**9. Conclusion**

In this systematic review we presented the most important studies dealing with ectopic pregnancy after *in vitro* fertilization. Also, important biological factors that play a role for EP has been presented. Case reports of ectopic pregnancies their position in the uterus, and the steps undertaken to preserve intrauterine pregnancy has been described. Complications of these treatments, where available, have been mentioned. Practices during *in vitro* fertilization treatment and their controversial role for this pregnancy complication have been described. Overall, cost-effectiveness studies in the ectopic pregnancy prediction and management has been described. New research directions have been pointed out.

Although ectopic pregnancies and more specific heterotopic pregnancies are rare, these increase due to infertility treatment. Active and aggressive management of hydrosalpinx has been proposed for heterotopic pregnancy minimization after IVF.

All combinations of heterotopic pregnancies have been described. The major complication was bleeding and rupture of pregnancy. Care was taken for intrauterine pregnancy continuation but many cases miscarried after some time. Laparoscopy and hysteroscopy were methods of choice but laparotomy was chosen when threat of major bleeding was expected. Another method of treatment was vaginal aspiration of embryo sac after a lethal injection with a pharmacological agent. Most cases have not recognized till rupture of ectopic pregnancy.

Chlamydia is not cost-effective when tested in general population (Buhaug et al., 1989; Roberts et al., 2007; van Valkengoed et al., 2001) and that only when women aged 18 to 24 years old tested or prevalence of Chlamydia is over 3% (Postma et al., 2000) or 2% (Trachtenberg et al., 1988), cost-effectiveness exist for prevention of ectopic pregnancy. Hu et al, pointed out that annual screening for Chlamydia is indicated for women 15 to 29 years of age and selective targeting with semiannual screening of those women with a history of infection (Hu et al., 2004). Partner treatment should be provided (Postma et al., 1999) to avoid re-infection. Another author (Schiøtz et al., 1991) found that routine post-treatment

In an emergency department, to rule out the possibility of ectopic pregnancy, the most cost effective strategy is to screen all patients with first trimester bleeding and lower abdominal cramping with ultrasound (Durston et al., 1999), even if the scan is performed by an emergency doctor. Obviously this technique is not cost-effective in symptoms free women

When laparoscopy is compared with methotrexate for its cost savings, methotrexate saves about 1000, Canadian dollars (Yao et al, 1996). In a decision and cost-effectiveness analysis, Seror et al., found that first line treatment with methotrexate is more cost-effective than conservative laparoscopy and radical laparoscopy in sub-acute ectopic pregnancy (Seror et al., 2006). Conservative laparoscopy was more cost-effective than radical laparoscopy in this group of patients, in terms of fertility preservation. Methotrexate treatment effectiveness was increased when diagnostic ultrasound accuracy is increased. If patient after an IVF ectopic pregnancy treated with methotrexate, then, in the next cycle, similar ovarian

In this systematic review we presented the most important studies dealing with ectopic pregnancy after *in vitro* fertilization. Also, important biological factors that play a role for EP has been presented. Case reports of ectopic pregnancies their position in the uterus, and the steps undertaken to preserve intrauterine pregnancy has been described. Complications of these treatments, where available, have been mentioned. Practices during *in vitro* fertilization treatment and their controversial role for this pregnancy complication have been described. Overall, cost-effectiveness studies in the ectopic pregnancy prediction and

Although ectopic pregnancies and more specific heterotopic pregnancies are rare, these increase due to infertility treatment. Active and aggressive management of hydrosalpinx has

All combinations of heterotopic pregnancies have been described. The major complication was bleeding and rupture of pregnancy. Care was taken for intrauterine pregnancy continuation but many cases miscarried after some time. Laparoscopy and hysteroscopy were methods of choice but laparotomy was chosen when threat of major bleeding was expected. Another method of treatment was vaginal aspiration of embryo sac after a lethal injection with a pharmacological agent. Most cases have not recognized till rupture of ectopic pregnancy.

management has been described. New research directions have been pointed out.

control of non- systematic genital Chlamydia infection is not cost-beneficial.

**8.1.2 Ultrasound for diagnosis of ectopic pregnancy-cost-effectiveness** 

**8.1.3 Laparoscopic treatment for Ectopic pregnancy-cost effectiveness** 

stimulation characteristics could be obtained (Orvieto et al., 2007).

been proposed for heterotopic pregnancy minimization after IVF.

(Mol et al., 2002).

**9. Conclusion** 

The majority of studies were case report and retrospective studies. Even if more studies exist in a specific issue (e. g. ectopic pregnancy rates in fresh and frozen IVF cycles) these are not, homogenously designed, and no data synthesis could be made. Also in the management of heterotopic pregnancies, a single methodology was not used, so no best practices outcome could be formed. Screening for ectopic pregnancy show better cost-effectiveness only when we expect increased prevalence of this entity (Roberts et al., 2007; van Valkengoed et al., 2001) or women age from 18 to 24 years old (Buhaug et al., 1990). Also general population screening program for C. Trachomatis, show that costs exceeds the benefits to avoid ectopic pregnancy. The method of choice for treatment is laparoscopy, because show similar costeffectiveness but less invasiveness (Gray et al., 1995) than laparotomy. Combination therapies, like uterine artery embolization and laparoscopy has been used for complications like hemorrhage. Although these therapies are expensive, the rare cases do not allow a costeffectiveness analysis to be performed.

Many heterotopic pregnancies were identified after EP rupture, thus leading to a laparoscopy or laparotomy and possible complications while an early identification may lead to MTX therapy, that is by far a more cost-effective treatment strategy. From the other side, close ultrasound monitoring has revealed heterotopic pregnancies developed in previous Caesarean scar pregnancy, cervical pregnancies etc. So for IVF patients, more intense ultrasound and b-hCG monitoring is required. It is not known yet whether this applies to all patients that had an ET or only in the subgroup of patients with risk factors for EP undergoing ET.

Many ectopic pregnancies remained unidentified with viable pregnancies till second trimester. It is important, for these cases, to improve our detection capabilities with new approaches. Heterotopic pregnancy may present with different combinations and uterine locations, at various gestational ages, even when the intrauterine pregnancy aborts. 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). Currently, no biomarker could early identify an ectopic pregnancy, especially a heterotopic one. A promising non invasive marker could be developed from the use of cervical trophoblastic cells and special markers on them.

Regarding the IVF procedure, infertility medication should be used cautiously from nonspecialists and ovulation induction has to be preformed always under close monitoring. In case of altered tubal motility, close monitoring of pregnancy as evolves, should be performed.

Chlamydia infections and tubal factor infertility still remain the major factor for EP after IVF. Active management for hydrosalpinx seems to lower EP rates, but still no minimal invasive test exists. No other IVF technique could be accounted for increased ectopic pregnancy rates except the transfer of multiple embryos, especially more than two. Where indications exist for increased EPs after specific techniques (e. g. assisted hatching), more clinical trials should be performed, controlled also for EP factors. Tubal transfer techniques (ZIFT) have been abandoned through years, so they could not account for EP in the modern era. Tubal reanastomosis also is not practiced in all IVF clinics, and only where it is practiced it has to be considered as a factor of tubal pregnancy.

Another issue that needs to be checked is the association of ectopic pregnancy and the abnormal embryogenesis. This is important for male factor infertility and increased age. It is not clear yet whether more intense pregnancy monitoring should apply in these patients.

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As a general policy, individual IVF practices should evaluate their EP rate in an attempt to identify factors that may increase or decrease the rate compared to national statistics (Keegan et al., 2007).

It is not clear yet, whether a single biological pathway should account for ectopic pregnancy. Although TB implantation mechanism is different from normal uterine mechanism, tubal pregnancies should be used to study embryo implantation. Invasive pathway, as described in ectopic pregnancy seems to be important. Another pathway that may be involved is the NO pathway that is altered through the Chlamydia infection altered immune response.

Researchers performing RCTs in ectopic pregnancies need to consider certain issues in their design. Patients differ in age and the infertility factor. A trial has to control for the number of embryos transferred, the quality of them and patients demography because a common underlying risk factor might exist. A clear measure of complications has to be developed, especially for cost effectiveness studies. Because ectopic pregnancies after IVF always need intervention, no placebo trials could be performed. Length of follow up and follow up plan need to be decided before hand, so pregnant women need to have standardized care. Level of training for the providers of IVF services seems to be important.

Ruptured ectopic pregnancies may present with severe complications, due to hemorrhage. Currently, no single treatment plan is chosen and different groups perform different approaches. Although these treatments are life saving, they are not cost effective. It is important for hospitals with large IVF groups to undertake such studies, so knowledge to be transferred to smaller groups. In case of heterotopic pregnancy, it is important to know how to protect the intrauterine embryo (as valuable pregnancy), so research should direct to this also.

#### **10. References**


As a general policy, individual IVF practices should evaluate their EP rate in an attempt to identify factors that may increase or decrease the rate compared to national statistics

It is not clear yet, whether a single biological pathway should account for ectopic pregnancy. Although TB implantation mechanism is different from normal uterine mechanism, tubal pregnancies should be used to study embryo implantation. Invasive pathway, as described in ectopic pregnancy seems to be important. Another pathway that may be involved is the NO pathway that is altered through the Chlamydia infection altered immune response. Researchers performing RCTs in ectopic pregnancies need to consider certain issues in their design. Patients differ in age and the infertility factor. A trial has to control for the number of embryos transferred, the quality of them and patients demography because a common underlying risk factor might exist. A clear measure of complications has to be developed, especially for cost effectiveness studies. Because ectopic pregnancies after IVF always need intervention, no placebo trials could be performed. Length of follow up and follow up plan need to be decided before hand, so pregnant women need to have standardized care. Level

Ruptured ectopic pregnancies may present with severe complications, due to hemorrhage. Currently, no single treatment plan is chosen and different groups perform different approaches. Although these treatments are life saving, they are not cost effective. It is important for hospitals with large IVF groups to undertake such studies, so knowledge to be transferred to smaller groups. In case of heterotopic pregnancy, it is important to know how to protect the intrauterine embryo (as valuable pregnancy), so research should direct to this

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**4** 

*USA* 

**Hysteroscopic Endometrial** 

It has been over 30 years since the first successful pregnancy using in vitro fertilization (IVF). There have been major advancements in the different components of IVF such as ovulation induction protocols, oocyte retrieval techniques, and culture medium tailored to improving embryo quality (Gardner 1998). However, the discrepancy between women undergoing IVF with normal embryo development and live pregnancy rates continues to exist. It is estimated that up to 85% of replaced embryos fail to implant despite the selection of apparently normal embryos for transfer (Sallam 2002). This failure rate suggests that the embryo transfer stage is a key step to successful live pregnancy rates in assisted

Embryo transfer is traditionally performed by "blindly" replacing the embryos into the uterine cavity utilizing a transcervical catheter at approximately 2-5 days of development. This technique relies highly on the skill and tactile senses of the clinician. Many clinicians will transfer the embryos at a fixed distance (6 cm) from the external os; however, with varying cervical lengths and uterine anatomy, this often does not ensure optimal placement (Brown 2007). Recently, there have been many studies proposing potential embryo transfer related factors to the low success rate in pregnancy outcomes such as uterine contractions, expulsion of embryos, blood or mucus on the catheter tip, bacterial contamination of the catheter, and retained embryos (Schoolcraft 2001). Ultrasound guided embryo transfer (UGET) is currently suggested as the standard clinical practice and appears to improve the chances of live/ongoing and clinical pregnancies compared with clinical touch methods (Brown 2007). However, controversies still remain regarding the actual benefit of UGET in successful clinical pregnancy rates (Kosmas 1999). The subendometrial embryo delivery (SEED) technique has been previously reported to increase pregnancy rates and eliminate ectopic pregnancies associated with ART (KAMRAVA 2010). In this study, we set out to use a similar technique which utilized a mini-hysteroscope with a flexible catheter for direct delivery of embryo(s) at the 4-12 cell stage onto the endometrium under direct visualization. The hysteroscopic visual guidance ensures more precise and reliable placement at the

**1. Introduction** 

reproductive technology (ART) (Meldrum 1987).

desired location of the endometrium.

**Embryo Delivery (HEED)** 

M.M. Kamrava, L. Tran and J.L. Hall

*2LA Center for Embryo Implantation 3UCLA, the Geffen School of Medicine* 

*1West Coast IVF Clinic* 

