Negative effects of drugs during pregnancy. The effect of drugs on the fetus Negative side effects on the fetus are called

Teratogenicity. Embryotoxicity.

Teratogenic effect can be in the first trimester of pregnancy, i.e. during organogenesis. During this period, some drugs can cause deformities, malformations, or death of the fetus. This effect can be observed even when a woman uses drugs in therapeutic doses. Embryotoxicity is observed in the second and third trimester of pregnancy when drugs are used by a pregnant woman in a large (toxic) dose. In this case, death or metabolic disorders of the fetus (embryo) may develop with a delay in its development.

The main principle of drug therapy in pregnant women: proven efficacy and proven safety of drugs for the fetus. There are problems with the evidence base about the safety of drugs for the fetus:

Conducting controlled clinical trials of drugs is difficult for ethical reasons;

There are no adequate, strictly controlled clinical trials of the efficacy and safety of drugs;

The ongoing research is short term.

In the Republic of Belarus, risk categories of drugs for the fetus have not been developed, therefore, in practice, the American classification of risk categories of drugs for the fetus is used. (FDA):

A- absolutely harmless to the fetus;

B- there is no evidence of risk to the fetus;

C- a risk to the fetus cannot be excluded;

D- there is convincing evidence of harm to the fetus;

In order to reduce the risk of side effects, you should consider:

1. Pharmacological effects of the drug.

2. Age of the patient. In the elderly, the dose is reduced by 30-50%; for children, the dose is set based on weight and age.

3. Functional state of organs and systems involved in drug biotransformation.

4. The functional state of the excretory organs. In patients with severe chronic renal failure, the excretion of drugs and their metabolites is reduced, their association with blood plasma proteins is impaired, which leads to an increase in the concentration of active substances in the blood plasma and the likelihood of side effects.

5. The presence of concomitant diseases. Appointment, for example, NSAIDs can cause exacerbation of gastritis, gastroduodenitis, peptic ulcer.

6. Lifestyle (during intense physical activity, the rate of drug excretion is increased), the nature of nutrition (in vegetarians, the rate of drug biotransformation is reduced), bad habits (smoking accelerates the metabolism of some drugs).

In the Republic of Belarus, there are documents regulating the procedure for organizing control over side effects of medicines: Law of the Republic of Belarus No. 161-3 dated 06/20/2006 "On Medicines", Order of the Ministry of Health of the Republic of Belarus No. 254 dated 08/13/1999 "On approval of the rules for conducting clinical trials of medicinal funds”, Decree of the Ministry of Health of the Republic of Belarus No. 52 dated 03.20.2008 “On approval of the instructions on the procedure for submitting information on identified adverse reactions to drugs and monitoring adverse reactions to drugs”, Decree of the Ministry of Health of the Republic of Belarus No. 50 dated 07.05.2009 “On certain issues of conducting clinical trials of medicines”, approved the code of practice “Good Clinical Practice”.

DRUG DAMAGES OF ORGANS AND SYSTEMS

Drug-induced liver injury. Among the side effects of pharmacotherapy, drug-induced liver damage makes up a small proportion, but has a high probability of adverse outcomes. Mechanisms of drug damage to hepatocytes are different, however, in most cases, these are acute lesions with cytolysis and (or) cholestasis. At the same time, there is a large group of chronic forms of liver damage of medicinal origin, and among them is cirrhosis. In these cases, cirrhosis is the result of fatty degeneration and chronic hepatitis, which can be caused by methyldopa, nitrofurans, tetracyclines, amiodarone, valproate, and many other drugs. The number of drugs that cause liver damage in 1992 numbered more than eight hundred items.

Drug-induced kidney injury. The kidneys, due to their large role in the excretion of drugs from the body, are also subject to their side effects. In the interstitium and lymphatic spaces of the kidneys, the concentration of many drugs exceeds their content in blood plasma. Intensive blood circulation and participation of the kidneys in the biotransformation of drugs also create conditions for prolonged contact of drugs and their metabolites with kidney tissues. Often, the cause of kidney damage can be an immune reaction leading to denaturation of the protein structures of the basement membrane. Some drugs (aminoglycosides, cephalosporins, cytostatics) are active inhibitors of complex enzyme systems in the kidneys, which can cause severe disorders of their functions. In some cases, there is a deposition of medicinal substances and their metabolites in the structures of the nephron - the basement membrane, mesangium, interstitium, around the vessels. Deposits of drugs in the pelvis can lead to drug nephropathy, which most often occurs during treatment with sulfonamides, gold preparations, and non-steroidal anti-inflammatory drugs.

The clinical manifestations of most drug nephropathies are similar to those of kidney disease. It can be glomerulonephritis, acute interstitial nephritis, urate crystalluria, calculous pyelonephritis (with prolonged use of drugs containing calcium).

Drug-induced lung injury. Although it is believed that the respiratory system is resistant to the adverse effects of drugs, lung lesions do occur. There are several variants of drug-induced lung lesions: BA, alveolitis, pulmonary eosinophilia, respiratory distress syndrome.

Bronchospasm is one of the most common allergic reactions to medications. Bronchospastic action is exerted by beta-blockers, cholinomimetics, sympatholytics.

The cause of alveolitis can be both hypersensitivity to drugs and their toxic effect on the lung tissue. Drugs that have a cytotoxic effect (methotrexate, azathioprine, bleomycin) often cause fibrosing alveolitis. Pathogenetically, it does not differ from idiopathic fibrosing alveolitis.

At the heart of the pathogenesis of lung phospholipidosis caused by amiodarone is their ability of amiodarone to bind lipids of lysosomes of alveolar macrophages, which disrupts the catabolism of their phospholipids, which are then deposited in the alveoli. Against this background, pulmonary fibrosis may develop. Eosinophilic infiltrates in the lungs can form when taking antibiotics, sulfonamides, etc. An extremely rare lung lesion is respiratory distress syndrome, which can be caused by acetylsalicylic acid, nitrofurans.

Medicinal lesions of the cardiovascular system. Many drugs have a side effect on the cardiovascular system, causing rhythm and/or conduction disturbances, impaired myocardial contractility, and an increase or decrease in blood pressure. Adverse reactions are especially pronounced in the presence of cardiovascular diseases and drug combinations. Some drugs (such as the ergot alkaloid ergotamine) can cause fibrous thickening of the cusps of the heart valves.

Drug-induced vascular lesions are often manifested by phlebitis, vasculitis, phlebosclerosis as a result of connective tissue hyperreactivity to the administered drug.

Medicinal lesions of the skin. Skin lesions can develop both with direct external contact with a medicinal substance, and with the systemic use of drugs. They appear in the form of rashes of a different nature: erythematous, vesicular, bullous, pustular, in the form of urticaria, purpura, erythema nodosum. Most of them have an allergic origin, appear on the 8-10th day of treatment and subsequently disappear without a trace.

Pustular rashes are a consequence of infection of the follicles of the sweat glands. Vesicular rashes with a significant distribution are manifested by erythroderma. Widespread bullous eruptions can lead to hemodynamic disturbances and hypotension. A severe form of erythema multiforme exudative (Stevens-Johnson syndrome) leads to death in a third of patients.

Medicinal lesions of connective, bone and muscle tissues. Atrophic changes in the connective tissue occur under the influence of glucocorticosteroids due to the inhibition of fibroblast activity, a decrease in the synthesis of connective tissue fibers and the main substance of the connective tissue. At the same time, striae form on the body, wound healing worsens. On the contrary, as a result of the proliferation of connective tissue in various organs and parts of the body - mediastinum, lungs, endocardium and pericardium - fibrosis can develop. The development of fibrosis is described in the treatment of ganglion blockers, b-blockers.

Medicinal systemic lupus erythematosus can be triggered by novocainamide, chlorpromazine, D-penicylamine, methyldopa, anticonvulsants. With the abolition of drugs, the reverse development of symptoms is possible, at least partially.

Side effects of many drugs are arthralgia and arthritis, which are based on allergic reactions.

Drug-induced bone lesions are observed most often in the form of osteoporosis, osteomalacia and rickets. Osteoporosis develops with long-term treatment with glucocorticosteroids, rarely with heparin. Osteomalacia and rickets are the result of a decrease in bone mineralization due to a lack of vitamin D. The breakdown of vitamin D can be caused by phenobarbital, phenytoin. Glucocorticosteroids inhibit the absorption of vitamin D.

An unfavorable side effect that occurs as a result of taking many drugs is muscle weakness. Muscle weakness may be due to myopathy, which is based on damage to myocytes, or myasthenia gravis, a violation of the transmission of excitation in neuromuscular synapses. In therapeutic practice, myasthenia can be expected in the treatment of aminoglycosides, tetracyclines, macrolides, chloroquine, quinidine, b-blockers. The defeat of the muscle cells themselves can be the result of rhabdomyolysis, necrotizing myopathy, atrophy of muscle fibers. There is also a vacuolizing, or hypokalemic form of myopathy, which can develop as a result of intensive therapy with diuretics or laxatives.

Rhabdomyolysis is an extremely rare but often fatal complication of drug therapy with cytostatics, statins. Rhabdomyolysis is characterized by swelling of large proximal muscles with a transition to flaccid paralysis, the development of fibrosis, compaction with contracture. Necrotizing myopathy can be considered as a mild form of rhabdomyolysis caused by the same drugs. In addition, necrotizing myopathy can be triggered by vincristine, clofibrate, beta-blockers.

Drug-induced polymyositis is usually one of the manifestations of drug-induced lupus erythematosus.

Lesions affecting connective tissue, muscles, skin and bones include algodystrophy - trophic changes in bones, muscles, joints and skin, accompanied by severe pain. Clinically, algodystrophy can manifest itself as shoulder-scapular syndrome due to fibrosis of the tissues of the capsules of the upper extremities. This complication can sometimes be observed during treatment with phenobarbital.

Medicinal lesions of hematopoiesis. Blood changes are among the most common adverse reactions. Their development has been described with the use of more than a thousand drugs. Thrombocytopenia, granulocytopenia, aplastic and hemolytic anemia have the greatest clinical significance.

Thrombocytopenia most often caused by cytostatics, gold preparations, penicillins, cephalosporins, tetracyclines, furosemide, quinidine. Its development is a consequence of toxic inhibition of megakaryocytes in the bone marrow.

Granulocytopenia- a rare, but very dangerous complication of drug treatment, sometimes leading to agranulocytosis, the lethality of which reaches 50%. Granulocytopenia is often caused by analgin, phenacetin, less often phenylbutazone, indomethacin and other non-steroidal anti-inflammatory drugs.

The most dangerous drugs that cause aplastic anemia include chloramphenicol, sulfa drugs, gold preparations, butadione. As a rule, aplastic anemia is an idiosyncratic reaction.

Hemolytic anemia develops as a result of the formation in the process of pharmacotherapy of antibodies that react with erythrocyte antigens. Induction of the formation of erythrocyte antibodies can cause penicillins, cephalosporins, insulin, levodopa, quinidine.

Hemolytic anemia can also develop with a deficiency in the erythrocytes of the enzyme glucose-6-phosphate dehydrogenase. In these cases, erythrocytes are not protected from the action of oxidants. As a result, when treated with drugs that have the properties of oxidants, idiosyncrasy develops and, as a result, hemolytic anemia develops. This mechanism of occurrence of hemolytic anemia is observed in the treatment of sulfonamides, nitrofurans, chloroquine, primaquine, phenacetin, acetylsalicylic acid and other antipyretics, ascorbic acid.

It is impossible to avoid the occurrence of side effects when using modern medicines. However, adverse reactions should be prevented whenever possible, which can be facilitated by the following recommendations:

Never use drugs in the absence of clear indications for their appointment; the use of drugs in pregnant women is advisable only when there is an urgent need for prescribed drugs;

When prescribing a specific drug, it should be clarified what other drugs, including self-medication drugs, herbs, nutritional supplements, the patient is taking; it is necessary to know this, since their interaction is possible, leading to undesirable consequences;

Allergic and idiosyncratic reactions are common adverse reactions to drugs, so patients should be asked if they have had any such reactions in the past;

Attention should be paid to the age of the patient, the presence of liver and kidney diseases, since these conditions can change the metabolism and excretion of drugs from the body, which, in turn, leads to the need to select the dose of the drug; it must also be taken into account that genetic factors may also be responsible for the variability in drug biotransformation;

If possible, the simultaneous administration of several drugs should be avoided; if necessary, limit the number of drugs used to the minimum necessary (no more than 3 on an outpatient basis);

Patients, especially the elderly, should be clearly instructed on how to take medicines, and they should be oriented towards strict adherence to the instructions for the use of medicines;

The patient must be warned about the possibility of serious adverse reactions, which are described in the instructions for the use of medicines;

When prescribing new drugs, special attention should be paid to probable and unexpected adverse reactions.

LITERATURE

1. Vdovichenko V.P. Pharmacology and pharmacotherapy.// Minsk, 2006.

2. Khapalyuk A.V. General issues of clinical pharmacology and evidence-based medicine.// Minsk, 2003.

3. Khapalyuk A.V. The value of the paradigm of evidence-based medicine in the practice of a doctor of the XXI century.// Recipe.- 2003.-№1.

4. Chuchalin A.G., Tsoi A.N., Arkhipov V.V. Diagnosis and treatment of pneumonia from the standpoint of evidence medicine.//Consilium Medicum.- 2002.-V.4.-No.12

The statement of T. Paracelsus: “Everything is poison, nothing is devoid of poisonousness, and everything is medicine. Only the dose makes the drug a poison or a medicine. It is known that 4 out of 5 pregnant women are taking some kind of medication that crosses the placenta to some extent. In the 1st trimester, during the period of formation of organs and systems, some drugs can affect embryonic tissues, causing congenital anomalies. However, medication is not the only reason for adverse effects on the development of the embryo.

The causes of many malformations are still unknown. Only a small percentage of deformities can be accurately attributed to the influence of certain factors: heredity, infections, radiation, medication. Most congenital pathologies occur in the 1st trimester of pregnancy, when embryonic cells divide rapidly and organs and systems develop.

The teratogenic effect of the drug depends on both the dose and the time of application. For example, the development and formation of the human cardiovascular system falls on the 20-40th day after fertilization, the limbs - on the 24-46th day, the nervous system - on the 15-25th day. Thus, from 15 to 25 days, the nervous system is exposed to teratogenic effects, but not the limbs. It is possible that teratogenic effects occur during the first 2 weeks after conception, when the woman is not yet aware of her pregnancy. However, most harmful drugs in the period between fertilization and implantation interrupt the occurrence of pregnancy rather than damage the fertilized egg. Only 3 groups of drugs have a clear teratogenic effect on the human embryo. These are antimetabolites, thalidomide and steroid hormones with androgenic activity. The risk of adverse effects of other drugs is generally lower. Medications given at a certain stage of pregnancy and childbirth can affect the physiology of the fetus and newborn. For example, anesthetics and analgesics used during childbirth or caesarean section can cause depression in a newborn, impairing his adaptation to new living conditions.

Medicines that are absolutely contraindicated during pregnancy:

Medications	Consequences for the fetus
Aminopterin	Multiple anomalies, postnatal fetal growth retardation, facial anomalies, fetal death
Androgens	Virilization, limb shortening, anomalies of the trachea, esophagus, defects of the cardiovascular system
Diethylstilbestrol	Adenocarcinoma of the vagina, defects of the cervix, penis, testicular hypotrophy
Streptomycin	Deafness
Disulfiram	Spontaneous abortions, split limbs, clubfoot
Ergotamine	Spontaneous abortions, symptoms of CNS irritation
Estrogens	Congenital heart defects, feminization of the male fetus, vascular anomalies
Halothane	Spontaneous abortions
Iodine 131	Cretinism, hypothyroidism
Methyltestosterone	Masculinization of the female fetus
Progestins	Masculinization of the female fetus, clitoral enlargement, lumbosacral fusion
Quinine	Mental retardation, ototoxicity, congenital glaucoma, genitourinary anomalies, fetal death
Thalidomide	Limb defects, anomalies of the heart, kidneys and gastrointestinal tract
Trimethadine	Characteristic face (V-shaped eyebrows and low-set eyes), anomalies of the heart, eyes, mental retardation
Retinoids	Anomalies of the limbs, facial part of the skull, heart and central nervous system, genitourinary system, underdevelopment of the auricles

Teratogenic drugs:

Medications	Consequences for the fetus
Streptomycin	Ototoxicity
Tetracycline	Tooth discoloration, tooth enamel hypoplasia
Lithium	Congenital heart disease, goiter, hypotension, cyanosis
Diazepam	Hypothermia, hypotension, bifurcation and anomalies of the limbs
Imipramine	Respiratory disorders, limb defects, tachycardia, urinary retention, neonatal distress syndrome
Nortriptyline	Neonatal distress syndrome, cyanosis, tremor, urinary retention
Aspirin	Neonatal hemorrhage, intracranial hemorrhage in preterm infants, persistent pulmonary hypertension
Indomethacin	Pulmonary hypertension, impaired cardiopulmonary adaptation, fetal death
warfarin	Ermbryopathy, developmental delay, optic nerve atrophy, convulsions, fatal bleeding
Phenobarbital	Hearing impairment, CNS depression, anemia, tremor, withdrawal syndrome, hypertension
Phenytoin	Anomalies of the extremities and craniofacial region, mental retardation, congenital heart disease, bleeding
sodium valproate	spina bifida
Ethosuximide	Mongoloid appearance, short neck, extra nipple, developmental delay, dermoid fistula
Chlorothiazide	cholestasis, pancreatitis
Reserpine	Ototoxicity
Azathioprine	Pulmonary stenosis, polydactyly, facial dysmorphogenesis
Busulfan	Intrauterine and postpartum developmental delay, corneal clouding
Chlorambucil	Kidney dysfunction
5-fluorouracil
Colchicine	Spontaneous abortions, trisomy 21
Mercaptopurine	Spontaneous abortions, facial defects of the skull
Methotrexate	Absence of the frontal bone, fusion of the skull bones, spontaneous abortions, postpartum growth retardation
Vincristine	Small fetus, abnormal fetal position
methimizole	Goiter, ulceration of the middle part of the scalp
Chlorpropamide	Multiple malformations, hypoglycemia
Chlordiazepoxide	Depression, semi-consciousness, withdrawal syndrome, hyperexcitability
Meprobamate	Congenital heart defects, withdrawal syndrome, diaphragmatic defects
Vitamin A in doses over 10,000 IU per day.	Defects of the cardiovascular system, auricles, etc.

Effects of alcohol and nicotine on fetal development

The influence of alcohol

The use of alcoholic beverages is firmly established in the tradition of celebrating any significant events in our lives. But even small doses of alcohol can harm a pregnant woman and her unborn child.

Complications of pregnancy: 2-4 more often miscarriages, slowing down the process of childbirth and other complications during childbirth.

:

Alcohol use by pregnant women results in 1/3 of babies having fetal alcohol syndrome, 1/3 some prenatal toxic effects and only 1/3 being normal babies.

fetal alcohol syndrome(AS) is characterized by a triad: growth retardation, mental retardation and specific facial features of the newborn (microcephaly, narrow palpebral fissure, flat maxillary region, low bridge of the nose, short nose, indistinct philtrum, thin upper lip). Alcohol is the most recognizable and preventable cause of mental retardation.

The effects of the alcohol syndrome do not decrease over time, although the specific manifestations change as the child grows older. Attention impairment and hyperactivity are characteristic of 75% of patients with AS, which makes it difficult for a child to adapt socially.

Characteristics of a child's behavior with toxic effects include aggressiveness, stubbornness, hyperactivity, and sleep disturbances.

When breastfeeding alcohol passes directly into mother's milk. If the mother drinks the amount of alcohol equal to one or two glasses of beer, then the child becomes sleepy and cannot suckle properly.

The influence of tobacco (nicotine)

Smoking is, one might say, a bad habit adopted by society. It often happens that smoking is the only reason for communication, a "good reason" for rest - a smoke break when colleagues go out on the stairs or somewhere else to talk about life. Sometimes, in order not to be deprived of such communication, pregnant women are present during such "talks over a cigarette" as a passive participant. But even inhaling the smoke of a nearby cigarette is very harmful.

Complications of pregnancy: vaginal bleeding, circulatory disorders in the placenta. Higher risk of delayed delivery, spontaneous abortion, premature birth - 14% (premature babies) or placental abruption (stillbirth).

Effects on the fetus:

• Fetal growth retardation (reduced length and birth weight)
• Increased risk of congenital anomalies.
• The possibility of sudden death of a newborn is increased by 2.5 times.
• Possible consequences for the further development of the child: a delay in the mental and physical development of the child, deviations in the behavior of the child, an increased predisposition to respiratory diseases.

Effect of drugs on fetal development

Influence of cocaine

Complications of pregnancy: in 8% of using mothers, pregnancy is completed by stillbirth due to placental abruption. The lifestyle of cocaine abusers often (in 25%) leads to premature birth (premature babies) and slowing down the birth process. In addition, the use of cocaine during pregnancy can lead to the development of convulsions, arrhythmias, seizures and other conditions during which injury or death of the fetus is likely. For pregnant women, cocaine is the most dangerous drug, especially in its pure form. More often than with other drugs, cocaine causes a stillbirth.

Effects on the fetus:

• Tachycardia.
• Decreased fetal growth.
• Decreased growth of the brain and body of the fetus.
• Newborns may suffer from a heart attack and / or cerebrovascular accident due to high blood pressure and vasospasm (the risk is especially increased if a pregnant woman consumes within 48 - 72 hours before delivery).
• The effects of cocaine on nerve receptors can contribute to the development of behavioral disorders in a child, increased irritability, delayed speech development, and impaired thinking abilities.

When breastfeeding cocaine passes directly into mother's milk. The child becomes restless, in some cases epileptic seizures are noted.

Influence of opiates (heroin, morphine, codeine, etc.)

Complications of pregnancy(associated with use and abrupt cessation):

• The lifestyle of opiate abusers often leads to premature births (premature babies).
• Slowing down the birth process of every second child.
• Stillbirth and miscarriage (due to abrupt cessation of use).

Consequences of exposure to the fetus:

• Fetal growth disorder.
• Increased or decreased (depending on the dose) excitability of the fetus.
• Increased risk of malposition of the fetus (breech presentation).

  Disorders manifesting during infancy:

• Small body weight.
• Microcephaly.
• Increased risk of sudden death.
• High morbidity and mortality (due to the suppression of systems responsible for the body's resistance to opiates).

Disorders manifesting at an older age:

• Slowed mental, motor and speech development of the child by 18 months.
• Attention deficit and hyperactivity.
• Sleep disorders.
• Anger and irritability.
• Bad speech skills.
• Tactile, visual and auditory perception is below normal.

: manifests itself depending on the level of use and on the child himself. Approximately three out of four newborns suffer from the same withdrawal syndrome as adults: chills, runny nose, severe agitation, insomnia, rapid breathing, crying. When breastfeeding Opiates can be passed to the newborn through mother's milk.

Influence of stimulants and ecstasy

Stimulants and ecstasy affect about the same as cocaine.

Influence of benzodiazepines

Effects on the fetus: Newborns may suffer from respiratory problems. At an older age, the consequences may manifest as a disturbed response to stress.

Withdrawal syndrome in a newborn: if the mother used daily, the infant may suffer from withdrawal problems - agitation, problems with sleep and eating, epileptic seizures. These phenomena can manifest themselves for quite a long time - from two weeks to eight months.

Influence of marijuana, hashish

Effects on the fetus:

• Slow fetal growth.
• It may subsequently affect the boys - their reproductive functions are reduced.
• It can manifest itself in disorders of the nervous system and vision.
• When breastfeeding, it is possible to transfer the drug to the newborn through the mother's milk.

Influence of hallucinogens (mushrooms of the genus psilotsibum, LSD, PCP or phencyclidine, cyclodol, diphenhydramine, taren).

Complications of pregnancy: increased risk of miscarriage.

Effects on the fetus:

• Microcephaly.
• Violation of attention.
• Sudden bouts of excitement, instability of mood.
• Limitation of joint mobility.
• Neurological disorders (weakened reflexes)

Similar information.

The effect of drugs on the fetus and newborn

(abstract).

1. Mechanisms of action of drugs on the fetus

and newborn 3

2. Medications and fetus 6

3. Medicines and breastfeeding 12

4. List of sources used 17

1. Mechanisms of action of drugs on the fetus and newborn

To date, considerable experience has been accumulated indicating that many drugs can have an adverse effect on the developing fetus and newborn. The ratio of risk to potential benefit from prescribing drugs is the main problem of pharmacotherapy during pregnancy.

Most drugs penetrate the fetus quickly enough. At the end of the gestational period, the main biological systems begin to function in the fetus, and the drug can cause its pharmacological effect. There are three pathological variants of the action of drugs on the fetus:

1. embryotoxic;

2.teratogenic;

3.fetotoxic.

The embryotoxic effect consists in the negative effect of the substance on the zygote and blastocyst located in the lumen of the fallopian tubes or in the uterine cavity. Most often, the result is the formation of gross malformations, which leads to termination of pregnancy. I.I. Ivanov and O.S. Sevostyanova note that the teratogenic (teratos - freak) effect of drugs pose the greatest danger, as they lead to the development of congenital anomalies in the fetus. The fetotoxic effect is manifested in the closure of the natural openings of the fetus, the development of hydrogenesis, hydrocephalus and specific organ damage.

It has been established that during pregnancy there are a number of metabolic features that affect both the mother and the fetus and can affect the pharmacokinetics of drugs. Pregnant women are characterized by “physiological hypervolemia”, which reaches a maximum at 29-32 weeks. The concentration of drugs per unit volume decreases, and the beneficial effect decreases, and an increase in the dose of drugs taken increases the risk of fetal pathologies. G.F. Sultanov, as well as O.I. Karpov and A.A. Zaitsev indicate that during pregnancy there is a slowdown in the absorption of drugs. Due to the decrease in intestinal motility, there is a decrease in the bioavailability of substances inactivated in the gastrointestinal tract. At the same time, the adsorption of medicinal substances administered by inhalation increases due to changes in the volume of inhaled air and pulmonary blood flow in pregnant women. An increase in the formation of hepatic microsomal enzymes (hydrolases) leads to an acceleration of the metabolism of xenobiotics. The excretion of medicinal substances during pregnancy increases due to an increase in renal blood flow and glomerular filtration, and at the beginning of childbirth, all indicators of the activity of the mother's kidneys decrease, the reverse transplacental flow of substances decreases, which leads to their accumulation in the child's body.

1.simple diffusion;

2. facilitated diffusion;

3. active transport;

4. entry through the pores of the membrane;

5. pinocytosis.

Simple diffusion is the most common way of transferring drugs, proceeding without energy consumption. It depends on the concentration gradient of the substance in the blood of the pregnant woman and the fetus, the transfer surface area, the membrane thickness, as well as the physicochemical characteristics of the drugs (molecular weight, lipid solubility, degree of ionization). Active transport is carried out with the expenditure of energy, does not depend on the concentration gradient, and obeys the laws of competitive inhibition. S.I. Ignatov established that fluorouracil penetrates the placenta in this way. The diaplacental passage of drugs is carried out through the pores in the chorionic membrane. Their diameter is 1 nm, which corresponds to the diameter of the pores in the intestinal tract and the blood-brain barrier. Pinocetosis is one of the possible ways of transferring drugs with a predominantly protein structure, the absorption of maternal plasma droplets by syncytium microvilli along with the substances they contain.

2. Medications and fetus

There are many drugs that are potentially dangerous in terms of teratogenesis, and their effect may be manifested in the presence of certain favorable factors. Drugs can affect the fetus at all stages of pregnancy, but most reliable data have been obtained when studying their action during the period of organogenesis (18-55 days) and the period of growth and development of the fetus (over 56 days). In this regard, when prescribing a drug to women of the childbearing period, it is important to take very seriously the assessment of the benefit-risk ratio of the prescribed device during pregnancy. No less important is the exclusion of pregnancy when prescribing devices with teratogenic properties.

Based on human or animal data, drugs are currently classified according to the degree of risk to the fetus in a number of countries (USA, Australia) into categories from A (safe) to D (contraindicated during pregnancy), as indicated by O.C. . Sevostyanov. There is also category X, which includes drugs that are absolutely contraindicated for pregnant women. V.A. Tabolin and A.D. Tsaregorodtseva argue that category X drugs do not have a sufficient therapeutic effect, and the risk of their use outweighs the benefits.

A - drugs that have been taken by a large number of pregnant women and women of childbearing age without any evidence of their effect on the incidence of congenital anomalies or damaging effects on the fetus.

B-drugs that were taken by a limited number of pregnant women and women of childbearing age without any evidence of their effect on the frequency of congenital anomalies or damaging effects on the fetus.

C-drugs that have shown teratogenic or embryotoxic effects in animal studies. It is suspected that they may cause reversible damaging effects on the fetus or newborn, but not causing congenital anomalies. No controlled studies have been conducted in humans.

D - drugs that cause or are suspected of causing congenital anomalies or irreversible damage to the fetus.

X - drugs with a high risk of congenital anomalies or permanent damage to the fetus, since there is evidence of their teratogenic or embryotoxic effects in animals and humans. Br. Bratanov and I.V. Markov, this group includes the following drugs:

- androgens represent a great danger due to the occurrence of hermaphroditism in female fetuses, the possibility of congenital anomalies (shortening of the limbs, anomalies of the trachea, esophagus, defects of the cardiovascular system) is also possible;

- diethylstilbestrol causes major changes. In girls whose mothers took this drug during pregnancy, there are modifications of the uterus and vagina. Most often, these changes occurred when the mother took the drug from the eighth to the sixteenth week of pregnancy. The action of this substance is manifested in a negative effect on the male fetus, namely, in the expansion of the ducts, wall hypotrophy and metaplasia of the prostate epithelium. Epididymal cysts were also found.

-ergotamine ( belongs to the group of ergot drugs) increases the risk of spontaneous abortion and symptoms of CNS irritation, as indicated by N.P. Shabalov.

- progestins can cause pseudohermaphroditism in girls, precocious puberty in boys, and lumbosacral fusion in fetuses of both sexes.

- quinine leads to pronounced changes in the central nervous system (underdevelopment of the cerebral hemispheres, cerebellum, quadrigemina, etc.), the formation of congenital glaucoma, anomalies of the genitourinary system, fetal death.

If taking the medicine during pregnancy cannot be avoided, then the consequences of treatment with various drugs should be clearly understood.

O.S. Sevostyanova notes that the most common manifestations of early toxicosis of pregnant women - nausea and vomiting, which occur in 80% of pregnant women in the first trimester and sometimes persist in the second and third - do not always require medical intervention. She also recommends primarily dietary measures. If necessary, appoint pyridoxine (10 mg) and dicyclomine (10 mg) 2-3 times a day inside. If there is no effect, drugs of the phenothiazine series (aminazine, promethazine, meclozine) are used, but they can cause the formation of fetal malformations.

According to V.A. Tabolin myotropic antihypertensive drugs (diabazol, magnesium sulfate) usually do not have a negative effect on the fetus, with the exception of magnesium sulfate, which can accumulate in the fetus, causing CNS depression.

Reserpine, raunatin cause fetal growth retardation. Once in the fetus, reserpine uses MAO for its metabolism, which leads to a delay in the inactivation of histamine (also oxidized by MAO) and the appearance of rhinorrhea, bronchorrhea.

The a-adrenoreceptor antagonist methyldopa (dopegyt, aldomet) acts on CNS receptors. The fetus is also able to accumulate the drug, which may be accompanied by a decrease in the excitability of the central nervous system. I.V. Markova considers dangerous complications of autoimmune hemolytic anemia, liver damage (with prolonged use).

b-Adrenergic blockers cause a decrease in renal blood flow and glomerular filtration. Removing the inhibitory effect of adrenomimetics on the muscles of the uterus, they can lead to premature birth and miscarriage. The use of these drugs is fraught with a delay in the development of the fetus, as noted by A.P. Kiryushchenkov and M.L. Tarakhovsky.

Calcium antagonists are contraindicated during pregnancy due to the risk of a sharp violation of cardiac activity.

Taking acetylsalicylic acid in early pregnancy can have a harmful effect on the fetus. Side effects of salicylates:

Embryotoxic effect, fetal resorption;

Teratogenic effect, manifested after birth by cardiovascular anomalies, diaphragmatic hernias;

Influence on the rate of fetal growth leading to congenital malnutrition.

Antihistamines are also teratogenic. In the experiment, meclizine and cyclizine caused the development of syndactyly, artesia of the anus, hypoplasia of the lungs, bladder, kidneys, hydrocephalus, and fetal resorption in early pregnancy in the fetus. According to the research results of F.I. Komarova, B.F. Korovkina, V.V. Menshikov frequency of anomalies was 5% versus 1.5-1.6% in the control. Histamine quickly passes through the placental barrier, provides normal conditions for implantation and development of the embryo, contributing to the transformation of endometrial stroma cells into decidual tissue, and regulates metabolic processes. Antihistamines can disrupt these processes. Taking diphenhydramine by the mother before childbirth can cause tremors and diarrhea in the baby a few days after birth, as indicated in the concise medical encyclopedia.

Of the anticoagulants during pregnancy, only heparin can be used without fear.

Of the anti-infective agents, sulfa drugs (87% of the dose) penetrate the fetus especially easily, then ampicillin, carbencillin, furadonin, gentamicin, streptomycin, tetracycline (50%) (Matsura S., 1997). Anti-infective agents that have got to the fetus can be excreted by the kidneys into amniotic fluid, from which they again enter the fetus, which maintains their concentration in its blood and tissues. N.P. Shabalov and I.V. Markov found that the safest for the fetus are penicillin, ampicillin, cephalosporins. Penicillin easily crosses the placenta and quickly penetrates the organs and tissues of the fetus. The patency of the placenta for him at the end of pregnancy is higher than at the beginning. This makes it possible to use penicillin for the treatment of intrauterine infections of the fetus. In the case of the use of ampicillin at the end of pregnancy, jaundice in the newborn may increase. Tetracyclines form complex compounds with calcium, accumulate in bone tissue, the laying of teeth, disrupting their development. In addition, they cause fatty hepatosis, disrupt protein synthesis. Aminoglycoside antibiotics (streptomycin, kanamycin) can disrupt the function of the auditory and vestibular nerves in the fetus, leading to hearing loss. Erythromycin due to accumulation in the fetal liver may increase the risk of hyperbilirubinemia.

Of the synthetic anti-infective agents, sulfanilamide preparations are contraindicated for pregnant women, since there is a high risk of hyperbilirubinemia in both the fetus and the newborn, followed by bilirubin encephalopathy. Biseptol and other drugs with trimethoprim are completely contraindicated, which disrupts the use of folic acid, inhibiting the formation of tetrahydrofolic acid, and, consequently, the synthesis of nucleic acids and proteins in developing tissues.

Nitrofuran drugs (furadonin, ffuragin, furazolidone) easily pass through the placenta and accumulate in the amniotic fluid. May cause hemolysis in the fetus. V.A. Tabolin concluded that their use at the end of pregnancy is undesirable.

3. Medicines and breastfeeding

O.I. Karpov, A.A. hares found that the effect of drugs on the fetus is also possible if the drug enters the baby with breast milk during feeding. Many drugs pass to some extent into the mother's milk. Therefore, without a doctor's prescription, in no case should breastfeeding medications be taken! This is especially true of antibiotics and sulfonamides, since they can, penetrating into milk, have an adverse effect on the child's body: the liver and kidneys may suffer, the balance of the intestinal microflora and the process of sexual development may be disturbed.

The penetration of drugs into milk depends on a number of factors (Gardner d., 1987): high doses of the substance contribute to the ingress into milk, its frequent administration, especially parenteral; limit - the rapid elimination of the substance from the mother's body, its binding to blood plasma proteins.

It was found that the substance can enter the milk only in a free state, not bound to plasma proteins. In the vast majority of cases, penetration is carried out by passive diffusion. Only non-ionized, low-polarity molecules, characterized by good solubility in lipids, are capable of such penetration.

A.P. Viktorov, A.P. Rybak notes that only a small amount of medicinal substances, such as lithium, amidopyrine, are actively secreted into milk by the mammary gland. Metabolites of sibazon, chloramphenicol, isoniazid are also found in milk, most of them, apparently, penetrate into it from the blood plasma, but some can also be formed directly in the gland. Ionized molecules and/or small molecules with a molecular weight of less than 200 can pass through the water-filled pores in the basement membrane. The non-ionized fraction of substances not associated with milk proteins can be reabsorbed back into the blood (sulfa drugs).

The concentration of most mineral substances in milk changes little when they are additionally prescribed to a woman, in addition to food. This also applies to iron, fluorine. Lithium is an important exception.

Not always all the substance that has entered the gastrointestinal tract to the child is absorbed. Both the physicochemical properties of the substance and the functional state of the intestine are important. Therefore, some drugs contained in milk in high concentrations, such as aminoglycoside antibiotics, are poorly absorbed (in the normal state of the mucous membrane; when it is inflamed, they can be absorbed). On the contrary, even small amounts of certain substances in milk, when they get to the child, can cause undesirable effects in him, often very dangerous.

The following drugs are considered contraindicated for lactating women: levomycetin, tetracyclines, metronidazole, nalidixic acid, iodine, reserpine, lithium preparations. It is undesirable to prescribe to nursing women: bromides (the child may have rashes, weakness), phenylin (hemorrhages), meprotan (CNS depression, decreased skeletal muscle tone), ergot alkaloids - ergotamine (vomiting, diarrhea, convulsions), butamide, chlorpropamide (hypoglycemia, jaundice, oliguria), amantadine (urinary retention, vomiting, rash).

The remaining substances should be prescribed with caution, monitor the occurrence of complications by warning the mother about them, and immediately stop the drug at the first sign of their occurrence. Otherwise, if the substance enters the child again, it may accumulate and develop a serious complication.

Nevertheless, it is permissible to prescribe a number of drugs to a nursing woman, since they either penetrate little into milk, or are poorly absorbed from the gastrointestinal tract of the child, or cause minor effects in him.

Medicines that can be prescribed to a nursing woman: penicillins, cephalosporins, erythromycin, oleandomycin, lincomycin, furadonin, salbutamol, fenoterol, orciprenaline, dicoumarin, heparin, digoxin, strophanthin, anaprilin, octadine, insulin, caffeine, vitamins, diuretics, anticalcium drugs.

V.A. Shileiko points out that drugs affect not only the child's body, but also the secretion of milk. The secretion of milk is regulated by the pituitary hormone - prolactin, the formation of which is influenced by the neurosecretory structures of the hypothalamus. The latter produce special hormones that inhibit or stimulate the release of prolactin. The synthesis and release of hypothalamic hormones with the help of neurotransmitters is influenced by other parts of the central nervous system, as well as trophism and blood supply to the mammary gland. As a result of the action of any drugs on the central structures, trophism and blood flow of the gland, various changes in milk secretion can be observed, for example, hypogalactia (a decrease in the amount of secretion).

Hypogalactia are early (in the first 2 weeks after birth) and late, primary and secondary (developing against the background of any disease). In the treatment of hypogalactia, it is very important for the mother to observe the correct daily regimen, including rational nutrition. Late toxicosis of pregnant women (nephropathy, eclampsia) and complications during childbirth can also lead to a delay in the appearance of milk and a decrease in its quantity. Severe toxicosis in most women leads to the development of hypogalactia. Anemia, both post-hemorrhagic and recorded throughout pregnancy, often cause a decrease in the amount of milk produced. Methylergometrine, used to prevent bleeding in the early postpartum period, often leads to the development of hypogalactia.

Drugs that enhance the secretion of milk: lactin, prolactin, oxytocin, mammophysin, nicotinic acid, ascorbic acid, vitamin A, thiamine, pyridoxine, glutamic acid, pyrroxan, methyldopa, metoclopromide, theophylline.

Substances that inhibit the secretion of milk: estrogens, progesterone, oral contraceptives, levodopa, bromocriptine, ergocryptine, furosemide, adrenaline, norepinephrine, ephedrine, pyridoxine.

In medicine, there are often phenomena that cannot be considered unambiguous in all cases. So it is with the release of drugs with milk. It has been established that too many different factors affect both the excretion of the drug with milk, and its absorption from the intestines of the child, and the reaction of the child to the substance.

Based on the foregoing, the following conclusions must be drawn. Medicines for a nursing woman can be prescribed only if they are really needed. When choosing a drug, one should take into account the possibility of their negative impact on the child. Do not prescribe medications that are contraindicated for a nursing woman. If the doctor is forced for any reason to prescribe such substances, then the child must be transferred to donor milk or artificial feeding.

4. List of sources used

1. Berezov T.T., Korovkin B.F. Biochemistry.-M.: Medicine, 1990.

2. Boytler E. Disturbance of erythrocyte metabolism and hemolytic anemia.- M.: Medicine, 1981.

3. Clinical Pediatrics /Ed. Br. Bratanov. - Sofia: Medicine and physical education, 1983.V.1.

4. Clinical Pediatrics / A. Anadoliyska, A. Angelov, V. Antonova et al. / Ed. Br. Bratanov. - 2nd ed. - Sofia: Medicine and physical education, 1987.V.1.

5. Bryazgunov I.P. Jaundice associated with breastfeeding // Issues of maternal health. 1989. No. 3. pp. 54-58.

6. Viktorov A.P., Rybak A.T. Excretion of drugs during lactation. - Kyiv: Health, 1989.

7. Golzand I.V. Diseases of the liver and gallbladder in children. - L .: Medicine, Leningrad branch, 1975. – 198 p.

8. Neonatology / Ed. T. L. Gomelly, M.D. Cunnigam. Per. from English. - M.: Medicine, 1995. - 636 p.

9. Grishchenko I.I. Hypogalactia. - Kyiv. 1957. - S. 161-165.

10. Ermolaev M.V. Biochemistry. – M.: Medicine, 1983.

11. Introduction to clinical biochemistry / Ed. I.I. Ivanova - L .: Medicine, Leningrad branch, 1969.

12. Ignatov S.I. Pharmacotherapy. (Guidelines for pediatricians) - 3rd ed. – M.: Medgiz, 1960.

13. Karpov O.I., Zaitsev A.A. The risk of using drugs during pregnancy and lactation. Ref. manual - St. Petersburg: From BHV, 1998. - 352 p.

14. Kiryutsenkov M.V., Tarakhovsky I.S. The effect of drugs on the fetus. – M.: Medicine, 1983. – 278 p.

15. Klimanov V.V., Sadykov F.G. Clinical pathophysiology of childhood: diagnosis of pathological conditions in children from the standpoint of pathological physiology. - St. Petersburg: Sotis: Lan, 1997. - 153 p.

In the early 60s of the XX century, when almost 10,000 children with phocomelia were born in Europe, the relationship of this developmental deformity with the intake of the tranquilizer thalidomide during pregnancy was proved, that is, the fact of drug teratogenesis was established. It is characteristic that preclinical studies of this drug, performed on several types of rodents, did not reveal a teratogenic effect in it. In this regard, at present, most developers of new drugs in the absence of embryotoxic, embryonic and teratogenic effects of the substance in the experiment still prefer not to recommend using during pregnancy until the full safety of such a drug is confirmed after statistical analysis of its use by pregnant women,

At the end of the 60s, the fact of drug teratogenesis was established, which was of a different nature. It was determined that many cases of squamous cell carcinoma of the vagina at puberty and young age are recorded in girls whose mothers during pregnancy took diethylstilbestrol, a synthetic drug of a nonsteroidal structure with a pronounced estrogen-like effect. Later it was found that, in addition to tumors, such girls more often had various anomalies in the development of the genital organs (saddle-shaped or T-shaped uterus, uterine hypoplasia, cervical stenosis), and in male fetuses, the drug caused the development of cysts of the epididymis, their hypoplasia and cryptorchidism in postnatal period. In other words, it has been proven that the side effects of using drugs during pregnancy can be recorded not only in the fetus and newborn, but also develop after a fairly long period of time.

In the late 80s - early 90s, during an experimental study of the effects on the fetus of a number of hormonal drugs (initially, synthetic progestins, and then some glucocorticoids) prescribed to pregnant women, the fact of the so-called behavioral teratogenesis was established. Its essence lies in the fact that until the 13-14th week of pregnancy there are no gender differences in the structure, metabolic and physiological parameters of the fetal brain. Only after this period, the features characteristic of male or female individuals begin to appear, which later determine the differences between them in behavior, aggressiveness, cyclicity (for women) or acyclicity (for men) in the production of sex hormones, which is obviously associated with the sequential inclusion of hereditarily deterministic mechanisms that determine sexual, including psychological differentiation of the male or female organism that is formed in the future.

Thus, if at first drug teratogenesis was understood literally (teratos - freak, genesis - development) and associated with the ability of drugs used during pregnancy to cause gross anatomical developmental anomalies, then in recent years, with the accumulation of factual material, the meaning of the term significantly expanded and currently teratogens are substances whose use before or during pregnancy causes the development of structural disorders, metabolic or physiological dysfunction, changes in psychological or behavioral reactions in a newborn at the time of his birth or in the postnatal period.

The cause of teratogenesis in some cases may be mutations in the germ cells of the parents. In other words, the teratogenic effect in this case is indirect (through mutations) and delayed (the effect on the body of the parents is carried out long before the onset of pregnancy). In such cases, the fertilized egg may be defective, which automatically leads either to the impossibility of its fertilization, or to its improper development after fertilization, which, in turn, can result in either spontaneous cessation of embryo development, or the formation of certain anomalies in the fetus. An example is the use of methotrexate in women for the purpose of conservative treatment of ectopic pregnancy. Like other cytostatics, the drug inhibits mitosis and inhibits the growth of actively proliferating cells, including germ cells. Pregnancy in such women is at high risk of fetal abnormalities. Due to the peculiarities of the pharmacodynamics of anticancer drugs, after their use in women of reproductive age, the risk of having a child with developmental anomalies will remain, which should be taken into account when planning pregnancy in such patients. After antineoplastic therapy, women of childbearing age should be attributed to the risk group for developing fetal anomalies, which further requires prenatal diagnosis, starting from early pregnancy.

A certain danger is also presented by drugs with prolonged action, which, when administered to a non-pregnant woman, are in the blood for a long time and can have a negative effect on the fetus if pregnancy occurs during this period. For example, etretinate, one of the metabolites of acitretin, a synthetic analogue of retinoic acid, widely used in recent years for the treatment of psoriasis and congenital ichthyosis, has a half-life of 120 days and has a teratogenic effect in the experiment. Like other synthetic retinoids, it belongs to the class of substances that are absolutely contraindicated for use during pregnancy, as it causes abnormalities in the development of the limbs, bones of the face and skull, heart, central nervous, urinary and reproductive systems, underdevelopment of the auricles.

The synthetic progestin medroxyprogesterone in depot form is used for contraception. A single injection provides a contraceptive effect for 3 months, but later, when the drug no longer has such an effect, its traces are found in the blood for 9-12 months. Synthetic progestins also belong to the group of drugs that are absolutely contraindicated during pregnancy. In case of refusal to use the drug before the onset of a safe pregnancy, patients should use other methods of contraception for 2 years.

How do drugs affect the fetus?

Most often, fetal developmental anomalies are the result of improper development of a fertilized egg due to the action of adverse factors, in particular drugs, on it. At the same time, the period of influence of this factor is important. Applicable to a person, there are three such periods:

1. up to 3 weeks pregnancy (the period of blastogenesis). It is characterized by rapid segmentation of the zygote, the formation of blastomeres and blastocysts. Due to the fact that during this period there is still no differentiation of individual organs and systems of the embryo, for a long time it was believed that in this period the embryo is insensitive to drugs. Later it was proved that the action of drugs in the earliest stages of pregnancy, although not accompanied by the development of gross anomalies in the development of the embryo, but, as a rule, leads to its death (embryo-lethal effect) and spontaneous abortion. Since the medicinal effect in such cases is carried out even before the fact of pregnancy is established, the fact of termination of pregnancy often goes unnoticed by the woman or is regarded as a delay in the onset of the next menstruation. A detailed histological and embryological analysis of the abortion material showed that the effect of drugs during this period is characterized mainly by a general toxic effect. It has also been proven that a number of substances are active teratogens during this period (cyclophosphamide, estrogens);
2. The 4th-9th weeks of pregnancy (the period of organogenesis) are considered the most critical period for inducing birth defects in humans. During this period, there is an intensive crushing of germ cells, their migration and differentiation into various organs. By the 56th day (10 weeks) of pregnancy, the main organs and systems are formed, except for the nervous, genital and sensory organs, the histogenesis of which lasts up to 150 days. During this period, almost all drugs are transferred from the mother's blood to the embryo and their concentration in the blood of the mother and fetus is almost the same. At the same time, the cellular structures of the fetus are more sensitive to the action of drugs than the cells of the mother's body, as a result of which normal morphogenesis may be disturbed and congenital malformations may form;
3. the fetal period, by the beginning of which differentiation of the main organs has already occurred, is characterized by histogenesis and fetal growth. During this period, the biotransformation of drugs in the mother-placenta-fetus system is already underway. The formed placenta begins to perform a barrier function, and therefore the concentration of the drug in the fetus, as a rule, is lower than in the mother's body. The negative effect of drugs during this period usually does not cause gross structural or specific developmental anomalies and is characterized by a slowdown in fetal growth. At the same time, their possible influence on the development of the nervous system, organs of hearing, vision, the reproductive system, especially the female one, as well as the metabolic and functional systems that are forming in the fetus, remains. So, atrophy of the optic nerves, deafness, hydrocephalus and mental retardation are observed in newborns whose mothers used the coumarin derivative warfarin in the II and even III trimesters of pregnancy. In the same period, the phenomenon of “behavioral” teratogenesis described above is formed, which is obviously associated with a violation of the processes of fine differentiation of metabolic processes in brain tissues and functional connections of neurons under the influence of sex steroid hormones.

In addition to the duration of exposure, the dose of the drug, the species sensitivity of the organism to the action of the drug, and the hereditarily determined sensitivity of an individual to the action of a particular drug are important for drug teratogenesis. Thus, the thalidomide tragedy largely occurred because the effect of this drug in the experiment was studied in rats, hamsters and dogs, which, as it turned out later, unlike humans, are not sensitive to the action of thalidomide. At the same time, mouse fetuses were sensitive to the action of acetylsalicylic acid and highly sensitive to glucocorticosteroids. The latter, when used in early pregnancy in humans, lead to cleft palate in no more than 1% of cases. It is important to assess the degree of risk of using certain classes of drugs during pregnancy. According to the recommendation of the US Food and Drug Administration (FDA), all drugs, depending on the degree of risk and the level of adverse, primarily teratogenic effects on the fetus, are divided into five groups.

1. Category X - drugs, the teratogenic effect of which has been proven in the experiment and clinic. The risk of their use during pregnancy exceeds the possible benefits, and therefore they are categorically contraindicated in pregnant women.
2. Category D - drugs, the teratogenic or other adverse effect of which on the fetus is established. Their use during pregnancy is associated with a risk, but it is lower than the expected benefit.
3. Category C - drugs, the teratogenic or embryotoxic effect of which has been established in the experiment, but clinical trials have not been conducted. The benefits outweigh the risks.
4. Category B - drugs, the teratogenic effect of which was not detected in the experiment, and the embryotoxic effect was not detected in children whose mothers used this drug.
5. Category A: in the experiment and in controlled clinical trials, no negative effect of the drug on the fetus was revealed.

Medicines absolutely contraindicated during pregnancy (category X)

Medications	Consequences for the fetus
Aminopterin	Multiple anomalies, postnatal fetal growth retardation, facial anomalies, fetal death
Androgens	Masculinization of the female fetus, shortening of the limbs, anomalies of the trachea, esophagus, defects in the cardiovascular system
Diethylstilbestrol	Adenocarcinoma of the vagina, pathology of the cervix, pathology of the penis and testicles
Streptomycin
Dieulfiram	Spontaneous abortions, split limbs, clubfoot
Ergotamine	Spontaneous abortions, symptoms of CNS irritation
Estrogens	Congenital heart defects, feminization of the male fetus, vascular anomalies
Inhalation anesthetics	Spontaneous abortions, malformations
Iodides, iodine 131	goiter, hypothyroidism, cretinism
	Mental retardation, ototoxicity, congenital glaucoma, anomalies of the urinary and reproductive systems, fetal death
Thalidomide	Limb defects, anomalies of the heart, kidneys and digestive tract
Trimethadione	Characteristic face (Y-shaped eyebrows, epicanthus, underdevelopment and low position of the auricles, sparse teeth, cleft palate, low-set eyes), anomalies of the heart, esophagus, trachea, mental retardation
Synthetic retinoids (isotretinoin, etretinate)	Anomalies of the limbs, the facial part of the skull, heart defects, central nervous system (hydrocephalus, deafness), urinary and reproductive systems, underdevelopment of the auricles. Mental retardation (>50%)
Raloxifene	Developmental disorders of the reproductive system
Progestins (19-norsteroids)	Masculinization of the female fetus, clitoral enlargement, lumbosacral fusion

Medicines associated with high risk during pregnancy (category B)

Medications	Consequences for the fetus and newborn
Antibiotics Tetracyclines (doxycycline, demeclopicline, minocycline) Aminoglycosides (amikacin, kanamycin, neomycin, netilmicin, tobramycin) Fluoroquinolones Chloramphenicol (levomycetin)	Safe during the first 18 weeks of pregnancy. In later periods, they cause discoloration of the teeth (brown color), hypoplasia of tooth enamel, impaired bone growth Congenital deafness, nephrotoxic effect Act on cartilage tissue (chondrotoxicity) Agranulocytosis, aplastic anemia, gray syndrome in the neonatal period
Nitrofurintoin	Hemolysis, yellow discoloration of teeth, neonatal hyperbilirubinemia
Antivirals Ganciclovir Ribavirin Zalcitabine	In the experiment, it has a teratogenic and embryotoxic effect. It has a teratogenic and/or embryo-lethal effect in almost all animal species. Described teratogenic effect in two animal species
Antifungals Griseofulvin Fluconazole	Arthropathy A single dose of 150 mg does not lead to a negative effect on the course of pregnancy. Regular intake of 400-800 mg / day causes fetal malformations
	In an experiment on some animal species, a teratogenic effect was registered.
Antidepressants lithium carbonate Tricyclic MAO inhibitors	Congenital heart defects (1:150), especially Ebstein's anomaly, cardiac arrhythmias, goiter, CNS depression, arterial hypotension, neonatal cyanosis Respiratory disorders, tachycardia, urinary retention, neonatal distress Slowdown in the development of the fetus and newborn, impaired behavioral responses
Coumarin derivatives	Warfarin (coumarin) embryopathy in the form of nasal hypoplasia, choanal atresia, chondrodysplasia, blindness, deafness, hydrocephalus, macrocephaly, mental retardation
Indomethacin	Premature closure of the ductus arteriosus, pulmonary hypertension, with prolonged use - growth retardation, impaired cardiopulmonary adaptation (more dangerous in the third trimester of pregnancy)
Anticonvulsants Phenytoin (difenin) Valproic acid Phenobarbital	Hydantoin fetal syndrome (expanded flat and low nail, short nose, ptosis, hypertelorism, maxillary hypoplasia, large mouth, protruding lips, upper lip cleft, etc.) Spina bifida, palate, often additional small anomalies - hemangiomas, inguinal hernia, divergence of the rectus abdominis muscles, telangiectasia, hypertelorism, deformity of the auricles, delayed development. CNS depression, hearing loss, anemia, tremor, withdrawal syndrome, arterial hypertension
ACE inhibitors	Oligohydramnios, malnutrition, contractures of the extremities, deformity of the facial part of the skull, lung hypoplasia, sometimes antenatal death (more dangerous in the second half of pregnancy)
Reserpine	Nasal hyperemia, hypothermia, bradycardia, CNS depression, lethargy
Chloroquine	Nervous disorders, hearing, balance, vision disorders
Anticancer drugs	Multiple malformations, miscarriage, intrauterine growth retardation
Antithyroid drugs (thiamazole)	Goiter, ulceration of the middle part of the scalp
Pituitary hormone inhibitors Danazol Gesterinone	When taken after 8 weeks, from the moment of conception, it can cause virilization of the female fetus. May cause masculinization of a female fetus
Benzodiazepine derivatives (diazepam, chlozepid)	Depression, drowsiness in the neonatal period (due to very slow elimination), Rarely - malformations resembling fetal alcohol syndrome, congenital heart and vascular defects (not proven)
Vitamin D in high dose	Organ calcification
Penicillamine	Possible defects in the development of connective tissue - developmental delay, skin pathology, varicose veins, fragility of venous vessels, hernias

In conclusion, I would like to note that despite the 40 years that have passed since the first description of cases of drug-induced teratogenesis, the study of this problem is still largely at the stage of accumulation and primary comprehension of the material, which is due to a number of reasons. Only a relatively small list of drugs is systematically used and cannot always be canceled in a patient due to pregnancy (anti-epileptic, anti-tuberculosis, tranquilizers for mental illness, oral hypoglycemic drugs for diabetes mellitus, anticoagulants after prosthetic heart valves, etc.). It is the side effects on the fetus of such drugs that have been studied most fully. Every year, a number of new drugs are introduced into medical practice, often with a fundamentally new chemical structure, and although their possible teratogenic effect is being investigated in accordance with international rules, there are species differences that do not allow at the stage of preclinical studies or clinical trials to fully assess the safety of the drug in in terms of its teratogenic effect. These data can only be obtained by conducting expensive multicenter pharmaco-epidemiological studies with an analysis of the use of a particular drug by a large array of patients. It is difficult to assess the long-term effects of the use of drugs during pregnancy, especially when it comes to their possible impact on the mental status or behavioral responses of a person, since their features can be not only a consequence of the use of drugs, but also be determined by hereditarily determined factors, social living conditions. and upbringing of a person, as well as the action of other adverse (including chemical) factors. When registering certain deviations in the development of the fetus or child after using the drug by a pregnant woman, it is difficult to differentiate whether this is the result of the action of the drug or a consequence of the influence of a pathogenic factor on the fetus, necessitating the use of the drug.

Taking into account by doctors of various specialties in their daily activities the facts already accumulated to date will optimize the pharmacotherapy of diseases both before and during pregnancy and avoid the risk of side effects of drugs on the fetus.

One of the most important periods in a woman's life is the period of bearing a child. And in these few months, the expectant mother must do everything in her power to give birth to a healthy baby.

Of course, a pregnant woman should lead a healthy lifestyle: eat right, pay the necessary attention to physical activity and try to avoid any health disorders. But pregnancy lasts nine calendar months - it is very difficult during this time to never feel any ailments or health problems.

How can a pregnant woman cope with possible ailments, and even diseases, if the number of drugs that are allowed for pregnant women is very limited?

Possible effects on the fetus of drugs

It has been repeatedly proven that different drugs can affect the developing fetus at any stage of pregnancy.

The most dangerous influence is in the first trimester of pregnancy, when in a rapidly growing organism, and then in the fetus, all organs and systems of the future organism are laid. The fact is that during this period the placenta is still in the process of formation and cannot become an obstacle to a variety of chemicals, including those that can have an extremely negative effect on the fetus.

Attention! Even drugs that are officially approved for use during pregnancy can sometimes cause various complications in the body of the fetus, and then in the newborn.

If it is necessary to use any drug during pregnancy, the expectant mother should remember:

• Any drug during pregnancy (at any time) can be used only in accordance with the indications and only as prescribed by the attending physician;
• When choosing a medicinal product, it is necessary to give preference only to those medicinal products that have proven tolerability;
• During the period of bearing a child, monotherapy should be preferred, that is, treatment should, if possible, be carried out with only one drug; combined treatment during this period is undesirable;
• A pregnant woman should remember that completely safe and absolutely harmless drugs do not exist.

Careless and / or excessive use of drugs during pregnancy can cause many complications of pregnancy, especially since it is almost impossible to predict the reaction of a pregnant woman's body to a particular drug, even if it is officially approved for use in pregnant women, since sensitivity to certain substances and, accordingly, to medicines can be genetically predetermined, and a substance that is safe in one case can be very dangerous in another.

Careless, thoughtless and improper use of medications during the period of bearing a child can cause such undesirable, and sometimes extremely dangerous consequences:

• Spontaneous abortion, or miscarriage, which can happen at any gestational age;
• Premature onset of the birth process (premature birth), which can result in death and / or the birth of a non-viable baby;
• Cases of stillbirth are possible;
• The result of the use of drugs in different periods of pregnancy may be congenital deformities and anomalies of various organs of the fetus;
• It is believed that one of the consequences of using pregnant medications can be cerebral palsy (cerebral palsy);
• The result of exposure to the fetus of various drugs can be behavioral disorders that appear over time, or mental retardation of the child.

Attention! Even if taking drugs during pregnancy does not cause organic lesions in the fetus, it is very likely that the child will develop allergic reactions.

Scientists and clinicians point out that the effects of taking medications during pregnancy can manifest themselves after the birth of the baby, including even after a few months or even after a few years.

Unfortunately, pregnant women also sometimes get sick, and diseases can be both acute and chronic. And almost any disease of the expectant mother can have an undesirable, that is, harmful, effect on the fetus, which can lead to serious consequences. In such cases, it is necessary to use different medicines to protect the unborn child.

In addition, sometimes pregnant women are prescribed drugs that have a specific effect on the fetus for therapeutic purposes, when it is necessary to correct the condition of the fetus during the prenatal period. And sometimes the fetus has to be treated, for which it is necessary to provide a very specific therapeutic effect.

Of course, these are very responsible appointments, therefore, when prescribing any medication to a pregnant woman, first of all, the doctor evaluates how the potential benefits and possible harm from taking any drug correlate.

Attention! Any medicines for pregnant women are prescribed only if the possible therapeutic effect for the mother's body will undoubtedly exceed the risk of undesirable or even harmful effects on the developing and growing fetus.

In medical practice, it is customary to prescribe to pregnant women only those medications that have been tested and have proven themselves well when used during childbearing.

Is there a list of medications that are safe for pregnant women? Unfortunately, such a list is impossible in principle, since the body of each woman is unique, as is the development of each pregnancy. In addition, as is known, some reactions to various substances in the body can be genetically determined.

Attention! To date, doctors can only assume that some drugs are safer for pregnant women to a greater extent than others, but they cannot be considered completely harmless to the body of the expectant mother, since the possibility of potential harm to a greater or lesser extent is never excluded.

The danger of using drugs during pregnancy

The most dangerous period for the use of any drugs, both of chemical and natural origin, is considered (the first 12 gestational weeks), when all organs and systems are laid in the fetus, which will only develop in the future. It is at this time that the fetus is considered the most vulnerable to any influences, including chemical (medicinal) substances. Among other things, the danger also increases because in the first weeks of pregnancy, the placenta, which will later filter the substances entering the fetal body, has not yet been formed and does not work at full strength.

It should also be taken into account that some medications can have a negative and even damaging effect on male (spermatozoa) and female (ovum) germ cells even before conception. That is, conception can occur with the participation of damaged cells, while it is completely unknown how the embryo will develop and what disorders will appear in the fetus, and then in the newborn.

Attention! Immunosuppressive drugs, certain antibacterial drugs (antibiotics), antitumor drugs, as well as psychotropic drugs and hormonal drugs that have a steroid structure can damage male and / or female germ cells even before pregnancy.

If a man and / or a woman took such drugs, then it makes sense for them to postpone pregnancy planning for about six months after taking such drugs. The fact is that taking certain drugs even at the stage of pregnancy planning can cause undesirable consequences:

• Some drugs are capable of exhibiting an embryotoxic effect, that is, an extremely negative effect on the developing embryo, and this is especially pronounced in the first, second and third gestational weeks - the development of the fetal egg in such cases simply stops.
• There are drugs that have a teratogenic effect on the embryo and fetus, which causes the appearance of a variety of developmental anomalies in the fetus. It is important to understand that the nature of the abnormal development of the fetus is highly dependent on the gestational age, since the fetus at any stage of its development reacts differently to the effects of the drug, although such a reaction is almost always negative.

The teratogenic properties of drugs, that is, their ability to provoke the formation of fetal mutilations, depends on several characteristics of the drug, including:

• The chemical structure of the drug is very important, that is, the structure of the molecules that make up the drug;
• Equally important is how easily the drug (drug molecules) is able to cross the placental barrier;
• Of course, the dosage of the drug and the duration of its administration are of great importance;
• Metabolic features are also important, that is, with what speed the half-life products of this drug can be excreted from the body of a pregnant woman.

Attention! Simultaneous intake of certain drugs enhances their teratogenic effects: if two or more drugs with a teratogenic effect are used simultaneously, this significantly (several times) increases the risk of possible development of various congenital malformations and defects in the fetus.

Drugs that have a fetotoxic effect can have a negative effect on the developing and growing embryo, and then on the fetus, that is, these drugs can have a toxic effect on the fetus after 12 weeks of gestation and until the very birth. The fetotoxic effect manifests itself in different ways: a delay in the general indicators of the fetus, low indicators of physical development (weight and length), dysfunction of various organs and systems of the fetus. It is very important that the fetotoxic effect of some drugs can manifest itself in an already born baby.

It must be remembered that any complications during the development of pregnancy, including such as and / or kidney problems, lead to the fact that drugs accumulate in the mother's body, creating higher concentrations in the blood than the fetotoxic effect increases.

Attention! To protect the fetus from the fetotoxic effects of various drugs, the placenta and its functional state are very important, on which the possibility of manifestation of protective functions depends. It is the placenta that is the barrier that protects the body of the developing fetus from the harmful effects of any factors that can pose a danger to it.

Metabolic processes associated with the excretion of harmful chemicals from the body include not only the placenta, but also the kidneys, liver, adrenal glands and pancreas, as well as other organs.

Five groups of drugs that affect the body of a pregnant woman and the fetus in different ways

• The first group includes those drugs that have successfully passed controlled trials, even on pregnant women. As a result of the tests, it was proved that taking these drugs does not carry any risk to the fetus and its development during the first trimester of pregnancy. Also, no data and / or evidence of possible harm to the fetus of these drugs in late pregnancy has been identified.
• The first group of drugs includes potassium chloride, triiodothyronine, iron preparations, many multivitamin complexes and some other drugs.
• The second group includes medicinal substances that have been tested. But no teratogenic effect on the fetus was found if the mothers took these drugs while carrying the child. However, when tested on animals, some deviations from the norm were observed in the offspring.
• The second group of drugs includes aspirin, insulin, heparin, penicillin antibiotics, metronidazole and other medications.
• The third group includes drugs that have shown teratogenic and / or embryotoxic effects during animal testing. Controlled clinical trials in humans have not been conducted or the possible results of taking this drug have not been studied. Such drugs are prescribed to pregnant women only when the expected potential benefit outweighs the potential risk.
• The third group of drugs includes fluoroquinolones, isoniazid, gentamicin, antidepressants, antiparkinsonian drugs, and other drugs.
• The fourth group includes drugs, the use of which during pregnancy carries some risk for the growing and developing fetus, but it has been proven that the benefits of using these drugs outweigh the possible harm from side effects.
• The fourth group of drugs includes diclofenac, doxycycline, kanamycin, anticonvulsants and other drugs.
• The fifth group includes drugs whose teratogenic effect has been proven, so their use during pregnancy and even during pregnancy planning is contraindicated. If the use of such drugs is absolutely necessary, for example, to save the life of the mother, then the pregnancy cannot be maintained and must be terminated.

Attention! At any gestational age, the decision on the need for a pregnant woman to take any drug can only be made by the attending gynecologist or a narrow specialist, and only after a detailed study of the pregnant woman's history, the results of all studies and clinical analyzes.During the first trimester of pregnancy, taking any medication is highly undesirable. Only drugs that belong to the first group can be safe during this period..

Attention! If conception occurred spontaneously while taking oral contraceptives, and if oral contraceptives are not stopped until the pregnancy is known for certain, then this almost three times increases the likelihood of chromosomal abnormalities in the fetus, and the risk of having a child with Down syndrome increases by 2 .8 times. In addition, the risk of developing neuroblastoma in newborns, especially in boys, increases (at least 1.2 times).

For reference: Neuroblastoma is a malignant tumor that affects the sympathetic nervous system.

conclusions

It is very important that every pregnant woman remember that any drug during pregnancy can bring not only benefits, but also considerable harm, therefore, any self-administration during this period is unacceptable, since their consequences are unpredictable and in many cases can cause irreparable harm to the developing fetus.