Distinction between early normal intrauterine pregnancies and pathological pregnancies by means of a logistic model.

The probability of an unclear very early pregnancy being a normal intrauterine pregnancy was estimated using a logistic model. Five diagnostic measures of prognostic value were identified in the model: (i) daily change in human chorionic gonadotrophin (HCG), (ii) results of transvaginal ultrasound, (iii) vaginal bleeding, (iv) serum progesterone level and (v) risk score for ectopic pregnancy. With the use of this model, the probability of a normal intrauterine pregnancy has been estimated as 96.7%.     

Simultaneous intrauterine and ectopic pregnancies following in-vitro fertilization and gamete intra-fallopian transfer. A review of nine cases

This paper reports nine cases of simultaneous intrauterine and ectopic pregnancies which followed in-vitro fertilization (three cases) and gamete intra-Fallopian transfer (six cases). The ectopic pregnancies were treated by aspiration and injection of potassium chloride and methotrexate (five cases), salpingectomy (three cases) or laparoscopic evacuation (one case). In five of the nine patients the intrauterine pregnancies continued until after the 35th week and the patients delivered live infants. The role of vaginal ultrasound scanning in making the diagnosis was emphasized. The literature on heterotropic pregnancy is reviewed.     

Pregnancy: Transvaginal sonography and human chorionic gonadotrophin measurements in suspected ectopic pregnancy: a detailed analysis of a diagnostic approach

In this prospective study among 208 high-risk patients withsuspected ectopic pregnancy, the diagnostic value of transvaginalsonography and serum human chorionic gonadotrophin (HCG) measurementswere analysed in detail. The absence of an intra-uterine gestationalsac obviously was the most constant sonographic finding amongpatients with ectopic pregnancy (n = 89), with a very high sensitivity(0.99) but a low specificity (0.41). The application of differentHCG cut-off levels improved specificity to 1.00 for values exceeding4500 IU/1. Clinical utility obviously decreased, as many patientspresented with HCG values well below this level. The additionaleffect of adnexal findings was analysed. Sonographic identificationof an ectopic pregnancy was very specific (0.99) but had lowsensitivity (0.56) because many ectopics were not detected.The additional effect of HCG values on these results was minor.The low HCG cut-off levels advocated in recent studies are questionedby the results of our analysis: whereas the combined use ofsonography and HCG measurements is shown to be of great benefit,the limitations are also documented, underlining the need forre-evaluation at intervals of patients with low HCG values.The question of which cut-off level should be used in practice,however, hinges on a difficult choice between a certain specificityand clinical utility.     

Pregnancy: Laparoscopy: a dispensable tool in the diagnosis of ectopic pregnancy?

Laparoscopy is regarded as the final decisive diagnostic testin suspected ectopic pregnancy. The new non-invasive diagnosticmethods of transvaginal sonography and serum human chorionicgonadotrophin (HCG) monitoring now challenge this pivotal roleof laparoscopy. In this prospective study the diagnostic valueof an algorithm, combining transvaginal sonography with an HCGcut-off level between 1000 and 1500 IU/I (IRP) was tested in208 consecutive women at risk for ectopic pregnancy. Three diagnosticcategories are designated by the algorithm: intra-uterine pregnancy(n = 73), ectopic pregnancy (n = 89), and trophoblast in regression(n = 46). The latter category represents patients in whom nopregnancy could be located by transvaginal sonography, withan initial HCG concentration < 1500 IU/I, declining duringfollow-up. The algorithm has a sensitivity of 0.97, a specificityof 0.95, a likelihood ratio for a positive test of 19.4, anda likelihood ratio for a negative test of 0.03. The describeddiagnostic strategy thus proved extremely reliable in the safemanagement of patients at risk for ectopic pregnancy, and renderslaparoscopy obsolete.     

Trophoblast tissue culture of human intrauterine and ectopic pregnancies and treatment with methotrexate.

The application of drugs for conservative treatment of patients with ectopic pregnancy has been used worldwide for several years. In-vitro studies, however, are very few. We therefore examined the effects of methotrexate on trophoblast tissue cultures derived from intrauterine and ectopic pregnancies. Methotrexate was administered either 12 h or 6 days after initiation of the culture. Human chorionic gonadotrophin (HCG) levels were measured in the culture medium. All cultures showed secretion of HCG within the first 16 days. Methotrexate concentrations less than 3.8 x 10(-4) mol/l had no effect on HCG secretion. Cultures of ectopic pregnancies required a concentration about 10x higher to induce an equivalent reduction of HCG levels compared to intrauterine pregnancies. A few intrauterine and ectopic pregnancies showed no reduction of HCG values after treatment. These results suggest that data obtained from studies on intrauterine pregnancies may not be transferable to ectopic pregnancies in all instances. In some regimens approximately 8 days are required before the effect becomes measurable. In combination with our clinical data, we therefore recommend not to repeat a methotrexate dose too early in treatment of patients with ectopic pregnancies. The possibility that non-responding patients could exist should be kept in mind.     

Evaluation of the sites of ectopic pregnancies subsequent to reconstructive tubal surgery

The sites of ectopic pregnancies in women who underwent varioustypes of reconstructive tubal surgery were analysed and comparedto the controls. Overall, ectopic pregnancies subsequent toall types of tubal surgeries were more often implanted proximallycompared to the control population.     

Analysis of ectopic pregnancies resulting from in-vitro fertilization and embryo transfer

The purpose of this study was to analyse the risk factors, stimulation characteristics, site and outcome of pregnancy and future fecundity of patients who develop ectopic pregnancies after in-vitro fertilization (IVF). Of 3145 transfer cycles between January 1981 and July 1989, 27 (3.3%) of the resulting 825 pregnancies were ectopic. There was a significantly greater incidence of a prior ectopic pregnancy in the study group compared to the controls. Compared to matched controls with intrauterine pregnancies, the study group had significantly higher peak oestradiol levels. Twenty-one ectopic pregnancies were ampullary, two were interstitial, one was abdominal, one was cervical and two were heterotopic. Sixteen of the patients subsequently underwent 40 IVF attempts with a pregnancy rate of 28% per transfer. We conclude that patients with a prior ectopic pregnancy are at risk for an IVF ectopic pregnancy. The subsequent IVF outcome of those who develop ectopic pregnancies after IVF is encouraging.     

Vascular endothelial growth factor (VEGF) and discrimination between abnormal intrauterine and ectopic pregnancy

BACKGROUND: This study evaluated serum vascular endothelial growth factor (VEGF) levels in women with abnormal intrauterine and ectopic pregnancies (EP) at 6 weeks gestation. METHODS: We conducted a prospective case-control study comparing serum VEGF concentrations among 84 women with abnormal intrauterine and EP matched for gestational age (42 women in each group). We analysed whether serum VEGF levels >200 pg/ml would discriminate between abnormal intrauterine pregnancies and EP at 6 weeks gestation, and we calculated sensitivity, specificity and positive predictive values. RESULTS: Serum VEGF concentrations did not show statistically significant differences between women with abnormal intrauterine pregnancies (median, 198.5 pg/ml; range, 0-701.6) and EP (median, 211.2 pg/ml; range 0-628.8). When threshold concentrations of a serum VEGF level >200 pg/ml were used, abnormal intrauterine pregnancy could be distinguished from EP with a sensitivity of 56%, a specificity of 51%, and a positive predictive value of 53%. CONCLUSIONS: VEGF does not discriminate ectopic from abnormal intrauterine pregnancies at 6 weeks gestation, and thus should not be used in clinical management.     

The dilemma of the optimal surgical procedure in ectopic pregnancies occurring in in-vitro fertilization.

Ectopic pregnancy remains one of the undesired sequelae of in-vitro fertilization (IVF) treatment. It seems that mechanical infertility increases the risk of this complication in IVF. Thus, the surgeon treating such a case faces the dilemma of the optimal surgical procedure because of the increased risk for repeated ectopic pregnancy in subsequent IVF cycles. Two cases are presented with repeated ectopic pregnancy occurring in IVF. One case underwent salpingectomy on the first occasion and eventually developed a contralateral repeat ectopic gestation ending with salpingectomy. The second case underwent a conservative salpingotomy in the first event and developed a repeated ectopic gestation on the same side, undergoing bilateral salpingectomy. In order to prevent repeated ectopic pregnancies in an IVF programme, a definitive surgical procedure, such as bilateral salpingectomy, should be considered in the first episode in patients referred for IVF because of tubal pathology.     

Serum vascular endothelial growth factor as a possible marker for early ectopic pregnancy

BACKGROUND: This study evaluated serum vascular endothelial growth factor (VEGF) concentrations in women with normal intrauterine pregnancy (IUP), arrested IUP and ectopic pregnancy (EP). METHOD: This was a prospective, case-control study evaluating serum VEGF concentrations among 45 early pregnant women who subsequently were found to have an EP, a normal IUP or an arrested IUP (15 women in each group). Patients were stratified according to serum VEGF concentrations above and below 200 pg/ml. RESULTS: There was a significant difference in VEGF concentrations among women with EP, arrested IUP and normal IUP (306.1 +/- 26.5, 169.7 +/- 16.6 and 27.0 +/- 4.4 pg/ml respectively, P < 0.001). With a cut-off concentration of 200 pg/ml, serum VEGF could distinguish normal IUP from EP with a sensitivity of 88%, a specificity of 100% and a positive predictive value of 100%. Between EP and arrested IUP, the sensitivity was 87.5%, specificity 75% and positive predictive value of 77.8%. CONCLUSIONS: VEGF is a potential marker for EP. Its concentrations in women with EP are higher than in those with normal and arrested IUP.     

Fertility outcome after ectopic pregnancy and use of an intrauterine device at the time of the index ectopic pregnancy

Fertility after ectopic pregnancy (EP) was investigated in a non-selected population taking into account intrauterine device (IUD) use at the time of the EP. Between January 1992 and June 1996, 647 women listed in the EP register of Auvergne (France) were followed up. The analysis included only the 328 women who were seeking to become pregnant: 23 women using IUD at the time of the index EP (IUD users) and 305 IUD non-users. Among IUD users, there was no recurrence of EP, and the 1 year cumulative rate was 87% [95% confidence interval (CI): 73-100%] for intrauterine pregnancies and 86% (95% CI: 72-100%) for deliveries. Among IUD non-users, the 2 year cumulative rate for recurrence of EP was 28% (95% CI: 17-39%), and the 1 year cumulative rates were 60% (95% CI: 53-66%) for intrauterine pregnancies and 44% (95% CI: 38-56%) for deliveries. The adjusted intrauterine pregnancy rate of IUD users was not significantly different from that of IUD non-users. However, IUD non-users had more miscarriages, so their delivery rate was lower.     

A review of 254 ectopic pregnancies in a teaching hospital in the Trent Region, 1977-1990.

A total of 254 cases of ectopic pregnancy were reviewed in a teaching hospital in Sheffield, in three defined periods: I, 1977-9; II, 1985-7 and III, 1988-90. A previous history of infertility was noted in 37% of cases. Overall, the presenting symptoms, clinical, laboratory, operative as well as histological findings, are in broad agreement with other series. The incidence increased steadily from 8.6 per 1000 total births in period I to 16.5 per 1000 total births in period III. A number of changes noted in recent years include: (1) the diagnosis of ectopic pregnancy was made significantly (P less than 0.05) earlier; (2) a significantly (P less than 0.05) greater proportion of ectopic pregnancies had an association with the following factors: previous tubal surgery, the diagnosis established with ultrasonography, laparotomy preceded by laparoscopy and treatment by conservative surgery; and (3) a significantly (P less than 0.05) smaller proportion of ectopic pregnancies had the diagnosis based on pelvic tenderness or pelvic mass. During the period 1988-90 a total of 126 laparoscopies were performed for suspected ectopic pregnancy, of which 82 (65%) were confirmed to have ectopic pregnancy and 44 (35%) were thought to have no evidence of ectopic pregnancy on laparoscopy. However, two of the latter cases were subsequently found to have an ectopic pregnancy within 2 weeks. The clinical implications of these findings are discussed.     

Placental protein 14 in human in-vitro fertilization early pregnancies.

Placental protein 14 (PP14) and human chorionic gonadotrophin (HCG) were analysed in patients participating in an in-vitro fertilization-embryo transfer programme which did not include any kind of luteal support. Women with normal pregnancies, spontaneous abortions, ectopic pregnancies, biochemical pregnancies and non-pregnant women were compared. A combination of HCG and PP14 analyses distinguished between normal and abnormal implantation as early as 15 days after oocyte retrieval. The product of HCG (IU/l) and PP14 (micrograms/l) concentrations differed significantly between normal pregnancy, spontaneous abortion and ectopic pregnancy (P = 0.0248). It is concluded that both endometrial (PP14) and trophoblastic (HCG) markers, when used in combination, exhibit changes in abnormal implantation which may be clinically useful.     

Spontaneous conception and intrauterine pregnancy in a symptomatic missed abortion of ectopic pregnancy conceived in the previous cycle

We encountered a rare case of combined intrauterine and extrauterinepregnancy that occurred following separate spontaneous ovulations.A 33 year old woman visited our hospital with the chief complaintof abdominal pain on April 16, 1993. Her last menstruation wasfrom March 23 for 6 days. However, the urinary human chorionicgonadotrophin (HCG) on April 19 was 1024 IU/L Pelvic examinationand ultrasonography indicated an extrauterine pregnancy, whichwas confirmed by laparotomy and histo-logical identificationof trophoblast cells. The urinary HCG concentration markedlydecreased after the operation. However, the HCG level increasedagain on the fifth postoperative day, and a gestational sac(11 mm) was identified in the uterine cavity on the 11th post-operativeday, indicating that this intrauterine pregnancy was establishedfollowing spontaneous ovulation which occurred before the removalof the extrauterine pregnancy. This case indicates that a combinedpregnancy can occur not only after simultaneous multiple ovulationsbut also after the separate spontaneous ovulations.     

Leukocyte populations, hormone receptors and apoptosis in eutopic and ectopic first trimester human pregnancies

The implantation of trophoblast cells at extrauterine sites still results in decidualization. The objective of the present study was to compare decidualization at eutopic and ectopic implantation sites. Tissues from women undergoing elective termination of uterine pregnancy and from women with ectopic pregnancy were used to detect the presence of cells important for the maintenance of pregnancy, such as BCL-2+, CD56+, CD3+, CD8+ and CD68+ cells, and the presence of oestrogen (ER) and progesterone receptors (PR) by immunohistochemistry. In-situ detection of fragmented DNA was performed to identify apoptotic cells. The percentage of CD3+ cells among all immunocompetent cells in the tubal epithelium was 46.6% (39.9% of CD3+ were also CD8+); the other 53.4% were CD68+ cells. CD56+ cells were undetectable in ectopic decidua at the feto-maternal interface in ectopic tissue. In uterine decidua, we found 29.9% CD3+ cells (2.2% of CD3+ were CD8+), 51.6% CD56+ cells and 18.5% CD68+ cells. The ratio of BCL2+ to CD3+ cells in ectopic pregnancy was 0.41. In uterine pregnancy, the ratio of BCL-2 to CD3 was 0.44 and 0.39 for CD56. Tissues from both ectopic and uterine pregnancies were positive for PR. Fewer apoptotic cell bodies were present in ectopic pregnancy. The use of tissue obtained from ectopic pregnancy may become an excellent model to identify the mechanism of trophoblast invasion in eutopic pregnancies.     

Time trends in ectopic pregnancies in a Norwegian county 1970-2004--a population-based study

BACKGROUND: The study objective was to estimate temporal trends in ectopic pregnancy in a well-defined population. METHODS: We identified patients with ectopic pregnancy in hospital discharge registries in S?r-Tr?ndelag County, Norway, 1970-2004, and retrieved data from medical records. We calculated age-specific ectopic pregnancy incidence, proportions of patients with first ectopic pregnancy/prior infertility treatment, incidence of ectopic pregnancy by birth cohort and age and ratio of ectopic pregnancy to live births (extrauterine ratio) by age and parity. RESULTS: Age-adjusted ectopic pregnancy incidence rates increased from 4.3 to 16.0 per 10 000 women-years over the period 1970-1974 to 1990-1994 and declined to 8.4 per 10 000 women-years in 2000-2004. Incidences were highest among women aged 25-34 years throughout the study period. We observed decreases in proportions of women with previous ectopic pregnancy and with prior infertility treatment after 1990-1994. Incidence rates were the highest for women born between 1960 and 1964 in all age groups. Extrauterine ratio increased with age and was higher for women with two or more previous births compared with women with none or one prior birth. CONCLUSIONS: The epidemic increase in ectopic pregnancy towards 1990-1994 was followed by a marked decrease.     

Salpingectomy - the laparoscopic surgical choice for ectopic pregnancy

The aim of this study was to assess the fertility outcome afterectopic pregnancy (EP) treated by laparoscopic salpingectomy.Among the 375 patients who underwent this operation betweenJanuary 1983 and December 1993, there were 145 patients whodesired pregnancy and whose contralateral tube was not obstructed.The overall rate of intrauterine pregnancy (IUP) was 50.3%,with an EP rate of 15.2%, These results were analysed accordingto the patients‘ past history together with the conditionof the contralateral tube at the time of the laparoscopy. Wedefined two groups. Group 1 included patients who had no previoushistory of tubal surgery and whose contralateral tube was normal.Group 2 comprised those patients who had a previous historyof tubal surgery and/or those whose tube was pathological, butnot obstructed. Postoperative fertility of the patients in group1 was significantly higher than that of the patients in group2, with IUP rates of 75 and 36.6% respectively (P < 0.001),and a risk of EP recurrence of 9.6 and 183% respectively. Ingroup 1, the actuarial IUP rate at 24 months was significantlyhigher than that for the patients in group 2 (66.7 versus 36.9%;P < 0.001). The patient’s past history and the conditionof the contralateral tube were the two major factors relatedto fertility outcome after laparoscopic salpingectomy for EP.In patients with no past history of tubal surgery or infertilityand whose contralateral tube was normal, the fertility resultsafter laparoscopic salpingectomy appeared comparable to thoseobserved after conservative laparoscopic treatment     

Diagnostic value of the plasmatic ADM level for early ectopic pregnancy

Objective: To analyze the plasmatic ADM level in early pregnancy and to investigate the diagnostic value of ADM in early ectopic pregnancy (EP). Methods: 70 patients with EP who had menopause for 5~8 weeks were included as study group, while 155 women with normal intrauterine pregnancy were also included as control group. The correlation between ADM level and menopause weeks was statistically analyzed and ROC curve was used to identify the diagnostic value of ADM. Results: (1) In 155 cases of normal intrauterine pregnancy, the plasmatic ADM level was increased with menopause weeks in linear relationship, and the correlation coefficient (R) was 0.991 (P<0.05). In 70 patients with EP, no significant increase was found with menopause weeks and no linear relationship can be found between ADM level and menopause weeks in EP group. The correlation coefficient (R) was 0.744 (P>0.05). (2) The multiple of median of plasmatic ADM level in EP group of menopause for 8 weeks was obviously lower than the intrauterine control group (P<0.01). (3) ROC curve was used to analyze the cut-off value of ADM level in the diagnosis of EP, and the area under the ROC curve was 0.523 (P>0.05) regardless of menopause weeks, however, the area under the ROC curve was 0.702 (P<0.05) at 8 weeks after menopause with sensitivity of 53.50% and specificity of 85.00%. Conclusions: Different from normal intrauterine pregnancy, plasmatic ADM level in early EP was relatively lower and no significant increase was found with menopause weeks; further studies are still needed for plasmatic ADM level as an indicator in the early diagnosis of EP.     

Medical treatment of ectopic pregnancies: a randomized clinical trial comparing methotrexate-mifepristone and methotrexate-placebo

BACKGROUND: Medical treatment of ectopic pregnancies is common. To increase the efficacy of methotrexate, the association of mifepristone has been proposed. METHODS: We performed a large prospective multicentre double-blind sequential randomized trial in order to compare the efficacy of methotrexate and mifepristone (600 mg given orally) versus methotrexate and placebo. RESULTS: A total of 212 ectopic pregnancies was randomized. There was no significant difference in the initial characteristics between the two groups. There was no significant difference in the success rate of medical treatment between the methotrexate-mifepristone (n = 113) and the methotrexate-placebo group (n = 99): 79.6% (90/113) versus 74.2% (72/97) respectively, RR (95% CI): 1.07 (0.92-1.25), P = 0.41, non-significant. However, there was a quantitative interaction between progesterone level and effect of treatment: when progesterone level was >/=10 ng/l, the efficacy of the combination of mifepristone and methotrexate was significantly higher than the combination of methotrexate and placebo, with an 83.3% success rate (15/18) versus 38.5% (5/13) respectively. CONCLUSIONS: Our study failed to demonstrate any benefit of the addition of mifepristone to methotrexate. By contrast, the quantitative interaction between treatment effect and baseline serum progesterone suggested that this combination could be limited to ectopic pregnancies associated with high serum progesterone concentrations.     

Pregnancy: The expectant management of early pregnancies of uncertain site

The role of expectant management was evaluated in 80 women inwhom clinical examination, including vaginal ultrasound, hadfailed to identify the location of an early pregnancy. In 45cases, spontaneous resolution of the pregnancy products occurred.A normal intra-uterine pregnancy was diagnosed in 12 patients.A total of 23 patients underwent active therapeutic measuresdue to an ectopic pregnancy (n = 16) or a spontaneous abortion(n = 7). The effectiveness of different diagnostic measuresto identify patients suitable for expectant management was analysed.In 33/34 patients (97%) with a relative daily human chorionicgonadotrophin (HCG) change of <–5%, and a serum progesteroneconcentration of <20 nmol/l, spontaneous resolution of thepregnancy products occurred. Among 46 cases, with a relativedaily HCG change of >–5% and/or serum progesterone>20 nmol/l, active therapeutic measures were carried outin 22 cases (48%), a normal intra-uterine pregnancy was diagnosedin 12 cases (26%) and spontaneous resolution of the pregnancyproducts occurred in 12 cases (26%). In conclusion, the combinationof a single progesterone assay and serial HCG determinationsretrospectively identified early pregnancies of uncertain locationin whom expectant management was a safe management option.