1.Introduction
The dependence on drugs is currently increasing throughout society, and hundreds of new drugs are still being introduced to the market every year in addition to the tens of thousands of existing drugs, while women during pregnancy need to be treated and managed with drugs due to certain physiological reactions and diseases. Therefore, the proper use of medications during pregnancy is undoubtedly important for the prevention of birth defects in newborns.
This lecture introduces the application of neuropsychiatric drugs in pregnancy for clinical reference according to the 5 categories of classification standard A, B, C, D, and X of drug risk to pregnancy issued by FDA, in increasing order of risk.
2. Drugs that mainly act on the central nervous system
2.1 Thalidomide
Thalidomide, also known as reactive stop, has the trade name of phthalimide piperidone, which is classified as Class X by FDA and is the first drug that is clearly classified as a human teratogen and has created the history of teratogenic research on drugs, which has significant clinical pharmacological effects on suppressing the central nervous system and is also very effective for pregnancy vomiting and influenza.
The teratogenic effect of thalidomide was once called the “Reactive Stop Incident”, and more than 10,000 cases of children with “Reactive Stop” malformation were reported in more than 30 countries between 1953 and 1962, which became a worldwide catastrophic incident of congenital malformation. The deformity caused by this disease is mainly missing (short) limb deformity, also known as “seal deformity”. Since 1962, all countries have stopped the use of stop reactions, but in recent years some countries in Europe and the United States began to use stop reactions to treat leprosy and graft-versus-host disease, the media called “stop reactions are back! . Therefore, clinicians should be familiar with the toxicity and teratogenicity of this drug.
Toxicity and teratogenicity: The general toxicity of RAD is extremely low in animals and humans, and several suicide attempts have been made without significant signs of toxicity after taking large amounts of RAD. However, it has different degrees of teratogenic effects on about fifteen species (lineages) of animals, and its toxicity to embryos is significantly greater than that of mothers, i.e., it acts selectively on embryos, and its teratogenic sensitivity varies greatly between species. The teratogenic dose is 500mg/kg for rabbits and 1mg/kg for humans.
Clinical manifestations: limb and limb girdle deformities are the main clinical manifestations of the reactive arrest deformity syndrome. In the mildest cases, only the thumb deformity is present, while in severe cases, complete limb deformity can be observed. The deformities are mostly symmetrical, but the severity of the two sides is significantly different, and the lower limbs are less severe than the upper limbs. The location and degree of limb deformity varies depending on the duration of maternal drug use, but there is no significant correlation with drug dose.
Reactive withdrawal can also cause malformations of internal organs and sensory organs, including: cardiac malformations, laryngeal and tracheal malformations, renal malformations (ectopic kidney, pelvic kidney, horseshoe kidney), double vagina, anal stenosis and atresia. Cardiac malformations are the main cause of death in these patients.
The mechanism of teratogenesis: The reactive stop can cross the placenta and enter the embryo by simple diffusion and maintain the concentration similar to that of the mother for more than 59 h. More than 20 theories have been proposed over the past 30 years to elucidate the teratogenic mechanism of the reactive stop, but it is still not clear. At present, the main theories to explain the teratogenic mechanism of reactive stop include nucleic acid embedding, folic acid antagonism and secondary peripheral neuropathy.
The mental retardation and mental retardation caused by the treatment are not considered to be the direct effect of the treatment, but may be secondary to sensory loss or other disabilities. Some scholars reported that 60 cases of men and women who were affected by the effects of reactive drugs had no congenital short limb deformities in their offspring after marriage.
2.2 Central Excitatory Drugs
Caffeine FDA classified as Class B. Caffeine can pass through the placenta, and the concentration of the drug in the umbilical cord blood is similar to that of the maternal blood. Animal experiments found that in non-mammalian animals, this product has mutagenic and carcinogenic effects, and when pregnant animals receive up to toxic doses of this product has a teratogenic effect on the fetus, but no such effect on humans.
The incidence of spontaneous abortion, preterm delivery, low birth weight babies and congenital malformations was not increased by moderate doses of caffeine in pregnant women. The half-life of caffeine in pregnant women is significantly longer, and the drug is present in the body about 2-3 times longer than in non-pregnant women. Continuous use of the drug in early pregnancy can lead to fetal limb deformities and osteogenic dysplasia.
2.3 Anti-convulsive paralytic drugs
Bromocriptine (bromocriptine) is classified as Class B by the FDA. It is currently considered safe for the fetus if the condition requires treatment during pregnancy. If a pregnancy is diagnosed during the course of treatment of infertility, the treatment should be terminated immediately.
2.4 Anti-psychotic drugs
2.4.1 Chlorpromazine (Dormant) is classified as Class C by the FDA. This product readily passes through the placenta. Animal studies have found embryotoxic effects on rodent
It has been found in animal studies to have embryotoxic effects on fetuses of rodents, and also has selective accumulation in the pigment epithelium of the fetal eye. In humans, there are no reports of retinopathy in the fetus due to long-term high dose use in pregnant women, but caution should be exercised for such potential adverse effects on the fetus.
It was widely used in the mid-1950s to treat pregnancy vomiting and was considered safe and effective. Its use during labor was associated with an excessive drop in blood pressure in about 18% of women and endangered both the mother and the fetus, so its use is now discouraged. The use of high doses of chlorpromazine in pregnant women with psychiatric disorders near delivery can cause hypotonia, lethargy, jaundice, and extrapyramidal symptoms in the newborn.
According to the 1977 U.S. National Perinatal Collaborative Program, 142 pregnant women who used this product in early gestation and #L& at various stages of pregnancy had no abnormalities in neonatal malformations, perinatal morbidity and mortality, birth weight, or IQ scores at & years of age.
2.4.2 Haloperidol (haloperidol) is classified as Class C by the FDA. It is a butylphenyl antipsychotic. Animal studies have not found teratogenic effects of this product. Its use in early pregnancy may cause fetal limb deformities, shortened limbs, curly toes, intrauterine growth retardation and gastrointestinal insufficiency. There are two cases reported in the literature that the use of this product in early pregnancy resulted in malformation of the newborn.
Central depression, respiratory distress, anxiety, extrapyramidal symptoms, muscle weakness, difficulty in sucking, jaundice and leukopenia may occur in fetuses and newborns during the middle and late stages of pregnancy. However, there is no epidemiological data to confirm the teratogenic effect of this product.
Data from the Michigan Institute for Experimental Drug Monitoring (MIEMR) from 1985 to 1992 showed that 56 pregnant women who used this product during the first trimester of pregnancy had three newborns with severe malformations, two of which were cardiovascular malformations. No adverse effects on the fetus were observed with the use of this product in the early, middle, and late stages of pregnancy for the treatment of pregnancy vomiting, gestational chorea, and bipolar disorder (previously known as manic-depressive psychosis), respectively.
2.4.3 Promethazine (Mipramine), classified as Class D by FDA. It is a typical drug of tricyclic antidepressant, and is used to treat major depressive disorder, depressive episode of bipolar disorder, poor mood, and panic-terror disorder with good efficacy. Animal experiments have found teratogenic effects on some animals. It has been reported in the literature that 161 pregnant women used this product during the first 3 months of pregnancy, and none of their newborns showed limb shortage deformities.
According to the data from the Michigan Institute for Experimental Drug Monitoring and Research (MIEMR) from 1985 to 1992, 75 pregnant women who used this drug during the first 3 months of pregnancy had 6 newborns with severe malformations, including 3 cases of cardiovascular malformations. The use of the drug in early pregnancy may cause multiple bone malformations, short limbs, cleft lip, cleft palate, herniated cerebrospinal membrane, hydrocephalus, brain herniation, cranial malformation, small jaw, diaphragm, abdominal muscle defects and stillbirth in the fetus. The use of the drug before delivery may cause tachycardia, heart failure, myoclonus, respiratory distress, excitement, urinary retention and feeding difficulties in the fetus and newborn. Do not use during pregnancy.
2.4.4 Lithium carbonate, classified as Class D by the FDA, is the only specific and effective drug for the prevention and treatment of bipolar disorder, and generally requires more than 2-3 weeks of continuous application to receive therapeutic effects. It is also effective in major depressive disorder. Bipolar disorder usually starts at the age of 20-30 years and is more common in women. Therefore, this drug is often used in pregnant women.
Lithium carbonate is highly likely to pass through the placenta into the circulation of the fetus and into the amniotic fluid. Animal studies have found that lithium carbonate has teratogenic effects on rat fetuses. According to the data from the Danish registry of intrauterine exposure to lithium preparations in 1986, 183 pregnant women who used lithium carbonate in the first three months of pregnancy had 20 newborns with severe malformations, 15 of which were cardiovascular malformations, and shockingly, 5 cases of Ebstein syndrome (a right atrioventricular valve malformation combined with atrial septal defect cardiovascular anomalies), compared to the normal population. Other malformations include hydrocephalus combined with spina bifida, spinal cord herniation, deformed foot and microtia.
However, a prospective study conducted by Jacobcon et al. in 1992 found that the use of lithium carbonate during the first trimester of pregnancy had a limited chance of causing fetal malformations. Based on the available information, pregnant women who used lithium carbonate during the first trimester had a 1 in 8000 chance of having a newborn with Ebstein’s syndrome, which is 2.5 times higher than the normal population. According to the Michigan Institute for Experimental Drug Monitoring and Research from 1985 to 1992, 62 pregnant women who used lithium carbonate during the first trimester had only 2 newborns with severe malformations, and none of them had cardiovascular malformations.
Late gestational drug use mainly results in cyanosis, hypotonia, respiratory distress, drowsiness, cardiac arrhythmias, and renal and thyroid dysfunction in newborns. Most of these toxic manifestations disappear 7-14 days after the birth of the newborn. Therefore, lithium carbonate should be avoided during pregnancy.
2.5 Anti-epileptic drugs
2.5.1 Phenytoin Phenytoin is the sodium salt of diphenhydramine, which is classified as Class D by the FDA; the same family of drugs includes methotrexate and etanercept, which are classified as Class C by the FDA. This class of drugs is mainly used for the treatment of epilepsy A.
Epilepsy A is a common disease in women of childbearing age. According to the data, about one in every 200 pregnant women is a patient with epilepsy A. About 50% of patients with epilepsy A have the same number of seizures after pregnancy as before pregnancy, and another 40% of patients with epilepsy A will have more frequent seizures after pregnancy.
Since 1963, when Muller-Kuppers first suspected that antiepileptic A drugs had teratogenic effects in humans, a growing body of data has shown that women with epilepsy A who take phenytoin antiepileptic A drugs during pregnancy have a significantly increased risk of congenital malformations in their offspring. in 1975 Hanson and Smisth reported five cases of newborns born to mothers taking etanercept with congenital malformations, and named for the first time the fetal ethaneurea syndrome. It is estimated that approximately 5-10% of fetuses born to mothers exposed to these drugs during embryonic development have the classic ethaneurea syndrome.
Clinical manifestations: (1) craniofacial deformities, the most common facial features are short nose, wide and flat nasal bridge, upper canthus, wide eye spacing, droopy eyelids, strabismus, wide mouth, cleft tongue, short neck with cervical web deformity, some patients have cleft lip or palate; (2) finger end deformities, including finger (toe) bones and finger (toe) nail hypoplasia; (3) growth abnormalities, prenatal growth retardation, postnatal dysplasia (3) abnormal growth, prenatal retardation, postnatal dysplasia, microcephaly; (4) behavioral abnormalities, mental retardation or retardation, or even obvious mental retardation and mental defects; (5) the use of drugs in the middle and late stages of pregnancy can lead to neonatal hemorrhagic tendency and withdrawal syndrome. The hemorrhage can be prevented with vitamin K in the last 30 days of pregnancy or during delivery.
Teratogenic mechanism: It is still not well understood, but some theories suggest that the epoxide produced by the metabolism of phenytoin interferes with the macromolecular function of the embryo in the developmentally sensitive stage, thus producing teratogenic effects and causing embryonic malformations. Genetic factors may also play a role in the development of fetal etanercept syndrome.
The only preventive measure available is to avoid intrauterine fetal exposure to teratogens, but no alternative drug for the treatment of epilepsy A that is safe for the fetus has been identified. Therefore, single-drug therapy should be used whenever possible, and women of childbearing age with epilepsy A should be informed of the teratogenicity of such drugs for the fetus before pregnancy. On the other hand, current prenatal diagnostic methods are not yet able to definitively determine whether the fetus has developmental abnormalities.
2.5.2 Trimethoprim Trimethoprim is also known as p-methoprim, both of which are classified as Class D by the FDA and are commonly used to treat petit mal seizures in A. Both drugs were first discovered in Germany in 1970 to cause congenital malformations in the fetus, which have since been named “trimethoprim syndrome”. Current data show that the incidence of trimethoprim syndrome in fetuses of women taking trimethoprim during pregnancy is as high as 69%, and some newborns have birth defects of varying degrees, with only about 17% being born normal, and about 30% of newborns with trimethoprim syndrome dying in the neonatal period. The teratogenic dose of these drugs in humans is about 13-22 mg/kg.d.
The clinical manifestations of trimethoprim syndrome are: developmental delay, mental retardation, V-shaped bones, medial canthus, low ears combined with anterior folded ears, palatal anomalies, irregular teeth, etc. Some children with trimethoprim syndrome also have intrauterine growth retardation, short stature, microcephaly, heart defects, strabismus and/or myopia, hypospadias, and inguinal hernia.
Pregnant women with petit mal seizures requiring treatment with trimethoprim should be informed prior to pregnancy that the drug may be teratogenic. This drug is contraindicated in pregnant women and in women who may become pregnant while taking the drug.
2.5.3 Brominating agents Brominating agents include sodium bromide, potassium bromide, and ammonium bromide, all classified as Class D by the FDA. The use of brominated agents in early pregnancy may result in fetal malformations, mainly polydactyly, clubfoot, gastrointestinal malformations, congenital hip dislocation, poor sucking response of the newborn, diminished clutch reflex, and hypotonia.
2.6 Sedative, hypnotic and anticonvulsant drugs
2.6.1 Diazepam (Valium) is classified as Class D by the FDA. This product easily passes through the placenta. The drug concentration in the mother’s blood is similar to that in the umbilical cord blood 5-10 minutes after intravenous injection of this product to a pregnant woman, and the drug concentration in the umbilical cord blood can be 1-3 times higher than that in the mother’s blood. Animal studies have found teratogenic effects of this product, and more fetuses have cleft palate, but there is not enough evidence to confirm the teratogenic effect of this product in humans. The use of the drug in early pregnancy can cause a variety of fetal malformations, including cleft lip, cleft palate, congenital inguinal hernia and heart malformation.
However, according to some research data, the use of this product during the first trimester of pregnancy has no significant effect on the occurrence of cleft lip and cleft palate, and the incidence of cleft lip and cleft palate is 0.2-0.4%, respectively. The incidence of hemangiomas and cardiac malformations can occur in the middle of pregnancy, and the incidence of congenital malformations is 3-7 times higher than in the normal population when combined with smoking.
The use of this product in late pregnancy or during delivery may result in loss of fetal heart rate variability and decreased fetal movement. In 1995, Pan Boshen et al. reported that intravenous injection of this product during active labor had a certain inhibitory effect on newborns, and its effect could be maintained for 4-6 hours, so this product should not be used when the mother enters active labor.
2.6.2 Phenobarbital mainly includes pentobarbital FDA classified as Class D, isopentobarbital FDA classified as Class B, scobarbital FDA classified as Class D. Phenobarbital has hypnotic and anticonvulsant effects. Animal studies have found that barbiturates may have teratogenic effects. The use of drugs in early pregnancy can cause fetal coagulation dysfunction, intrauterine asphyxia, stunted growth, droopy eyelids, wide eye spacing, low nasal bridge, harelip and cleft palate, etc. The use of drugs in the middle and late pregnancy can cause neonatal central nervous depression, brain injury hemorrhagic tendency and withdrawal syndrome.
In the late pregnancy near delivery, larger doses or long-term use can cause respiratory depression or withdrawal syndrome in newborns, such as hyperactivity, tremor, crying and sleep disturbance, etc. Therefore, use with caution in pregnant women.
2.6.3 Chloral hydrate is classified as Class C by the FDA. This product is an older hypnotic drug. Because of its rapid, safe and effective action, it is still commonly used as a hypnotic drug. It has a sedative effect on the fetus, but there are no reports of fetal malformations caused by its application. The drug concentration in umbilical cord blood is similar to that in maternal blood when applied during delivery.
Both the drug and its active metabolites can enter breast milk. The drug concentration in breast milk peaked at 8 mg/L 45 minutes after rectal application of 1.5 g of this product in lactating women, and only trace amounts of the drug could be detected in breast milk 10 hours after administration. The American Academy of Pediatrics considers that the application of this product during lactation can continue to breastfeed.
2.7 Antipyretic and anti-inflammatory drugs
2.7.1 Antipyretic and analgesic drugs such as aspirin and other salicylates are classified as Class C by the FDA, which are easily absorbed into the placenta and can cause damage to fetal cartilage, lung, kidney and cornea. It may also be related to the high absorption rate of the drug during pregnancy; the use of the drug during the perinatal period may inhibit the platelet function of the fetus and the newborn, causing internal bleeding in the newborn; long-term use of the drug may inhibit the excretion of maternal estrogen, prolonging labor and increasing the incidence of stillbirth, so it should be used with caution or contraindicated in pregnant women.
Paracetamol (acetaminophen, paracetamol), classified as Class C by FDA. It can cause fetal and neonatal liver damage, kidney damage, kidney failure, congenital cataract and amniotic fluid overload, etc. Large doses can cause accelerated destruction of red blood cells and cause severe anemia in mothers.
2.7.2 Anti-inflammatory and analgesic drugs Indomethacin, classified as Class B by FDA. It may cause fetal cleft lip, cleft palate and other malformations in early pregnancy, and may cause cardiac and pulmonary dysfunction, pulmonary hypertension and hemorrhage in newborns in middle and late pregnancy and during labor. The combination of this product and aminopterin may cause renal dysfunction.
2.8 Analgesics and morphine antagonists
Morphine FDA classified as Class C, opioid FDA classified as Class C, pethidine (dulcolax) FDA classified as Class B, are suspected of teratogenic drugs, early pregnancy, may cause fetal chromosomal aberrations, immature children or stillbirth, prenatal use of drugs can lead to maternal and neonatal respiratory depression, and can cause neonatal excitement, tremors, seizures, nausea, vomiting and other withdrawal-like symptoms. Addiction in pregnant women can increase the incidence of miscarriage, and pregnant women should use caution in early pregnancy and contraindicated in the perinatal period.
3. Drugs that mainly act on the autonomic nervous system
3.1 Cholinomimetic drugs
These drugs are classified as Class C by FDA. Among them, acetylcholine and neostigmine have teratogenic or fetocidal effects in animal experiments, so use with caution during pregnancy. These drugs also include pyridostigmine, ampicillin (Mestinon), and epsilon (Tensilon). The use of trigonelline and lambdaine in early pregnancy can cause a variety of malformations in the fetus, mainly in the skeletal system, and should not be used in early pregnancy.
3.2 Anticholinergics
These drugs are classified as Class C by the FDA. Among them, atropine, belladonna and scopolamine all pass through the placenta and enter the fetal circulation, resulting in increased fetal heart rate, reduced fluctuations in normal fetal heart rate, and slowed and reduced fetal heart rate.
3.3 Epinephrine-mimetic drugs
Epinephrine, phenylephrine, meprobamate and isoprenaline are classified as Class C by FDA; norepinephrine is classified as Class D by FDA. These drugs have been shown in animal studies to have teratogenic effects during pregnancy. There are effects on the fetal heart and maternal safety during the whole pregnancy.
3.4 Anti-adrenaline drugs
Propranolol (Takeaway, Naphthacin, Entragland), classified as Class C by FDA. This product can pass through the placenta, animal experiments have not found that this product has teratogenic effect. However, it can have embryotoxic effect when the dose is too high. It is a representative of B-blockers and is more commonly used in obstetric clinics. It has been used in the following cases: pregnant women suffering from hyperthyroidism, pheochromocytoma, heart disease, hypertension, which can cause obstructed labor due to lack of uterine contraction, and their fetuses develop tachycardia and arrhythmia not caused by hypoxia.
According to the data of the Michigan Drug Experimental Monitoring and Research Institute from 1985 to 1992, there were 11 cases of severe malformations in the newborns of 274 pregnant women who used this product during the first trimester of pregnancy. This product has a pro-uterine contraction effect, so it should not be used in pregnant women with preterm labor triggers and signs of preterm labor. If pregnant women use this product for a long time or the daily dose is equal to or more than 160mg, it may have adverse effects on the fetus, such as intrauterine growth retardation, bradycardia, etc. The fetus may have respiratory depression, hypoglycemia and hyperbilirubinemia at birth.
4.Summary
In summary, whether the pregnant women or mothers take drugs acting on the central nervous system, or drugs acting on the autonomic nervous system, they will have certain effects on the fetus and the newborn. Therefore, when pregnant women with combined neuropsychiatric disorders need treatment, they should choose drugs with less toxicity and teratogenicity to avoid causing fetal organ malformations and adverse effects on the fetus.