> Prenatal screening for trisomy in the first and second trimesters of pregnancy

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What is prenatal screening and why is it needed?

Prenatal screening is a series of medical procedures aimed at identifying congenital chromosomal abnormalities of fetal development. It is based on the determination of some biochemical markers in the blood of a pregnant woman, analysis of the results obtained taking into account the data ultrasound examination fetus In particular, with the help of screening, it is possible to identify a pathology such as trisomy - the presence of an additional chromosome.

For pregnant women, prenatal screening for trisomy is carried out in the first trimester, the so-called “double test”, and in the second trimester – the “triple test”.

Who prescribes prenatal screening, where are the tests taken?

A referral for these tests is issued by an obstetrician-gynecologist or medical geneticist. Blood, which acts as a biological material, is donated in a biochemical laboratory or in a treatment room antenatal clinic. An ultrasound scan of the fetus is performed by an ultrasound specialist.

Indications for prenatal screening for trisomy

The “double test” is carried out during pregnancy from weeks 10 to 13. It is used to determine the risk of developing Down syndrome (trisomy 21), Edwards syndrome (trisomy 18) and NTD (neural tube defect). NTD is a severe developmental disorder nervous system, as a result of which a spinal hernia is formed. The “triple test” is carried out during pregnancy from 14 weeks to 22 weeks.

Tests are not prescribed to all women in a row, but under the following conditions: the woman is over 35 years old, has a history of severe pregnancy complications or miscarriage. Congenital anomalies in children from previous pregnancies, the presence of a similar pathology in close relatives, infection, and use of mutagenic drugs are grounds for screening for trisomy.

How to screen for trisomy, preparation for analysis

To calculate the risk of trisomy, pregnant women donate blood to determine the concentration of certain hormones in it. Screening in the first trimester involves determining the concentrations of human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein A. In the second trimester, hCG, alpha-fetoprotein (AFP) and free estriol are determined.

In addition to studying biochemical markers, an ultrasound examination of the fetus is performed, during which the thickness of the nuchal zone, coccygeal-parietal size of the fetus, and biparietal size are assessed.

Normal screening results

The results obtained are entered into a special computer program – PRISCA. In addition to the values ​​of biochemical parameters and ultrasound data, it takes into account the presence bad habits, exact gestational age, presence of multiple pregnancies.

The program issues a conclusion in the form of a form that displays all of the above indicators and a conclusion about the likelihood of having a child with a pathology. For example, a result of 1:500 suggests that one woman out of 500 with similar indicators can give birth to a child with trisomy.

Clinical significance of the study

Patients should be aware that screening for trisomy only calculates the likelihood of having a child with the disorder, and does not indicate that the child will certainly have the disorder. Therefore, if the risk is very high, the patient should undergo additional research - amniocentesis followed by a study of the genetic material of the fetus. Only the results of this study are the basis for the doctor to make a decision to terminate the pregnancy.

Prenatal screening for trisomy in the second trimester of pregnancy is also called a triple test - this is a study that allows you to determine the likely risk of developing chromosomal diseases such as Down's syndrome, Edwards' syndrome, Patau's syndrome, neural tube defect, as well as other fetal anomalies.

What are the dangers of genetic abnormalities for the fetus?

Down syndrome is the most common genetic abnormality. Children with this diagnosis experience serious physical and mental abnormalities, and half of the newborns are diagnosed with heart disease. Immediately or over time, problems with vision, the thyroid gland, and hearing may appear. Statistics say that every 700-800th child is born with this pathology. This fact does not depend on the lifestyle of the parents, their state of health or the environment. Scientists have determined that the reason lies in trisomy of the 21st chromosome (the presence of three homologous chromosomes instead of a pair).

Edwards syndrome is also a chromosomal abnormality; in the full form of this disease, mental retardation develops to a complicated degree; in the mosaic form, it may not manifest itself so clearly. In this case, the syndrome in the woman in labor is traced to trisomy on the 18th chromosome.

Patau syndrome is also characterized by physical defects and abnormalities in mental development. The disease is caused by trisomy on chromosome 13.

One of the most common reasons morbidity and mortality of newborns - neural tube defects (NTD), including anencephaly and spina bifida. The first defect is a gross malformation of the brain, the second is a malformation of the spine, often combined with defects in the development of the spinal cord.

How is the triple test performed?

To identify an anomaly on early stage, screening is carried out between 14 and 22 weeks of pregnancy. Blood is taken from the mother in labor as a biomaterial. The day before, the patient is contraindicated from eating fatty foods; half an hour before the examination, it is necessary to exclude physical and emotional stress, as well as smoking.

The test checks the levels of human chorionic gonadotropin (hCG), alpha-fetoprotein and free estriol. Based on these indicators, one can judge the successful course of pregnancy or identify fetal development disorders.

During the research, age, weight, number of fetuses, race, bad habits, presence of diabetes mellitus and medications taken. At the end of the test, the pregnant woman is scheduled for a consultation with an obstetrician-gynecologist.

Important! Screening results do not make a diagnosis, nor are they a reason for artificial interruption pregnancy. The test makes it possible to determine the need for invasive methods of fetal examination. If the risks of anomaly are high, then a mandatory additional study is prescribed.

Where to get prenatal screening for second trimester trisomy

You can conduct the study quickly and comfortably at any convenient branch of the Medical Commission No. 1 network. The centers are located in 7 districts of the city, equipped with their own modern laboratories and have all the necessary equipment. We employ certified specialists with great experience work. The test results will be ready as soon as possible.

General information about the study

Prenatal screening for second trimester trisomy is performed to assess the likelihood of the most common fetal anomalies - trisomy 21 (Down syndrome), trisomy 18 (Edwards syndrome) and neural tube defect between 14 and 22 weeks of pregnancy. Risk factors for the development of such anomalies include childbirth after the age of 35 years, multiple pregnancies, a history of fetuses with chromosomal abnormalities (trisomy 21, 13 or 18), concomitant HIV infection, pregnancy resulting from IVF, smoking and diabetes mellitus . In this case, the age of the mother is the most significant factor. Thus, the risk of developing chromosomal abnormalities in the fetus increases sharply after 35 years (1:179 compared to 1:476 in a woman 25 years old).

Determination of AFP together with human chorionic gonadotropin and estriol (the so-called triple test) at 15-20 weeks of pregnancy is used to screen for fetal development defects and chromosomal abnormalities. This screening analysis allows you to assess the likelihood of the presence of genetic diseases and developmental defects, but its result is not an absolute indicator of pathology or normal development fetus

Human chorionic gonadotropin (hCG) is produced in the membranes of the human embryo. It is an important indicator of the development of pregnancy and its deviations. The hCG level reaches its maximum in the 10-11th week, and then gradually decreases. Using this indicator, one can judge the successful course of pregnancy and identify fetal development disorders.

Alpha-fetoprotein is produced in the embryonic yolk sac, liver and intestinal epithelium of the fetus, its level depends on the state of the gastrointestinal tract, fetal kidneys and placental barrier. He takes an active part in the full development of the fetus. In the mother's blood, its concentration gradually increases from the 10th week of pregnancy and reaches a maximum at 30-32 weeks. In this regard, AFP is used as a nonspecific marker of fetal condition and the presence of obstetric pathology.

Free estriol is the main estrogen of pregnancy and has great importance for the normal development and functioning of the fetoplacental complex. Its concentration increases from the moment the placenta is formed and increases progressively as pregnancy progresses. Low concentrations of free estriol in combination with high levels of beta-hCG and alpha-FP are associated with an increased risk of intrauterine growth restriction and complications of the third trimester of pregnancy (premature placental abruption and preeclampsia).

It is very important to know the exact gestational age of the fetus, since the levels of AFP, hCG and free estriol in the blood differ at different weeks of pregnancy.

In this screening study, the risk of pathologies is calculated using the PRISCA (Prenatal Risk Calculation) computer program developed by Typolog Software (Germany) and having an international certificate of conformity. For the study, the content of human chorionic gonadotropin (hCG), alpha-fetoprotein (AFP) and unconjugated (free) estriol in the blood of a pregnant woman is determined.

Clinical data must be taken into account (pregnant woman’s age, body weight, number of fetuses, presence and characteristics of IVF, race, bad habits, presence of diabetes, medications taken). If an ultrasound is performed, the gestational age is determined by its results, and not by the date of the last menstruation.

After research and calculation of the risk of pathologies, the pregnant woman is scheduled for a consultation with an obstetrician-gynecologist.

Screening results cannot serve as criteria for diagnosis or as a reason for artificial termination of pregnancy. Based on them, a decision is made on whether it is advisable to use invasive methods of examining the fetus. If the risk is high, additional examinations are necessary, including cordocentesis, amniocentesis with genetic testing of the obtained material.

What is the research used for?

• For screening examination of pregnant women to assess the risk of chromosomal pathology of the fetus - Down syndrome (trisomy 21), Edwards syndrome (trisomy 18), neural tube defect.

When is the study scheduled?

• When examining pregnant women in the second trimester (analysis is recommended for a period of 14 weeks 3 days - 22 weeks), especially in the presence of risk factors for the development of pathology:

• • age over 35 years;
  • history of miscarriage and severe pregnancy complications;
  • chromosomal pathologies, Down's disease or congenital malformations in previous pregnancies;
  • hereditary diseases in the family;
  • past infections, radiation exposure, admission to early stages pregnancy or shortly before it medicines which have a teratogenic effect (can cause congenital defects and fetal anomalies).

Prenatal or antenatal screening is a special examination of pregnant women, during which the risk of having children with severe congenital chromosomal pathology is determined.

A “triple biochemical test” in the second trimester of pregnancy is aimed at diagnosing trisomies - chromosomal pathologies in which an additional chromosome appears in the karyotype.

This test is carried out to identify women who have a very high risk of giving birth to a child with a chromosomal abnormality such as trisomy (Down or Edwards syndrome). These women are recommended to undergo further examination to confirm or completely exclude these diseases in the fetus.

Indications for trisomy screening in the 2nd trimester

Screening for trisomy is recommended for absolutely all pregnant women. However, some categories of women must undergo this examination without fail.

The indications are as follows:

• the age of the pregnant woman is over 35 years;
• presence in the family of children with the mentioned syndromes;
• a family history of any other hereditary diseases;
• suspicion that one of the parents was exposed to one of the mutagenic factors before conception: radiation exposure or chemical poisoning.

2nd trimester screening should be carried out at 15-20 weeks, the optimal time to donate blood for screening is 16-18 weeks.

Preparing for the study

Before donating blood, you should eliminate fatty foods from your diet 24 hours before donating blood. You should refrain from smoking for 30 minutes and also not worry.

How the research is carried out

The material for the study is the blood of a pregnant woman. Using chemiluminescence immunoassay, the level of the following substances in the blood is determined:

• human chorionic gonadotropin (better known by the abbreviation hCG);
• free estriol;
• alpha-fetoprotein.

The woman being examined, in addition to donating blood, must fill out a questionnaire that reflects other parameters used to calculate risk: age, race, presence of chronic diseases and bad habits.

Interpretation of results

The test results are processed using the PRISCA computer program, which produces the result. The calculations also take into account not only test results, but also anamnestic data: the woman’s age, race, whether she has serious illnesses(diabetes mellitus or arterial hypertension), the presence of bad habits, etc.

The results form indicates the probability of having a child with a particular pathology. For example, a result of 1:300 indicates that one woman out of 300 with similar results may give birth to a child with a congenital pathology.

The risk level indicator is indicated for each pathology separately:

• Down syndrome (extra 21 chromosome);
• Edwards syndrome (extra chromosome 18);
• neural tube defect (spina bifida or anencephaly).

An indicator of 1:100 or less is a very high risk, 1:1000 is a high risk,<1:1000 низкий риск и <1:10000 – крайне низкий риск.

Additional Information

Patients should be aware that a diagnosis is not made based on the results of the PRISCA-2 study! This indicator determines the subsequent tactics of examining a pregnant woman - she needs to undergo other, more invasive methods for diagnosing genetic and chromosomal pathologies. These methods include amniocentesis and cordocentesis, which are used to obtain fetal biomaterial for genetic research. These studies do not need to be done if the screening examination and ultrasound do not show any abnormalities.

The high estimated risk of having a child with a genetic pathology, calculated according to the PRISCA program, is not a reason to terminate the pregnancy. Even a diagnosis confirmed by genetic analysis is not the basis for an abortion; only a woman’s conscious choice can serve as a reason for terminating a pregnancy.

Literature:

1. Kashcheeva T.K. “Prenatal biochemical screening - system, principles, clinical diagnostic criteria, algorithms”
2. Order of the Ministry of Health of the Russian Federation dated December 28, 2000. No. 457 O improving prenatal diagnostics in the prevention of hereditary and congenital diseases in children (along with instructions for organizing prenatal examinations of pregnant women in order to identify congenital and hereditary pathologies in the fetus, for conducting invasive diagnostics of the fetus and genetic testing of cell biopsies).

The Center for Immunology and Reproduction has been successfully working for many years prenatal screening program. Our specialists are invited to give lectures at specialized conferences and in other clinics. Our laboratory receives consistently good marks in the quality control system. Specially trained specialists carry out risk calculations.

What is prenatal diagnosis?

The word "prenatal" means "before birth." Therefore, the term “prenatal diagnosis” means any studies that make it possible to clarify the condition of the intrauterine fetus. Since human life begins at the moment of conception, various health problems can occur not only after birth, but also before birth. Problems can be different:

• fairly harmless, which the fetus can handle on its own,
• more serious when timely medical care will preserve the health and life of the intrauterine patient,
• severe enough that modern medicine cannot cope with.

To determine the health status of the intrauterine fetus, prenatal diagnostic methods are used, which include ultrasound, cardiotocography, various biochemical studies, etc. All these methods have different capabilities and limitations. Some methods are quite safe, such as ultrasound. Some carry some risk to the fetus, such as amniocentesis (sample of amniotic fluid) or chorionic villus sampling.

It is clear that prenatal diagnostic methods associated with the risk of pregnancy complications should be used only when there are compelling indications for their use. In order to narrow as much as possible the circle of patients in need of invasive (i.e., associated with intervention in the body) methods of prenatal diagnosis, the selection is used risk groups development of certain problems in the intrauterine fetus.

What are risk groups?

Risk groups are those groups of patients among whom the likelihood of detecting a particular pregnancy pathology is higher than in the entire population (among all women in a given region). There are risk groups for the development of miscarriage, gestosis (late toxicosis), various complications during childbirth, etc. If a woman, as a result of an examination, is found to be at risk for a particular pathology, this does not mean that this pathology will necessarily develop. This only means that this patient is more likely to develop one or another type of pathology than other women. Thus, the risk group is not identical to the diagnosis. A woman may be at risk, but there may not be any problems during pregnancy. And vice versa, a woman may not be at risk, but she may have a problem. The diagnosis means that this or that pathological condition has already been discovered in this patient.

Why are risk groups needed?

Knowing that the patient is in one or another risk group helps the doctor correctly plan the management of pregnancy and childbirth. Identification of risk groups makes it possible to protect patients who are not included in risk groups from unnecessary medical interventions, and vice versa, it allows us to justify the prescription of certain procedures or studies for patients included in risk groups.

What is screening?

The word screening means "sifting." In medicine, screening means conducting simple and safe studies on large groups of the population in order to identify groups at risk of developing a particular pathology. Prenatal screening refers to studies carried out on pregnant women to identify groups at risk of pregnancy complications. A special case of prenatal screening is screening to identify groups at risk of developing congenital defects in the fetus. Screening does not allow identifying all women who may have one or another problem, but it makes it possible to identify a relatively small group of patients, within which the majority of people with this type of pathology will be concentrated.

Why is screening for fetal defects necessary?

Some types of congenital defects in the fetus are quite common, for example, Down syndrome (trisomy 21 pair of chromosomes or trisomy 21) - in one case in 600 - 800 newborns. This disease, like some other congenital diseases, occurs at the time of conception or in the earliest stages of fetal development and can be diagnosed quite early in pregnancy using invasive prenatal diagnostic methods (chorionic villus sampling and amniocentesis). However, such methods are associated with the risk of a number of pregnancy complications: miscarriage, the development of a conflict regarding the Rh factor and blood group, infection of the fetus, the development of hearing loss in the child, etc. In particular, the risk of developing a miscarriage after such studies is 1:200. Therefore, these studies should be prescribed only to women at high risk. Risk groups include women over 35 and especially over 40, as well as patients who have given birth to children with developmental defects in the past. However, children with Down syndrome can be born to very young women. Screening methods - completely safe studies carried out at certain stages of pregnancy - make it possible with a very high degree of probability to identify groups of women at risk of Down syndrome who may be indicated for chorionic villus sampling or amniocentesis. Women who are not at risk do not need additional invasive examinations. Detection of an increased risk of developing fetal defects using screening methods is not a diagnosis. The diagnosis can be made or rejected with additional tests.

What types of birth defects are screened for?

• Down syndrome (trisomy of the twenty-first pair of chromosomes)
• Edwards syndrome (trisomy eighteenth pair)
• Neural tube defects (spina bifida and anencephaly)
• Smith-Lemli-Opitz syndrome
• Corneille de Lange syndrome

What types of tests are performed to screen for the risk of birth defects in the fetus?

By types of research highlight:

• Biochemical screening: blood test for various indicators
• Ultrasound screening: identifying signs of developmental abnormalities using ultrasound.
• Combined screening: a combination of biochemical and ultrasound screening.

The general trend in the development of prenatal screening is the desire to receive reliable information about the risk of developing certain disorders as early as possible in pregnancy. It turned out that combined screening at the end of the first trimester of pregnancy (10-13 weeks) makes it possible to approach the effectiveness of classical biochemical screening in the second trimester of pregnancy.

Ultrasound screening, used for mathematical processing of the risks of fetal abnormalities, is carried out only once: at the end of the first trimester of pregnancy.

Concerning biochemical screening, then the set of indicators will be different at different stages of pregnancy. During pregnancy 10-13 weeks the following indicators are checked:

• free β-subunit of human chorionic hormone (free β-hCG)
• PAPP-A (pregnancy associated plasma protein A), pregnancy-associated plasma protein A

A calculation of the risk of measuring fetal anomalies based on the measurement of these indicators is called double biochemical test in the first trimester of pregnancy.

Using a double test in the first trimester, the risk of detection in the fetus is calculated Down syndrome (T21) And Edwards syndrome (T18), trisomy on chromosome 13 (Patau syndrome), triploidy of maternal origin, Shereshevsky-Turner syndrome without dropsy. The risk of neural tube defects cannot be calculated using a double test, since the key indicator for determining this risk is α-fetoprotein, which begins to be determined only from the second trimester of pregnancy.

Special computer programs make it possible to calculate the combined risk of fetal developmental anomalies, taking into account biochemical indicators determined in a double test in the first trimester and the results of an ultrasound scan done at 10-13 weeks of pregnancy. This test is called combined with TVP double test in the first trimester of pregnancy or triple test in the first trimester of pregnancy. The risk calculations obtained using the combined dual test are much more accurate than risk calculations based on biochemical parameters alone or on ultrasound alone.

If test results in the first trimester indicate that the fetus is at risk for chromosomal abnormalities, the patient may be tested to exclude the diagnosis of chromosomal abnormalities. chorionic villus biopsy.

During pregnancy 14 - 20 weeks by last menstruation ( recommended time frame: 16-18 weeks) the following biochemical parameters are determined:

• α-fetoprotein (AFP)
• Inhibin A

Based on these indicators, the following risks are calculated:

• Down syndrome (trisomy 21)
• Edwards syndrome (trisomy 18)
• neural tube defects (spina bifida and anencephaly).
• Risk of trisomy 13 (Patau syndrome)
• Triploidy of maternal origin
• Shereshevsky-Turner syndrome without hydrops
• Smith-Lemli-Opitz syndrome
• Corneille de Lange syndrome

This test is called quadruple test in the second trimester of pregnancy or quadruple biochemical screening in the second trimester of pregnancy. A truncated version of the test is the so-called triple or double tests of the second trimester, which includes 2 or indicators: hCG or free β-hCG subunit, AFP, free estriol. It is clear that the accuracy of the second trimester double or double test is lower than the accuracy of the second trimester quadruple test.

Another option for biochemical prenatal screening is biochemical risk screening for neural tube defects only in the second trimester of pregnancy. In this case, only one biochemical marker is determined: α-fetoprotein

At what stage of pregnancy is second trimester screening performed?

At 14 - 20 weeks of pregnancy. The optimal period is 16 - 18 weeks of pregnancy.

What is the quadruple test in the second trimester of pregnancy?

The main option for biochemical screening of the second trimester in the Center is the so-called quadruple or quadruple test, when the determination of inhibin A is added to the determination of the three above indicators.

Ultrasound screening in the first trimester of pregnancy.

In the first trimester of pregnancy, the main measurement used in calculating risks is the width of the cervical translucency (English “nuchal translucency” (NT)”, French “clarté nuchale”). In Russian medical usage, this term is often translated as “neck space” (TVP) or “cervical fold”. Cervical translucency, nuchal translucency and cervical fold are complete synonyms that can be found in various medical texts and mean the same thing.

Cervical translucency - definition

• Cervical transparency is what the accumulation of subcutaneous fluid on the back of the fetal neck looks like during ultrasound examination in the first trimester of pregnancy.
• The term cervical translucency is used regardless of whether it is septated or whether it is limited to the cervical region or surrounds the entire fetus
• The frequency of chromosomal and other abnormalities is related primarily to the width of the transparency, and not to how it looks overall
• During the second trimester, the transparency usually resolves, but in some cases it can develop into either cervical edema or cystic hygromas with or without generalized edema.

Cervical translucency measurement

Gestation period and coccygeal-parietal size

The optimal period of pregnancy for measuring PB is from 11 weeks to 13 weeks 6 days. The minimum KTR size is 45 mm, the maximum is 84 mm.

There are two reasons for choosing 11 weeks as the earliest time to measure PN:

1. Screening requires the ability to perform chorionic villus sampling before the time when this study may be complicated by amputation of fetal limbs.
2. On the other hand, many gross fetal defects can be detected only after 11 weeks of pregnancy.

• A diagnosis of omphalocele is possible only after 12 weeks.
• Diagnosis of anencephaly is possible only after 11 weeks of pregnancy, since only from this period ultrasound signs of ossification of the fetal skull appear.
• Assessment of the four chambers of the heart and large vessels is possible only after 10 weeks of pregnancy.
• The bladder is visible in 50% of healthy fetuses at 10 weeks, in 80% at 11 weeks, and in all fetuses at 12 weeks.

Image and measurement

To measure SB, the ultrasonic device must have a high resolution with a video loop function and calibrators that can measure the size with an accuracy of tenths of a millimeter. PB can be measured using an abdominal probe in 95% of cases; in cases where this is not possible, a vaginal probe should be used.

When measuring HF, only the head and upper part of the fetal chest should be included in the picture. The magnification should be at its maximum, so that a slight shift of the markers results in a change in measurement of no more than 0.1 mm. When enlarging a picture, before or after capturing the image, it is important to reduce the gain. This avoids measurement errors when the marker falls into a blurred area and thus the size of the BL will be underestimated.

A good sagittal section should be obtained, the same quality as when measuring CTE. The measurement should be made in the neutral position of the fetal head: extension of the head can increase the TVP value by 0.6 mm, flexion of the head can decrease the value by 0.4 mm.

It is important not to confuse the fetal skin and the amnion, since at this stage of pregnancy both formations look like thin membranes. If in doubt, you should wait until the fetus moves and moves away from the amnion. An alternative method is to ask the pregnant woman to cough or lightly tap the pregnant woman's abdominal wall.

The greatest perpendicular distance between the internal contours of the cervical transparency is measured (see figure below). Measurements are taken three times, the largest size value is used for calculation. In 5-10% of cases, the umbilical cord is found entangled around the fetal neck, which can significantly complicate measurement. In such cases, 2 measurements are used: above and below the umbilical cord entanglement site, and the average of these two measurements is used to calculate the risks.

Standards for ultrasound scanning at the end of the first trimester of pregnancy are being developed by the England-based Fetal Medicine Foundation (FMF). In the CIR group of companies, ultrasound is performed according to the FMF protocol.

Additional ultrasound signs of risk for Down syndrome

Recently, in addition to the measurement of spinal cord, the following ultrasound signs have been used to diagnose Down syndrome at the end of the first trimester of pregnancy:

• Nasal bone definition. At the end of the first trimester, the nasal bone not defined using ultrasound in 60-70% of fetuses with Down syndrome and only 2% of healthy fetuses.
• Assessment of blood flow in the Arantium (venous) duct. Abnormalities in the waveform of blood flow in the duct of arantia are found in 80% of fetuses with Down syndrome and only in 5% of chromosomally normal fetuses
• Reduction in the size of the maxillary bone
• Enlarged bladder (“megacystitis”)
• Moderate tachycardia in the fetus

The shape of blood flow in the Arantium duct during Doppler measurements. Top: normal; bottom: with trisomy 21.

Not just Down syndrome!

During an ultrasound scan at the end of the first trimester, fetal contour assessment also helps identify the following fetal abnormalities:

• Exencephaly - anencephaly
• Cystic hygroma (swelling at the level of the neck and back of the fetus), in more than half of cases is caused by chromosomal abnormalities
• Omphalocele and gastroschisis. The diagnosis of omphalocele can be made only after 12 weeks of pregnancy, since before this period a physiological umbilical hernia, which is often detected, has no clinical significance
• Single umbilical artery (in a large percentage of cases combined with chromosomal abnormalities in the fetus)

How are risks calculated?

Special software is used to calculate risks. Simply determining the level of indicators in the blood is not enough to decide whether the risk of developmental abnormalities is increased or not. The software must be certified for use for prenatal screening purposes. At the first stage of computer calculation, the indicator numbers obtained during laboratory diagnostics are converted into the so-called MoM (multiple of median, multiple of the median), characterizing the degree of deviation of a particular indicator from the median. At the next stage of calculation, the MoM is adjusted for various factors (the woman’s body weight, race, the presence of certain diseases, smoking, multiple pregnancies, etc.). The result is the so-called adjusted MoM. In the third calculation step, the adjusted MoMs are used to calculate the risks. The software is specially configured for the methods used in the laboratory for determining indicators and reagents. It is not acceptable to calculate risks using tests done in another laboratory. The most accurate calculation of the risk of fetal abnormalities is when using data from an ultrasound examination performed at 10-13 weeks of pregnancy.

What is MoM?

MoM is an English abbreviation of the term “multiple of median”, which means “multiple of the median”. This is a coefficient showing the degree of deviation of the value of a particular prenatal screening indicator from the average value for the gestational age (median). MoM is calculated using the following formula:

MoM = [Value of the indicator in the patient’s blood serum] / [Value of the median indicator for the gestational age]

Because the indicator value and median have the same units, the MoM value has no units. If the patient’s MoM value is close to one, then the value of the indicator is close to the population average, if it is above one, it is above the population average, if it is below one, it is below the population average. With congenital fetal defects, there may be statistically significant deviations of MoM markers. However, pure MoMs are almost never used in calculating the risk of fetal anomalies. The fact is that in the presence of a number of factors, the average MoM values ​​deviate from the average in the population. Such factors include the patient’s body weight, smoking, race, pregnancy as a result of IVF, etc. Therefore, after obtaining MoM values, the risk calculation program makes adjustments for all these factors, resulting in the so-called “corrected MoM value”, which used in risk calculation formulas. Therefore, in the conclusion forms based on the analysis results, next to the absolute values ​​of the indicators, the corrected MoM values ​​for each indicator are indicated.

Typical MoM profiles in pregnancy pathologies

With various fetal anomalies, MoM values ​​are combined deviated from the norm. Such combinations of MoM deviations are called MoM profiles for a particular pathology. The tables below show typical MoM profiles at different stages of pregnancy.

Typical MoM Profiles - First Trimester

Typical MoM Profiles - Second Trimester

Indications for prenatal screening of the 1st and 2nd trimester for the risk of fetal anomalies

Prenatal screening is currently recommended for all pregnant women. An order of the Ministry of Health of the Russian Federation of 2000 obliges antenatal clinics to conduct biochemical prenatal screening for all pregnant patients in the second trimester of pregnancy for two indicators (AFP and hCG).

Order No. 457 of December 28, 2000 “On improving prenatal diagnostics in the prevention of hereditary and congenital diseases in children”:

The importance of monitoring congenital diseases on an ongoing basis in Moscow is also discussed in the resolution of the Moscow government on the establishment of the city program “Children's Health” for 2003-2005.

On the other hand, prenatal screening should be a purely voluntary matter. In most Western countries, it is the physician's responsibility to inform the patient about the possibility of such tests and about the purposes, possibilities and limitations of prenatal screening. The patient herself decides whether to have tests done or not. The CIR group of companies shares the same point of view. The main problem is that there is no treatment for the detected abnormalities. If the presence of anomalies is confirmed, the married couple is faced with a choice: terminate the pregnancy or continue it. This is not an easy choice.

What is Edwards syndrome?

This is a condition caused by the presence of an extra 18th chromosome in the karyotype (trisomy 18). The syndrome is characterized by gross physical abnormalities and mental retardation. This is a lethal condition: 50% of sick children die in the first 2 months of life, 95% - during the first year of life. Girls are affected 3-4 times more often than boys. The incidence in the population ranges from 1 case in 6,000 births to 1 case in 10,000 births (about 10 times less common than Down syndrome).

What is the free β-subunit of hCG?

The molecules of a number of hormones of the pituitary gland and placenta (thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), luteinizing hormone (LH) and human chorionic hormone (hCG)) have a similar structure and consist of α and β subunits. The alpha subunits of these hormones are very similar and the main differences between the hormones lie in the structure of the beta subunits. LH and hCG are very similar not only in the structure of the α-subunits, but also in the structure of the β-subunits. This is why they are hormones with the same effect. During pregnancy, LH production by the pituitary gland drops to almost zero, and hCG concentrations are very high. The placenta produces very large amounts of hCG, and although this hormone mainly enters the bloodstream in assembled form (a dimeric molecule consisting of both subunits), the free (not associated with the α-subunit) β-subunit of hCG also enters the bloodstream in small quantities. Its concentration in the blood is many times lower than the concentration of total hCG, but this indicator can more reliably indicate the risk of problems in the intrauterine fetus in the early stages of pregnancy. Determination of the free β-subunit of hCG in the blood is also important for the diagnosis of trophoblastic disease (hydatidiform mole and chorionepithelioma), some testicular tumors in men, and monitoring the success of in vitro fertilization procedures.

Which indicator: total hCG or free hCG β-subunit is preferable to use in the second trimester triple test?

Using the free β-hCG subunit assay rather than the total hCG assay provides a more accurate estimate of the risk of Down syndrome, but classic statistical calculations of the risk of Edwards syndrome in a population have used maternal total hCG levels. No such calculations have been made for the hCG β subunit. Therefore, a choice must be made between a more accurate calculation of the risk of Down syndrome (in the case of the β-subunit) and the possibility of calculating the risk of Edwards syndrome (in the case of total hCG). Let us remember that in the first trimester, only the free β-subunit of hCG, but not total hCG, is used to calculate the risk of Edwards syndrome. Edwards syndrome is characterized by low numbers of all 3 indicators of the triple test, so in such cases, both versions of the triple test can be done (with total hCG and with the free β-subunit).

What is PAPP-A?

Pregnancy-associated plasma protein-A (PAPP-A) was first described in 1974 as a high-molecular-weight protein fraction in the blood serum of women in late pregnancy. It turned out to be a large zinc-containing metaloglycoprotein with a molecular weight of about 800 kDa. During pregnancy, PAPP-A is produced by syncytiotrophoblast (tissue that is the outer layer of the placenta) and extravillous cytotrophoblast (islets of fetal cells in the thickness of the uterine mucosa) and enters the mother's bloodstream

The biological significance of this protein is not fully understood. It has been shown to bind heparin and is an inhibitor of granulocyte elastase (an enzyme induced by inflammation), so PAPP-A is believed to modulate the maternal immune response and is one of the factors that ensures the development and survival of the placenta. In addition, it was found to be a protease that cleaves insulin-like growth factor binding protein 4. There are serious reasons to believe that PAPP-A is one of the factors of paracrine regulation not only in the placenta, but also in some other tissues, in particular in atherosclerotic plaques. It is proposed to use this marker as one of the risk factors for coronary heart disease.

Concentrations of PAPP-A in maternal blood continuously increase with increasing gestational age. The greatest increase in this indicator is observed at the end of pregnancy.

Over the past 15 years, PAPP-A has been studied as one of three risk markers for trisomy 21 (Down syndrome) (together with free hCG β-subunit and nuchal translucency thickness). It turned out that the level of this marker at the end of the first trimester of pregnancy (8-14 weeks) is significantly reduced if the fetus has trisomy 21 or trisomy 18 (Edwards syndrome). The uniqueness of this indicator is that its significance as a marker of Down syndrome disappears after 14 weeks of pregnancy. In the second trimester, its levels in maternal blood in the presence of trisomy 21 in the fetus do not differ from those in pregnant women with a healthy fetus. If we consider PAPP-A as an isolated risk marker for Down syndrome in the first trimester of pregnancy, its determination at 8-9 weeks would be most significant. However, free hCG β-subunit is a stable risk marker for Down syndrome at 10–18 weeks, i.e., later than PAPP-A. Therefore, the optimal time for donating blood for a double test in the first trimester of pregnancy is 10-12 weeks.

The combination of measuring PAPP-A levels with determining the concentration of the free β-subunit of hCG in the blood and determining TVP using ultrasound at the end of the first trimester of pregnancy can identify up to 90% of women at risk of developing Down syndrome in the older age group (after 35 years). The probability of false positive results is about 5%.

In addition to prenatal screening for the risk of Down syndrome and Edwards syndrome, in obstetrics the PAPP-A determination is also used for the following types of pathology:

• Threat of miscarriage and stopping the development of pregnancy in the short term
• Cornelia de Lange syndrome.

Risk diagnosis stoppage of fetal development in early pregnancy was the historically first clinical application of PAPP-A determination in blood serum, proposed in the early 1980s. It has been shown that women with low levels of PAPP-A in early pregnancy are at risk of subsequent pregnancy loss and severe forms of late toxicosis. Therefore, it is recommended to determine this indicator at 7-8 weeks for women with a history of severe pregnancy complications.

Cornelia de Lange syndrome is a rare form of congenital malformations of the fetus, found in 1 case in 40,000 births. The syndrome is characterized by mental and physical retardation, heart and limb defects, and characteristic facial features. It has been shown that in this condition, PAPP-A levels in the blood at 20-35 weeks are significantly lower than normal. A study by Aitken's group in 1999 showed that this marker could be used to screen for Cornelia de Lange syndrome in the second trimester of pregnancy, since levels in such pregnant women were on average 5 times lower than normal.

The reagents used to determine PAPP-A and the free β-subunit of hCG are orders of magnitude more expensive than the reagents used for most hormonal parameters, making this test a more expensive test compared to the determination of most reproductive hormones.

What is α-fetoprotein?

It is a fetal glycoprotein produced first in the yolk sac and then in the liver and gastrointestinal tract of the fetus. This is a transport protein in the fetal blood that binds a number of different factors (bilirubin, fatty acids, steroid hormones). It is a dual regulator of intrauterine fetal growth. In an adult, AFP does not perform any known functions, although it can increase in the blood in liver diseases (cirrhosis, hepatitis) and in some tumors (hepatocellular carcinoma and germinal carcinoma). In the mother's blood, the level of AFP gradually increases with increasing pregnancy and reaches a maximum at 30 weeks. The level of AFP in the mother's blood increases with neural tube defects in the fetus and with multiple pregnancies, and decreases with Down syndrome and Edwards syndrome.

What is free estriol?

Estriol is synthesized in the placenta from 16α-hydroxy-dehydroepiantrosterone sulfate supplied from the fetus. The main source of estriol precursors is the fetal adrenal glands. Estriol is the main estrogenic hormone of pregnancy and ensures the growth of the uterus and the preparation of the mammary glands for lactation.

90% of estriol after 20 weeks of pregnancy is formed from fetal DEA-S. The high release of DHEA-S from the fetal adrenal gland is associated with low 3β-hydroxysteroid dehydrogenase activity in the fetus. A protective mechanism that protects the fetus from excess androgenic activity is the rapid conjugation of steroids with sulfate. The fetus produces more than 200 mg of DHEA-S per day, 10 times more than the mother. In the mother's liver, estriol quickly undergoes conjugation with acids, mainly hyaluronic acid, and is thus inactivated. The most accurate method for determining fetal adrenal activity is to determine the level of free (unconjugated) estriol.

Free estriol levels gradually increase as pregnancy progresses and in the third trimester of pregnancy can be used to diagnose fetal well-being. If the condition of the fetus worsens in the third trimester of pregnancy, a sharp drop in the level of free estriol may be observed. Free estriol levels are often reduced in Down syndrome and Edwards syndrome. Taking dexamethasone, prednisolone or metipred during pregnancy suppresses the function of the fetal adrenal glands, so the level of free estriol in such patients often decreases (reduced estriol intake from the fetus). When taking antibiotics, the rate of estriol conjugation in the mother's liver increases and the reabsorption of conjugates from the intestine decreases, so the level of estriol also decreases, but due to the acceleration of its inactivation in the mother's body. For accurate interpretation of the triple test data, it is very important that the patient indicate a complete list of medications taken or taken during pregnancy with doses and timing of use.

Algorithm for prenatal screening in the first and second trimester of pregnancy.

1. Calculate the duration of pregnancy, preferably after consultation with a doctor or with the help of a consultant.

First trimester screening has its own characteristics. It is carried out between 10 and 13 weeks of pregnancy and is quite strictly limited in terms of timing. If you donate blood too early or too late, if you make a mistake in calculating the gestational age at the time of donating blood, the accuracy of the calculation will sharply decrease. Pregnancy dates in obstetrics are usually calculated based on the first day of the last menstruation, although conception occurs on the day of ovulation, that is, with a 28-day cycle - 2 weeks after the first day of menstruation. Therefore, periods of 10 - 13 weeks on the day of menstruation correspond to 8 - 11 weeks on conception.

To calculate the gestational age, we recommend using the obstetric calendar posted on our website. Difficulties in calculating the timing of pregnancy can occur with an irregular menstrual cycle, with pregnancy occurring shortly after birth, with a cycle that deviates from 28 days by more than a week. Therefore, it is best to trust the professionals and consult a doctor to calculate the timing of pregnancy, perform an ultrasound and donate blood.

2. We do an ultrasound.

The next step should be an ultrasound scan between 10 and 13 weeks of pregnancy. Data from this study will be used by the risk calculation program in both the first and second trimester. It is necessary to begin the examination with an ultrasound, since during the examination problems with the development of pregnancy may be revealed (for example, a stop or delay in development), multiple pregnancies, and the timing of conception will be calculated quite accurately. The doctor performing the ultrasound will help the patient calculate the timing of blood donation for biochemical screening. If the ultrasound turns out to be done too early in the pregnancy, then perhaps the doctor recommends repeating the study after some time.

To calculate risks, the following data from the ultrasound report will be used: date of ultrasound, coccygeal-parietal dimension (CPR) and nuchal translucency thickness (NTT) (English abbreviations CRL and NT, respectively), as well as visualization of the nasal bones.

3. Donate blood.

Having the results of the ultrasound and knowing the exact stage of pregnancy, you can come to donate blood. Blood collection for analysis for prenatal screening in the CIR group of companies is carried out daily, including weekends. On weekdays, blood collection is carried out from 7:45 to 21:00, on weekends and holidays: from 8:45 to 17:00. Blood is drawn 3-4 hours after the last meal.

During pregnancy 14 - 20 weeks after the last menstruation (recommended periods: 16-18 weeks), the following biochemical indicators are determined:

• Total hCG or free β-subunit of hCG
• α-fetoprotein (AFP)
• Free (unconjugated) estriol
• Inhibin A

4. We get the result.

Now you need to get the analysis results. The turnaround time for prenatal screening analysis results in the CIR group of companies is one business day (except for the quadruple test). This means that tests taken from Monday to Friday will be ready on the same day, and tests taken from Saturday to Sunday will be ready on Monday.

Conclusions based on the results of the study are issued to the patient in Russian.

Table. Explanations of terms and abbreviations

Report date	Date of computer processing of results
Gestational age	Weeks + days
Date of ultrasound	Date of ultrasound. Usually does not coincide with the date of blood donation.
Fruit	Number of fruits. 1 - singleton pregnancy; 2 - twins; 3 - triplets
ECO	Pregnancy resulted from IVF
KTR	Coccygeal-parietal size determined during ultrasound
MoM	Multiple of median, the degree of deviation of the result from the average for a given period of pregnancy
Accor. MoM	Adjusted MoM. MoM value after correction for body weight, age, race, number of fetuses, presence of diabetes, smoking, infertility treatment using IVF.
NT	Thickness of the collar space (nuchal translucency). Synonym: neck fold. Various reporting options may provide either absolute values ​​in mm or degree of deviation from the median (MoM)
Age risk	Average statistical risk for this age group. No factors other than age are taken into account.
Tr. 21	Trisomy 21, Down syndrome
Tr. 18	Trisomy 18, Edwards syndrome
Biochemical risk	Risk of fetal anomalies after computer processing of blood test data without taking into account ultrasound data
Combined risk	The risk of fetal anomalies after computer processing of blood test data taking into account ultrasound data. The most accurate indicator of risk level.
fb-HCG	Free β-subunit of hCG
DPM	Date of last menstruation
AFP	α-fetoprotein
HCG	General hCG (human chorionic gonadotropin)
uE3	Free estriol (unconjugated estriol)
+NT	The calculation was carried out taking into account ultrasound data
mIU/ml	mIU/ml
ng/ml	ng/ml
IU/ml	IU/ml

Additional Information.

Information for patients: Please note that if you plan to undergo prenatal screening in the CIR group of companies, then ultrasound data performed in other institutions will be taken into account only if there is a special agreement between the CIR group of companies and these institutions.

Information for doctors

Dear Colleagues! In accordance with Order of the Ministry of Health No. 457 and Decree of the Moscow Government No. 572, the CIR group of companies provides services to other medical institutions for prenatal screening for the risk of chromosomal abnormalities. You can invite our employees to come to you with a lecture on this program. To refer a patient for screening, the attending physician must fill out a special referral. The patient can come to donate blood on her own, but it is also possible to have blood taken at other institutions with subsequent delivery to our laboratory, including by our courier. If you want to receive the results of double, triple and quadruple tests of the first and second trimesters of pregnancy, combined with ultrasound data, the patient must come to us for an ultrasound, or we must sign a special agreement with your institution and include your ultrasound specialists in the program, but only after visit of our expert in functional diagnostics to your institution and familiarization with the quality of equipment and qualifications of specialists.