Effect of drugs on the fetus

The problem of assessing the possible negative effects of drugs on the fetus is one of the most difficult when dealing with safe pharmacotherapy, both before and during pregnancy. According to the literature, currently 10 to 18% of children born have some deviation in development. In 2/3 cases of congenital anomalies, the underlying etiologic factor, as a rule, can not be established. It is believed that these are combined (including medicinal) effects and, especially, genetic disorders and other defects of the hereditary apparatus. However, no less than 5% of anomalies are established by their direct causal relationship with the use of drugs during pregnancy.

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The history of studying the effects of drugs on the fetus

In the early 60-ies of the XX century, when almost 10,000 children with focomelia were born in Europe, the relationship between this malformation of development and the reception of thalidomide tranquilizer during pregnancy was proved, that is, the fact of drug teratogenesis was established. It is characteristic that the preclinical studies of this drug, performed on several species of rodents, did not reveal a teratogenic effect. In this regard, at present most of the developers of new drugs in the absence of embryotoxic, embryonic and teratogenic action of the substance in the experiment prefer not to be recommended to use during pregnancy until the complete safety of this drug is confirmed after a statistical analysis of its use by pregnant women,

In the late 60-ies, 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 pubertal and young age are registered in girls whose mothers during pregnancy took diethylstilbestrol - a synthetic drug of a nonsteroidal structure with a pronounced estrogen-like effect. In the future, it was revealed that in addition to tumors, various abnormalities of genital organs (saddle or T-shaped uterus, uterine hypoplasia, cervical stenosis) were more often found in these girls, and in the 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 the newborn, but also develop after a fairly long period of time.

At the end of the 1980s and the beginning of the 1990s, during the experimental study of the effects on the fetus of a number of hormonal preparations (first - synthetic progestins and then some glucocorticoids) prescribed to pregnant women, the fact of so-called behavioral teratogenesis was established. The essence of it is that before the 13-14th week of pregnancy there are no sex differences in the structure, metabolic and physiological parameters of the fetal brain. Only after this period, the characteristics characteristic of individuals of the male or female gender begin to manifest themselves, which further determine the differences between them in behavior, aggression, cyclicity (for women) or acyclicity (for men), the production of sex hormones, which is obviously connected with successive inclusion of hereditary deterministic mechanisms that determine sexual, including psychological, differentiation of the male or female organism that forms in the future.

Thus, if at the beginning the drug teratogenesis was understood literally (teratos - genus, development) and associated with the ability of drugs used during pregnancy to cause gross anatomical developmental anomalies, in recent years, with the accumulation of factual material, the meaning of the term is significantly expanded and at the present time teratogens are those substances whose use before or during pregnancy causes the development of structural disorders, metabolic or physiological dysfunction, 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 can be mutations in the parental cells of parents. In other words, the teratogenic effect in this case is indirectly (through mutations) and delayed (the effect on the parents' organism takes place long before the onset of pregnancy). In such cases, the fertilized egg may be inferior, which automatically leads either to the impossibility of fertilization or to its inadequate development after fertilization, which in turn can result either in the spontaneous cessation of embryo development or in the formation of certain anomalies in the fetus. An example is the use of methotrexate in women with a view to conservative treatment of ectopic pregnancy. Like other cytotoxic drugs, the drug suppresses mitosis and inhibits the growth of actively proliferating cells, including genital cells. Pregnancy in such women occurs with a high risk of abnormalities of fetal development. Due to the peculiarities of pharmacodynamics of antitumor agents after their application 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 the antineoplastic therapy of women of childbearing age should be attributed to the risk of development of fetal anomalies, which in future requires prenatal diagnosis, beginning with the early stages of pregnancy.

A certain danger is also presented by drugs with prolonged action, which, when introduced to a non-pregnant woman, are in the blood for a long time and can have a negative effect on the fetus in the event of pregnancy in 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 a class of substances absolutely contraindicated for use during pregnancy, as it causes anomalies in the development of the limbs, bones of the face and skull, heart, central nervous, urinary and reproductive systems, underdevelopment of the auricles.

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

How do drugs affect the fetus?

Most often, fetal development abnormalities are the result of improper development of a fertilized egg due to unfavorable factors, in particular, drugs. In this case, the period of influence of this factor is of great importance. Applicable to a person distinguish three such periods:

1. up to 3 weeks. Pregnancy (blastogenesis period). It is characterized by rapid segmentation of the zygote, formation of blastomeres and blastocysts. Due to the fact that in this period there is no differentiation of separate organs and systems of the embryo, for a long time it was believed that at this time the embryo is insensitive to medicines. Later, it was proved that the action of drugs in the earliest stages of pregnancy, although not accompanied by the development of gross anomalies of embryo development, 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, often the fact of the termination of pregnancy remains unnoticed by a woman or is regarded as a delay in the onset of another menstruation. A detailed histological and embryological analysis of abortion showed that the effect of drugs during this period is characterized mainly by general toxicity. It is also proved that a number of substances are active teratogens in this period (cyclophosphamide, estrogens);
2. 4-9th week of pregnancy (organogenesis period) is considered the most critical time for induction of birth defects in humans. During this period there is an intensive crushing of the germ cells, their migration and differentiation into various organs. By the 56th day (10 weeks) of pregnancy, the main organs and systems are formed, besides the nervous, genital organs 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 fetal cellular structures are more sensitive to the action of drugs than the cells of the mother's organism, as a result of which normal morphogenesis can be disturbed and congenital malformations can be formed;
3. fetal period, to the beginning of which the differentiation of the basic organs has already occurred, is characterized by histogenesis and fetal growth. During this period biotransformation of medicinal preparations in the mother-placenta-fetus system is already underway. The formed placenta begins to fulfill the barrier function, and therefore the concentration of the drug in the fetus is usually 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 slowing of fetal growth. At the same time, their possible impact on the development of the nervous system, hearing, vision, the sexual system, especially the female, and also the metabolic and functional systems that form in the fetus are preserved. Thus, atrophy of the optic nerves, deafness, hydrocephalus and mental retardation are observed in newborns whose mothers used 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 connected with the violation of the processes of fine differentiation of metabolic processes in the brain tissues and functional neuronal connections under the influence of sex steroid hormones.

In addition to the period of exposure, the dose of the drug, the specific sensitivity of the organism to the action of the drug, and the hereditarily determined sensitivity of an individual to the action of a given drug are of great importance for drug teratogenesis. So, thalidomide tragedy in many respects occurred because the action of this drug in the experiment was studied in rats, hamsters and dogs, which, as it turned out, are not sensitive to the action of thalidomide in the future. At the same time, the fruit of the mouse proved to be sensitive to the action of acetylsalicylic acid and highly sensitive to glucocorticosteroids. The latter when applied in the early stages of pregnancy in humans lead to cleavage of the palate in no more than 1% of cases. It is important to assess the degree of risk of use during pregnancy of certain classes of drugs. According to the recommendation of the Office of Food and Drug Administration (FDA), all drugs, depending on the degree of risk and the level of adverse, especially teratogenic effects on the fetus, are divided into five groups.

1. Category X - preparations, teratogenic effect of which is proved in the experiment and clinic. The risk of their use during pregnancy exceeds the possible benefits, in connection with which they are categorically contraindicated to pregnant women.
2. Category D - preparations, teratogenic or other adverse effect of which on the fetus is established. Their use during pregnancy is risky, but it is lower than the expected benefit.
3. Category C - preparations whose teratogenic or embryotoxic effect is established in the experiment, but no clinical trials have been conducted. The use of the application exceeds the risk.
4. Category B - preparations, teratogenic effect of which was not detected in the experiment, and embryotoxic effect was not found in children whose mothers used this drug.
5. Category A: no adverse effects of the drug on the fetus were detected in the experiment and in controlled clinical trials.

Medicines that are absolutely contraindicated during pregnancy (category X)

Medications	Effects on the fetus
Aminopterin	Multiple anomalies, postnatal retardation of fetal development, abnormalities of the facial part of the skull, death of the fetus
Androgens	Masculinization of the female fetus, shortening of the limbs, tracheal anomalies, esophagus, cardiovascular system defects
Diethylstilbestrol	Adenocarcinoma of the vagina, pathology of the cervix, pathology of the penis and testicles
Streptomycin	Deafness
Diyulphirs	Spontaneous abortions, cleavage of limbs, club foot
Ergotamine	Spontaneous abortions, symptoms of irritation of the central nervous system
Estrogens	Congenital heart defects, feminization of the male fetus, vascular anomalies
Inhalation anesthetics	Spontaneous abortions, malformations
Iodides, iodine 131	Goiter, hypothyroidism, cretinism
Quinine	Mental retardation, ototoxicity, congenital glaucoma, abnormalities of the urinary and reproductive systems, death of the fetus
Thalidomide	Defects of limbs, anomalies of the heart, kidneys and digestive tract
Trimetadione	Characteristic face (Y-shaped eyebrows, epicenture, underdevelopment and low position of the auricles, rare teeth, cleft of the upper palate, low set eyes), abnormalities of the heart, esophagus, trachea, mental retardation
Synthetic retinoids (isotretinoin, etretinate)	Anomalies of the extremities, facial part of the skull, heart defects, central nervous system (hydrocephalus, deafness), urinary and reproductive systems, underdevelopment of the auricles. Mental retardation (> 50%)
Raloxifene	Violations of the development of the reproductive system
Progestins (19-norsteroids)	Masculinization of the female fetus, an increase in the clitoris, lumbosacral fusion

Medicines, the use of which during pregnancy is associated with a high risk (Category B)

Medications	Consequences for the fetus of a newborn
Antibiotics Tetracyclines (doxycycline, demeclopicline, minocycline) Aminoglycosides (amikacin, kanamycin, neomycin, netilmicin, tobramycin) Fluoroquinolones Chloramphenicol (levomycetin)	Safe for the first 18 weeks of pregnancy. In later terms, discoloration of the teeth (brown color), hypoplasia of the tooth enamel, impaired bone growth Congenital deafness, nephrotoxic effect Act on cartilaginous tissue (chondrotoxicity) Agranulocytosis, aplastic anemia, gray-syndrome in the neonatal period
Nitrofurintoin	Hemolysis, yellow color of teeth, hyperbilirubinemia in the neonatal period
Antiviral drugs 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. A teratogenic effect is described in two species of animals
Antifungal means 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 intrauterine malformations
Antiparasitic products Albendazole	In an experiment on some species of animals, the teratogenic effect was registered
Antidepressants Lithium carbonate Tricyclic MAO inhibitors	Congenital heart diseases (1: 150), especially often Ebstein's anomaly, cardiac arrhythmias, goitre, CNS depression, arterial hypotension, neonatal cyanosis Respiratory disorders, tachycardia, urinary retention, newborn's distress syndrome Slowing fetus and newborn development, reactions
Coumarin derivatives	Warfarin (coumarinic) embryopathy in the form of hypoplasia of the nose, atresia, khon, 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 III trimester of pregnancy)
Anticonvulsant drugs Phenytoin (diphenin) Valproic acid Phenobarbital	Hydantoin fetal syndrome (expanded flat and low situated, short nose, ptosis, hypertelorism, upper jaw hypoplasia, large mouth, protruding lips, non-extension of the upper lip, etc.) Splitting of the spine, palate, often additional minor anomalies - hemangiomas, inguinal hernia, divergence of direct abdominal muscles, telangiectasia, hypertelorism, deformation of the auricles, delayed development. CNS depression, hearing loss, anemia, tremor, withdrawal syndrome, hypertension
ACE Inhibitors	Malignant, hypotrophy, limb contractures, deformation of the facial part of the skull, lung hypoplasia, sometimes antenatal death (more dangerous in the second half of pregnancy)
Reserpine	Hyperemia of the nasal mucosa, hypothermia, bradycardia, CNS depression, lethargy
Chlorokhin	Nervous disorders, hearing, balance, vision
Antineoplastic agents	Multiple deformities, frozen pregnancy, intrauterine growth retardation of the fetus
Antithyroid drugs (thiamazole)	Goiter, ulceration of the middle part of the scalp
Inhibitors of pituitary hormones Danazol Gesterinon	At reception after 8 ned, from the moment of conception can cause virilization of a fetus of a female. May cause masculinization of a female fetus
Benzodiazepine derivatives (diazepam, hlozepid)	Depression, drowsiness in the neonatal period (due to very slow elimination), Rarely - developmental abnormalities resembling alcoholic fetal syndrome, congenital heart and vascular malformations (not proven)
Vitamin D in a large dose	Calcification of organs
Penicillamine	Possible defects in the development of connective tissue - developmental delay, skin pathology, varicose veins, fragility of venous vessels, hernia

In conclusion, I would like to note that despite the 40 years that have passed since the first description of cases of drug teratogenesis, the study of this problem is still largely in the stage of accumulation and initial comprehension of the material, which is due to a number of reasons. Only a relatively small list of drugs is systematically applied and can not always be abolished in the patient due to pregnancy (antiepiletic, anti-tuberculosis, tranquilizers for mental illnesses, oral hypoglycemic drugs for diabetes, anticoagulants after prosthetic cardiac valves, etc.). It is the side effect on the fetus of such drugs that has 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 in accordance with international rules, their possible teratogenic effect is investigated, there are specific differences that prevent the preclinical research or clinical trials from fully assessing drug safety in the plan for having a teratogenic effect. These data can be obtained only by conducting costly multicenter pharmaco-epidemiological studies with the analysis of the use of a given medicine by a large number of patients. Significant difficulties are the evaluation of the long-term effects of the use of drugs during pregnancy, especially if it is a question of their possible impact on the mental status or behavioral reactions of a person, since their characteristics may be not only a consequence of the use of drugs, but also be determined by hereditarily deterministic factors, social conditions of life and upbringing of a person, as well as by the action of other unfavorable (including chemical) factors, by recording various deviations in fetal development Does the child after using the drug pregnant, it is difficult to differentiate whether this is the result of a drug or a consequence of effects on the fetus pathogen that caused the need for the drug.

The consideration by physicians of various specialties in their daily activities already accumulated to date the facts will allow to optimize the pharmacotherapy of diseases both before and during pregnancy and avoid the risk of side effects of drugs on the fetus.