**9. ELI-P-complex method**

Immune abnormalities reflecting changes in blood serum content of autoantibodies may be found in 85-95% of women suffering from habitual miscarriages or other complications of pregnancy. Long-lasting immune deviations do not necessarily lead to unsatisfactory pregnancy outcomes, but obligatory accompanied by sharp raise of probability of miscarriages, fetal deaths, or developmental malformations [Poletaev, 2008]. Another important issue is the influence of maternal immune deviations upon the health state of her future child. Abnormal maternal changes in serum autoantibodies content during pregnancy if not lead to fetal loss, practically always influence on the newborn health state by means of direct transplacental transfer and by means of maternal immune imprinting [Poletaev, 2008]. Accordingly, evaluation of embryotropic autoantibodies before planned pregnancy (especially in women with obstetrical complications in anamnesis) may became an important preventive measure aimed to decrease of unsatisfactory results of pregnancy. imprinting related

ground for possible induction of the inborn resistance to infectious diseases in a child after an active immunization of the mother before her pregnancy. If such approaches will be introduced in medical practice, it should help to reject certain vaccinations or at least

Unfortunately, the Nature is lack of perfectness, and there is another (negative) side of the coin. If mother has been suffered from any kind of immune deviations, the undesirable effects can be produced upon her child directly, as well as indirectly by mechanism of maternal immune imprinting. For example systemic lupus erythematosus in the mother may lead to the development of newborn's lupus in babies at 4-8 months of the postnatal life [Poletaev, 2008]. Woman with abnormally elevated production of autoantibodies against insulin and/or insulin receptors can "imprint" these features in the immune state of her child. As a result, an abnormally elevated production of the same Autoantibodies may be revealed in a 4-6 years old child, and may become a risk factor for the early development of the diabetes mellitus [Budykina, 1998]. The elevated production of anti-thyroid autoantibodies may be revealed for years in children, whose mothers had thyroid problems, and may become the risk factor for the thyroid gland diseases in child [Poletaev, 2008]. Elevated rates of the same forms of pathology in children (endocrine, cordial, nephrological, etc.) which was presented in mothers during pregnancy course [Khlystova, 1987] may be

The main mechanisms of the maternal immune imprinting remain obscure although, we can propose that the fact of antigenic specificity of the phenomenon implies the participation of specialized autoantibodies (probably anti-idiotypic autoantibodies) and/or AG-specific lymphocytes. Transferred trans-placentally maternal anti-idiotypic autoantibodies and/or memory lymphocytes can be the basic elements, which provide a specific activation and tuning of certain clones of the fetal T- and B-lymphocytes, and become main triggers of the inborn pre-formation of the Immunculus of the fetus-newborn-child (similar to maternal ones). Future investigations of the maternal immune imprinting may provide the new approaches in prediction and treatment of a large group of inborn abnormalities. Besides, the comprehension of the phenomenon may serve as an impetus for the promotion of the

Immune abnormalities reflecting changes in blood serum content of autoantibodies may be found in 85-95% of women suffering from habitual miscarriages or other complications of pregnancy. Long-lasting immune deviations do not necessarily lead to unsatisfactory pregnancy outcomes, but obligatory accompanied by sharp raise of probability of miscarriages, fetal deaths, or developmental malformations [Poletaev, 2008]. Another important issue is the influence of maternal immune deviations upon the health state of her future child. Abnormal maternal changes in serum autoantibodies content during pregnancy if not lead to fetal loss, practically always influence on the newborn health state by means of direct transplacental transfer and by means of maternal immune imprinting [Poletaev, 2008]. Accordingly, evaluation of embryotropic autoantibodies before planned pregnancy (especially in women with obstetrical complications in anamnesis) may became an important preventive measure aimed to decrease of unsatisfactory results of pregnancy.

decrease their number and frequency for the babies [Poletaev, 2010].

directly related to the phenomenon of maternal immune imprinting.

fundamental research in the fields of maternal-fetal interactions.

**9. ELI-P-complex method** 

Especially if predictive diagnosis was combined with treatment, run over under control of immune parameters. It should be noted - in opposite to genetic aberrations, the immune deviations may be effectively treated in the most cases.

Soon after Chernobyl disaster the specialized immunochemical methods for mass-scale investigation of the general health state as well as reproductive health state inhabitants of polluted areas were worked out in the former Soviet Union. These methods were generally named as ELI-Tests (from: **E**nzyme-**L**inked-**I**mmune-**Tests)**. One of these methods, just method ELI-P-Complex (abbreviation "**P**" – from Pathology in Pregnancy) was intended for preventive investigations of a fertile age women. Since 1994 the method ELI-P-Complex has been used successfully for prognosis of the development of planned pregnancy in general obstetrician practice in Russia. Method is intended for analysis of individual "profiles" (patterns) of twelve autoantibodies of IgG class in the sample of blood serum. It is based upon evaluation of partial changes in the contents of autoantibodies against choriogonadotropin, ds-DNA, β2-Glycoprotein I, collagen II type, Fc-fragment of IgG, insulin, thyroglobulin, S100, Spr-06, ANCA, TrM-03, and KiM-05 [Poletaev, 2010]. In spite of diagnostic and prognostic effectiveness of the method proved in thousands investigations, the detailed mechanisms mediating influence of immune deviations measured by ELI-P-Complex upon the gestation process should be elucidated. Nevertheless, there is basis for some propositions. For example, any long-lasting active infection process (viral or bacterial) may be etiologically related to antiphospholipid syndrome induction and accompanied, in particular, by abnormally elevated serum levels of autoantibodies against β2-Glycoprotein I and DNA [Poletaev, 2008]. The mentioned autoantibodies could be pathogenically related to changes in blood coagulation [Sherer & Shoenfeld, 2004] which, in turn, may cause vascular problems in placenta and affect the gestation process. Relative surplus of anti-collagen II autoantibodies may indicate inborn or acquired defects of the connective tissue and active adhesion process. Changes in serum autoantibodies against S100 are typical for some women with still-births and fetal/newborns neural malformations in anamnesis, and are related in most cases with active replicated papilloma viruses. A surplus of autoantibodies against choriogonadotropin may be the reason for deficiency in this hormone, which is important for placenta development and maturation, as well as for cases of premature ovarian failure [Tuohy & Altuntas, 2007]. Excess of autoantibodies against Fc-fragments of IgG (Rheumatoid factor) is indicator of inflammatory processes of any localization. Elevated peak of autoantibodies against Spr-0.6 may be indication of declining fertility and in most cases is sensitive marker sign of endometritis and/or inflammatory processes in other pelvic organs. Abnormal rise of autoantibodies against insulin, thyroglobulin, ANCA, TrM-03, and KiM-05 in detected profiles may be markers of diabetic fetopathy, thyroidal abnormalities, vasculopathy and kidney-related disorders in pregnant women [Poletaev, 2010]. An early detection (especially before planned pregnancy) of relative deviations in serum content some of measured autoantibodies is especially important for revealing of individuals with elevated risk of abnormalities expected at pregnancy and implementation of necessary prophylactic measures. help of

#### **10. Clinical illustrations**

The main field for using of ELI-P-Complex method is screening of women planning their pregnancy, IVF including. Immune deviations revealed by this method are related to or reflect some individual health problems, and characteristic changes of autoantibodies profiles, that

Maternal Immunity, Pregnancy and Child's Health 53

Excess of autoantibodies against this AG usually is indication of endocrine dysfunction and may be the cause of the functional insufficiency of

choriogonadotropin. The last may lead to infertility, placental malformation, and placental insufficiency. Most cases of prolonged (months and years) abnormally elevated production of such autoantibodies is related to recent treatment by Pregnyl or Choragon during preparation for IVF. Besides excess of autoantibodies against this AG can be a marker sign of premature ovarian insufficiency. Rarely it may be

induced mainly). Rarely it may be indication for systemic autoimmune disease or malignancy. Excess of such autoantibodies may reveal embryotoxic effects.

syndrome which may be the cause of a small vessels thrombosis in placenta and other organs and leads to placental insufficiency. Rarely it may be indication for systemic autoimmune disease or malignancy. Excess of such autoantibodies may reveal

Besides excess of autoantibodies against this AG may be sign of pathological changes in a connective tissue. Excess of such autoantibodies may reveal embryotoxic effect.

inflammatory processes of any localization as well as of elevated production of proinflammatory cytokines. Excess of such autoantibodies may reveal embryotoxic

fetopathy. Besides elevated autoantibodies against insulin can be sign of the endothelial disfunction and vasculopathy, and may indicate initiated or forming

forming disturbances in the thyroid gland. Excess of such autoantibodies may reveal

human papilloma virus infection (by mechanism of molecular mimicry). Excess of

morphogenesis and cellular differentiation in embryo, and be cause for stillbirth at the beginning, in the middle, or at the end of pregnancy. Besides it may be reason of malformation of the nervous system because S100 is involved in differentiation and

cases) and/or inflammatory processes in other pelvic organs (rarely). Excess of autoantibodies against Spr-06 may be cause of declining fertility in women and men.

vessel vasculitis and vasculopathy. The last may be reason for deterioration of placental blood flow, as well as other organ malfunction related to the problems with

the following deviations: 1) Elevated lysis of platelets which leads to pathological bleeding; 2) excessive aggregation of platelets (without their lysis) and trombotic

autoantibodies against S100 proteins may lead to deviations of general

**Antigen Possible clinical consequences of abnormal changes in relative serum content of** 

indication for malignancy (tumor of pituary gland mostly). **DNA** Rise of autoantibodies against this AG may indicate for activation of apoptosis (virus-

**Collagen II** Excess of such autoantibodies usually is indication for adhesions and scars formation.

**Β2-Glycoprotein I** Excess of autoantibodies against this AG is marker sign of anti-phospholipid

**Fc-fragment of IgG** Excess of autoantibodies against this AG (Rheumatoid factor) is indicator of

**Insulin** Excess of autoantibodies against this AG may be pathogenic factor for diabetic

gestational diabetes or insulin-dependent diabetes type I **Thyroglobulin** Excess of autoantibodies against this AG may be marker sign of the existing or

**S100** The most often reason for long-term elevated production of such autoantibodies is

migration of neuroblasts of primordial nervous system. **Spr-06** Excess of such autoantibodies usually is marker sign of endometritis (in the most

**ANCA** Excess of ANCA-specific autoantibodies is typical sign of different forms of small

**TrM-03** Excess of autoantibodies against TrM-03 is sign of trombocytopathy and may lead to

*KiM-05* Excess of autoantibodies against KiM-05 should be considered as marker sign of

active inflammatory process in the renal tissue Table 1. List of antigens used for detection and analysis of changes in relative serum

contents of according autoantibodies by ELI-P-Complex method.

**according natural autoantibodies** 

embryotoxic effects.

embryotoxic effects.

blood circulation.

events

effects.

**Chorionic Gonadotropin** 

should be considered as prompting message for obstetrician about peculiar changes in woman' organism, which may be additionally investigated and effectively treated before pregnancy.

#### **10.1 Some examples**

In accordance to observations by Zhegulina [2002] 94% of women suffering from thyroid pathology were characterized by changes in serum content of embryotropic autoantibodies. Adequate preventive treatment under control of ELI-P-Complex method leads to 2,5-fold decreasing of unsatisfactory result frequency of the following pregnancy compared to pregnancy of women without immune control.

In accordance to observations by Nukhnin [2007] normal serum content of embryotropic autoantibodies has been found only in 7,4% of pregnant women with obstetrician complications in anamnesis, and deviations were typical in 93,6% of such women. Abnormal decreasing of numerous embryotropic autoantibodies was directly associated with miscarriages, placental insufficiency, and preeclampsia. Abnormal serum rise of them was typical for miscarriages, stillbirth, preeclampsia, and inborn anomalies.

In accordance to observations by Cherepanova [2008] there are direct relations between changes in serum content of some of embryotropic autoantibodies in early pregnancy and cases of pre-term abruption of placenta, preeclampsia at late pregnancy, and abnormal uterine bleedings at delivery. Special algorithm for evaluation of risk level of the noted complications was proposed. Abnormal decreasing of some of embryotropic autoantibodies as well as abnormal elevation was associated with deviations in the blood coagulation.

In accordance to observations by Makarov [2009] decreasing in serum content of some of embryotropic autoantibodies in early pregnancy gives possibility to screen women of the high risk for the future preeclampsia developing. Some changes in embryotropic autoantibodies serum levels provide possibility to differentiate between group of women with preeclampsia and chronic hypertension.

In accordance to Serova [2000] very different factors (infection agents, endocrine disfunction, environmental pollutions, drugs, chronic stresses, etc.) can be ground for steady changes in production and blood serum content of embryotropic autoantibodies. Characteristic of individual serum profiles of embryotropic autoantibodies may indicate to the main cause of revealing changes, and effective individualized correction (etiologic treatment) of women under control of embryotropic autoantibodies provides 5 to 8-fold rise of satisfactory result of pregnancy following.

In accordance to observations by Kluchnikov et al., [2001]., if children were born by women with the normal parameters of ELI-P-Complex method, at least 70% of them was evaluated as practically healthy persons at ages 4-6 years old. In opposite, no more then 15% children were evaluated as practically healthy if were born from women with steady deviated parameters of serum' autoantibodies.

Described examples represent only a small part of the general massive data obtained during the last twenty years and indicate clear necessity of wide using of preliminary evaluation of different embryotropic autoantibodies in women serum before planned pregnancy, especially in women belonging to a group of obstetrician risk.

should be considered as prompting message for obstetrician about peculiar changes in woman' organism, which may be additionally investigated and effectively treated before pregnancy.

In accordance to observations by Zhegulina [2002] 94% of women suffering from thyroid pathology were characterized by changes in serum content of embryotropic autoantibodies. Adequate preventive treatment under control of ELI-P-Complex method leads to 2,5-fold decreasing of unsatisfactory result frequency of the following pregnancy compared to

In accordance to observations by Nukhnin [2007] normal serum content of embryotropic autoantibodies has been found only in 7,4% of pregnant women with obstetrician complications in anamnesis, and deviations were typical in 93,6% of such women. Abnormal decreasing of numerous embryotropic autoantibodies was directly associated with miscarriages, placental insufficiency, and preeclampsia. Abnormal serum rise of them

In accordance to observations by Cherepanova [2008] there are direct relations between changes in serum content of some of embryotropic autoantibodies in early pregnancy and cases of pre-term abruption of placenta, preeclampsia at late pregnancy, and abnormal uterine bleedings at delivery. Special algorithm for evaluation of risk level of the noted complications was proposed. Abnormal decreasing of some of embryotropic autoantibodies as well as abnormal elevation was associated with deviations in the blood coagulation.

In accordance to observations by Makarov [2009] decreasing in serum content of some of embryotropic autoantibodies in early pregnancy gives possibility to screen women of the high risk for the future preeclampsia developing. Some changes in embryotropic autoantibodies serum levels provide possibility to differentiate between group of women

In accordance to Serova [2000] very different factors (infection agents, endocrine disfunction, environmental pollutions, drugs, chronic stresses, etc.) can be ground for steady changes in production and blood serum content of embryotropic autoantibodies. Characteristic of individual serum profiles of embryotropic autoantibodies may indicate to the main cause of revealing changes, and effective individualized correction (etiologic treatment) of women under control of embryotropic autoantibodies provides 5 to 8-fold rise

In accordance to observations by Kluchnikov et al., [2001]., if children were born by women with the normal parameters of ELI-P-Complex method, at least 70% of them was evaluated as practically healthy persons at ages 4-6 years old. In opposite, no more then 15% children were evaluated as practically healthy if were born from women with steady deviated

Described examples represent only a small part of the general massive data obtained during the last twenty years and indicate clear necessity of wide using of preliminary evaluation of different embryotropic autoantibodies in women serum before planned pregnancy,

was typical for miscarriages, stillbirth, preeclampsia, and inborn anomalies.

**10.1 Some examples** 

pregnancy of women without immune control.

with preeclampsia and chronic hypertension.

of satisfactory result of pregnancy following.

especially in women belonging to a group of obstetrician risk.

parameters of serum' autoantibodies.


Table 1. List of antigens used for detection and analysis of changes in relative serum contents of according autoantibodies by ELI-P-Complex method.

Maternal Immunity, Pregnancy and Child's Health 55

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**4** 

*Iran* 

**Female Fertility** 

Leila Roshangar and Jafar Soleimani Rad *Tabriz University of Medical Sciences, Tabriz,* 

**Environmental Electromagnetic Field and** 

Human beings are unavoidably exposed to ambient electromagnetic fields (EMFs) generated by every instrument that uses electricity. Electromagnetic fields are made by the combination of an electric field and a magnetic field and is propagated in a wave like manner. Thus sometimes called electromagnetic waves and or electromagnetic radiation. Under such condition the indoor and outdoor environment we live are bombarded by electromagnetic waves/radiations produced by home appliances; such as computer, television , mobile phone, industrial instruments; such as power transmission lines railway stations, medical and diagnostic tools; such as MRI, physiotherapy equipments and so on. The EMF which we are encountered everywhere, have a non ionizing nature and has two distinct parts; electrical and magnetic. The electrical part is generated by a voltage gradient and measured in volts. The magnetic part is produced by current flow and is measured in tesla. Therefore in any field, we are exposed to an electrical voltage gradient and a magnetic field. The electrical field is due to the difference between the voltage of the electricity used by the device and earth. The magnetic field is proportional to the current flowing through the device. Both types of field would induce biological effects, but magnetic field is more damaging because it penetrates living tissue more easily. Magnetic fields as low as around one microtesla can produce biological effects ( Goldsworthy 2007; Sage et al. 2007; Jokela et al. 2004 ). The effect of EMF on human health vary widely depending on the frequency and intensity of the fields. Extremely low frequencies (ELF) such as those from home appliances are more potent than higher frequencies of radio waves (Genuis 2007; Zymslony 2007; Torregrossa 2005). According to WHO, EMFs of all frequencies represent one of the most common and fastest growing environmental influences, about which anxiety and speculation are spreading. All populations are now exposed to varying degree of EMF, and the levels will continue to increase as technology advances. It is obvious that in almost all societies the ambient EMFs are encountered everywhere and cause unavoidable exposure. There are body of information regarding adverse effects of EMF, especially chronic exposure to EMF (Wu 2008; Marek 2004; Adey 1993). Thus the concern about the public health

Based on the functional and or structural disorders it is shown that in a biological system, EMF may harm any organ. Epidemiological studies suggest a possible link between EMF exposures and clinically recognized medical disorders such as leukemia, brain cancer,

**1. Introduction** 

hazards of EMFs has highly increased.

