 |
CHAPTER 4. Prenatal diagnosis of congenital malformations and hereditary diseases of the fetus
|
|
|
|
CHAPTER 4. Prenatal diagnosis of congenital malformations and hereditary diseases of the fetus
Congenital malformations (CM) and hereditary diseases are the most frequent causes of perinatal mortality, infant death rate and various forms of child disability. In accordance with the data of the WHO 2. 5-3% of all newborns have different anomalies at birth. However, about 1% of them are genetic diseases, 0. 5 % - chromosomal disturbances, and 1. 5-2% - are congenital malformations, caused by the effects of adverse exogenous and endogenous factors. High perinatal and early neonatal mortalities, as well as infant death rate because of fetus’ congenital malformations and hereditary diseases aroused the interest of many researchers to this issue. However, despite significant progress in solving this problem, the frequency of congenital malformations and hereditary diseases has no tendency to decrease, and is constantly increasing
In these conditions, prenatal detection of malformations and hereditary diseases is of particular importance to reduce perinatal mortality and morbidity of newborns, to prevent the birth of children with serious, often fatal malformations, genetic and chromosomal diseases, which reduces the genetic load of a population.
SCREENING RESEARCHES
Screening researches are researches, conducted in certain groups of the population regardless of the presence or absence of
complaints and clinical characteristics of the studied pathology. In English the verb “to screen” means to sift, to sort. The essence of the term encompasses the basic meaning of the method. Under rules established by WHO, we can't talk about screening, if it is attended lees then 85% of the studied population. A screening study is not aimed at diagnosing a disease, it is aimed the " sorting" of patients, the selection of " group at risk ", threatened by the development of the studied pathology.
The most popular types of screening in prenatal diagnosis (PD) are ultrasound and biochemical methods.
BIOCHEMICAL SCREENING
From the earliest stages of pregnancy, the fetoplacental unit begins to develop pregnancy-specific substances, mostly proteins, which in different ways enter the mother's blood, and then partially removed from her body. In a normal pregnancy the levels of these substances in the mother's serum and urine vary depending on pregnancy term, condition of fetoplacental unit, the presence of somatic pathology of the mother, etc. In the occurrence of fetal malformations, chromosomal aberrations and other abnormalities (for example IUFGR), the level of these specific proteins vary considerably, which allows the use of these substances as markers of various pathological conditions of the fetus.
Alpha fetoprotein (AFP) is a protein specific to the fetus. Its production begins in syncytiotrophoblast and yolk sac, and with 11-12 weeks of gestation, the fetal liver becomes a source of AFP secretion. AFP enters the amniotic fluid due to renal function of the fetus, in the mother's blood AFP enters mainly by diffusion taking place in the placental part of the fetoplacental unit, and only
|
|
|
6% of AFP gets into the mother's blood via the transmembrane transport of amniotic fluid. Two ways of permeation of the AFP in the mother's blood do not allow to determine the specific cause of increase of its level in the mother.
The function of AFP is not fully understood, but the main ones are:
· the maintenance of oncotic pressure of a fetus blood;
· protection of the fetus from maternal immune system;
· the binding of maternal estrogens;
· participation in the organogenesis of liver.
The content of AFP in the fetal serum, amniotic fluid and maternal serum depends on the term of gestation. The maximum concentration of AFP in fetal serum occurs between 1 and 13 weeks of pregnancy. Then, the level of AFP in fetal blood is gradually reduced until birth. The concentration of AFP in the amniotic fluid is strictly correlated with its concentration in fetal blood.
Change the content of AFP in maternal blood has dynamics that differ from that of f fetal blood and amniotic fluid. The concentration of AFP in maternal serum increases with the end of the first trimester and reaches a maximum at 32-33 weeks of pregnancy, and reduced to the term of labor.
The optimal time for studies of maternal serum is considered gestation at 15th to a 20th week. Up to 15 weeks, the concentration of AFP is insufficiently reliable as an indicator of neural tube defects, but from 20 weeks the level of AFP describes the functional maturity of the fetus.
Traditionally, levels of AFP are measured in international units (IU) per unit blood volume. Studies have shown that in normal pregnancy in the II trimester the concentration of AFP in the mother's blood changes with increasing gestation. From 15 to 20 weeks of pregnancy, AFP levels increase linearly to 15% weekly on average from 25 to 52 IU/ml.
Currently, the international standard is the definition of AFP levels and other biochemical markers in multiple of the median ( MoM ). A multiple of the median is a measure of how far an individual test result deviates from the median. MoM is commonly used to report the results of medical screening tests, particularly where the results of the individual tests are highly variable. MoM is a the quotient of the blood of the specific patient at the average level of AFP for a given gestational age (norms for that lab). This makes it easy to compare results obtained in different laboratories. Normal values in diagnostic term of pregnancy are the levels of AFP from 0. 5 to 2 MoM.
A significant increase (5-10 fold) of AFP level in the blood serum of pregnant in the II trimester indicate the presence of neural tube defects in the fetus (anencephaly, meningocele, encephalocele. A high level of AFP is detected in the presence of such fetal malformations as gastroschisis, omphalocele, kidney’s abnormality, as well as in twins pregnancy, threatened miscarriage. When conducting AFP-screening the specificity of the method for anencephaly was 100%, for open forms of spinal hernias - 86%, for gastroschisis - 100%, for omphalocele - 50%.
Reduced or low levels of AFP are observed in the pathology of the trophoblast, missed abortion, in the presence of fetal chromosomal abnormalities, HIV infection in pregnant. The level of AFP from 15 th to 18 th week of pregnancy is reduced in 25-30% of cases of chromosomal abnormalities (Down's syndrome).
|
|
|
Human chorionic gonadotropin (HCG) - is a glycoprotein which is produced by syncytiotrophoblast and gets into the maternal bloodstream soon after implantation of the ovum in the uterine wall. HCG composed of 2 subunits: with an α (alpha) subunit, identical to that of luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), and β (beta) subunit that is unique to hCG. Several fractions of HCG: the biologically active form of HGC, an inactive form, free and bound α - and β - fractions of HCG can be detected in maternal and fetal blood serum.
The content of HCG reaches a maximum at 8-10 weeks of pregnancy and is about 60-500 IU/ml this pregnancy. It drops sharply after 10 weeks due to differentiation of the trophoblast and development of the placenta, and remains at the same level prior to delivery with a small lift on 33-35 week. HCG disappears in the mother's blood for 10-14 days after birth.
The most important function of HCG is to stimulate the synthesis of steroid hormones, first in the yellow body, and then in the placenta. It is assumed that HCG affects the expression of enzymes involved in steroidogenesis, or activates the synthesis of non-enzymatic protein fractions According to some authors, HCG plays a protective role in preventing of detachment of embryo from the uterine wall. HCG is one of the most sensitive marker in screening for Down’ syndrome, therefore, different fractions of HCG included in most screening programs, currently used.
Increased HCG level in the maternal blood serum indicates the possibility of development of chromosomal abnormalities in the fetus in 61% of cases, the number of false-positive results - 8. 3%. HCG level is increased in trisomy 21(Down syndrome), and reduced in trisomy 18 (Edwards syndrome).
Unconjugated estriol (uE3) - placental steroid hormone. uE3 produced by the follicular cells of the ovary, and partly by the granulosa cells lining the cavity of the follicle. In a normal pregnancy the contents Unconjugated estriolin maternal blood depends on the gestational age and linearly increases from an average of 0. 6 to 2. 0 ng/mL or 20 -25% weekly from 15 to 22 weeks of pregnancy. Its concentration decreases rapidly 1-2 weeks before birth. A significant influence on the content of uE3 in the blood has smoking. Maternal age and body mass do not affect the level of unconjugated estriol in the blood. 90% of uE3 in maternal blood is of fetal origin. A direct correlation between the decrease in the level of ue3 to 0. 5 MoM and the development of hypertension, miscarriage, growth retardation and fetal death discovered in retrospective studies. IUFGR can be suspected in case of low level uE3e already in the 2nd trimester. Estrogen deficiency at an anencephalic fetus, appears to be associated with the lack of stimulation of the adrenal gland hormones of the pituitary gland of the fetus. A sharp decrease in the content of uE3 (to 0. 01 MoM) due to the lack of placental sulfatase identified in X-linked ichthyosis. Very low ue3 values are defined in case of violation of the synthesis of sex hormones (for example, in Smith – Lemley – Opitz syndrome). In a fetus with Down syndrome, the average value of uE3 is 0. 79 MoM and correlated with AFP levels. The degree of detection of fetal chromosomal abnormalities when using only one marker (AFP) is from 20 to 42%/ю The sensitivity of double test (using AFP and HCG), taking into account maternal age, varies in the range of 56-70% with a 5% false positive results. When using AFP, HCG and uE3 (triple test) screening efficiency reaches 60-70% and even 80% (developmental defects), 5% for chromosomal abnormalities, with 5% false positive results. The combined use of 4 markers improves detection of congenital malformations of the fetus up to 70-88%. Replacement of uE3 to inhibin A while conducting the triple test can detect 97% of cases of Down syndrome.
|
|
|
