Current Progress In Early Pregnancy Investigation And The Steps Ahead

Eytan R. Barnea

Editorial

This is a first of a two part editorial from the editor-in-chief. This first part will deal with early pregnancy within the context of reproduction. The second part will address the multitude of applications and implications of early pregnancy investigation throughout all other medical specialties.

In the past few years, understanding of the early stages of pregnancy has grown exponentially. Fertilization can be readily achieved in vitro or through ICSI if the sperm is not fully functional in high percentage of cases. Initial attempts to improve gamete quality when the cytoplasm is defected or aged, through the transfer of healthy DNA to a donor cytoplasm are currently made. Using this approach maternal derived mitochondrial DNA would not be transferred, with implications that remain uncertain.

Initial stages of embryonal growth are considered to be autonomous, and are not likely to require major maternal input. Shortly after fertilization the embryo secretes specific factors that lead to its recognition by the maternal organism. This may appear a paradox since very early recognition of the embryo as a partial alograft may be detrimental for the embryo, leading to an attack by the maternal immune system. On the other hand, such an early recognition can help create a favorable endometrial environment and also allow the embryo to develop to a stage where it can better interact with the maternal endometrium.

What about embryo derived signaling and pregnancy recognition? Maternal recognition of pregnancy occurs very early. This recognition appears to be mainly humoral, becoming systemic rather quickly as evidenced by the presence of different factors, including EPF, PAF and preimplantation factor (PIF), in the circulation prior to implantation. Changes in this embryo specific factor’s secretion may help in providing insight into embryonal viability.

The embryo can be probed through blastomere biopsy providing a valuable tool for the early identification of some genetic abnormalities and thus avoiding the transfer of embryos that have recognizable chromosomal defects, or other metabolic disorders. The list of what can already be diagnosed at that stage continues to grow. We have advanced our ability to grow embryos into the blastocyst stage. The fact is that those that fail to reach that developmental stage are inherently defective. Indeed there is a high pregnancy rate with blastocyst transfer even when only two of them are transferred at a time.

There is no dispute that the endometrium is a far more preferable site for embryo-maternal interaction during implantation than any other site in the body. But the ability of the embryo to implant occasionally elsewhere is a strong evidence pointing to the resiliency of embryonal development under adverse conditions. However, at this point it appears that the more we get to know the more limited becomes our understanding of the whole integration process between mother and embryo.

This apparent confusion is most likely due to the high degree of redundancy that is present in the system. The presence of specific maternal and embryonal factors that act in parallel and sequential manner makes difficult to dissect out which is the most important aspect of the whole process. It is evident that it takes a number of days until implantion is successfully completed therefore the likelihood of a cascade phenomena becomes a much more plausible scenario.

Attributing the most critical role to one signaling pathway or factor is not likely to resolve the puzzle. More likely successful implantation is due to a unique combination of multiple factors. It is very possible that the process of implantation since it requires the acceptance of a partial alograft under physiological conditions is unique in its complexity in biology. However, one thing is clear maternal embryonal dialog must be very active, since only a viable embryo will implant.

The role of the decidua as an active participant as well as involvement of the immune system in the fetal interphase becomes gradually defined. Current attempts to unravel the intricacies of the system using specific receptor blockers, inhibitors and transgenic animals are steps in the right direction.

Clinically, identification of the time of implantation remains elusive since there are no specific markers. As recently reported delayed implantation as documented by urine hCG measurements are not conducive to successful pregnancy. Circulating markers such as hCG are detectable only following implantation. Development of more sensitive markers could provide part of the answer. Identification of embryo specific markers that are present already prior to implantation could be also steps in the right direction.

Another critical point where information is currently scant is what triggers embryo development following implantation and how does take that place in such a tightly coordinated time period. We are becoming aware of the ongoing embryoblast- trophoblast dialog. The embryoblast cells are located right behind the trophoblast as implantation proceeds, i.e the presence of an embryonal polarity is a physiologic necessity. Unfortunately, we do not understand as yet what specific interchanges do take place.

It is unclear how the trophoblast is able to signal the embryoblast that implantation has been successfully accomplished and therefore the embryo is safe to start to differentiate. We know from experimental and clinical data of the existence of such a dialog during embryogenesis. Embryo derived factors were shown to control trophoblastic hormonal secretion. In essence embryo demise leads to reduced trophoblastic function and therefore to the resolution of pregnancy.

There has been a major progress in understanding cellular and molecular aspects of embryonal development. Gene imprinting is its infancy and it appears to add a further layer of complexity to the process. Several genes have been identified that are responsible for one or more functions and various organs development in the embryo but we still are a long way from reaching an integrated view of the whole process. The theory of complexity and the emerging organization out of apparent chaos provides a major conceptual framework.

Shortly following implantation we start to be able to visualize the gestational sac. This identification with advancing technology appears to occur earlier and earlier. For example the use of Doppler and the 3D ultrasound are important tools in understanding early pregnancy. The first visualizes the blood flow in and around the gestational sac while the other allows for virtual dissection of the embryo in vivo visualizing in detail external well as its internal organ structures.

By now, we know that adverse environment plays a major role in damaging the conceptus. However, recent teratologic investigations have revealed that the embryo because of its unique environment and because of its own defense mechanisms is rather resilient in lowering the impact of teratogenic agents. First, because the metabolic role of the placenta which serves as a metabolic sink helps to inactive mutagens/carcinogens. Further the low oxygen environment surrounding the embryo reduces local oxygen radical formation.

On the other hand, the conceptus that has been damaged is frequently eliminated spontaneously through internal control mechanisms. Of concern are those pathologic pregnancies that are not eliminated since they provide a risk for the remainder of the pregnancy and even after that throughout adult life. Linkage between certain exposures like cigarette smoking and damage to the embryo has been strengthened. Also the ability to prevent neural tube defects by the use of folic acid has been deemed to be successful at least partially.

Thus teratology has moved a long way in becoming much more rationale and less alarmistic. The diagnosis of chromosomal abnormalities has also been moving towards the first trimester, for example by the use of PAPP-A. However promising it is, the need for further testing later in gestation due to structural anomalies that are identified later or certain blood indices that are more accurate later in gestation i.e. alpha fetoprotein remains.

When embryogenesis has been largely completed and hCG has peaked signals that the trophoblast is being transformed into a vascular placenta. At that point the likelihood that the pregnancy will be lost becomes rather low, ~2%.

The passage of pregnancy towards the second trimester heralds the beginning of era of relative quiescence where most defective pregnancies have already been identified and self eliminated or otherwise have ended.

How far are we from the point that practically all defective and non salvageable pregnancies would have already been identified and eliminated by the end of the first trimester? Apparently we are making significant strides in that direction. In this discussion one has to distinguish between using ART versus not using ART technologies. In ART having an embryo that its viability could be enhanced in vitro by adding embryo trophic substances is still a thing of the future. However, when the embryo is capable of reaching the blastocyst stage that event by itself is a strong evidence for embryonal viability. Probing the embryo by different genetic markers eliminates defective embryos and may become even more thorough.

In both ART and non ART conceptions, the process of implantation still remains a major hazard. For increasing implantation an agent will have to be found that promotes pregnancy recognition and maintenance. As for post implantation period, markers start to emerge which provide both visual and biochemical signals that identify defective pregnancies.

What we can not control at present is the process of embryogenesis. Our ability to identify the governing forces that allow for embryogenesis would go a long way in transforming chemical into clinical pregnancies. The development of markers that are specific for the embryo and reflect functionality of various organs would be a great asset. Finally, by the end of the first trimester the likelihood of loss of pregnancies in which the embryo intact will consequently become very low. This may be due to the fact that most defective pregnancies have already been identified and corrected. While those that are not treatable have been already eliminated.

The goal of the society and its mission is to make this goal as close to reality as possible. It has been already recognized that such an achievement may have a major impact on pregnancy outcome and postnatal life. I look forward seeing your contributions to the journal, participation in the chatrooms, and conferences in helping to transform these observations and thoughts into clinical realities. 

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