THREE MONTHS IN REVIEW

S. M. Stemmer, M.D., M.S.

The format of the review is now to focus on a small number of selective and relevant articles that according to the editor can make a contribution in advancing early pregnancy investigation. Also included are few reports that have clinical relevance to the practicing clinician treating patients in early pregnancy.

Immunoregulatory Activity of Decidua in Spontaneous Early Pregnancy Loss
The ability of the fetus to prevent maternal rejection is assumed to be mediated by factors released by the decidua that inhibit cell-mediated immunity. The present study¹ investigates whether the properties of molecules secreted within the decidua of 25 women suffering from a spontaneous miscarriage differs from 22 women that underwent therapeutic pregnancy termination. The effect of decidual supernatants on phytohaemagglutinin-induced peripheral blood lymphocyte proliferation was investigated.

Immunosupression activity was found in 24-hour cell culture supernatants from 91% of the therapeutic pregnancy termination group compare to only 64% of spontaneous abortions. At 72-hour supernatants were used, of all of the therapeutic abortion group and 90% of spontaneous abortion suppressed proliferation of lymphocytes.

The present study confirmed the importance of immunosupression by the fetus to avoid maternal rejection.

Elevated Expression of Activation Molecules by Decidual Lymphocytes in Women Suffering Spontaneous Early Pregnancy Loss
T cells, macrophages and endometrial granulocytes are the most abundant leukocyte populations within first trimester deciduas. Endometrial granulated lymphocytes account for up to 70% of endometrial leukocytes. Activation molecules that are expressed on leukocytes can be classified as early activation markers such as CD69 and CD25 and late activation markers, such as human leukocyte antigen (HLA) DR, very late antigen (VLA)1. The aim of the present study² was to compare the expression of activation markers by decidual leukocytes in spontaneous early pregnancy loss and apparently normal first trimester human pregnancy.

In the decidua from patients experiencing spontaneous early pregnancy loss significantly increase in numbers of CD69-positive and CD25-positive cells compared to the group of women who underwent therapeutic abortion were detected. About 50% of women experiencing spontaneous pregnancy loss had a significantly elevated numbers of HLA DR-positive cells within the decidua.

Increased T cell expression of activation markers occurs in a group of women experiencing spontaneous miscarriage. Further studies are needed to correlate the altered decidual immune function in spontaneous abortion with fetal chromosomal status, ultrasonography data and endocrine profile.

The Emerging Role of Immunoregulation of Fibrinogen-Related Procoagulant Fgl2 in the Success or Spontaneous Abortion of Early Pregnancy in Mice and Humans
A simple model of events leading to abortions are: pro-inflammatory cytokines such as interleukin (IL)-1, tumor necrosis factor (TNF)-a , interferon (IFN)-g , collaborate to activate procoagulant expression in endothelial cells that are in direct contact with maternal blood. Thrombin then catalyzes generation of fibrin and recruitment of polymophonuclear leukocytes, such that the blood supply to the embryo is shut off and it dies. Antibody to fibrinogen-related procoagulant fgl2 reduces the spontaneous abortion rate to a minimum of 5%.³  In spontaneous abortion of normal embryo, fgl2 positivity was seen in syncytiotrophoblast and extravillous cytotrophoblast.  In contrast in tissue from normal first trimester pregnancy minimal fgl2 positivity was seen.

The presence of fgl2 in trophoblast and villous stroma should attenuate bleeding into the fetus, bleeding from the fetus, and passage of undesirable numbers of potentially aggressive maternal or fetal cells. Fgl2 presence in trophoblast and villous stroma appears to protect against the danger of internal maternal or fetal bleeding which may result in an abortion. However, when there are external dangers, such as stress or infection it appears that a physiologic mechanism to prevent bleeding namely fg12, is activated to terminate the pregnancy.

Expression of Leukemia Inhibitory Factor and Its Receptor in Preimplantation Embryos
Several factors play a role in modulating differentiative and proliferative changes in the endometrium for a successful embryo implantation. Factors such as steroid hormones, growth factors and cytokines have been investigated. It has been reported that among the cytokines expression of leukemia inhibitory factor (LIF) in the endometrium is essential for mouse embryo implantation. Spare human oocytes and embryos were obtained from patients undergoing IVF treatment.

Leukemia inhibitory factor and its receptor (LIF-R) were detected in most human preimplantation embryos.⁴  The expression of these genes indicates the potential autocrine or paracrine role of LIF in the regulation of preimplantation embryo development.

Hypoxic Microenvironment Within an Embryo Induces Apoptosis and Is Essential for Proper Morphological Development
Several studies have shown the importance of hypoxia in normal embryonic development with respect to gene expression changes. Hypoxia inducible factor (HIF-1) has been implicated in activating physiological responses to hypoxia including angiogenesis, vasodilatation, anaerobic glycol sis, elevated respiratory rate and increased erythrocyte production. In this study the role of hypoxia was investigated by measuring hypoxia marker EF5, which binds to protein, RNA and DNA in cells exposed to a hypoxic environment.⁵   In vitro rat embryo culture system allows for changes in the oxygen environment of the developing embryo while keeping all other independent variables constant.

Rat embryos, which were grown at 45% oxygen from gestational day 9-11, showed gross morphological abnormalities. Embryos grown at 5% oxygen during the same period were stunted in overall growth yet morphological normal, and displayed prominent areas of apoptosis. Since hypoxia in a tumor can modulate the apoptotic and angiogenic processes that influence cell growth and death, hypoxia may also provide a signal to the embryo so proper development of certain regions occurs.

The Value of Sonography in Early Pregnancy For the Detection of Fetal Abnormalities in an Unselected Population
Benefits of first trimester diagnosis of fetal abnormalities include decrease in surgical and emotional morbidity by allowing the option of an early termination of pregnancy. First trimester (11 to 14 weeks) transabdominal and transvaginal ultrasound scans were offered to 6634 sequential unselected women to determine the ability to detect fetal abnormalities.⁶  There were 92 anomalous fetuses including 43 with chromosomal abnormalities (incidence of 1.4%). Sensitivity of detection was 59% and specificity was 99.9%. Combining first and second trimester scans a detection rate of 89% was observed. The detection rate of chromosomal abnormal fetuses was 78% and 65% for trisomy 21.

This study showed that the majority of fetal structural defects can be diagnosed by an early pregnancy scan however, a second trimester ultrasound would detect even more cases and therefore should be continued to be offered to all patients.

Prevalence and Significance of Isolated Fetal Choroid Plexus Cysts Detected in Early Pregnancy by Transvaginal Sonography in Women of Advanced Maternal Age
Choriod plexus cysts (CPC) can be diagnosed as early as 11 and 12 weeks.⁷  More than 90 percent of the cases they resolve by 28 weeks and are of no pathological significance. Rarely they are associated with chromosomal abnormalities. The purpose of the present retrospective study was to determine the prevalence of isolated fetal CPCs diagnosed in early pregnancy by transvaginal sonography and the risk of associated chromosomal abnormalities in women of advanced maternal age (>37).

An early transvaginal ultrasound was offered to 1692 women over 37 years of age and with a singleton pregnancy. In 26 cases transvaginal sonography showed the presence of significant CPC. In only one case multiple fetal abnormalities were detected. Trisomy 13 was identified in one of the fetuses. Cysts were noted to regress by delivery in 91.3% of the cases.

This study suggests that there is no association between isolated CPCs and aneupoidy. Therefore a routine amniocentesis is not recommended.

Implantation Rates After In Vitro Fertilization and Transfer of a Maximum of Two Embryos That Have Undergone Three to Five Days of Culture
Embryo transfer at day five might allow better assessment of embryo quality and possibly increase implantation rate. Comparison of implantation and pregnancy rates in one thousand seven hundred eighty-seven couples who underwent their first IVF cycle and embryo transfer after 3,4, or 5 days was done.⁸ A maximum of two embryos were transferred.

Forty-one percent of all fertilized oocytes developed into blastocyts. The overall implantation rates and pregnancy rates were not significantly different between the three groups. However if blastocysts were available for transfer after 5 days, and two blastocysts were transferred, the implantation rate was 26% per embryo transfer compared to 18% for an eight-cell embryo on day 3.

Although the overall implantation and pregnancy rate was similar for embryo transferred after 3,4 or 5 days of culture, Embryo transferred after five days with the best morphologic appearance have a significant increased implantation rate over day three eight-cell embryos.

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1. N. Vassiliadou, R.F. Searle, J.N. Bulmer: Immunoregulatory activity of deciduas in spontaneous early pregnancy loss. Hum Reprod, 1999; 14: 2252-2256

2. N. Vassiliadou, R.F. Searle, J.N. Bulmer: elevated expression of activation molecules by decidual lymphocytes in women suffering spontaneous early pregnancy loss. Hum Reprod, 1999; 14:1194-1200

3. D. Clark, J. Ding et al: The emerging role of immunoregulation of fibrinogen-related procoagulant Fgl2 in the success or spontaneous abortion of early pregnancy in mice and humans. Am J Reprod Immunol, 1999; 42:37-43

4. L. Guariglia, P. Rosati: Prevelance and significance of isolated fetal choroid plexus cysts detected in early pregnancy by transvaginal sonography in women of advanced maternal age. Prenat Diagn, 1999; 19:128-131

5. G.J Hisman, B. Fauser, et al: Implantation rates after in vitro fertilization and transfer of a maximum of two embryos that have undergone three to five days of culture. Fertil Steril, 2000; 73:117-122

6. H. Chen, J. Shew, et al: Expression of leukemia inhibitory factor and its receptor in preimplantation embryos, Fertil Steril, 1999; 72:713-719

7. E. Chen, M. Fujinga, A. Giaccia: Hopoxic microenvironment within an embryo induces apoptosis and is essential for proper morphological development. Teratol 1999; 60:215-225

8. B.J. Whitlow, I.K. Chatzipapas, et al: The value of sonography in early pregnancy for the detection of fetal abnormalities in an unselected population. Br J Obstet Gynecol, 1999; 106:929-936