Improved sensitivity and specificity of a single measurement of serum progesterone over serial quantitative beta-human chorionic gonadotrophin in screening for ectopic pregnancy.

The sensitivity and specificity of a single serum progesterone measurement was compared against two beta-human chorionic gonadotrophin (HCG) measurements 48 h apart in screening for abnormal pregnancy, i.e. ectopic pregnancy, completed or incomplete abortion. Of 1120 patients in the first trimester presenting with a positive urinary pregnancy test, 116/1120 (10.4%) had an ectopic pregnancy, 755/1120 (67.4%) had ultrasonographically confirmed intra-uterine pregnancies, and 249/1120 (22.2%) had abnormal intra-uterine pregnancies documented as complete, incomplete or missed abortions. Of the ectopic pregnancies, 113/116 (97.4%) had a serum progesterone level less than 25 ng/ml while 516/755 (68.3%) viable intra-uterine pregnancies had a serum progesterone level greater than or equal to ng/ml. Of the 1120 patients screened, 402 (35.9%) had both a serum progesterone and two HCG measurements and were eligible for inclusion in this study. Setting a cut-off of 25 ng/ml, the sensitivity and specificity of a single serum progesterone measurement was then compared against two serial HCG measurements, utilizing receiver operating characteristic curves. This analysis demonstrated that a single serum progesterone measurement was significantly more sensitive (P less than 0.05) than two HCG measurements in screening for an abnormal pregnancy. In some patients, a single serum progesterone makes possible the diagnosis of ectopic pregnancy 2 days earlier than two HCG determinations because a second blood sample was not required. We conclude that a single serum progesterone measurement should be added to serial HCG determinations as a standard diagnostic screening test for ectopic pregnancy.     

Pregnancy: Corpus luteum failure in ectopic pregnancy

The endocrinology of ectopic pregnancy was studied in orderto investigate the origin of the discordance in the circulatingamounts of human chorionic gonadotrophin (HCG) and those ofoestradiol and progesterone. Serial maternal blood samples wereobtained at 4–9 weeks gestation from 93 patients who becamepregnant following in-vitro fertilization and embryo transferincluding 10 ectopic, 21 anembryonic and 62 normal singletonpregnancies. The samples were analysed for HCG, Schwangerschaftprotein-1 (SP-1), pregnancy-associated plasma protein-A (PAPP-A),progesterone and oestradiol. In ectopic pregnancies, concentrationsof all substances analysed were significantly reduced comparedto singleton pregnancies from 5 weeks gestation (P < 0.05–0.001)but they were not significantly different from those of anembryonicpregnancies. In ectopic pregnancies, associations were foundbetween the concentration of both HCG and SP-1 and those ofprogesterone and oestradiol. No associations were found betweenPAPP-A and any other substances analysed. This may be due toinsensitivity of the PAPP-A assay; alternatively PAPP-A concentrationsmay be differentially reduced in ectopic pregnancy. These findingssuggest that progesterone and oestradiol are derived from thecorpus luteum in early ectopic pregnancy but that the corpusluteum fails rapidly and the dominant source of both hormonesbecomes the trophoblast as early as 5 weeks.     

Pregnancy: The prediction of ectopic pregnancy after in-vitro fertilization and embryo transfer

Data from 135 patients who suffered ectopic pregnancies andfrom 135 patients who progressed to singleton deliveries afterin-vitro fertilization and embryo transfer have been analysedretrospectively. The ectopic pregnancies represent all suchcases observed at Bourn Hall Clinic between 1983 and 1993. Thedelivered group was randomly selected from the same time period.The ectopic pregnancies included 20 heterotopic, eight ovarianand six bilateral tubal pregnancies; the remainder were singletontubal pregnancies. The aim of this study was to identify thevariables which differed systematically for the two groups ofpatients and to explore whether such variables could be usedto predict ectopic pregnancy at an early stage. The mean plasmaconcentration of human chorionic gonadotrophin and progesteronefor the ectopic pregnancy group was significantly lower thanthat for the singleton delivery group (P < 0.001). However,there was such a degree of overlap that it was impossible todevise a cut-off concentration for either hormone which wouldoffer a clinically useful predictor of ectopic pregnancy. Nevertheless,using the discriminant function analysis of these data, togetherwith the history of pelvic inflammatory disease, we could predictup to 90% of cases of ectopic pregnancy by day 23 after embryotransfer, long before ultrasound imaging would be useful.     

Spontaneous resolution of ectopic pregnancy in a surrogate after oocyte donation and frozen embryo transfer

A case of tubal pregnancy in a young and healthy woman participatingin a programme of in-vitro fertilization (IVF) gestational surrogacyis reported. The gestational surrogate was the 30 year old fertilesister of a 25 year old patient affected by stage 1 ovariancancer. After mandatory oncological consultation, the donorwas recommended to prospectively undergo controlled ovarianhyperstimulation cycles for embryo banking before being treatedby total hysterectomy. Available embryos were cryopreservedand after adequate endometrial preparation using artificialcycles of hormone replacement therapy, three thawed frozen embryoswere transferred to the surrogate. At 17 days following embryotransfer the surrogate was noted to have a negative -human chorionicgonadotrophin (HCG) serum concentration. All medication wassuspended and a few days later normal menstrual bleeding occurred.After 2 weeks, the (-HCG concentrations, performed as part ofroutine follow-up evaluation, were showing signs of trophoblastactivity (236 mIU/ml). Taking into account the stable conditionof the patient, a decision was made to undertake expectant managementAt 43 days after embryo transfer, a complete tubal abortionwas apparently seen in the posterior cul-de-sac by ultrasoundassociated with a subtle and short lasting pelvic pain. We stressthat this ectopic gestation was able to maintain prolonged viabilityin conditions of absent corpus luteum and exogenous steroidsupplementation.     

Pregnancy: Function of the corpus luteum, the endometrium and the trophoblast after treatment of tubal pregnancy by prostaglandin F2{alpha}

The activity of the corpus luteum, the endometrium and the trophoblastwas studied after local medical treatment of 31 women with tubalpregnancy. We measured the serum concentration of progesterone,the secretory endometrial protein placental protein 14 (PP14),and human chorionic gonadotrophin (HCG) before and after treatmentby injection of prostaglandin F₂ into the site of the gestationand into the corpus luteum. There was no significant differencein the pre-treatment serum progesterone and serum PP14 concentrationsof 26 women who were treated successfully and of five women,who were operated on after failure of the treatment. After theprostaglandin treatment the serum progesterone and PP14 concentrationsdecreased simultaneously with the serum HCG concentration orremained at a low, constant concentration. We conclude thatmeasurement of serum progesterone and PP14 cannot be used forselection of patients for treatment by prostaglandin F₂ or formonitoring the effect of the treatment. The injection of prostaglandininto the ovary has either no effect on the activity of the corpusluteum or induces only a partial luteolysis.     

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.     

Human chorionic gonadotrophin concentrations in early pregnancy after in-vitro fertilization.

There is increased risk of early pregnancy loss after assisted reproduction. In this study the use of serum human chorionic gonadotrophin (HCG) concentrations on day 12 after in-vitro fertilization (IVF) and embryo transfer was evaluated to predict pregnancy outcome. A total of 417 IVF pregnancies were included. Early pregnancy loss was defined as biochemical pregnancies, ectopic pregnancies and first trimester abortions. Vital pregnancies were defined as delivered singletons, multiple pregnancies and second trimester abortions. On the post embryo transfer day 12, the mean HCG concentration of the vital pregnancy group was significantly higher than in early pregnancy loss outcomes (P < 0.00001). Receiver operating characteristic (ROC) curve analysis was performed to evaluate the cut-off value of HCG giving maximal sensitivity and specificity in order to discriminate early pregnancy losses from vital pregnancies. A patient with a HCG value higher than the calculated cut-off value (55 IU/l) had a 90% chance of having a vital pregnancy after IVF and embryo transfer. It can be concluded that a discriminatory HCG value on day 12 after IVF and embryo transfer cycles may be useful in predicting pregnancy outcome and may guide clinicians in identifying those pregnancies at risk for adverse outcomes and instituting more intensive surveillance in this population.     

Pregnancy: Cytogenetic characteristics of ectopic pregnancy

During a 12 month period, tissue was collected from 30 surgicallymanaged patients presenting with vital ectopic pregnancies.Chorionic villi of the removed tissue were successfully karyotypedby (semi-) direct chromosome technique in 22 cases. Only oneabnormal chromosomal complement, a triploidy (69,XXX) was found-As controls, 10 cases of intrauterine pregnancies were investigated,all showing a normal karyotype. These findings do not suggestan important role for chromosome abnormalities in the aetiologyof vital ectopic pregnancies.     

Pregnancy: Temporal relationship between the human chorionic gonadotrophin peak and the establishment of intervillous blood flow in early pregnancy

The purpose of this study was to investigate the temporal relationshipbetween the early pregnancy peak of circulating human chorionicgonadotrophin (HCG) concentration and the establishment of maternalblood flow in the placental intervillous space. The presenceof blood flow echoes within intervillous space was determinedby colour Doppler imaging from 44 women with clinically uncomplicatedpregnancy between 6 and 18 weeks gestation. Circulating HCG,free - and HCG subunits, oestradiol and progesterone concentrationswere immunoassayed in blood samples collected at the time ofDoppler examination. A continuous intervillous blood flow wasdetected in all cases with a gestational age 11.7 weeks (n =18) but never before this time. Circulating concentrations offree HCG, oestradiol and progesterone were linearly or exponentiallycorrelated with gestational age (r = 0.860, 0.903 and 0.538respectively, all with P < 0.001), indicating steady increaseof these hormones with advancing gestation. However, the bestfitted lines were found to be parabolic for HCG (r = 0.771,P < 0.001) and HCG (r = 0.695, P < 0.001), their highestpoints corresponding to 11.24 and 10.74 weeks gestational agerespectively. The close temporal relationship between the Doppleradvent of intervillous maternal blood flow and the HCG peaksuggests that the establishment of the intervillous blood flowis associated with the decline in circulating HCG concentrations.     

Laparoscopic management of an ectopic pregnancy in a previous Caesarean section scar.

A case of laparoscopic management of an ectopic pregnancy in a previous Caesarean section scar is reported. A 30 year old woman was admitted to our hospital for profuse vaginal bleeding 2 weeks after an abortion had been performed. A urine pregnancy test was positive. Abdominal ultrasound revealed a well-encapsulated bulging mass over the lower anterior uterine wall measuring 7x5 cm. Hysteroscopy revealed retained gestational tissue in the lower corpus despite a normal uterine cavity. An incision was made over the most prominent area of the mass by operative laparoscopy. Dark reddish tissue suggestive of the products of conception was removed using grasping forceps. One-layer of continuous endoscopic sutures along the affected uterine wall was made with 1-0 Prolene. Laparoscopy enabled the successful treatment of an unruptured ectopic pregnancy in a previous Caesarean scar and made it possible to preserve the patient's reproductive capability.     

The use of a pretherapeutic, predictive score to determine inclusion criteria for the non-surgical treatment of ectopic pregnancy.

Non-surgical management of ectopic pregnancy has recently become an alternative to surgery. We have investigated a pretherapeutic score to define the indication for non-surgical and surgical treatment in 61 patients with ectopic pregnancy. The score was performed before the patients' inclusion in a nonsurgical management scheme. The score used six criteria which were evaluated on a scale from 1 to 3: gestational age, human chorionic gonadotrophin (HCG) level, progesterone level, abdominal pain, haemoperitoneum volume and haematosalpinx diameter (estimated by laparoscopy or transvaginal ultrasound). Three scores, 10, 11 and 12, were studied in order to define a threshold beyond which surgical treatment should be performed. For each one, sensitivity, specificity and positive and negative predictive values were analysed. The success rate of non-surgical treatment was 75% (46/61). For patients undergoing medical treatment with a score less than or equal to 12, the success rate was significantly higher compared with a success rate of 50% when the score was greater than 12. We conclude that a score less than or equal to 12 permits non-surgical management with a success rate of 82%. A score greater than 12 indicates that laparoscopic surgery may be more suitable. The choice between different non-surgical approaches, did not influence the success rate. When ultrasound reveals embryo heart activity, medical treatment is always possible if the score is less than or equal to 12.     

Evaluation of ectopic pregnancy by magnetic resonance imaging.

Patients (n = 37) suspected of ectopic pregnancy were prospectively evaluated with magnetic resonance (MR) imaging to assess the capability of MR imaging in the diagnosis of ectopic pregnancy. Five levels of confidence were defined: diagnostic, suspicious, equivocal, questionable, and negative. Tubal wall enhancement and presence of tubal haematoma or gestational sac-like structure were considered diagnostic findings. There were 21 diagnostic, two suspicious, eight equivocal, and six negative findings. MR findings were compared with the surgical findings in 18 patients. Surgical confirmation was obtained in 12 diagnostic, two suspicious, and four equivocal studies. Using the MR diagnostic criteria for tubal pregnancy, MR had 12 true positive, three true negative, three false negative, and no false positive results for the diagnosis of tubal pregnancy. Retrospective analysis of the signal intensity of haematoma and ascites was performed for these 18 surgically confirmed cases. The predominant signal intensity of tubal haematoma was an intermediate signal on T1-weighted image (WI) and a low signal on T2WI. Ascites showed signal intensity higher than that of urine on T1WI in 100% of 13 cases. In conclusion, MR imaging with use of intravenous contrast material allows a specific diagnosis of tubal pregnancy, recognizing tubal wall enhancement and fresh tubal haematoma.     

Reliability of serial urine HCG as a biomarker to detect early pregnancy loss

BACKGROUND: To examine the reliability of HCG as a biomarker for early pregnancy loss, five experienced researchers independently assessed data from 153 menstrual cycles, determining whether each cycle represented 'no conception,' a 'continuing conception' or a 'conception lost.' METHODS: Urine samples were analysed by immunoradiometric assay using a combination of capture antibodies for the intact heterodimer (B109) and for an epitope common to the beta subunit and the beta core fragment (B204). For each cycle, HCG data were presented as graphs of daily assay results. Summary statistics for HCG assays from 46 women who had undergone bilateral tubal ligation represented baseline values. RESULTS: Pairwise agreement among the assessors for any of the three options ranged from 78-89%. At least three experts agreed for 147 cycles (96%), accounting for 28 conception losses and 19 continuing conceptions. The multi-rater kappa was 0.62 for the conception lost category and 0.68 for continuing conceptions, indicating substantial agreement. CONCLUSION: The main sources of disagreement involved deciding whether there was sufficient information for assessment, interpreting cycle parameters such as cycle length or bleeding event, and interpreting a distinct HCG rise pattern that does not exceed the baseline value obtained from the sterilized women.     

Incidence of ectopic pregnancy. First results of a population-based register in France

A population-based register of ectopic pregnancy was establishedin 1992 for two French departments, with the primary aim ofmonitoring the trend in ectopic pregnancy over a prolonged period.In this paper, data collected pregnancy over a prolonged period.In this paper, data collected during the first year of registration(1992) are analysed. The rate of ectopic pregnancy was 20.2per 1000 live birth, 15.8 per 1000 reported pregnancies and9.5 per 10 000 women aged 15–44 years. The ectopic pregnancyrate per 1000 live births increased steeply after the age of30 years and especially after the age of 35 years, whereas ratesper 10 000 women of reproductive age steadily increased untilthe age of 35 years and decreased thereafter. The rates of ectopicpregnancy were lower in spring and summer than autumn and winter.These results are discussed and comparisions with similar studiesconducted in the USA and Scandinavia are attempted.     

Return of reproductive performance after expectant management and local treatment for ectopic pregnancy.

The purpose of this study was to examine hysterosalpingographic findings and reproductive performance in patients previously managed non-surgically for ectopic pregnancy. Forty-nine patients with unruptured ectopic pregnancies were treated either by expectant management (n = 16) or medically (n = 33), using transvaginal methotrexate or sulprostone injection. The treatment was successful in 35 patients (71.5%), 12 out of 16 and 23 out of 33 in the two groups respectively. For all patients, follow-up currently varies from 3 to 52 months with a median follow-up of 16.6 +/- 11.2 months and 7.3 +/- 4.3 months in the two groups respectively. Hysterosalpingography was performed in 25 out of 26 patients who desired further pregnancy. We found evidence of tubal patency on the ectopic pregnancy treated side in 23 cases (92%). In this group, no recurrent ectopic pregnancy was observed. In the expectant management group, eight out of nine patients became pregnant, and the mean time to achieve pregnancy was 16.6 +/- 11.2 months. In the medical treatment group, eight out of 17 patients became pregnant and the mean time to achieve pregnancy was 8.6 +/- 4.2 months. In this last group, seven out of nine non-pregnant patients have had only a short follow-up, 4.5 +/- 3.2 months since treatment completion. No recurrent ectopic pregnancy was observed in this successfully treated group of patients who desired further pregnancy. We conclude that the medical approach to unruptured ectopic pregnancy is associated with a high rate of tubal patency and a reproductive performance similar to conservative surgical methods.     

An aggressive philosophy in controlled ovarian stimulation cycles increases pregnancy rates

To assess the effect of timing of human chorionic gonadotrophin(HCG) administration in ovarian stimulation cycles, the serumoestradiol concentration and follicle profile were comparedwith the clinical pregnancy rate in 582 ovarian stimulation— intra-uterine insemination (OS—IUI) cycles and3917 in-vitro fertilization—embryo transfer (IVF—ET)cycles. The pregnancy rates increased exponentially with increasingoestradiol in both OS—IUI and IVF—ET cycles (R²= 0.720, P < 0.001) but then decreased in OS-IUI cycles whenthe oestradiol concentration exceeded 5000 pmol/l (R² = 0.936,P < 0.004) at HCG administration. In OS—IUI cyclesthe percentage of cycles with three or more mature follicles( 18 mm diameter) increased up to an oestradiol concentrationof 5000 pmol/l then declined, mirroring the pregnancy rate (R²= 0.900, P = 0.01). The exponential increase in pregnancy ratewith increasing oestradiol concentration in IVF—ET cyclessuggests that high oestradiol concentration does not have adeleterious effect on endometrial receptivity. The decreasein pregnancy rate in OS-IUI cycles when oestradiol concentrationexceeded 5000 pmol/l reflected fewer mature follicles, resultingfrom premature administration of HCG to avoid severe ovarianhyperstimulation syndrome (OHSS). We recommend that HCG administrationbe delayed until multiple follicles have reached maturity, andreducing the risk of severe OHSS by converting high risk OS—IUIcycles to IVF—ET, or if funds or facilities are unavailable,transvaginally draining all but four or five mature follicles.     

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.     

Ultrastructure of epithelial plaque formation and stromal cell transformation by post-ovulatory chorionic gonadotrophin treatment in the baboon (Papio anubis).

BACKGROUND: To understand factors controlling endometrial responses to pregnancy, we have established a model using the baboon and examined the effects of infused human chorionic gonadotrophin (HCG) on the preparation of the luminal epithelium and stromal cell differentiation for the establishment of pregnancy. METHODS: The ultrastructure of endometrium from normal day 10 post-ovulation animals, cycling females treated with either HCG or FSH (control), and a day 15 pregnant animal has been compared. RESULTS: In the control endometrium, the luminal epithelium was smooth and regular, with underlying spindle shaped stromal cells. In pregnancy, the luminal epithelium underwent a plaque reaction, while stromal cells enlarged and developed filament-rich cell processes. Infusion of HCG produced changes similar to those seen in pregnancy, with generalized plaque formation and stromal decidualization, while in the animal treated with FSH there was no response. CONCLUSIONS: This study indicates that infusion of HCG into the uterus can duplicate many of the responses of the endometrium to pregnancy, although in this case the plaque reaction involved the whole of the luminal epithelium, rather than only the implantation site as in pregnancy.     

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.