Ectopic Pregnancy and Maternal Mortality

Ectopic Pregnancy and Maternal Mortality–Morbidity: Why is it Vital to Identify It in Time? 

The article was designed as a basic overview of the main determinants behind ectopic pregnancy with special emphasis given to the basic complexities and risks which are in close correlation with this disease. Four main causes determining the occurrence of ectopic pregnancy were established. Complications, interconnected with ectopic pregnancy were inclusively represented.

Introduction

Medically termed, Extrauterine Pregnancy (EUP) or Ectopic Pregnancy (EP) is the abnormal implantation of an embryo outside the uterus (outside the intrauterine cavity), which causes adverse consequences, such as maternal morbidity or maternal mortality in the first trimester in case if the surgical management was not performed in time, therefore early diagnosis is an essential preventive strategy. Identification of pathophysiological determinants indicating on possibilities of ectopic pregnancy incidence has been neither inclusively investigated nor completely elucidated, consequently the research of implicit factors, which may indicate its probability is still extensive and the received through the investigation multivariate results are highly debated theme among researchers and clinicians.

More detailed interpretation of this definition includes such multivariable versions as: 

1. ‘Ectopic pregnancy is an empty endometrial cavity with: 

1. An inhomogeneous adnexal mass or 

2. An extrauterine gestational sac with or without a yolk sac and/or fetal pole’ [Condous et al., 2005] or more conclusive one can be inclusively represented as ‘Ectopic pregnancy is diagnosed by transvaginal ultrasound if any of the following were noted in the adnexal region: 

1. An inhomogeneous mass or blob sign adjacent to the ovary and moving separately from the ovary; or 
2. A mass with a hyper–echoic ring around the gestational sac or bagel sign; or 
3. A gestational sac with a fetal pole with cardiac activity (a viable extra–uterine pregnancy) or 
4. A gestational sac with a fetal pole without cardiac activity (non–viable extra–uterine pregnancy). 

The final diagnosis is based on the findings at surgery and subsequent histology of removed tissues’ [Condous et al., 2005].

Most ectopic pregnancies (>96–98%) occurs in the Fallopian tube, especially in the mid–portion of the Fallopian tube, but has also been noted in both the proximal (cranial) ampulla (the ampullary region is the widened region near the ovary) and interstitial region of the Fallopian tube, causing the potential emergency condition. The pathophysiology of ectopic tubal pregnancy results from a tubal mechanical block to the antegrade progress of the developing embryo. It was also postulated that either the embryo or the Fallopian tube actively participates in a pathological process leading to abnormal embryo implantation outside the uterine cavity [Revel et al., 2008].

Currently, there are four management strategies, implemented in clinical practice, for ectopic pregnant Fallopian tubes’ Treatment: 

1. Medical Treatment by methotrexate injection; 
2. Surgical therapy (laparoscopy); 
3. Conservative surgery (preservation of the tube, salpingostomy) and 
4. Radical surgery (removal of the Fallopian tube, salpingectomy) [Fernandez et al., 2013].

1. Four Main Causes of Ectopic Pregnancy: Embryo implantation failure because of decreased levels of endometrial receptivity markers; Chronic inflammation of the Fallopian tube, caused by infection; Structural and functional abnormalities of the Fallopian tube; Endometriosis adhesions around the Fallopian tubes

1.1.Decreased levels of endometrial receptivity markers negatively affect intrauterine embryo implantation

The role of the uterus in the process of conception is limited to a critical period termed the ‘window of implantation’ spanning between Day 20 and Day 24 of a regular menstrual cycle. During this phenomenal period, the endometrium is primed for blastocyst attachment, given that it has acquired an accurate morphological and functional state initiated by ovarian steroid hormones, in other words, endometrial receptivity enables the apposition, adhesion and invasion of the extravillous trophoblast (embryo) into the uterine decidua (uterine wall).

When the blastocyst enters through one of the Fallopian ostia, 4 days after ovulation, it appears to move freely in the uterine cavity. Selectins were proposed to have an important role in this phase to ensure suitable rolling of the blastocyst. Because the embryo is required to attach to the endometrium in a polarized way and because the embryo is looking for the best area in the endometrium for implantation, this ‘rolling’ phenomenon is strictly regulated to ensure that the blastocyst will eventually settle in the proper spot and in the correct orientation [Achache and Revel, 2006]. To prevent the blastocyst from adhering to an area with poor chances of implantation, an important role is played by progesterone stimulation of an estrogenized endometrium, what leads to the production of proteins and adhesion molecules (for instance, integrins and cadherins) and pinopods, which are considered to be associated with the implantation window. Conditions negatively affecting intra–uterine embryo implantation are decreased levels of endometrial receptivity markers. 

There are no absolute conclusive interpretations about molecular basis of reciprocal interactions between the blastocyst and the uterus during implantation period. Verified theories represent multivariate paradigms of exclusion–inclusion criteria of implantation’s molecular basis, with special accent on complexity and synchrony, but asynchronous interactions between the blastocyst and the uterus during implantation period have not been investigated thoroughly.

Implantation involves a complex sequence of signalling events, based on various molecular changes that are critical to the establishment of pregnancy. It has been postulated that under the influence of ovarian hormones many of identified molecular mediators are involved in this early feto–maternal interaction. These mediators embrace a large variety of interrelated molecules including cell adhesion molecules, cytokines, growth factors, lipids and others [Achache and Revel, 2006]. Cell adhesion molecules, cytokines and lipids are vital for successful embryo implantation, especially for initial interaction between the embryo and the endometrium [Revel et al., 2008]. Endometrial receptivity consists in the acquisition of adhesion ligands together with the loss of inhibitory components that may act as a barrier to an attaching embryo [Achache and Revel, 2006].

1.2. Chronic inflammation of the Fallopian tube, caused by infection, interferes with embryo transfer process

Normally, blastocyst implantation involves three unique consecutive processes: apposition, attachment and invasion. It is noteworthy to mention that uterine–implantation molecules and disrupted related signalling pathways are in close correlation with tubal implantation. Synchronized transformation of molecules and related molecular signalling pathways is of absolute necessity for embryo–uterine interactions in the implantation process. Chronic inflammation of the Fallopian tube, caused by infection, can alter molecular signals emanating from tubal tissues, which compete with the uterus as a site for embryo implantation. In tubal pregnancy, a blastocyst receiving inductive signals from the tubal epithelium respond by adhering and implanting into the Fallopian tube [Ping Li et al., 2013]. Scarring and subsequent occlusion of the Fallopian tube tend to be frequent sequelae to inflammation arising from bacterial infection [Hunter, 2002].

1.3. Structural and functional abnormalities of the Fallopian tube interfere with the embryo transfer process

The Fallopian tube plays an excessively essential role in oocyte transport, fertilization and early embryogenesis, particularly, provides an optimum environmental medium for three main events, initially supports and enhances fertilization phenomenon [the Fallopian tubes facilitate capacitation, enhance and maintain sperm motility, induce the acrosome reaction and enhance sperm binding to the oocyte’s zona pellucida [Refaat and Ledger, 2011] and after the fertilization has occurred, the Fallopian tube is an exclusive environmental medium for the early embryonic development.

For successful intrauterine implantation to occur, both oocytes and embryo need to be transported within a well–defined time frame. This precisely timed process is affected by contractions of the tubal musculature, ciliary activity and the flow of tubal secretions. Both tubal ciliary beats and tubal contractions are supposed to be important for successful transport of the embryo along the tube and to ensure transfer of the embryo at the endometrial cavity at the optimum time for adhesion and implantation [Lyons et al., 2006].

The ability of the Fallopian tube to transfer the early embryo into the uterus is an excessive modality for successful pregnancy. Apparently, structural abnormalities and functional abnormalities of the Fallopian tube will interfere with the embryo transfer process that can lead to tubal pregnancy. It was revealed that tubal malformation is associated with altered gene expression in tubal epithelial cells [Ping Li et al., 2013].

1.4. Endometriosis adhesions around the Fallopian tubes facilitate and encourage the processes of embryo attachment and embryo implantation

Endometriosis is a complex chronic inflammatory estrogen–dependent disease in which endometrial–like tissue (endometrial–type mucosa) is located outside the uterus. It is characterized by the growth of endometrial epithelial and stromal cells outside the uterine cavity and associated with debilitating pelvic pain and reduced fertility.

In this pathology, endometrial tissue shed during menstruations is displaced in a retrograde manner through the Fallopian tubes into the peritoneal cavity, there to attach to the surface of abdominal organs covered with visceral peritoneum. In such sites, the tissue (glands and stroma) may 

1. proliferate, 
2. respond in a cyclical manner to ovarian steroid hormones, and 
3. cause episodes of discomfort or pain to a lesser or greater degree. 

What appears not to have been sufficiently considered is the extent to which fragments of refluxed endometrial tissue may be arrested within a Fallopian tube to generate a region possessing uterine characteristics. This could conceivably occur spontaneously in a healthy Fallopian tube under an inappropriate pattern of contractile activity or with a degree of stasis associated with stress. More probably, arrest of an endometrial tissue fragment would have occurred in a Fallopian tube whose epithelium had been damaged, and patency perhaps compromised by a previous history of disease. Such an endometrial fragment could show a marked phase of angiogenesis and would respond to the cyclical secretion of estradiol and progesterone in a tubal site; indeed, it might hyper–respond in a locally privileged manner and proliferate actively. This would be a reflection of locally–elevated concentrations of ovarian steroid hormones reaching the vascular arcade of the Fallopian tube via a counter–current transfer system in the region of the plexus between the ovarian vein and tubal branch of the ovarian artery [Hunter, 2002].

Whereas sperm might be able to progress within a Fallopian tube containing one or more endometrial fragments, the possibility of an oocyte or embryo descending such a tube would be much reduced—a point already made in terms of relative dimensions of spermatozoon and oocyte. Not only might an embryo be arrested or trapped in such a manner, but the fluid microenvironment of the pseudo–endometrial surface together with its specific molecular architecture might act to promote and sustain development and implantation of an embryo. In a phrase, an embryo might perceive components characteristic of a uterine milieu, albeit within the constraints of a tubal site, these facilitating and indeed encouraging the processes of attachment and implantation [Hunter, 2002].

2. Symptoms of ectopic pregnancy: are there the most relevant ones?

Ectopic pregnancy can be multisymptomatic or asymptomatic. Despite there are can be distinguished the multitude of symptoms, the most relevant one is abdominal pain. Abdominal pain (including abdominal pain with bleeding) must be considered as a strong indicator of ectopic pregnancy. Despite the other two symptomatic indicators, particularly 

1. the absence of a mass at ultrasonography because of pelvic pain and/or 
2. the presence of a haemoperitoneum on ultrasound [Condous et al., 2005] are in close correlation with a Pregnancy of Unknown Location (PUL), it should be noted that the pain–predominant signal intensity must be considered as a possible ectopic pregnancy.

3. Diagnostics of ectopic pregnancy: which non–invasive methods can be used for diagnosis validation?

The accurate or preliminary diagnosis of extrauterine pregnancy can be established non–invasively, using Transvaginal Ultrasonography (TVS) prior to surgery even without symptomatology. The diagnosis of ectopic pregnancy should be based on the positive visualization of an adnexal mass using Transvaginal Ultrasound scan (TVS) rather than on the basis of a scan that fails to demonstrate an intrauterine gestational sac. If the scan does not reveal any pregnancy, a knowledge of the behavior of serial human Chorionic Gonadotrophin (hCG) and progesterone is essential to evaluate which cases are at risk of developing into ectopic pregnancy [Condous et al., 2005].

Tubal pregnancy can be diagnosed for the presence of an adnexal mass and no intrauterine implantation by pelvis ultrasound. The diagnosis of ectopic pregnant Fallopian tubes presupposes the possibility of tubal rupture (the Fallopian tubes rupture), therefore, requires surgical intervention.

Ectopic pregnancy associated with haemoperitoneum on Transvaginal Ultrasonography (TVS) suggests the possibility of tubal rupture, and this situation requires surgical intervention. It is very difficult to quantify the volume of haemoperitoneum on ultrasound scan. Blood in the pouch of Douglas on ultrasound does not imply that tubal rupture has occurred, because most of ectopic pregnancies have ‘leakage’ from the lumen of the fimbrial end of the fallopian tube [Condous et al., 2005].

4. Clinical management of ectopic pregnancy: which Treatment Options can be proposed by clinicians?

There was established a perfect diagnostic gold standard, particularly, an accurate ultrasound visualization of the current pregnancy with inclusion only conclusive ultrasound scans and exclusion of inconclusive ultrasound scans during the interpretation and the diagnosis establishment. Early diagnosis, by transvaginal ultrasound and serum β–hCG monitoring, usually early in the first trimester, allow for intervention prior to Fallopian tube rupture.

The ectopic pregnancies are managed expectantly, medically or surgically depending on their clinical state, the size of the ectopic pregnancy, the presence or absence of fetal cardiac activity, the presence or absence of haemoperitoneum in the pouch of Douglas and the level of the serum human Сhorionic Gonadotrophin (hCG).

As it has been already mentioned, there four methods for clinical management of ectopic pregnancy: 

1. Medical Treatment by methotrexate injection; 
2. Surgical therapy (laparoscopy); 
3. Conservative surgery (preservation of the tube, salpingostomy) and 
4. Radical surgery (removal of the Fallopian tube, salpingectomy), but it should be noted that surgical management is usually the most preferable one.

Nowadays, early diagnosis has enabled conservative surgery by salpingotomy. Salpingotomy preserves the tube, but carries the risks of persistent trophoblast and repeat tubal pregnancy in the same tube. Salpingectomy minimizes these risks, but leaves only one tube available for conception, which might reduce fertility potential [Mol et al., 2015]. The main risk in conservative surgery is incomplete placental removal and persistent disease necessitating further surgery or methotrexate Treatment.

4.1. Medical Treatment of ectopic pregnancy by methotrexate injection

The reasons for methotrexate injection usually include ectopic pregnancies, ectopic pregnant Fallopian tubes, persisting Pregnancies of Unknown Locations (PULs) and Persistent Trophoblastic Tissue (PTT) after salpingotomy. General clinical inclusion criteria for Methotrexate Treatment are asymptomatic women, who are haemodynamically stable presenting with unruptured embryonic mass size of <4 cm, absence of fetal heart beat and low blood β–hCG levels. This version of expectant clinical management is advised in women with low serum hCG concentrations who are willing to accept the potential risks of tubal rupture and haemorrhage. Exclusion criteria for medical management of ectopic pregnancy by methotrexate injection include an acute abdomen, haemodynamic instability, haemoperitoneum on transvaginal ultrasound, positive fetal cardiac activity, renal impairment and liver impairment.

A single injection of methotrexate at a dose of 50 mg/m² should be given. After that serum hCG and progesterone levels should be also checked on days 1, 3, 4, 5 and 7. If the hCG levels decreased by ≥15% between days 4 and 7, then the levels should be measured on a weekly basis until they reached ≤15 IU/l. If the hCG decreased by <15% between days 4 and 7, a second dose of methotrexate should be given.

The adverse effects of methotrexate include acute abdominal pains, impaired liver functions, stomatitis, cytopenia and, rarely, pneumonitis.

4.2. Medical Treatment of ectopic pregnancy by surgical therapy (laparoscopy)

The traditional form of ectopic pregnancy Treatment has been laparotomy, but with developing advanced surgical techniques, laparoscopy, being less invasive and safer, is nowadays the Treatment of clinicians’ preference. Laparoscopy is considered to be the gold standard for the diagnosis of ectopic pregnancy, but also is the invasive procedure. The diagnostic value of laparoscopy with or without histological verification enables the surgeons–gynecologists to visualize the ectopic pregnancy and confirm the conclusive diagnosis on histological examination. 

Surgical findings are mainly minimal, with possible adhesions mostly being filmy or local and treatable by way of modern laparoscopic techniques.

4.3. Medical Treatment of ectopic pregnancy by conservative surgery (preservation of the tube, salpingostomy) 

Salpingostomy is an alternative Surgical Treatment strategy to tubal clipping or salpingectomy. Primarily, performance of salpingostomy it is an alternative management strategy, which conserves a woman’s Fallopian tubes. Techniques used to perform salpingostomy have changed significantly throughout time due to advancements in technology.

4.4. Medical Treatment of ectopic pregnancy by radical surgery (removal of the Fallopian tube, salpingectomy)

The Fallopian tube plays an excessively essential role in oocyte transport, fertilization and early embryogenesis. The crucial capture of the oocyte released from the ovary is accomplished by the fimbriated (distal) end of the Fallopian tube, which ‘floats’ in the pelvis over the ovarian surface and the peritoneum of the pouch of Douglas.

Salpingectomy is in general preferred to salpingotomy for Treatment of ectopic pregnancy. It is the surgical removal of a Fallopian tube. Whether salpingectomy affects ovarian function is controversial issue. One of the concerns against salpingectomy is the possibility of impairing the ovarian function after the procedure. The most important blood supply to the Fallopian tube is the medial tubal artery, which originates at the same point as the median ovarian artery. If the salpingectomy procedure is not properly performed close to the tube, it may disrupt the normal blood flow to the ovary [Chan et al., 2003].

Conclusion

Medically termed, Extrauterine Pregnancy (EUP) or Ectopic Pregnancy (EP) is the abnormal implantation of an embryo outside the uterus (outside the intrauterine cavity), which causes adverse consequences, such as maternal morbidity or maternal mortality in the first trimester in case if the surgical management was not performed in time, therefore early diagnosis is an essential preventive strategy.

Most ectopic pregnancies (>96–98%) occurs in the Fallopian tube, especially in the mid–portion of the Fallopian tube, but has also been noted in both the proximal (cranial) ampulla (the ampullary region is the widened region near the ovary) and interstitial region of the Fallopian tube, causing the potential emergency condition.

The gold standard for conclusive establishing of the diagnosis of ectopic pregnancy and its medical management is primarily laparoscopy.

Currently, there are four management strategies, implemented in clinical practice, for ectopic pregnant Fallopian tubes’ Treatment: 

1. Medical Treatment by methotrexate injection; 
2. Surgical therapy (laparoscopy); 
3. Conservative surgery (preservation of the tube, salpingostomy) and
4. Radical surgery (removal of the Fallopian tube, salpingectomy)

References: 

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