How to use psychiatric drugs during pregnancy to minimize adverse effects on the pregnant woman, fetus and family? How can medication be used to maximize the benefits and avoid the harms?
In clinical practice, psychiatric disorders in women during pregnancy often cause difficulties in treatment. Theoretically, no medication should be taken during pregnancy because of the potential for adverse effects on the fetus. However, without medication, mental disorders can have a negative impact on the mother, the family, and consequently on the fetus. This requires physicians to understand the reproductive safety of commonly used psychotropic medications and to take a comprehensive approach to treatment, considering both the potential effects of the psychiatric disorder on the mother, fetus, and family and evaluating the potential effects of the medication on the fetus and mother. Avoid harm and choose the least risky treatment.
Because it is unethical to test the effects of drugs on the fetus in pregnant women, information on the reproductive safety of drugs comes primarily from post-marketing surveillance, retrospective case reports, and case analyses. A small amount of information comes from retrospective or prospective pregnancy registries and case-control studies. Differences in the population, number of cases, and methods of study have resulted in conflicting results in some studies. Various congenital malformations also occur in normal populations. To prove that a drug is not associated with congenital malformations requires a large sample of subjects for controlled studies, which is labor-intensive, financially and time-consuming, and also causes research difficulties. This uncertainty in the field of research has led pharmaceutical manufacturers to generally recommend contraindication or caution in drug instructions for pregnant and lactating women, which simply does not provide helpful guidance for physicians in the use of medications. In order to provide a reference for the use of medications during pregnancy, the United States and Australia have established a classification system for the use of medications during pregnancy to provide general guidance for the use of medications during pregnancy. The following.
The U.S. Food and Drug Administration (FDA) has established a classification of drug safety during pregnancy.
The U.S. FDA classifies the risk of harm to the fetus from drugs into five classes: A, B, C, D, and X.
Grade A: Appropriate, well-controlled studies in pregnant women have shown no increased risk of fetal abnormalities.
Grade B: Animal studies showing no harm to the fetus, but appropriate, well-controlled studies in pregnant women are lacking; or, animal studies showing an adverse effect on the fetus, but appropriate, well-controlled studies in pregnant women have not found harm to the fetus.
Grade C: Animal studies showed adverse effects, but appropriate, well-controlled studies in pregnant women were lacking; or, no animal studies and no appropriate, well-controlled studies in pregnant women were done.
Grade D: Appropriate, well-controlled studies or observational studies in pregnant women have shown adverse effects on the fetus, but the therapeutic benefit outweighs the potential harm.
Grade X: Appropriate, well-controlled studies or observational studies in animals or humans have clearly demonstrated fetal harm. Contraindicated in pregnant women or women who are expecting a baby.
The current 5-level labeling method is useful in guiding the use of medications, but it has the potential to mislead medical professionals and patients into believing that the risk of harm increases sequentially as the drug is labeled from A to X. However, this is not the case. Because the C, D, and X levels are based on a risk-benefit comparison, a C- or D-rated drug may possess the same risk of harm as an X-rated drug. In addition, whether evidence of drug harm comes from human trials or from animal experiments, its frequency of occurrence, severity, and the presence or absence of developmental toxicity are not reflected by such a classification and labeling approach. Moreover, this classification system does not reflect new research findings in a timely manner and makes it difficult to account for inconsistent findings. Due to the lack of research evidence, most psychotropic drugs are classified as Class C, and it is still up to the physician, patient, or family to weigh whether to use them during pregnancy. In view of the drawbacks of this classification, the FDA issued a new solution in May 2008, which is still under revision for comments.
U.S. FDA Classification of Safety of Commonly Used Psychotropic Drugs.
Anti-epileptic drugs: carbamazepine, phenobarbital, phenytoin sodium, and sodium valproate are all graded D. Lamotrigine, gabapentin, oxcarbazepine, topiramate, and tiagabine are all Grade C.
Lithium carbonate is grade D.
Antidepressants: amitriptyline, promethazine, paroxetine are all grade D. Doxepin, clomipramine, fluoxetine, sertraline, citalopram, fluvoxamine, mitazepine, trazodone, venlafaxine, bupropion, and duloxetine are all grade C.
Antipsychotics: chlorpromazine, fenetylline, haloperidol, risperidone, oxcarbazepine, quetiapine, ziprasidone, aripiprazole are all grade C, clozapine grade B. Drugs used in the treatment of adverse reactions to antipsychotics, benzhexol, propranolol are grade C.
Anxiolytics and hypnotics: eszopiclone and triazolam are all grade X. Alprazolam, clonazepam, diazepam, lorazepam are grade D. Zaleplon is grade C. Zolpidem is grade B.
Drugs for dementia: Advil, Esnon, all pregnancy C.
Whether and how to use psychotropic drugs during pregnancy involves complex clinical and ethical issues for physicians, as well as potential legal consequences that require careful consideration. The following content presents current clinical research findings in response to common questions from clinical considerations for reference in clinical decision making.
I. Risks of psychotropic drug use during pregnancy.
When a woman has a mental disorder during pregnancy and postpartum and needs to use medication, there are generally four aspects: ◎ Pregnancy causes changes in the course of mental illness and requires adjustment of the treatment plan. ◎ Medications that are effective in treating the mother’s mental illness have the potential to harm the fetus. ③Mother’s medication treatment during pregnancy may cause toxicity or withdrawal symptoms in the fetus after birth, so the medication needs to be reduced earlier before delivery. ④Most psychotropic drugs can be secreted into breast milk and have potential effects on the nursing infant. Of the four areas, the primary issue is to evaluate the potential effects of the drug on the fetus and to select the drug that will cause the least damage to the fetus. Only after determining which drugs can be used, which drugs should be used with caution, and which drugs should be used as little as possible, can the medication be adjusted according to changes in psychiatric symptoms; the dose be adjusted according to changes in drug effects; and the dosage be reduced in advance according to the prodromal period.
In general, the possible hazards to the fetus caused by the use of drugs during pregnancy are: miscarriage, stillbirth, preterm birth, various malformations, organ dysfunction, growth retardation, neonatal toxicity or withdrawal symptoms, long-term neurodevelopmental effects (behavioral neurotoxicity). In the pre-embryonic period (0 – 14 days), drugs that produce harm generally result in the death of the pregnant body. During the embryonic period (3–8 weeks of gestation), major organ tracts and somatic features are formed. Drugs, if harmful, can cause various malformations. During the fetal period (9 weeks – birth), the growth and function of organs develop and drugs can cause growth retardation, structural abnormalities, and organ dysfunction. Structural development of the nervous system begins on day 16 – 18 of gestation, and the neural tube closes at the end of the fourth week of gestation. The single heart tube forms on day 22, the atrial septum and ventricular septum on days 27–37, and the valves on day 35. The use of lithium salts, sodium valproate or carbamazepine in early pregnancy should be of particular concern for the neurological and cardiac effects.
Second, commonly used psychotropic drugs risk of harm during pregnancy.
(i) Anti-epileptic drugs.
The incidence of congenital malformations in the fetus is 2–3 times higher than in the normal group with the use of antiepileptic drugs during pregnancy, even after the disease effects are controlled. Among the more studied antiepileptic drugs, the highest teratogenic risk is that of sodium valproate. The next highest in descending order is phenytoin sodium, phenobarbital, and carbamazepine. Lamotrigine has a lower teratogenic risk. The higher the therapeutic dose, the greater the teratogenic risk. The teratogenic risk increases with the combination of antiepileptic drugs. The newer antiepileptic drugs have been in clinical use for a relatively short time and have yet to be studied further.
The main types of congenital malformations caused by antiepileptic drugs are: various craniofacial malformations, abnormal finger and toe development, cardiac defects, neural tube defects, growth retardation, microcephaly, and impaired cognitive development. The incidence of neural tube defects in the normal population is only 0.03%, increasing to 0.5% with carbamazepine and 3.8% with valproate; this teratogenic effect is also dose-dependent, and the risks are additive when the two drugs are combined. The pathogenesis of neural tube defects may be related to the interference of antiepileptic drugs with folic acid synthesis. Recent clinical guidelines have recommended 5 mg of folic acid daily for women taking valproate or carbamazepine in early pregnancy. Valproate administration during pregnancy may also lead to impaired cognitive function in children in the distant future, as evidenced by reduced verbal IQ.
Higher doses of carbamazepine in late pregnancy can accelerate vitamin K metabolism due to its enzyme-inducing effects, resulting in fetal vitamin K deficiency and the need for vitamin K supplementation after birth. higher doses of sodium valproate and carbamazepine in late pregnancy can result in toxicity or withdrawal symptoms in newborns after birth. Symptoms that have been reported include: excitation, respiratory depression, apnea, impaired thermoregulation, hypoglycemia, and toxic liver damage. Symptoms can last 24 – 48 hours.
(ii) Lithium salts.
Lithium salts taken during pregnancy also have teratogenic effects on the fetus, mainly cardiac abnormalities. The incidence of fetal cardiac abnormalities is about 10 times higher than the normal group when lithium salts are taken in early pregnancy. The most serious of these is tricuspid valve inferior displacement to the right ventricular wall (Ebstein anomaly), with an incidence of about 0.1%. The use of high-resolution ultrasound during 16–18 weeks of gestation reveals most of the more severe cardiac anomalies. Those taking lithium salts in the first trimester should be examined early. Complications similar to adult adverse effects can occur in newborns who continue lithium therapy in the second trimester. Symptoms that have been reported include goiter with hypothyroidism, cardiac arrhythmias, and hypotonia.
(iii), antidepressants.
The more studied are tricyclic antidepressants and selective 5-hydroxytryptamine reuptake inhibitors. Clomipramine and paroxetine have been found to have similar teratogenic effects, and their use during pregnancy causes fetal cardiac abnormalities, mainly captive septal and ventricular septal defects, with an incidence about twice that of the normal group. Other tricyclic antidepressants and selective 5-hydroxytryptamine reuptake inhibitors have not been found to have significant teratogenic effects. Other new antidepressants have been introduced late and have yet to accumulate research data.
The risk of persistent pulmonary hypertension in the newborn increases approximately sixfold with selective 5-hydroxytryptamine reuptake inhibitors taken after 20 weeks of gestation, with an incidence of 0.6% to 1.2%. Both tricyclic antidepressants and selective 5-hydroxytryptamine reuptake inhibitors taken in late pregnancy can cause withdrawal symptoms in newborns. They include tremor, trembling, elevated muscle tone, irritability, excessive crying, poor sleep, and poor feeding. Symptoms generally disappear within 2 weeks.
(iv) Antipsychotics.
The first generation of antipsychotics have been used in clinical practice for more than 50 years and have not been found to have significant teratogenic effects. The potential teratogenicity of the commonly used chlorpromazine, endorphin and haloperidol is even more limited. Second-generation antipsychotics have not been found to be significantly teratogenic, although there is little research data. However, when first-generation antipsychotics are taken in the second trimester, the infant may have extrapyramidal reactions, high muscle tone, restlessness, crying, and poor sucking and swallowing after birth.
(v), benzodiazepine anxiolytics.
Early studies found that benzodiazepine anxiolytics taken in the first trimester of pregnancy were teratogenic, mainly increasing the risk of cleft lip and palate. Later studies again showed that the teratogenic effect of this class of drugs was not significant. The results of studies on the neurobehavioral developmental effects of such drugs during pregnancy on postnatal infants are also inconsistent, but animal studies have shown that such drugs can affect the development of learning and memory functions. When benzodiazepines are taken continuously from late pregnancy until birth, newborns can develop flaccid infant syndrome, with the main symptoms being sedation, hypotonia, difficulty sucking, apnea, cyanosis, and hypothermia. Infant withdrawal symptoms such as high muscle tone, increased reflexes, restlessness, sleep disturbances, and tremors may also occur.
(vi) Summary.
Among psychotropic drugs, antipsychotics have the least teratogenic risk and antiepileptic drugs have a greater teratogenic risk. Among the drugs commonly used to treat bipolar disorder, sodium valproate has the highest teratogenic risk, followed by carbamazepine, followed by lithium, and antipsychotics have the lowest teratogenic risk. Among the drugs commonly used to treat depression and anxiety, the overall safety of antidepressants is better than that of benzodiazepines, with the exception of paroxetine and clomipramine.
Third, general recommendations.
1. For milder mental disorders in pregnancy, if non-pharmacological treatment modalities can be considered, non-pharmacological treatment should be chosen as far as possible provided that the disease will not be aggravated.
2.People with more severe mental disorders in pregnancy, which are potentially more harmful to the mother, fetus and family, should choose pharmacological treatment if there is no other suitable non-pharmacological treatment.
3.For patients who are fertile and have the possibility of pregnancy, they should be considered in advance. When choosing drugs, first choose those that are less harmful to the fetus.
4.In the course of drug treatment is not considered in time, pregnancy occurs when taking high teratogenic risk drugs, there is no urgency to terminate pregnancy. You can reduce the variety of medication, reduce the dose given or adjust the variety of medication, and do ultrasound examination early. Determine whether to terminate the pregnancy according to the examination results.
5.For those who continue to use drugs during pregnancy, the dose of drugs should be gradually reduced in the prenatal period, and the original treatment amount should be gradually restored after delivery.
6. For those who need to continue medication during breastfeeding, given that: ① existing psychotropic drugs can be secreted into breast milk, only in different amounts; ② psychotropic drugs, regardless of the amount, are not beneficial to the development of the baby, and the adverse effects cannot be ruled out; ③ illness and medication can affect the quality of the mother’s care for the fetus; ④ unlike pregnancy, artificial feeding during infancy can replace breastfeeding. Therefore, although breastfeeding is good, it is better not to use breastfeeding during the medication period in a comprehensive comparison. We should fully communicate with the patient and family, explain the pros and cons, and let the patient and family make the final choice.