**3. Conclusion**

144 Ectopic Pregnancy – Modern Diagnosis and Management

Fig. 3. Scatter diagram of the Rp/v-HCG levels for active bleeding group and without active bleeding (No) group when HCG of venous serum was more than 1500U/L or less than 1500U/L. No suggested Rp/v-HCG cut-off value for the distribution of the active tubal

deliveries, giving an incidence of 0.34 per 1, 000 deliveries. The diagnoses were missed in 10 cases and there was one maternal death. The rate of 50% missed diagnosis in this analysis highlights the need for a high index of suspicion in the diagnosis of abdominal pregnancies as the clinical features are varied. The maternal and fetal outcomes relate to early diagnosis and skilled management, which calls for vigilance on the part of the obstetrician (Sunday-

In this study, two SEPs whose Rp/v-HCG was of > 1.0 showed normal fallopian tube and ovary but hemoperitoneum during the laparotomy. They were both diagnosed as abdominal pregnancy (one was splenic pregnancy) finally after thorough pelvic and abdominal exploration. One of the splenic pregnancy suffered second exploration and splenectomy because it is mistaken as hemorrhagic corpus luteum combined with pregnancy by the gynecologist who ignored of Rp/v-HCG was of > 1.0. Hence, the criteria of diagnosis for abdominal pregnancy may be considered: 1) No evidence of gestational sac or chorionic villi in the adnexa is seen during the surgery, 2) Rp/v-HCG, however, is of >

Transvaginal ultrasound and serial β-hCG level are of little use for the differential diagnosis between hemoperitoneum with intrauterine pregnancy and ectopic pregnancy including abdominal pregnancy, however, the overall specificity of Rp/v-HCG> 1.0 in the diagnosis of ectopic pregnancy is 100 % (95% CI: 93.0–100), a PPV of 100 % (95% CI: 98.5–100). Therefore, we may consider the definitive diagnosis of ectopic pregnancy when preoperative Rp/v-HCG is of > 1.0 and consider the diagnosis of abdominal pregnancy when preoperative or intraoperative Rp/v-HCG is of > 1.0, however, the adnexa sees no evidence of gestational sac. It is useful for gynecologists to reduce omission diagnostic rate of abdominal pregnancy, especially during the emergency surgery without enough preoperative preparation. Due to the rare case, further study with more data of abdominal pregnancy is

hemorrhage was shown when HCG of venous serum was more than 1500U/L.

Adeoye, et al., 2011.).

1.0.

needed.

Early diagnosis of ectopic pregnancy is the key to optimal treatment, especially is essential in order to minimize the morbidity and to assess the need for urgent surgical intervention. Intervention prior to rupture prevents hemorrhage, potentially enhances fertility, and allows for nonsurgical methods (Segal, et al., 2010.). Observational studies indicate that among women treated with salpingostomy as compared with those treated with salpingectomy, rates of subsequent intrauterine pregnancy are higher (73% vs. 57%) though the rates of subsequent ectopic pregnancy are also higher (15% vs. 10%) (Seeber, et al., 2006; Mol, et al., 2008.).

Though the advent of β-HCG measurements and improved transvaginal ultrasound techniques has made laparoscopic diagnosis of ectopic pregnancy almost redundant and allowed for both expectant and medical management options, combing transvaginal ultrasonography with gonadotropin quantification could not give the most satisfactory results since it takes an average of 36 h to diagnose EP, not including the resources devoted to collecting blood samples (Garcia, et al., 2001.). Hence, additional new tests or diagnostic methods are necessary to be established for a rapid and accurate diagnosis of EP prior to initiation of either medical or surgical intervention.

Besides laparoscopy and transvaginal sound, serum biomarkers (including HCG) may be helpful for the early diagnosis of EPs. Over 20 serum biomarkers have been identified to date in an attempt to permit earlier diagnosis of ectopic pregnancy, the instigation of earlier management and reduce healthcare costs (Cartwright, et al., 2009; Pedersen, et al., 1991.). The ideal marker for the diagnosis of ectopic pregnancy would be specific for tubal damage or present only after endometrial implantation. Various markers have been assessed, including creatinine kinase (Lavie, et al., 1993.) and fetal fibronectin (Ness, et al., 1998.), but none is sufficiently sensitive or specific for the diagnosis of ectopic pregnancy.

Certain serum biomarkers have been shown initially to be of discriminatory value but then subsequent studies have found them to be of limited use (such as placental protein 14) (Daponte, et al., 2008; Mantzavinos, et al., 1991.). A number of biomarkers (such as estradiol, pregnancy associated plasma protein A, cancer antigen 125) can distinguish a tubal ectopic from a viable intrauterine pregnancy but are unable to distinguish the former from a nonviable intrauterine pregnancy (miscarriage) (Mueller, et al., 2004; Katsikis, et al., 2006).

Clinical Application of One-Step Diagnosis for

studies.

Ectopic Pregnancy by HCG Ratio: Hemoperitoneum Versus Venous Serum 147

Other markers (such as vascular endothelial growth factor, creatinine kinase and progesterone) have been studied extensively in relation to ectopic pregnancy but the results have been so conflicting that none have been put into clinical use (Develioglu, et al., 2002.). The clinical utility of these biomarkers is limited because of variable results due, for the most part, to limitations in study design. In many studies, the cohort examined was very small and the prevalence of ectopic pregnancy within the study population was not constant. In some studies, patients were not accurately matched for gestation. This reflects the difficulty in determining the gestational age of an ectopic pregnancy. Some of the serum biomarkers also limited their own use, as they did not follow a steady pattern (increase or decrease) with a normal gestation. Moreover, changes in the serum assays and the reagents used to detect the biomarkers over the decades have led to conflicting results between

It was once concluded that culdocentesis is not a useful tool in the diagnosis of suspected ectopic pregnancies because the false negative rate for culdocentesis was 14.8% or so. What is more important, it does not distinguish an ectopic pregnancy from hIUP (Elliot, et al., 1990; Glezerman, et al., 1992.). According to our data, culdocentesis could be routinely, safely and simply performed during clinical practice without any complications. The success rate of the culdocentesis was 89.2 %, even though the peritoneal fluid depth by ultrasound was only 8-12 mm. Moreover, positive culdocentesis could contribute to a quick and accurate differential diagnostic algorithm for SEPs. In this study, we proved that a patient whose Rp/v-HCG is more than 1.0 may be diagnosed and treated instantly as an EP to avoid tubal rupture. The overall sensitivity of Rp/v-HCG ≥ 1.0 in the diagnosis of ectopic pregnancy is 98.5 % with a specificity of 100 %, whilst the small kappa coefficient of 0.956 for the prospective test demonstrates that the predicted outcome according to the Rp/v-HCG agreed extremely with the final true diagnosis. At least, Rp/v-HCG involving the culdocentesis provides a new method for rapid diagnosis of EP, which is helpful for fullfilling the diagnostic flow chart of EPs (see Fig 2), though the patients should be

managed according to Garcia et al if culdocentesis is negative (Garcia, et al., 2001.).

serum (RC/V-HCG) alone also could provide a rapid diagnosis of EP.

**4. Acknowledgment** 

study for their detailed record.

The culdocentesis will reveal nonclotting blood if intra-abdominal bleeding has occurred. Although nonclotting blood is assumed to be from a ruptured ectopic, similar results can also be obtained under other circumstances (eg, a hemorrhagic corpus luteum), and thus a positive results is not diagnostic of a ruptured ectopic pregnancy. In other words, not all the positive hemoperitoneum on ultrasound examination or by culdocentesis be an absolute contraindication to conservative management of tubal ectopic pregnancy (Bignardi, et al., 2009.). Therefore, whether Rp/v-HCG could predict the existence of active bleeding is important for the prognosis of EPs. Though there was a statistically significant difference between the Rp/v-HCG of the patients with or without active bleeding when the venous hCG (hCGv) of EP was >1500 U/L (Wang, et al., 2010.), no diagnostic value was seen in this study, that is, it is of no use for predicting the prognosis of fallopian tube or EP patient. In order to expand the application of the new one-step protocol for not only the SEPs whose hemoperitoneum and culdocentesis are positive but also those whose hematocolpos is positive, it is necessary to determine whether the HCG ratio of hematocolpos versus venous

We gratefully acknowledge all the postgraduates of JiaoTong University engaged in the

Note: IUP: intrauterine pregnancy; PUL: pregnancies of unknown location; SEP: suspected ectopic pregnancy; GS: gestational sac; FH: fetal heart; Rp/v-hCG: hCG ration of peritoneum versus venous serum. Discriminatory zone or discriminatory concentration is depent on the standard utilized in any given labortory, in general, 6500 IU/L for abdominal ultrasound and 1500 IU/L (or 2400U/L) for transvaginal ultrasound. Uterine curettage may be useful following endocrine documentation that suggests a nonviable pregnancy regardless of it's location.

Wang et al., 2010; Barnhart et al., 1994; Barnhart et al., 2002; Kirk et al., 2007; Stovall et al., 1992; Anonymous., 1992; Dart et al., 2002; Kadar et al., 1988.

Fig. 5. Diagnostic flow chart of EP

Fig. 6. Pink fluid from not ruptured fallopian tube but hemorrhagic salpingitis of an EP (A); dark red fluid from fallopian tube abortion of an EP (B)

Note: IUP: intrauterine pregnancy; PUL: pregnancies of unknown location; SEP: suspected ectopic pregnancy; GS: gestational sac; FH: fetal heart; Rp/v-hCG: hCG ration of peritoneum versus venous serum. Discriminatory zone or discriminatory concentration is depent on the standard utilized in any given labortory, in general, 6500 IU/L for abdominal ultrasound and 1500 IU/L (or 2400U/L) for transvaginal ultrasound. Uterine curettage may be useful following endocrine documentation that

Wang et al., 2010; Barnhart et al., 1994; Barnhart et al., 2002; Kirk et al., 2007; Stovall et al.,

Fig. 6. Pink fluid from not ruptured fallopian tube but hemorrhagic salpingitis of an EP (A);

suggests a nonviable pregnancy regardless of it's location.

Fig. 5. Diagnostic flow chart of EP

1992; Anonymous., 1992; Dart et al., 2002; Kadar et al., 1988.

dark red fluid from fallopian tube abortion of an EP (B)

Other markers (such as vascular endothelial growth factor, creatinine kinase and progesterone) have been studied extensively in relation to ectopic pregnancy but the results have been so conflicting that none have been put into clinical use (Develioglu, et al., 2002.). The clinical utility of these biomarkers is limited because of variable results due, for the most part, to limitations in study design. In many studies, the cohort examined was very small and the prevalence of ectopic pregnancy within the study population was not constant. In some studies, patients were not accurately matched for gestation. This reflects the difficulty in determining the gestational age of an ectopic pregnancy. Some of the serum biomarkers also limited their own use, as they did not follow a steady pattern (increase or decrease) with a normal gestation. Moreover, changes in the serum assays and the reagents used to detect the biomarkers over the decades have led to conflicting results between studies.

It was once concluded that culdocentesis is not a useful tool in the diagnosis of suspected ectopic pregnancies because the false negative rate for culdocentesis was 14.8% or so. What is more important, it does not distinguish an ectopic pregnancy from hIUP (Elliot, et al., 1990; Glezerman, et al., 1992.). According to our data, culdocentesis could be routinely, safely and simply performed during clinical practice without any complications. The success rate of the culdocentesis was 89.2 %, even though the peritoneal fluid depth by ultrasound was only 8-12 mm. Moreover, positive culdocentesis could contribute to a quick and accurate differential diagnostic algorithm for SEPs. In this study, we proved that a patient whose Rp/v-HCG is more than 1.0 may be diagnosed and treated instantly as an EP to avoid tubal rupture. The overall sensitivity of Rp/v-HCG ≥ 1.0 in the diagnosis of ectopic pregnancy is 98.5 % with a specificity of 100 %, whilst the small kappa coefficient of 0.956 for the prospective test demonstrates that the predicted outcome according to the Rp/v-HCG agreed extremely with the final true diagnosis. At least, Rp/v-HCG involving the culdocentesis provides a new method for rapid diagnosis of EP, which is helpful for fullfilling the diagnostic flow chart of EPs (see Fig 2), though the patients should be managed according to Garcia et al if culdocentesis is negative (Garcia, et al., 2001.).

The culdocentesis will reveal nonclotting blood if intra-abdominal bleeding has occurred. Although nonclotting blood is assumed to be from a ruptured ectopic, similar results can also be obtained under other circumstances (eg, a hemorrhagic corpus luteum), and thus a positive results is not diagnostic of a ruptured ectopic pregnancy. In other words, not all the positive hemoperitoneum on ultrasound examination or by culdocentesis be an absolute contraindication to conservative management of tubal ectopic pregnancy (Bignardi, et al., 2009.). Therefore, whether Rp/v-HCG could predict the existence of active bleeding is important for the prognosis of EPs. Though there was a statistically significant difference between the Rp/v-HCG of the patients with or without active bleeding when the venous hCG (hCGv) of EP was >1500 U/L (Wang, et al., 2010.), no diagnostic value was seen in this study, that is, it is of no use for predicting the prognosis of fallopian tube or EP patient.

In order to expand the application of the new one-step protocol for not only the SEPs whose hemoperitoneum and culdocentesis are positive but also those whose hematocolpos is positive, it is necessary to determine whether the HCG ratio of hematocolpos versus venous serum (RC/V-HCG) alone also could provide a rapid diagnosis of EP.
