**5. Section 2**

50 Ectopic Pregnancy – Modern Diagnosis and Management

Regulators T cells (Treg) express LH/CG receptor on their surface during pregnancy and are present at the fetal-maternal interface, attracted by high levels of human chorionic gonadotrophin. In ectopic pregnancies, regulatory T cells are not attracted to the same

Another possible biomarker for ectopic pregnancy after IVF is E-cadherin, because it is highly expressed in cytotrophoblast cells of chorionic villi from these pregnancies, when

From micro-array studies, Savaris et al, by using the model of ectopic pregnancy, found that the transcriptome of the decidua is influenced by trophoblast products, in endocrine fashion

In close proximity of the tubal implantation site, MUC-1 and TAG-72 are present in the epithelial cells and might contribute to the deeper trophoblast invasion in the tubal wall (von Rango et al., 2003) while a significant reduction in NK-cell numbers at the tubal implantation site, could be seen, induced by local antigen-presenting cells in the presence of

Viable tubal pregnancies implant at the mesosalpingeal side of the tubal wall show a massively increased invasion of extravillous trophoblast cells (EVT) into the tubal wall, and the proliferation of trophoblast cells extends deeply into the invasive zone in the invasive pathway (Kemp et al., 1999). Tubal pregnancies that will undergo tubal abortion implant at the antimesometrial side which show shallow invasion and poor trophoblast proliferation (Kemp et al., 1999). In extrauterine pregnancy, expression of integrin subunit α3 is nearly exclusively restricted to the basal plasmalemma of the first layer of trophoblast cells while only the first proximal layer of EVT (in direct contact to the basement membrane) expresses integrin α6. The switch to the integrin subunits αv and α5 takes place already in the second layer of trophoblast cells, as soon as the latter detach from the basement membrane (Kemp

In tubal pregnancies, MMP-9 and TIMP-1, -2 and -3 are produced by all types of extravillous cytotrophoblast (EVCT) cells, while MMP-2 and -14 mainly exist in distal column cytotrophoblast (CCT) cells and invasive EVCT cells (Bai et al., 2005). In parallel, MMP-14 and TIMP-1 and -2 are increased along the invasive pathway toward maternal interstitium. MMP-2, -9 and -14 and TIMP-1, -2 and -3 were all detected in the villous CT (VCT) cells (Bai

Another promising technique for early detection of an ectopic pregnancy is that trophoblast cells can be reliably obtained and identified among cervical cells in the first trimester and labeled with antibody to HLA-G. The number of trophoblast cells per total cervical cells (trophoblast frequency) is significant lower in ectopic pregnancy when compared to intrauterine pregnancy but not to blighted ovum (Imudia et al., 2009). Using ROC curves the positive predictive value for abnormal pregnancy was 97% and the negative predictive value was 87%. From intrauterine tissue and sera, Horne et al, examined PIGF, localized to the cytotrophoblast cells (Horne et al, 2010). Expression of PIGF mRNA was significantly reduced in trophoblast cells, isolated from women with ectopic pregnancy compared with intrauterine pregnancies. Serum PIGF was undetectable in women with tubal ectopic pregnancies and reduced, or undetectable, in miscarriage compared with viable intrauterine

From the other side, it seems that SLT/ROBO pathway and protein expression in endometrium and fallopian tube, is not implicated in ectopic pregnancy because known factors that contribute to EP (e.g. smoking/cotinine or chlamydial infection) do not alter

degree by the lower levels of hCG (Schumacher et al., 2009).

(Savaris et al., 2008).

et al., 2002).

et al., 2005).

pregnancies.

mucins (Laskarin et al., 2010).

compared with spontaneous ectopic pregnancy (Revel et al., 2008).

#### **5.1 Ectopic pregnancy and IVF**

A total of 56 abstracts were retrieved and further screened. Out of 40 included studies, 10 (25%) were performed in USA, 3 (7.5%) in England, India and in Netherlands, 2 (5%) in France, Greece, Israel, Italy and Nepal, while 1 (2.5%) in Australia, Canada, Germany, Japan, Jordan, Korea, Norway, Singapore, Taiwan, Thailand and between USA/Sweden. 17 (42.5%) of them considered themselves retrospective, 11 (27.5%) as case report, and from 1 (2.56%) as cohort study, prospective randomized double blinded cross over study, prospective cohort study, population based cost-effectiveness study, epidemiological study, economical analysis, cost effectiveness analysis, cost benefit analysis, cost analysis, while 3 (7.5%) do not mentioned the type of study. The type of study per country initiated can be seen in Fig 5.

Fig. 5. The type of study per country initiated examining IVF and ectopic pregnancy

All studies selected used human tissue. Fourteen studies mentioned embryo (35%) as tissue examined plus 4 (10%) mentioned especially the blastocyst, 4(10%) used fallopian tube and

Ectopic Pregnancy and Assisted Reproductive Technologies: A Systematic Review 53

Fig. 7. The distribution of type of study per Journal examining IVF and ectopic pregnancy

Fig. 8. Funding source of each study per Journal published examining IVF and ectopic

Pyrgiotis et al, retrospectively analyzed a large series of fresh (n=2812) and frozen embryo transfers (n=405) showing a 2.4% and 7.6% EP rate, respectively (Pyrgiotis et al., 1994). Tubal factor presented as 85.7% of all causes of ectopic pregnancies. In a previous study, an EP rate of 3.3% was found (26 patients) and the major contributing factor was a prior ectopic (Karande et al., 1991). Heterotopic pregnancy rates remained low in both studies while the

**5.2.1 Factors contributing to ectopic pregnancy after IVF** 

majority of them were tubal. Also cervical pregnancies were low.

pregnancy

**5.2 Outcomes** 

from 1 (2.5%) used embryos with thickened zona pellucida, fallopian tube ectopic pregnancy and sperm with abnormal characteristics, hydrosalpinx, ovarian tissue and trophoblastic tissue, while one tested newborns for congenital abnormalities after failed emergency contraception while 12 (30%) did not specified the tissue examined. The type of study per tissue used can be seen in Fig 6.

Fig. 6. The type of study per tissue used examining IVF and ectopic pregnancy

12 (30.0%) of the studies were published in Fertility & Sterility,5 (12.5%) in Human Reproduction, 5 (12.5%) in the Journal of Assisted Reproduction & Genetics, and from 1 (2.5%) in Acta Obstetricia et Gynecologica Scandinavica, American Journal of Emergency Medicine, Annals Academy of Medicine, BMC Pregnancy & Childbirth, BMJ, British Journal of General Practice, British Journal of Obstetrics & Gynecology, Clinical Chemistry, Contraception, European Journal of Obstetrics, Gynecology & Reproductive Biology, International Federation of Gynecology & Obstetrics, International Journal of Gynecology & Obstetrics and Journal of Obstetrics & Gynecology, Kathamandu University Medical Journal, Nepal Medical College Journal, Obstetrics & Gynecology, Sex Transmission Infections and The Lancet. The distribution of type of study per Journal is seen in Fig 7. Samples size examined ranged from 1 (case reports) to 44. Disease distribution examined presented as: ectopic pregnancy (17/42.5%), and from 1 (2.5%) bilateral tubal ligation, chlamydial infection-tubal infertility-ectopic pregnancy ,ectopic pregnancy on patients after IVF with abnormal sperm characteristics, ectopic pregnancy after oocyte donation in menopausal patients, ectopic pregnancy after donation surviving even with the absence of exogenous steroids, ectopic pregnancy after embryos with thickened zona pellucida, ectopic pregnancy after empty follicle syndrome, ectopic pregnancy after exposure to levonorgestrel, heterotopic abdominal pregnancy, heterotopic abdominal pregnancy, ectopic pregnancy after hydrosalpinx, menopause and oocyte donation, ovarian heterotopic pregnancy, ectopic pregnancy after pelvic inflammatory disease, pelvic inflammatory disease-ectopic pregnancy and neonatal complications, primary infertility, tubal factor infertility and bilateral ovarian pregnancy, tubal sterilization while 3 (7.5%) did not mentioned disease. Funding source of each study per Journal published is seen on Fig 8.

Fig. 7. The distribution of type of study per Journal examining IVF and ectopic pregnancy

Fig. 8. Funding source of each study per Journal published examining IVF and ectopic pregnancy

#### **5.2 Outcomes**

52 Ectopic Pregnancy – Modern Diagnosis and Management

from 1 (2.5%) used embryos with thickened zona pellucida, fallopian tube ectopic pregnancy and sperm with abnormal characteristics, hydrosalpinx, ovarian tissue and trophoblastic tissue, while one tested newborns for congenital abnormalities after failed emergency contraception while 12 (30%) did not specified the tissue examined. The type of

Fig. 6. The type of study per tissue used examining IVF and ectopic pregnancy

12 (30.0%) of the studies were published in Fertility & Sterility,5 (12.5%) in Human Reproduction, 5 (12.5%) in the Journal of Assisted Reproduction & Genetics, and from 1 (2.5%) in Acta Obstetricia et Gynecologica Scandinavica, American Journal of Emergency Medicine, Annals Academy of Medicine, BMC Pregnancy & Childbirth, BMJ, British Journal of General Practice, British Journal of Obstetrics & Gynecology, Clinical Chemistry, Contraception, European Journal of Obstetrics, Gynecology & Reproductive Biology, International Federation of Gynecology & Obstetrics, International Journal of Gynecology & Obstetrics and Journal of Obstetrics & Gynecology, Kathamandu University Medical Journal, Nepal Medical College Journal, Obstetrics & Gynecology, Sex Transmission Infections and The Lancet. The distribution of type of study per Journal is seen in Fig 7. Samples size examined ranged from 1 (case reports) to 44. Disease distribution examined presented as: ectopic pregnancy (17/42.5%), and from 1 (2.5%) bilateral tubal ligation, chlamydial infection-tubal infertility-ectopic pregnancy ,ectopic pregnancy on patients after IVF with abnormal sperm characteristics, ectopic pregnancy after oocyte donation in menopausal patients, ectopic pregnancy after donation surviving even with the absence of exogenous steroids, ectopic pregnancy after embryos with thickened zona pellucida, ectopic pregnancy after empty follicle syndrome, ectopic pregnancy after exposure to levonorgestrel, heterotopic abdominal pregnancy, heterotopic abdominal pregnancy, ectopic pregnancy after hydrosalpinx, menopause and oocyte donation, ovarian heterotopic pregnancy, ectopic pregnancy after pelvic inflammatory disease, pelvic inflammatory disease-ectopic pregnancy and neonatal complications, primary infertility, tubal factor infertility and bilateral ovarian pregnancy, tubal sterilization while 3 (7.5%) did not mentioned disease. Funding source of each study per Journal published is seen on Fig 8.

study per tissue used can be seen in Fig 6.

#### **5.2.1 Factors contributing to ectopic pregnancy after IVF**

Pyrgiotis et al, retrospectively analyzed a large series of fresh (n=2812) and frozen embryo transfers (n=405) showing a 2.4% and 7.6% EP rate, respectively (Pyrgiotis et al., 1994). Tubal factor presented as 85.7% of all causes of ectopic pregnancies. In a previous study, an EP rate of 3.3% was found (26 patients) and the major contributing factor was a prior ectopic (Karande et al., 1991). Heterotopic pregnancy rates remained low in both studies while the majority of them were tubal. Also cervical pregnancies were low.

Ectopic Pregnancy and Assisted Reproductive Technologies: A Systematic Review 55

Ghosh et al, described a right ampullary ruptured ectopic pregnancy after the failure of levonorgestrel as emergency contraception (Ghosh et al., 2009), while Fabunmi and Perks, reported a case of Caesarean section scar pregnancy after the same LNG failure (Fabunmi & Perks, 2002). From the other side, opposite to the numerous case reports, De Santis et al, in a retrospective observational cohort study found no association of LNG failure with ectopic

Controversy exists in this issue. Jun et al, found no difference in ectopic pregnancy rates between fresh and frozen cycles while Yanaihara et al, found a significant difference in ectopic pregnancies when two frozen blastocysts were transferred, than one (Jun et al., 2007; Yanaihara et al., 2008). From the other side, Ishihara et al, in a large registry retrospective study, found that frozen-thawed single blastocyst transfer significantly reduce EP rates (Ishihara et al., 2010). Even when data were stratified for age, EP rates varied, but remained

Milki et al, found no difference in ectopic pregnancy rates when blastocyst transfer compared with day 3 embryo transfer (Milki et al., 2003). In this study important confounding factors like tubal disease between the two groups, cryopreserved transfers but not number of embryos transferred were checked between the two groups and no

Knopman et al, reported a heterotopic abdominal pregnancy after the transfer of two blastocysts (Knopman et al., 2006). Intrauterine pregnancy miscarried first while abdominal pregnancy ruptured two weeks later and ectopic removed by laparoscopy. Ectopic pregnancies are significant lower when single frozen-thawed blastocysts transferred

Cohen et al, found that hydrosalpinx patients that undergo oocyte donation have higher ectopic pregnancy rates than patients in the same program with no hydrosalpinx (Cohen et al., 1999). Possible explanation for that is the chronic alteration of endometrium rather the direct embryotoxic effect of hydrosalpinx fluid. In case, after oocyte donation, an ectopic takes place, minimal monitoring may allow rupture of ectopic with significant complication (Ledger et al., 1992). Mantzavinos et al, reported three case of ovarian pregnancy after oocyte donation (Mantzavinos et al., 1994). Cases were resolved with laparoscopy and removal of ovarian pregnancy tissue. Pantos et al, in a large series of donation patients found only one ectopic pregnancy (Pantos et al., 1993). Rosman et al, in a large retrospective study (4186 non-donor IVF cycles vs. 884 donor ET cycles found that there is no difference in ectopic pregnancy rates between donor and IVF cycles (Rosman et al., 2009). From the other side, donor patients showed significant lower incidence of tubal disease than standard IVF

**5.2.4 Contraception as a risk factor** 

pregnancy (De Santis et al., 2005).

**5.2.6 Day 3 versus day 5** 

significant difference was found.

low.

patients.

**5.2.5 Ectopic pregnancy rates in fresh vs. frozen cycles** 

**5.2.7 Blastocyst (single vs. double blastocyst transfer)** 

compared with two blastocysts (Yanaihara et al., 2008).

**5.2.8 Oocyte donation and ectopic pregnancy rates** 

Clayton et al, in the largest series of 94.118 pregnancies found an EP rate of 2.2% in fresh non-donor cycles while ZIFT procedures EP rate was 3.6% (Clayton et al., 2006). Tubal factor with or without hydrosalpinx was the main factor of ectopic pregnancy while endometriosis, uterine factor and diminished ovarian reserve was some of the less but important factors. Although all other factors may be well understood, the last factor could be explained from the fact that when higher implantation embryo potential was present, EP rate was minimal. When two or less embryos transferred, then the EP rate was less than when three or more embryos transferred.

To the extent of the previous study, abnormal embryogenesis was a major factor for ectopic pregnancy. From this study it was found that DNA aneuploidy was associated with tubal implantation in 33% (Karikoski et al., 1993). Similar rates (24%) of abnormal amount of DNA content in tubal pregnancies was found also by Toikkanen et al., 1993.

In a recent study Chang et al, found that tubal factor infertility and endometriosis was the main factor (Chang et al., 2010). Tubal surgery and previous ectopic pregnancies was another important factor while risk for EP was seriously decreased with a previous live birth. Donor oocytes do not attribute to more ectopic pregnancies and this apply to higher embryo implantation potential, as mentioned above.

Contradictory to previous results, Bhattacharya et al, found that ectopic pregnancies in IVF are associated with significantly lower percentage of motile sperm (Bhattacharya et al., 2010).

A more detailed approach follows:

### **5.2.2 Heterotopic pregnancy**

It is considered a rare entity of ectopic pregnancy (1/30000) and could be seen especially after IVF(<0. 01) (Dimitry et al, 1990; Molloy et al., 1990). It has been presented in literature in various forms: 1) Triplet heterotopic pregnancy a) in a previous caesarian scar and intrauterine pregnancy b) a tubal singleton and two intrauterine pregnancies and an ovarian abscess c) bilateral tubal and intrauterine pregnancy 2) Cornual pregnancy a) recurrent cornual pregnancy b) cornual pregnancy and twin intrauterine pregnancy 3) heterotopic pregnancy with intrauterine dizygotic twins after blastocyst transfer 4) heterotopic cervical pregnancy a) intrauterine and twin cervical pregnancy b) cervico-istmic pregnancy 5) Heterotopic pregnancy in parallel with ovarian hyperstimulation syndrome 6) heterotopic pregnancy ruptured after spontaneous abortion.

Eventually the presence of an intrauterine gestation sac in a patient without symptoms should not exclude the diagnosis of a concomitant extrauterine pregnancy until the pelvis is carefully visualized (Rizk et al., 1991).

### **5.2.3 Differences in the prevalence in different countries of the world**

EP complicates about 2% of all pregnancies. Although no studies exists that specifically describe the prevalence in different countries, especially after IVF treatment, certain studies present this, as a secondary outcome. In Nigeria (Okohue et al., 2010), prevalence for EP was 7.8% after IVF, while in general population in the same country, EP rate was 1.74% (Musa et al., 2009). The same percentage in Jordan was 0.005% (Obeidat et al., 2010). In Cameroon, this percentage is 0.72% (Leke et al., 2004). In a large follow up study, in Sweden, ectopic pregnancy rates where compared between women from different countries of birth, but small differences were found (Eggert et al., 2008). In New York, ectopic pregnancy rates in black women are 4.78% (Fang et al., 2000).

## **5.2.4 Contraception as a risk factor**

54 Ectopic Pregnancy – Modern Diagnosis and Management

Clayton et al, in the largest series of 94.118 pregnancies found an EP rate of 2.2% in fresh non-donor cycles while ZIFT procedures EP rate was 3.6% (Clayton et al., 2006). Tubal factor with or without hydrosalpinx was the main factor of ectopic pregnancy while endometriosis, uterine factor and diminished ovarian reserve was some of the less but important factors. Although all other factors may be well understood, the last factor could be explained from the fact that when higher implantation embryo potential was present, EP rate was minimal. When two or less embryos transferred, then the EP rate was less than

To the extent of the previous study, abnormal embryogenesis was a major factor for ectopic pregnancy. From this study it was found that DNA aneuploidy was associated with tubal implantation in 33% (Karikoski et al., 1993). Similar rates (24%) of abnormal amount of DNA

In a recent study Chang et al, found that tubal factor infertility and endometriosis was the main factor (Chang et al., 2010). Tubal surgery and previous ectopic pregnancies was another important factor while risk for EP was seriously decreased with a previous live birth. Donor oocytes do not attribute to more ectopic pregnancies and this apply to higher

Contradictory to previous results, Bhattacharya et al, found that ectopic pregnancies in IVF are associated with significantly lower percentage of motile sperm (Bhattacharya et al.,

It is considered a rare entity of ectopic pregnancy (1/30000) and could be seen especially after IVF(<0. 01) (Dimitry et al, 1990; Molloy et al., 1990). It has been presented in literature in various forms: 1) Triplet heterotopic pregnancy a) in a previous caesarian scar and intrauterine pregnancy b) a tubal singleton and two intrauterine pregnancies and an ovarian abscess c) bilateral tubal and intrauterine pregnancy 2) Cornual pregnancy a) recurrent cornual pregnancy b) cornual pregnancy and twin intrauterine pregnancy 3) heterotopic pregnancy with intrauterine dizygotic twins after blastocyst transfer 4) heterotopic cervical pregnancy a) intrauterine and twin cervical pregnancy b) cervico-istmic pregnancy 5) Heterotopic pregnancy in parallel with ovarian hyperstimulation syndrome 6)

Eventually the presence of an intrauterine gestation sac in a patient without symptoms should not exclude the diagnosis of a concomitant extrauterine pregnancy until the pelvis is

EP complicates about 2% of all pregnancies. Although no studies exists that specifically describe the prevalence in different countries, especially after IVF treatment, certain studies present this, as a secondary outcome. In Nigeria (Okohue et al., 2010), prevalence for EP was 7.8% after IVF, while in general population in the same country, EP rate was 1.74% (Musa et al., 2009). The same percentage in Jordan was 0.005% (Obeidat et al., 2010). In Cameroon, this percentage is 0.72% (Leke et al., 2004). In a large follow up study, in Sweden, ectopic pregnancy rates where compared between women from different countries of birth, but small differences were found (Eggert et al., 2008). In New York, ectopic pregnancy rates in

content in tubal pregnancies was found also by Toikkanen et al., 1993.

when three or more embryos transferred.

A more detailed approach follows:

carefully visualized (Rizk et al., 1991).

black women are 4.78% (Fang et al., 2000).

**5.2.2 Heterotopic pregnancy** 

2010).

embryo implantation potential, as mentioned above.

heterotopic pregnancy ruptured after spontaneous abortion.

**5.2.3 Differences in the prevalence in different countries of the world** 

Ghosh et al, described a right ampullary ruptured ectopic pregnancy after the failure of levonorgestrel as emergency contraception (Ghosh et al., 2009), while Fabunmi and Perks, reported a case of Caesarean section scar pregnancy after the same LNG failure (Fabunmi & Perks, 2002). From the other side, opposite to the numerous case reports, De Santis et al, in a retrospective observational cohort study found no association of LNG failure with ectopic pregnancy (De Santis et al., 2005).

### **5.2.5 Ectopic pregnancy rates in fresh vs. frozen cycles**

Controversy exists in this issue. Jun et al, found no difference in ectopic pregnancy rates between fresh and frozen cycles while Yanaihara et al, found a significant difference in ectopic pregnancies when two frozen blastocysts were transferred, than one (Jun et al., 2007; Yanaihara et al., 2008). From the other side, Ishihara et al, in a large registry retrospective study, found that frozen-thawed single blastocyst transfer significantly reduce EP rates (Ishihara et al., 2010). Even when data were stratified for age, EP rates varied, but remained low.

### **5.2.6 Day 3 versus day 5**

Milki et al, found no difference in ectopic pregnancy rates when blastocyst transfer compared with day 3 embryo transfer (Milki et al., 2003). In this study important confounding factors like tubal disease between the two groups, cryopreserved transfers but not number of embryos transferred were checked between the two groups and no significant difference was found.

#### **5.2.7 Blastocyst (single vs. double blastocyst transfer)**

Knopman et al, reported a heterotopic abdominal pregnancy after the transfer of two blastocysts (Knopman et al., 2006). Intrauterine pregnancy miscarried first while abdominal pregnancy ruptured two weeks later and ectopic removed by laparoscopy. Ectopic pregnancies are significant lower when single frozen-thawed blastocysts transferred compared with two blastocysts (Yanaihara et al., 2008).

### **5.2.8 Oocyte donation and ectopic pregnancy rates**

Cohen et al, found that hydrosalpinx patients that undergo oocyte donation have higher ectopic pregnancy rates than patients in the same program with no hydrosalpinx (Cohen et al., 1999). Possible explanation for that is the chronic alteration of endometrium rather the direct embryotoxic effect of hydrosalpinx fluid. In case, after oocyte donation, an ectopic takes place, minimal monitoring may allow rupture of ectopic with significant complication (Ledger et al., 1992). Mantzavinos et al, reported three case of ovarian pregnancy after oocyte donation (Mantzavinos et al., 1994). Cases were resolved with laparoscopy and removal of ovarian pregnancy tissue. Pantos et al, in a large series of donation patients found only one ectopic pregnancy (Pantos et al., 1993). Rosman et al, in a large retrospective study (4186 non-donor IVF cycles vs. 884 donor ET cycles found that there is no difference in ectopic pregnancy rates between donor and IVF cycles (Rosman et al., 2009). From the other side, donor patients showed significant lower incidence of tubal disease than standard IVF patients.

Ectopic Pregnancy and Assisted Reproductive Technologies: A Systematic Review 57

(Condous et al., 2005) and there is difficulty in diagnosis and management. Serial measurements of hCG and progesterone should be performed on a wait and see approach,

an hCG ratio of >1.66 – correlates well with a developing intrauterine pregnancy. The use of discriminatory zone technique (Condous et al., 2005), is currently evaluated for prediction of probability of ectopic pregnancy. By this technique, if an intra-uterine sac cannot be seen on ultrasound scan above the threshold value, then steps must be taken to determine whether the pregnancy is abnormal or ectopic. After that a D&C can be safely performed only when a non-viable pregnancy has been documented by either a serum progesterone level of 15.9 nM or the absence of a rise in serum hCG after 2 days; that is, an hCG ratio of <1.50

With the use of TVS, before 35 days a pregnancy could be considered as a pregnancy of unknown location, from 35 to 41 days a pregnancy of uncertain viability and from 42 days a viable intrauterine pregnancy (Bottomley et al., 2009. Time for diagnosis of ectopic pregnancy was 48 days. In case, previous ectopic pregnancies took place, then diagnosis could be made before this time. Viability scans should be deferred until 49 days of gestation with a minimal benefit delaying after that. The addition of abdominal pain and vaginal bleeding ads to ectopic pregnancy risk. Statistical models have been developed, based on the hCG ratio to predict the outcome of pregnancies of unknown location and especially ectopic

pregnancies (Kirk et al., 2006), but this is not easily implemented in clinical practice.

tissue even if they are negative for cervical Chlamydia (Toth et al., 2000).

Daniel et al, tested for serum sVCAM-1, ectopic and normal pregnancies, but did not found

C. trachomatis antigen and nucleic acid could be found at 33% among ectopic pregnancies

Activin A subunit, type II receptors, follistatin, and iNOS show increased expression within the fallopian tube of ectopic pregnancy patients tested serologically positive for C. trachomatis (Refaat et al., 2009). Especially for iNOS, elevated activity positively correlates with protection from hydrosalpinx formation and prevention of the systemic spread of C. trachomatis. In a clinical setting, Florio et al, found that Activin A levels were significantly lower in spontaneous abortions and intrauterine pregnancies than ectopic ones,and at the cutoff of 0.37ng/ml a sensitivity and a specificity of 100 and 99.6%, respectively, was achieved, for prediction of EP (Florio et al., 2007). From the other side, on a different approach, Kirk et al, found no more discriminatory capacity of Activin A and inhibin than serum hCG levels for ectopic pregnancy in case of a pregnancy of unknown location (Kirk et

In this section, a total of 26 abstracts were retrieved and further screened. Only studies that performed clinical interventions for ectopic pregnancy after IVF were included in this part. Out of 16 included studies, 5 (31.25%) were performed in Taiwan, 4 in USA (25%), 2 in Italy

in parallel with TVS. Serum hCG increase over 48 h of more than 66% – that is,

**6.2 Transvaginal ultrasound and hCG levels for prediction** 

**6.3 Newer biomarkers for ectopic pregnancy** 

**7.1 Management of specific ectopic pregnancies** 

any difference (Daniel et al., 2000).

al., 2009).

**7. Section 4** 

(Pisarska et al., 1998).

### **5.2.9 The ICSI role**

In a large retrospective study, Clayton et al, found that use of ICSI was not associated with EP while male factor infertility was associated more with EP with all other races than whitenon-Hispanic (Clayton et al., 2006).
