear. Ectopic pregnancy arising from reproductive or contraceptive failure should be considered as separate entities with differing aetiology, risk factors, and reproductive outcomes. The main risk factors for reproductive failure are: previous ectopic pregnancy, previous pelvic inflammatory disease, previous pelvic and tubal surgery, infertility, smoking, and use of assisted conception. The main risk factor for contraceptive-failure ectopic pregnancy is IUD failure. IUDs do not increase the absolute risk of ectopic pregnancy, but a pregnancy occurring with an IUD is more likely to be ectopic than intrauterine. Other risk factors for ectopic pregnancy include prior spontaneous miscarriage, endometriosis, uterotubal anomalies, and prior in utero exposure to diethylstilbestrol. However, less than half of diagnosed ectopic pregnancies are associated with risk factors.
Prognosis
Ectopic pregnancies: As the pregnancy advances, tubal pregnancies may either diminish in size and spontaneously resolve, or increase in size and eventually lead to tubal rupture, with consequent maternal morbidity and mortality. There are no reliable clinical, sonographic, or biological markers (e.g., serum beta hCG or serum progesterone) that can predict rupture of tubal ectopic pregnancy. Maternal mortality following ectopic pregnancy is an uncommon short-term outcome in resource-rich countries. The 2003–2005 UK Confidential Enquiry into Maternal Deaths cited ectopic pregnancy as a cause of 10 maternal deaths (0.47/100,000 pregnancies). Short-term maternal morbidity relates to pain, transfusion requirement, and operative complications. Primary treatment success and long-term fertility outcomes depend on the clinical characteristics of the ectopic pregnancy (e.g., whether the ectopic pregnancy occurred in a woman using contraception or not, tubal rupture or not, contralateral tubal disease) and the type of surgical or medical treatment chosen. A 10-year follow-up of ectopic pregnancies showed that the rate of repeat ectopic pregnancy was much higher in women with an IUD in place at the time of the index ectopic pregnancy, compared with women whose ectopic pregnancy was not associated with IUD use. By contrast, the rate of intrauterine pregnancy was 1.7 times higher (fecundity rate ratio [FRR] 1.7, 95% CI 1.3 to 2.3) in women who had an IUD in place at the time of the index ectopic pregnancy compared with women whose index ectopic pregnancy was not associated with IUD use. Short- and long-term consequences on health-related quality of life and psychological issues (e.g., bereavement) are also important, but are rarely quantified. Pregnancies of unknown location (PUL): PUL is the absence of pregnancy localisation (either intrauterine or extrauterine) by transvaginal sonography when serum beta hCG levels are below the discriminatory zone (1000–1500 IU/L). One observational study of pregnancies of unknown location has shown that 55% spontaneously resolve, 34% are subsequently diagnosed as viable, and 11% are subsequently diagnosed as ectopic pregnancies.
Aims of intervention
Short term: Primary treatment success; to reduce maternal morbidity and mortality related to ectopic pregnancy (tubal rupture and haemorrhage), or the treatment method used (e.g., surgical complications, medical drug toxicity), or both. Long term (all women): To reduce risk of recurrent ectopic pregnancy. Long term (for subgroup of women desiring subsequent pregnancy): To maximise the chance of future intrauterine pregnancy and live birth rate from unassisted spontaneous conception, or following use of assisted reproductive technology techniques (e.g., in vitro fertilisation).
Outcomes
Primary outcomes: persistent trophoblast; primary treatment success. Secondary outcomes: subsequent pregnancy; future fertility/spontaneous intrauterine pregnancy; live birth rate; and repeat ectopic pregnancy in women desiring subsequent pregnancy (this should ideally be expressed as FRRs over specific time intervals corrected for known confounders [e.g., history of infertility and contraception use at time of index ectopic pregnancy]). Other outcome measures: health-related quality-of-life assessments; ipsilateral tubal patency following tubal-preserving treatment (salpingotomy, methotrexate, or expectant management); maternal morbidity and mortality (prior to ectopic treatment [natural history of ectopic pregnancy] and following treatment alternatives); tubal rupture; and adverse effects of treatment, including complications of surgery (injury, infection, thromboembolism).
Methods
Clinical Evidence search and appraisal July 2011. The following databases were used to identify studies for this systematic review: Medline 1966 to July 2011, Embase 1980 to July 2011, and The Cochrane Database of Systematic Reviews, June 2011 [online] (1966 to date of issue). An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA) database. We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews, meta-analyses, RCTs, controlled clinical trials, cohort studies, prospective or retrospective, with a control or comparison treatment group, and case-control studies; in any language; open or blinded studies acceptable; and containing 20 or more individuals. There was no maximum loss to follow-up or minimum length of follow-up. Cohort studies were reported when there were insufficient data from RCTs. FRRs have been calculated by the Clinical Evidence contributor, where indicated. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied applying the same study design criteria for inclusion as we did for benefits. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. The contributors of the review also carried out their own systematic search to enhance the clinical guide statements and comments section of the review. They searched Medline and Pubmed databases from 1996 to July 2011, using the following search terms: pregnancy, ectopic; pregnancy, tubal; laparoscopy or salpingectomy; fallopian-tube diseases; methotrexate; mifepristone; salpingotomy; pregnancy outcome; methotrexate and mifepristone, in combination with subheadings of: complications; diagnosis; drug therapy; mortality; surgery; and therapy. They included systematic reviews, non-systematic reviews with meta-analysis, RCTs, cohort, and case-control studies. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table.
GRADE Evaluation of interventions for Tubal ectopic pregnancy.
| Important outcomes | Primary treatment success, Subsequent pregnancy, Tubal patency | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What treatments improve outcomes in women with unruptured tubal ectopic pregnancy? | |||||||||
| 1 (440) | Primary treatment success | Salpingectomy versus salpingotomy | 2 | 0 | 0 | –1 | 0 | Very low | Directness point deducted for no direct statistical comparison between groups |
| 3 (1907) | Subsequent pregnancy | Salpingectomy versus salpingotomy | 2 | –1 | –1 | 0 | 0 | Very low | Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results |
| 1 (214) | Primary treatment success | Salpingectomy versus methotrexate | 2 | –1 | 0 | 0 | 0 | Very low | Quality point deducted for incomplete reporting of results |
| 1 (797) | Subsequent pregnancy | Salpingectomy versus methotrexate | 2 | –1 | 0 | 0 | 0 | Very low | Quality point deducted for incomplete reporting |
| 2 (165) | Primary treatment success | Salpingotomy by laparoscopy versus salpingotomy by laparotomy | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 2 (110) | Tubal patency | Salpingotomy by laparoscopy versus salpingotomy by laparotomy | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 2 (127) | Subsequent pregnancy | Salpingotomy by laparoscopy versus salpingotomy by laparotomy | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 6 RCTs and 23 studies (1606) | Primary treatment success | Systemic single- versus multiple-dose methotrexate regimens | 4 | –2 | –1 | 0 | 0 | Very low | Quality points deducted for incomplete reporting of results and uncertainty about quality of studies. Consistency point deducted for different results between studies |
| 6 (471) | Primary treatment success | Systemic single- or multiple-dose methotrexate versus salpingotomy | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for early termination of planned recruitment in 1 RCT |
| 4 RCTs (215) | Tubal patency | Systemic single- or multiple-dose methotrexate versus salpingotomy | 4 | 0 | 0 | 0 | 0 | High | |
| 5 (295) | Subsequent pregnancy | Systemic single- or multiple-dose methotrexate versus salpingotomy | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for early termination of planned recruitment in 1 RCT |
| 3 (334) | Primary treatment success | Systemic methotrexate plus mifepristone versus systemic methotrexate alone | 4 | –2 | 0 | 0 | 0 | Low | Two quality points deducted for inclusion of observational study |
| 2 (163) | Primary treatment success | Systemic single-dose methotrexate plus salpingotomy versus salpingotomy alone | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 2 (232) | Subsequent pregnancy | Expectant management versus salpingectomy or salpingotomy | 2 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for differences in inclusion criteria |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
Glossary
- Beta hCG
The pregnancy hormone beta human chorionic gonadotropin.
- Contralateral tube
The opposite tube to that affected by the ectopic pregnancy.
- Discriminatory zone
A serum beta hCG level at which it is assumed that all intrauterine pregnancies will be visualised by transvaginal ultrasound. This may vary according to sonographic expertise, but is often between 1000 and 1500 IU/L.
- Expectant management
This is where ectopic pregnancy treatment involves a watch-and-wait policy in conjunction with close clinical, ultrasonographic, and serum beta hCG surveillance.
- Fecundity rate ratio (FRR)
The fecundity rate represents the probability of spontaneous intrauterine pregnancy (IUP) per time unit elapsed, derived from analysing the cumulative probability of pregnancy over the study duration. Only women trying to conceive are included in the calculation, and women who have conceived using additional treatments (e.g., in vitro fertilisation) are excluded up until the start of their additional treatment. The FRR is the ratio of fecundity between the test treatment (e.g., salpingotomy) and the reference treatment (e.g., salpingectomy). A significant treatment difference between salpingotomy compared with salpingectomy is indicated if 1 is not included in the 95% confidence interval (CI) for the FRR of salpingotomy compared with salpingectomy. Thus, an FRR of 1.9 for intrauterine pregnancy indicates that the probability of intrauterine pregnancy is 90% higher with salpingotomy than salpingectomy.
- Fertility outcome
This outcome reports the rates of subsequent intrauterine pregnancy, repeat ectopic pregnancy, and live birth rate. Such pregnancies may either be spontaneous or achieved through assisted reproductive technology, and this should be stated clearly in the fertility outcome. Furthermore, fertility outcome rates differ according to the ectopic pregnancy-associated reproductive and pathological characteristics, and treatment method chosen. The denominator will differ in those women who desire future fertility and who are trying to conceive, compared with those women taking contraceptive measures.
- High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
- Persistent trophoblast
Suboptimal falling, increasing, or plateauing serum beta hCG concentrations following initial ectopic pregnancy treatment for which additional treatment (surgical or medical) is needed. This rarely occurs following salpingectomy, but may arise following salpingotomy, methotrexate, or expectant management.
- Pregnancy of unknown location
Absence of pregnancy localisation (either intrauterine or extrauterine) by transvaginal sonography when serum beta hCG levels are below the discriminatory zone (1000–1500 IU/L). If there is an absence of pregnancy localisation with the serum beta hCG above the discriminatory zone, then this, along with other clinical, ultrasonographic, and serum beta hCG features, increases the likelihood of ectopic pregnancy.
- Primary treatment success
This is defined as progressive decline of serum beta hCG to undetectable levels following initial treatment without reintervention (surgical or medical) for persistent trophoblast or supervening clinical sequelae (e.g., tubal rupture or worsening clinical symptoms).
- Salpingotomy
This is where the ectopic conceptus is removed from the affected tube through a linear incision of the tube overlying the ectopic pregnancy. This incision is not surgically closed and is allowed to heal through secondary intention. This surgical treatment conserves the affected tube.
- Tubal excision or salpingectomy
The surgical removal of the tube affected by the ectopic pregnancy.
- Tubal patency
Tubal patency examines the homolateral tube for the passage of dye at hysterosalpingogram, or at second-look laparoscopy, or the passage of contrast media at transvaginal ultrasound. Only those cases that have been managed by tubal preservation, rather than salpingectomy, are eligible for tubal patency testing.
- Very low-quality evidence
Any estimate of effect is very uncertain.
Chlamydia (uncomplicated, genital)
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
Contributor Information
Dr Rajesh Varma, Guy's and St. Thomas' Hospital NHS Foundation Trust, London, UK.
Dr Janesh Gupta, Birmingham University, Birmingham, UK.
References
- 1.Bouyer J, Coste J, Fernandez H, et al. Sites of ectopic pregnancy: a 10 year population-based study of 1800 cases. Hum Reprod 2002;17:3224–3230. [DOI] [PubMed] [Google Scholar]
- 2.Bakken IJ, Skjeldestad FE. Incidence and treatment of extrauterine pregnancies in Norway 1990–2001. Tidsskr Nor Laegeforen 2003;123:3016–3020. [PubMed] [Google Scholar]
- 3.Boufous S, Quartararo M, Mohsin M, et al. Trends in the incidence of ectopic pregnancy in New South Wales between 1990–1998. Aust N Z J Obstet Gynaecol 2001;41:436–438. [DOI] [PubMed] [Google Scholar]
- 4.Lewis, G. Saving Mothers’ Lives: reviewing maternal deaths to make motherhood safer 2003–2005. London: CEMACH, 2007. [Google Scholar]
- 5.Hoover KW, Tao G, Kent CK. Trends in the diagnosis and treatment of ectopic pregnancy in the United States. Obstet Gynecol 2010;115:495–502. [DOI] [PubMed] [Google Scholar]
- 6.Bouyer J. Epidemiology of ectopic pregnancy: incidence, risk factors and outcomes. J Gynecol Obstet Biol Reprod (Paris) 2003;32:S8–S17. [In French] [PubMed] [Google Scholar]
- 7.Coste J, Bouyer J, Ughetto S, et al. Ectopic pregnancy is again on the increase. Recent trends in the incidence of ectopic pregnancies in France (1992–2002). Hum Reprod 2004;19:2014–2018. [DOI] [PubMed] [Google Scholar]
- 8.Condous G, Okaro E, Khalid A, et al. The accuracy of transvaginal ultrasonography for the diagnosis of ectopic pregnancy prior to surgery. Hum Reprod 2005;20:1404–1409. [DOI] [PubMed] [Google Scholar]
- 9.Mol 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;14:2855–2862. [DOI] [PubMed] [Google Scholar]
- 10.Bouyer J, Fernandez H, Coste J, et al. Fertility after ectopic pregnancy: 10-year results in the Auvergne Registry. J Gynecol Obstet Biol Reprod (Paris) 2003;32:431–438. [PubMed] [Google Scholar]
- 11.Virk J, Zhang J, Olsen J. Medical abortion and the risk of subsequent adverse pregnancy outcomes. N Eng J Med 2007;357:648–653. [DOI] [PubMed] [Google Scholar]
- 12.Barnhart KT, Sammel MD, Gracia CR, et al. Risk factors for ectopic pregnancy in women with symptomatic first-trimester pregnancies. Fertil Steril 2006;86:36–43. [DOI] [PubMed] [Google Scholar]
- 13.Ankum WM, Mol BW, van Der Veen F, et al. Risk factors for ectopic pregnancy: a meta-analysis. Fertil Steril 1996;65:1093–1099. [PubMed] [Google Scholar]
- 14.Shaw JL, Dey SK, Cricthley HO, et al. Current knowledge of the aetiology of human tubal ectopic pregnancy. Hum Reprod Update 2010;16:432–444. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Dart RG, Kaplan B, Varaklis K. Predictive value of history and physical examination in patients with suspected ectopic pregnancy. Ann Emerg Med 1999;33:283–290. [DOI] [PubMed] [Google Scholar]
- 16.Latchaw G, Takacs P, Gaitan L, et al. Risk factors associated with the rupture of tubal ectopic pregnancy. Gynecol Obstet Invest 2005;60:177–180. [DOI] [PubMed] [Google Scholar]
- 17.Job-Spira N, Fernandez H, Bouyer J, et al. Ruptured tubal ectopic pregnancy: risk factors and reproductive outcome: results of a population-based study in France. Am J Obstet Gynecol 1999;180:938–944. [DOI] [PubMed] [Google Scholar]
- 18.Condous G, Lu C, Van Huffel SV, et al. Human chorionic gonadotrophin and progesterone levels in pregnancies of unknown location. Int J Gynaecol Obstet 2004;86:351–357. [DOI] [PubMed] [Google Scholar]
- 19.Yao M, Tulandi T. Current status of surgical and nonsurgical management of ectopic pregnancy. Fertil Steril 1997;67:421–433. [DOI] [PubMed] [Google Scholar]
- 20.Bangsgaard N, Lund CO, Ottesen B, et al. Improved fertility following conservative surgical treatment of ectopic pregnancy. BJOG 2003;110:765–770. [PubMed] [Google Scholar]
- 21.Bouyer J, Job-Spira N, Pouly JL, et al. Fertility following radical, conservative-surgical or medical treatment for tubal pregnancy: a population-based study. BJOG 2000;107:714–721. [DOI] [PubMed] [Google Scholar]
- 22.Mol BW, Matthijsse HC, Tinga DJ, et al. Fertility after conservative and radical surgery for tubal pregnancy. Hum Reprod 1998;13:1804–1809. [DOI] [PubMed] [Google Scholar]
- 23.Silva PD, Schaper AM, Rooney B. Reproductive outcome after 143 laparoscopic procedures for ectopic pregnancy. Obstet Gynecol 1993;81:710–715. [PubMed] [Google Scholar]
- 24.Morlock RJ, Lafata JE, Eisenstein D. Cost-effectiveness of single-dose methotrexate compared with laparoscopic treatment of ectopic pregnancy. Obstet Gynecol 2000;95:407–412. [DOI] [PubMed] [Google Scholar]
- 25.Mol F, Strandell A, Jurkovic D, et al. The ESEP study: salpingostomy versus salpingectomy for tubal ectopic pregnancy; the impact on future fertility: a randomised controlled trial. BMC Womens Health 2008;8:11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Hajenius PJ, Mol F, Mol BWJ, et al. Interventions for tubal ectopic pregnancy. In: The Cochrane Library: Issue 2, 2011. Chichester, UK: John Wiley & Sons Ltd. Search date 2006. [Google Scholar]
- 27.Mol F, Mol BW, Ankum WM, et al. Current evidence on surgery, systemic methotrexate and expectant management in the treatment of tubal ectopic pregnancy: a systematic review and meta-analysis. Hum Reprod Update 2008;14:309–319. [DOI] [PubMed] [Google Scholar]
- 28.Lundorff P, Hahlin M, Kallfelt B, et al. Adhesion formation after laparoscopic surgery in tubal pregnancy: a randomized trial versus laparotomy. Fertil Steril 1991;55:911–915. [DOI] [PubMed] [Google Scholar]
- 29.Lundorff P, Thorburn J, Lindblom B. Fertility outcome after conservative surgical treatment of ectopic pregnancy evaluated in a randomized trial. Fertil Steril 1992;57:998–1002. [DOI] [PubMed] [Google Scholar]
- 30.Jansen FW, Kapiteyn K, Trimbos-Kemper T, et al. Complications of laparoscopy: a prospective multicentre observational study. Br J Obstet Gynaecol 1997;104:595–600. [DOI] [PubMed] [Google Scholar]
- 31.Garry R. Towards evidence-based laparoscopic entry techniques: clinical problems and dilemmas. Gynecol Endosc 1999;8:315–326. [Google Scholar]
- 32.Rabischong B, Larrain D, Pouly JL, et al. Predicting success of laparoscopic salpingostomy for ectopic pregnancy. Obstet Gynecol 2010;116:701–707. [DOI] [PubMed] [Google Scholar]
- 33.Chapron C, Fauconnier A, Goffinet F, et al. Laparoscopic surgery is not inherently dangerous for patients presenting with benign gynaecologic pathology. Results of a meta-analysis. Hum Reprod 2002;17:1334–1342. [DOI] [PubMed] [Google Scholar]
- 34.Krag Moeller LB, Moeller C, Thomsen SG, et al. Success and spontaneous pregnancy rates following systemic methotrexate versus laparoscopic surgery for tubal pregnancies: a randomized trial. Acta Obstet Gynecol Scand 2009;88:1331–1337. [DOI] [PubMed] [Google Scholar]
- 35.Barnhart KT, Gosman G, Ashby R, et al. The medical management of ectopic pregnancy: a meta-analysis comparing "single dose" and "multidose" regimens. Obstet Gynecol 2003;101:778–784. Search date 2001. [DOI] [PubMed] [Google Scholar]
- 36.Guvendag Guven ES, Dilbaz S, Dilbaz B, et al. Comparison of single and multiple dose methotrexate therapy for unruptured tubal ectopic pregnancy: a prospective randomized study. Acta Obstet Gynecol Scand 2010;89:889–895. [DOI] [PubMed] [Google Scholar]
- 37.Alleyassin A, Khademi A, Aghahosseini M, et al. Comparison of success rates in the medical management of ectopic pregnancy with single-dose and multiple-dose administration of methotrexate: a prospective, randomized clinical trial. Fertil Steril 2006;85:1661–1666. [DOI] [PubMed] [Google Scholar]
- 38.Sowter MC, Farquhar CM, Petrie KJ, et al. A randomised trial comparing single dose systemic methotrexate and laparoscopic surgery for the treatment of unruptured tubal pregnancy. BJOG 2001;108:192–203. [DOI] [PubMed] [Google Scholar]
- 39.Nieuwkerk PT, Hajenius PJ, Ankum WM, et al. Systemic methotrexate therapy versus laparoscopic salpingostomy in patients with tubal pregnancy. Part I. Impact on patients′ health-related quality of life. Fertil Steril 1998;70:511–517. [DOI] [PubMed] [Google Scholar]
- 40.Isaacs JD, Jr, McGehee RP, Cowan BD. Life-threatening neutropenia following methotrexate treatment of ectopic pregnancy: a report of two cases. Obstet Gynecol 1996;88:694–696. [DOI] [PubMed] [Google Scholar]
- 41.Straka M, Zeringue E, Goldman M. A rare drug reaction to methotrexate after treatment for ectopic pregnancy. Obstetr Gynecol 2004;103:1047–1048. [DOI] [PubMed] [Google Scholar]
- 42.Zullo F, Pellicano M, Di Carlo C, et al. Late complications after systemic methotrexate treatment of unruptured ectopic pregnancies: a report of three cases. Eur J Obstet Gynecol Reprod Biol 1996;70:213–214. [DOI] [PubMed] [Google Scholar]
- 43.Kelly H, Harvey D, Moll S. A cautionary tale: fatal outcome of methotrexate therapy given for management of ectopic pregnancy. Obstet Gynecol 2006;107:439–441. [DOI] [PubMed] [Google Scholar]
- 44.Parker J, Bisits A, Proietto AM. A systematic review of single-dose intramuscular methotrexate for the treatment of ectopic pregnancy. Aust N Z J Obstet Gynaecol 1998;38:145–150. [DOI] [PubMed] [Google Scholar]
- 45.Gervaise A, Masson L, de Tayrac R, et al. Reproductive outcome after methotrexate treatment of tubal pregnancies. Fertil Steril 2004;82:304–308. [DOI] [PubMed] [Google Scholar]
- 46.Chapron C, Fernandez H, Dubuisson JB. Treatment of ectopic pregnancy in 2000. J Gynecol Obstet Biol Reprod (Paris) 2000;29:351–361. [PubMed] [Google Scholar]
- 47.Floridon C, Thomsen SG. Methotrexate treatment of ectopic pregnancy. Acta Obstet Gynecol Scand 1994;73:746–752. [DOI] [PubMed] [Google Scholar]
- 48.Elson J, Tailor A, Banerjee S, et al. Expectant management of tubal ectopic pregnancy: prediction of successful outcome using decision tree analysis. Ultrasound Obstet Gynecol 2004;23:552–556. [DOI] [PubMed] [Google Scholar]
- 49.Royal College of Obstetricians and Gynaecologists. The management of tubal pregnancy. Guideline no 21. London: RCOG Press, 2004. [Google Scholar]
- 50.Gamzu R, Almog B, Levin Y, et al. Efficacy of methotrexate treatment in extrauterine pregnancies defined by stable or increasing human chorionic gonadotropin concentrations. Fertil Steril 2002;77:761–765. [DOI] [PubMed] [Google Scholar]
- 51.Lecuru F, Robin F, Bernard JP, et al. Single-dose methotrexate for unruptured ectopic pregnancy. Int J Gynaecol Obstet 1998;61:253–259. [DOI] [PubMed] [Google Scholar]
- 52.Lipscomb GH, McCord ML, Stovall TG, et al. Predictors of success of methotrexate treatment in women with tubal ectopic pregnancies. N Engl J Med 1999;341:1974–1978. [DOI] [PubMed] [Google Scholar]
- 53.Nazac A, Gervaise A, Bouyer J, et al. Predictors of success in methotrexate treatment of women with unruptured tubal pregnancies. Ultrasound Obstet Gynecol 2003;21:181–185. [DOI] [PubMed] [Google Scholar]
- 54.Tawfiq A, Agameya AF, Claman P. Predictors of treatment failure for ectopic pregnancy treated with single-dose methotrexate. Fertil Steril 2000;74:877–880. [DOI] [PubMed] [Google Scholar]
- 55.Erdem M, Erdem A, Arslan M, et al. Single-dose methotrexate for the treatment of unruptured ectopic pregnancy. Arch Gynecol Obstet 2004;270:201–204. [DOI] [PubMed] [Google Scholar]
- 56.Cho GJ, Lee SH, Shin JW, et al. Predictors of success of repeated injections of single-dose methotrexate regimen for tubal ectopic pregnancy. J Korean Med Sci 2006;21:86–89. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 57.Menon S, Colins J, Barnhart KT. Establishing a human chorionic gonadotropin cutoff to guide methotrexate treatment of ectopic pregnancy: a systematic review. Fertil Steril 2007;87:481–484. [DOI] [PubMed] [Google Scholar]
- 58.Rabischong B, Tran X, Slemain AA, et al. Predictive factors of failure in management of ectopic pregnancy with single-dose methotrexate: a general population-based analysis from the Auvergne Register, France. Fert Steril 2011;95:401–404. [DOI] [PubMed] [Google Scholar]
- 59.Balci O, Ozdemir S, Mahmoud AS, et al. The efficacy of multiple-dose methotrexate treatment for unruptured tubal ectopic pregnancy and conversion rate to surgery: a study on 294 cases. Fertil Steril 2010;93:2415–2417. [DOI] [PubMed] [Google Scholar]
- 60.Kirk E, Van Calster B, Condous G, et al. Ectopic pregnancy: using the hCG ratio to select women for expectant or medical management. Acta Obstet Gynecol Scand 2011;90:264–272. [DOI] [PubMed] [Google Scholar]
- 61.Dilbaz S, Caliskan E, Dilbaz B, et al. Predictors of methotrexate treatment failure in ectopic pregnancy. J Reprod Med 2006;51:87–93. [PubMed] [Google Scholar]
- 62.Lipscomb GH, Givens VA, Meyer NL, et al. Previous ectopic pregnancy as a predictor of failure of systemic methotrexate therapy. Fertil Steril 2004;81:1221–1224. [DOI] [PubMed] [Google Scholar]
- 63.Bixby S, Tello R, Kuligowska E. Presence of a yolk sac on transvaginal sonography is the most reliable predictor of single-dose methotrexate treatment failure in ectopic pregnancy. J Ultrasound Med 2005;24:591–598. [DOI] [PubMed] [Google Scholar]
- 64.Potter MB, Lepine LA, Jamieson DJ. Predictors of success with methotrexate treatment of tubal ectopic pregnancy at Grady Memorial Hospital. Am J Obstet Gynecol 2003;188:1192–1194. [DOI] [PubMed] [Google Scholar]
- 65.Perdu M, Camus E, Rozenberg P, et al. Treating ectopic pregnancy with the combination of mifepristone and methotrexate: a phase II nonrandomized study. Am J Obstet Gynecol 1999;180:1599–1600. [DOI] [PubMed] [Google Scholar]
- 66.Gazvani MR, Baruah DN, Alfirevic Z, et al. Mifepristone in combination with methotrexate for the medical treatment of tubal pregnancy: a randomized, controlled trial. Hum Reprod 1998;13:1987–1990. [DOI] [PubMed] [Google Scholar]
- 67.Rozenberg P, Chevret S, Camus E, et al. Medical treatment of ectopic pregnancies: a randomized clinical trial comparing methotrexate-mifepristone and methotrexate-placebo. Hum Reprod 2003;18:1802–1808. [DOI] [PubMed] [Google Scholar]
- 68.Graczykowski JW, Mishell DR, Jr. Methotrexate prophylaxis for persistent ectopic pregnancy after conservative treatment by salpingostomy. Obstet Gynecol 1997;89:118–122. [DOI] [PubMed] [Google Scholar]
- 69.Helmy S, Sawyer E, Ofili-Yebovi D, et al. Fertility outcomes following expectant management of tubal ectopic pregnancy. Ultrasound Obstet Gynecol 2007;30:988–1292. [DOI] [PubMed] [Google Scholar]
- 70.Strobelt N, Mariani E, Ferrari L, et al. Fertility after ectopic pregnancy. Effects of surgery and expectant management. J Reprod Med 2000;45:803–807. [PubMed] [Google Scholar]
- 71.Buster JE, Krotz S. Reproductive performance after ectopic pregnancy. Semin Reprod Med 2007;25:131–133. [DOI] [PubMed] [Google Scholar]
- 72.van Mello NM, Mol F, Adriaanse AH, et al. The METEX study: methotrexate versus expectant management in women with ectopic pregnancy: a randomised controlled trial. BMC Womens Health 2008:8;10. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 73.Cohen MA, Sauer MV. Expectant management of ectopic pregnancy. Clin Obstet Gynecol 1999;42:48–54. [DOI] [PubMed] [Google Scholar]
- 74.Rantala M, Makinen J. Tubal patency and fertility outcome after expectant management of ectopic pregnancy. Fertil Steril 1997;68:1043–1046. [DOI] [PubMed] [Google Scholar]
- 75.Banerjee S, Aslam N, Woelfer B, et al. Expectant management of early pregnancies of unknown location: a prospective evaluation of methods to predict spontaneous resolution of pregnancy. BJOG 2001;108:158–163. [DOI] [PubMed] [Google Scholar]
- 76.Condous G, Okaro E, Khalid A, et al. The use of a new logistic regression model for predicting the outcome of pregnancies of unknown location. Hum Reprod 2004;19:1900–1910. [DOI] [PubMed] [Google Scholar]
- 77.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;34:703–710. [DOI] [PubMed] [Google Scholar]
- 78.Hahlin M, Thorburn J, Bryman I. The expectant management of early pregnancies of uncertain site. Hum Reprod 1995;10:1223–1227. [DOI] [PubMed] [Google Scholar]
- 79.Kooi S, Kock HC, van Etten FH. Tubal rupture despite low and declining serum hCG levels. Eur J Obstet Gynecol Reprod Biol 1992;46:56–59. [DOI] [PubMed] [Google Scholar]
- 80.Tulandi T, Hemmings R, Khalifa F. Rupture of ectopic pregnancy in women with low and declining serum beta-human chorionic gonadotropin concentrations. Fertil Steril 1991;56:786–787. [DOI] [PubMed] [Google Scholar]