Effects of medications on the fetus

The problem of assessing the possible negative effect of drugs on the fetus is one of the most difficult when solving issues of safe pharmacotherapy both before and during pregnancy. According to literature data, at present, from 10 to 18% of children born have some kind of developmental abnormality. In 2/3 of cases of congenital anomalies, the etiological factor that caused them, as a rule, cannot be established. It is believed that these are combined (including medicinal) effects and, especially, genetic disorders and other defects of the hereditary apparatus. However, for at least 5% of anomalies, their direct cause-and-effect relationship with the use of drugs during pregnancy is established.

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History of the study of the effects of drugs on the fetus

In the early 1960s, when almost 10,000 children with phocomelia were born in Europe, the relationship between this developmental deformity and the use of the tranquilizer thalidomide during pregnancy was proven, i.e. the fact of drug teratogenesis was established. It is characteristic that preclinical studies of this drug, carried out on several types of rodents, did not reveal any teratogenic effect. 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 it during pregnancy until the complete safety of such a drug is confirmed after conducting a statistical analysis of its use by pregnant women,

In the late 1960s, the fact of drug-induced teratogenesis was established, which had a different nature. It was determined that many cases of squamous cell vaginal cancer in puberty and adolescence were registered in girls whose mothers took diethylstilbestrol during pregnancy - a synthetic drug of non-steroidal structure with a pronounced estrogen-like effect. It was later found that in addition to tumors, such girls more often had various anomalies in the development of the genitals (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 the postnatal period. In other words, it was proven that the side effects of drug use during pregnancy can be registered 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 of a number of hormonal drugs (initially synthetic progestins, and then some glucocorticoids) prescribed to pregnant women on the fetus, the fact of so-called behavioral teratogenesis was established. Its essence lies in the fact that until the 13th-14th week of pregnancy there are no sex differences in the structure, metabolic and physiological indices of the fetal brain. Only after this period do the features characteristic of males and females begin to appear, which subsequently determine the differences between them in behavior, aggressiveness, cyclicity (for women) or acyclicity (for men) of the production of sex hormones, which is obviously associated with the sequential inclusion of hereditarily determined mechanisms that determine the sexual, including psychological differentiation of the subsequently forming male or female organism.

Thus, if at first drug-induced 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 has been 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 birth or in the postnatal period.

In some cases, teratogenesis may be caused by mutations in the parents' germ cells. In other words, the teratogenic effect in this case is indirect (through mutations) and delayed (the effect on the parents' body occurs long before pregnancy). In such cases, the fertilized egg may be defective, which automatically leads either to the impossibility of its fertilization or to its abnormal development after fertilization, which, in turn, may end either in spontaneous termination of embryo development or in the formation of certain anomalies in the fetus. An example is the use of methotrexate in women for the conservative treatment of ectopic pregnancy. Like other cytostatics, the drug suppresses mitosis and inhibits the growth of actively proliferating cells, including germ cells. Pregnancy in such women occurs with a high risk of fetal developmental anomalies. Due to the pharmacodynamics of antitumor agents, after their use in women of reproductive age, there will be a risk of giving birth to a child with developmental anomalies, which should be taken into account when planning pregnancy in such patients. After antineoplastic therapy, women of childbearing age should be classified as a risk group for developing fetal developmental anomalies, which subsequently requires prenatal diagnostics, starting from the early stages of pregnancy.

A certain danger is also posed by drugs with prolonged action, which, when administered to a non-pregnant woman, remain 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 to treat psoriasis and congenital ichthyosis - has a half-life of 120 days and has an experimental teratogenic effect. Like other synthetic retinoids, it belongs to the class of substances that are absolutely contraindicated for use during pregnancy, as it causes developmental abnormalities of the limbs, facial and cranial bones, heart, central nervous, urinary and reproductive systems, and 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 a group of drugs that are absolutely contraindicated during pregnancy. In case of refusal to use the drug before the onset of safe pregnancy, patients must use other methods of contraception for 2 years.

How do medications affect the fetus?

Most often, fetal developmental anomalies are the result of abnormal development of the fertilized egg due to the effect of unfavorable factors, in particular drugs. The period of influence of this factor is of great importance. Three such periods are distinguished in relation to humans:

1. up to 3 weeks of pregnancy (the period of blastogenesis). Characterized by rapid segmentation of the zygote, formation of blastomeres and blastocyst. Due to the fact that during this period there is no differentiation of individual organs and systems of the embryo, it was believed for a long time that at this stage the embryo is insensitive to drugs. Later it was proven that the effect 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 (embryolethary effect) and spontaneous abortion. Since the drug effect in such cases occurs even before the fact of pregnancy is established, the fact of termination of pregnancy often remains unnoticed by the woman or is regarded as a delay in the onset of the next menstruation. Detailed histological and embryological analysis of the abortion material showed that the effect of drugs in this period is characterized mainly by a general toxic effect. It has also been proven that a number of substances are active teratogens in this period (cyclophosphamide, estrogens);
2. The 4th-9th weeks of pregnancy (the period of organogenesis) are considered the most critical period for the induction of birth defects in humans. During this period, there is intensive division 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 continues 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 can be disrupted and congenital malformations can form;
3. the fetal period, by the beginning of which the differentiation of the main organs has already occurred, is characterized by histogenesis and growth of the fetus. During this period, biotransformation of drugs in the mother-placenta-fetus system is already taking place. The formed placenta begins to perform a barrier function, due to which 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 abnormalities and is characterized by a slowdown in fetal growth. At the same time, their possible impact on the development of the nervous system, organs of hearing, vision, the reproductive system, especially the female, as well as the metabolic and functional systems forming in the fetus remains. Thus, atrophy of the optic nerves, deafness, hydrocephalus and mental retardation are observed in newborns whose mothers used the coumarin derivative warfarin in the second and even third trimesters of pregnancy. During this same period, the phenomenon of “behavioral” teratogenesis described above is formed, which is obviously associated with the disruption of the processes of fine differentiation of metabolic processes in the tissues of the brain and the functional connections of neurons under the influence of sex steroid hormones.

In addition to the duration of action, the dose of the drug, the species-specific sensitivity of the organism to the action of the drug, and the hereditary sensitivity of an individual to the action of a particular drug are of great importance for drug teratogenesis. Thus, the thalidomide tragedy largely occurred because the effect of this drug was experimentally 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 turned out to be 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 recommendations of the US Food and Drug Administration (FDA), all drugs are divided into five groups depending on the degree of risk and the level of adverse, primarily teratogenic, effects on the fetus.

1. Category X - drugs whose teratogenic effect has been proven experimentally and clinically. The risk of their use during pregnancy exceeds the possible benefit, and therefore they are strictly contraindicated for pregnant women.
2. Category D - drugs whose teratogenic or other adverse effects on the fetus have been established. Their use during pregnancy is associated with risk, but it is lower than the expected benefit.
3. Category C - drugs whose teratogenic or embryotoxic effects have been established experimentally, but clinical trials have not been conducted. The benefits of use outweigh the risks.
4. Category B - drugs whose teratogenic effect has not been detected in experiments, and whose embryotoxic effect has not been detected in children whose mothers used this drug.
5. Category A: Experimental and controlled clinical trials have not revealed any negative effects of the drug on the fetus.

Medicines absolutely contraindicated during pregnancy (category X)

Medicines	Consequences for the fetus
Aminopterin	Multiple anomalies, postnatal growth retardation, facial anomalies, fetal death
Androgens	Masculinization of the female fetus, shortening of the limbs, anomalies of the trachea, esophagus, defects of the cardiovascular system
Diethylstilbestrol	Vaginal adenocarcinoma, cervical pathology, penile and testicular pathology
Streptomycin	Deafness
Dieulfiram	Spontaneous abortions, cleft limbs, clubfoot
Ergotamine	Spontaneous abortions, symptoms of CNS irritation
Estrogens	Congenital heart defects, feminization of the male fetus, vascular anomalies
Inhalational anesthetics	Spontaneous abortions, malformations
Iodides, iodine 131	Goiter, hypothyroidism, cretinism
Quinine	Mental retardation, ototoxicity, congenital glaucoma, urinary and reproductive system abnormalities, fetal death
Thalidomide	Limb defects, cardiac, renal and gastrointestinal tract abnormalities
Trimethadione	Characteristic face (Y-shaped eyebrows, epicanthus, underdeveloped and low-set ears, sparse teeth, cleft palate, low-set eyes), abnormalities of the heart, esophagus, trachea, mental retardation
Synthetic retinoids (isotretinoin, etretinate)	Anomalies of the limbs, facial part of the skull, heart defects, central nervous system (hydrocephalus, deafness), urinary and reproductive systems, underdevelopment of the auricles. Mental retardation (>50%)
Raloxifene	Disorders of the reproductive system development
Progestins (19-norsteroids)	Masculinization of the female fetus, clitoral enlargement, lumbosacral fusion

Medicines associated with high risk during pregnancy (category B)

Medicines	Consequences for the fetus and newborn
Antibiotics Tetracyclines (doxycycline, demeclopicline, minocycline) Aminoglycosides (amikacin, kanamycin, neomycin, netilmicin, tobramycin) Fluoroquinolones Chloramphenicol (chloramphenicol)	Safe during the first 18 weeks of pregnancy. At later stages, they cause tooth discoloration (brown coloring), hypoplasia of tooth enamel, and impaired bone growth. Congenital deafness, nephrotoxic effect. Affects cartilage tissue (chondrotoxicity). Agranulocytosis, aplastic anemia, and gray syndrome in the neonatal period.
Nitrofurintoin	Hemolysis, yellowing of teeth, hyperbilirubinemia in the neonatal period
Antiviral agents Ganciclovir Ribavirin Zalcitabine	In experiments, it has a teratogenic and embryotoxic effect. It has a teratogenic and/or embryolethal effect in almost all animal species. A teratogenic effect has been described in two animal species.
Antifungal agents Griseofulvin Fluconazole	Arthropathies A single dose of 150 mg does not have a negative effect on the course of pregnancy. Regular intake of 400-800 mg/day causes intrauterine malformations
Antiparasitic drugs Albendazole	In experiments 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 syndrome Delayed fetal and neonatal development, behavioral disorders
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 (diphenin) Valproic acid Phenobarbital	Hydantoin fetal syndrome (widened flat and low-lying nasal bridge, short nose, ptosis, hypertelorism, hypoplasia of the maxilla, large mouth, protruding lips, cleft upper lip, etc.) Spina bifida, palate, often additional minor anomalies - hemangiomas, inguinal hernia, divergence of the rectus abdominis muscles, telangiectasias, hypertelorism, deformation of the auricles, delayed development. CNS depression, hearing loss, anemia, tremor, withdrawal syndrome, arterial hypertension
ACE inhibitors	Oligohydramnios, hypotrophy, contractures of the limbs, deformation of the facial part of the skull, hypoplasia of the lungs, sometimes antenatal death (more dangerous in the second half of pregnancy)
Reserpine	Hyperemia of the nasal mucosa, hypothermia, bradycardia, CNS depression, lethargy
Chloroquine	Nervous disorders, hearing, balance, vision disorders
Antitumor agents	Multiple deformities, frozen pregnancy, intrauterine growth retardation of the fetus
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 may cause virilization of the female fetus. It may cause masculinization of the female fetus.
Benzodiazepine derivatives (diazepam, clozepide)	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	Calcification of organs
Penicillamine	Connective tissue development defects are possible - developmental delay, skin pathology, varicose veins, venous fragility, hernias

In conclusion, it should be noted that despite the 40 years that have passed since the first description of drug-induced teratogenesis cases, 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 discontinued in a patient due to pregnancy (antiepileptic, antituberculosis, tranquilizers for mental illness, oral hypoglycemic drugs for diabetes, anticoagulants after cardiac valve replacement, etc.). It is the side effects of such drugs on the fetus 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 studied in accordance with international rules, there are species differences that do not allow a full assessment of the safety of the drug in terms of its teratogenic effect at the stage of preclinical studies or clinical trials. These data can be obtained only by conducting expensive multicenter pharmaco-epidemiological studies with an analysis of the use of a particular drug by a large number of patients. Significant difficulties are associated with the assessment of the remote effects of drug use during pregnancy, especially when it comes to their possible impact on a person's mental status or behavioral reactions, since their characteristics may not only be a consequence of drug use, but also be determined by hereditary factors, social conditions of life and upbringing of a person, as well as the effect of other unfavorable (including chemical) factors. When registering certain deviations in the development of the fetus or child after the use of a drug by a pregnant woman, it is difficult to differentiate whether this is a result of the drug or a consequence of the effect on the fetus of a pathogenic factor that necessitated the use of this drug.

Taking into account the facts already accumulated by now by doctors of various specialties in their daily activities will allow optimizing drug therapy of diseases both before and during pregnancy and avoiding the risk of side effects of drugs on the fetus.