The combination of transvaginal ultrasound (US) and serum human chorionic gonadotropin (hCG) determination has proven to be reliable for the early diagnosis of ectopic pregnancy (EP) 1234. The goal of early diagnosis is the prevention of tubal rupture 5, which is the cause of most EP-related deaths 67, and is a surgical emergency. Accordingly, suspicion of tubal rupture is an absolute contraindication for medical treatment of EP using methotrexate 89101112.

Although, the diagnosis of tubal rupture is obvious when patients are haemodynamically unstable, symptoms in most cases of tubal rupture are more subtle 13141516. The only diagnostic method to rule out tubal rupture would be to perform a laparoscopy in all cases 15.

However, considering that most tubal rupture would cause significant haemoperitoneum and that the latter would often correspond to tubal rupture is clinically sound. Evidence for haemoperitoneum is usually found on US examination. Nevertheless, the various US criteria used to quantify the amount of the haemoperitoneum prior to surgery 121718192021 have not been validated yet.

The aim of our study was therefore to identify criterias in the pre operative work-up that could be useful to predict the haemoperitoneum volume, in a homogeneous series of patients operated upon EP.

During the study period 119 patients were operated upon EP, of whom 30 (25.2%) were excluded, as no adequate US image were available (N = 15) or when the haemoperitoneum had not been measured intraoperatively (N = 15). This left 89 patients to constitute the study population. Baseline characteristics of the population are shown in Table 1.

The median volume of the haemoperitoneum measured at the time of surgery was 300 ml. Forty eight (53.9%) patients presented haemoperitoneum ≥ 300 ml and 41 patients (46.1%) presented no haemoperitoneum or < 300 ml (Table 1). Thirty eight patients had tubal rupture (40.4%). The proportion of ruptured tubes was markedly higher among patients with a haemoperitoneum ≥ 300 ml (60.4 versus 17.1%; p < 0.0001).

The crude associations between the studied variables and the existence of massive haemoperitoneum are summarised in Table 2. There was a linear trend between the volume of intraperitoneal fluid at transvaginal sonogram of the uterus and the probability of haemoperitoneum ≥ 300 ml at surgery: indeed, 83.3% of patients with fluid above the uterine fundus, 70.6 with fluid reaching the uterine body and 24.3% with fluid under the uterine isthmus or absent had haemoperitoneum ≥ 300 ml respectively (Chi-square for linear trend = 20.9 with 1 degree of freedom; p < 0.0001).

The diagnostic values of the variables associated with haemoperitoneum ≥ 300 ml in the univariate analysis are shown in Table 3. Three variables had a high sensitivity with sufficiently low negative LR: any pelvic pain, moderate to severe pelvic pain, and the presence of any amount of fluid in the pouch of Douglas (Table 3). Four variables a had high specificity and sufficiently high positive LR: a serum haemoglobin concentration < 10 g/dl, a systolic blood pressure < 100 mm Hg, fluid above the uterine fundus, and fluid around the ovary (Table 3). As the latter two variables were not inter-connected (Chi-square with 1 degree of freedom = 1.1; p = not significant) and each represented a small number of patients, they were combined into a single variable: fluid above the uterine fundus OR fluid around the ovary.

These variables were all introduced into a multiple regression analysis model. After using the selection procedure, three variables independently predicted the finding of a haemoperitoneum ≥ 300 ml at surgery: moderate to severe pelvic pain, fluid above the uterine fundus OR fluid around the ovary, and a serum haemoglobin concentration < 10 g/dL (Table 4). Although Serum hCG < 5000 had no interesting diagnostic value (Table 3) it was still included in the multiple regression analysis model in order to avoid any confusion bias. Indeed the Serum hCG concentration was used to select patients who may undergo medical therapy.

Assessment for the best combination of these three variables is given in Table 5. Given a 53.9% prevalence of haemoperitoneum ≥ 300 ml in the overall population, a patient with none of the three criteria would have a probability of 5.3% for a haemoperitoneum ≥ 300 ml. Inversely when two or more criteria are present, the probability for a haemoperitoneum ≥ 300 ml is in between 92.6 and 100.0%.

Relations between the quantification of haemoperitoneum, expressed in percentile, and the three variables of the model are plotted on figure 1. There is an increasing relationship between the amount of the haemoperitoneum and each of the three variable used in the prediction model.

We have developed a clinical prediction model for the diagnosis of significant haemoperitoneum in patients with EP. This model was based on three simple and reproducible criteria: The presence of moderate to severe spontaneous pelvic pain, the presence of intraperitoneal fluid above the uterine fundus or around the ovary at transvaginal US, and the existence of a serum haemoglobin concentration < 10 g/dL. We found that this model may reliably rule out or confirm preoperatively, the existence of a significant haemoperitoneum at surgery.

One of the biggest limitations of our study is that it was retrospective. As an example, assessment of the severity of the pain was based on the attending phycisian's interpretation of the patient's pain and no strict criteria such as self-evaluation by a visual analog scale was used 27. This may lead to a substantial interobserver difference in graded pain. There is nonetheless a fair agreement between physicians and patients' estimates of pain 28. The quality of US data used in this study relies in the fact the fact that the information was not gathered from a written report in the patient's notes, but that they were obtained by re-interpreting standardised sonograms blind to surgical findings. Patients for whom we did not retrieve standardised transvaginal sonograms were excluded from the study. Nevertheless, prospective validation studies of samples from different centres are important to evaluate the actual predictive ability of a diagnostic model 29.

Although our criteria appeared to be reliable to exclude the presence of massive haemoperitoneum, there may be a tubal rupture in the absence of any significant haemoperitoneum in up to 27% of the cases 1730. However, this type of tubal rupture is probably unlikely to cause active bleeding at the time of diagnosis, but secondary resumption of bleeding could explain some of the failures observed after treatment by methotrexate, including cases with no intraperitoneal effusion 1119. This was the case for two patients in our study who had a tubal rupture with no active bleeding and a haemoperitoneum of 30 ml and 120 ml respectively. Anyway, our model, which was specifically designed to predict the existence of massive haemoperitoneum, is in agreement with a previously developed model for prediction of tubal rupture or active bleeding in EP 15. Indeed, in this model, the three most important criteria were the existence of an intraperitoneal effusion at transvaginal US, any spontaneous abdominal pain and Hb ≤ 9.7 g/dl. The match between this model and ours confirms the fact that pre operative diagnosis of tubal rupture is mostly based on the presence of haemoperitoneum.

Appropriate quantification of intraperitoneal fluid at US is important because fluid in the Pouch of Douglas may be present in up to 80% of EP whether ruptured or not 1731. A semi-quantitative estimate of haemoperitoeum volume, using transvaginal US examination of the uterus in a midsagittal plane, which we have used (adapted from 18) showed an excellent correlation with the volume of haemoperitoneum measured during surgery. We elected to use this classification because it is based on a standard ultrasound plane that is easy to obtain, and on criteria that seem reproducible. Two other ultrasound classifications have been proposed to assess the quantity of haemoperitoneum. One author 20 differentiates three classes of effusion: ≤ 10 ml, 10 ml to 100 ml and > 100 ml, without however setting any precise ultrasound criteria. Others 2132 subjectively quantified the amount of intraperitoneal fluid as small, moderate or large. Although these last two classifications are often used to predict the haemoperitoneum volume prior to medical treatment of EP, they have never been subjected to a correlation with the volume found at surgery.

Our clinical model for prediction of massive haemoperitoneum may be useful for the medical management of EP. When none of the three criteria is present, medical treatment and follow-up as an outpatient is, to our opinion, possible. Accordingly, the model fits well with well-known countraindications for methotrexate 19 Sowter, 2001; Rozenberg, 2003]. However these contraindications were so far solely based on clinical opinion. Because the absence of all three criteria in the population study was rather uncommon, one may question the usefulness of the model in clinical practice. Our centre has been supporting medical treatment for EP for the last 10 years 1033 and most patients with obvious criterias for medical treatment were unlikely to be selected in the present study. When used in a more general population of women with EP, the negative predictive value of our model for the diagnosis of significant haemoperitoneum is therefore likely to increase.

Finally, our clinical prediction model should be further tested and may prove useful to monitor patient with methotrexate treatment. Indeed, spontaneous pelvic pain occurs frequently during this treatment. Although in most cases the outcome is spontaneously favourable, this situation does raise concerns and often leads to unnecessary laparoscopy 303435. Our model may help in the management of these patients: as increasing haemoperitoneum at transvaginal US or a drop in haemoglobin concentration would suggest that laparoscopy should be performed.

Three criteria may predict massive haemoperitoneum in EP: moderate to severe spontaneous pelvic pain, fluid above the uterine fundus or around the ovary at ultrasound, and low serum haemoglobin concentration. The proposed model accurately predicted significant haemoperitoneum in patients diagnosed to have EP. It could be used to select patients who should not undergo medical treatment. The usefulness of the proposed model should be tested prospectively as part of routine triage of patients with suspected EP in the emergency department.

EP: Ectopic pregnancy

US: ultrasound

hCG: human chorionic gonadotropin

The author(s) declare that they have no competing interests.

All authors read and approved the final manuscript.

AF conceived of the study, and participated in its design and coordination and drafted the manuscript.

AM participated in the design of the study, carried out the review of sonograms, abstracted the data and performed the statistical analysis.

LS helped to perform the statistical analysis, and helped to draft the manuscript.

J-PB participated in the design of the study and helped to carried out the review of sonograms.

YV participated in the design and coordination of the study and helped to draft the manuscript.