Even couples who are physically and mentally normal can hardly guarantee that they will produce “normal” offspring. Studies have found that the rate of spontaneous abortion in early pregnancy is 10% to 20% and the incidence of congenital malformations is 2% to 3%; lifestyle has a significant impact on pregnancy outcomes, and it has been shown that smoking, alcohol consumption, excessive coffee intake and poor nutrition during pregnancy can have adverse effects on the fetus; pre-pregnancy obesity can increase the risk of fetal neural tube defects. In addition, psychiatric disorders during pregnancy are an independent risk factor for fetal congenital malformations and perinatal mortality.
In fact, drug-induced fetal malformations account for about 5% of all fetal malformations. Possible malformations caused by drugs include major malformation (first trimester), neonatal toxicity (second trimester), and long-term neurological effects and increased physical health problems in adulthood.
The safety of psychotropic treatment during pregnancy cannot be determined because it is not possible to conduct prospective controlled experimental studies in humans. Therefore, the choice of psychopharmacological treatment during pregnancy is based on limited information, mainly on the inability to control for the effect of the disease itself or the drug, bias in case report data, and lack of data on human trials. For some new drugs, earlier reported adverse outcomes may or may not be replicated, and the risks and benefits of discontinuing or continuing the drug are based on what is called a best guess assessment. Even for drugs used for many years, there is little information on the long-term consequences.
In addition, because pregnancy increases the risk of mental illness and relapse, how patients and their families view the pros and cons of medication is critical, and sometimes a key factor in the decision making of therapists.
I. Discussion of treatment options for pregnant women
For a pregnant woman with a mental illness, a thorough discussion with the patient and her guardians is needed before deciding on a medication regimen. If possible, it is best to provide individualized written materials to explain the various risks. The absolute and relative risks of medication should be discussed together. Risks should be expressed using natural probabilities, rather than percentages, such as 1 in 10 rather than 10%. In general, the discussion needs to address the following.
(i) The ability of the pregnant woman to deal with the untreated or subthreshold symptoms of the disorder (subthreshold symptoms).
The potential impact of untreated mental disorders on the fetus or infant.
③The risk associated with abrupt discontinuation of medication.
④Severity of previous episodes of illness, response to medication and personal preference for treatment.
⑤ For pregnant women without psychiatric disorders, what is the risk of congenital malformations in their fetus.
(6) The possible harms of medication during pregnancy and postpartum, including those caused by drug overdose and some uncertain risks.
(7) For women who are taking medication and are pregnant, stopping the use of medication does not relieve the risk of fetal malformation.
II. Basic principles of prescribing psychotropic drugs during pregnancy
(1) For all female patients with mental disorders of childbearing age: ①The possibility of pregnancy should be discussed with them frequently (as many pregnancies are unplanned). (2) Pregnant women should be advised to avoid as much as possible the use of drugs that are contraindicated in pregnancy (especially valproate and carbamazepine). If these medications are prescribed, the patient should be informed that they are teratogenic, even if she does not intend to become pregnant.
(2) For pregnant women with newly diagnosed psychiatric disorders: (1) All medications should be avoided in the first trimester of pregnancy (major organ formation period) unless the benefits clearly outweigh the harms. (ii) When medication must be used, the lowest effective dose of the drug should be used.
(3) For those who are taking psychotropic drugs and intend to become pregnant: ①If the patient is currently well and the likelihood of relapse is low, discontinuation of medication may be considered. (2) For patients with severe psychosis and a high risk of relapse, discontinuing the medication is not a wise choice. Switching to a medication that has less effect on the fetus can be considered, but the patient should be informed that switching may increase the risk of relapse.
(4) For those who are taking antipsychotics and are pregnant: (1) It is not wise to stop medication abruptly in patients with severe mental illness and a high rate of relapse. Relapse will be more harmful to the mother and child than continuing effective medication. (2) It is recommended to maintain the current effective medication and not to change medication easily or to minimize medication reduction in order to reduce the exposure of the fetus.
(5) For patients who smoke: Nicotine replacement therapy is recommended.
(6) For all pregnant women: ①Ensure that both parents are involved in all decisions. (2) Use the lowest effective dose of medication that is least harmful to the pregnant woman and fetus. (3) Minimize the variety of drugs. (4) Adjust the dose of medication according to the course of pregnancy. The total amount of blood in the body increases by almost 30% in the second trimester, which often requires an increase in the drug dose. Blood level monitoring is useful. It is important to note that the activity of liver enzymes varies greatly during pregnancy, with CYP2D6 activity increasing by almost 50% and CYP1A2 activity decreasing by more than 70% in the second trimester. ⑤ Consider referral for perinatal medical services. (6) Ensure necessary fetal monitoring and be aware of the potential problems the drug may have on the fetus at birth. (vii) Inform the obstetrician of the patient’s psychotropic drug use and possible complications. ⑧ Monitor the infant for withdrawal symptoms after delivery. ⑨ Keep a record of all the patient’s consultation and decision-making process.
III. Psychiatric disorders during pregnancy and postpartum
Pregnancy increases the incidence and recurrence of psychiatric disorders. In the general female population, the probability of developing a perinatal psychiatric disorder is 0,1% to 0,25%, and the relative risk of developing a psychiatric disorder increases 20-fold (to 30% to 50%) in the month following delivery. The probability of recurrence after a second delivery is 50-90% for those who have had previous postpartum psychosis. Untreated perinatal psychosis in pregnant women may lead to serious consequences. Therefore, medication is necessary for those with severe disease.
1.Anti-psychotic drug treatment
(1) First-generation antipsychotics (FGAs) are generally considered to have the least teratogenic risk. Most of the information comes from low-dose phenothiazines for primary eclampsia of pregnancy (which has an increased risk of congenital malformations), and some of these studies suggest an increased risk of congenital malformations, but no clustering of congenital malformations (clustering) occurs. This result suggests that the severity of maternal eclampsia may have a greater impact on malformations than the therapeutic drugs. Haloperidol may cause limb malformations, but even if true, the probability of this is quite low. In addition, there have been reports of neonatal dyskinesia due to FGAs and neonatal jaundice due to phenothiazines. In summary, it is still not clear whether FGAs are completely harmless to the fetus and its subsequent growth and development. However, the results of decades of use of these drugs suggest that any risk is not significant, and most studies confirm this hypothesis.
(2) Information on second-generation antipsychotics (SGAs) is accumulating, and there are relatively more studies on olanzapine and clozapine. One study found that olanzapine may cause low birth weight and increase the probability of neonatal admission to the intensive care unit, and may result in the birth of a large baby, which may be associated with an increased risk of gestational diabetes with olanzapine. Although olanzapine is relatively safe in causing congenital malformations in the fetus, it has been reported to cause hip dysplasia, meningeal protrusion, lid margin adhesions, and neural tube defects. Of these, neural tube defects are more likely to be related to pre-pregnancy obesity rather than drug effects. Most importantly, olanzapine has not been found to cause congenital malformations with aggregation.
Clozapine does not appear to increase the risk of fetal malformations, although there may be an increased incidence of gestational diabetes and neonatal convulsions. NICE (National Institute for Health and Clinical Excellence) recommends that pregnant women switch to other antipsychotic drugs. However, most pregnant women taking clozapine relapse after switching. Therefore, on the basis of the available information, it is recommended that clozapine be continued.
Limited data suggest that risperidone and quetiapine have no significant teratogenic effects in humans. Research data on other second-generation antipsychotics are lacking to date.
2. Summary of antipsychotic treatment recommendations for pregnant women
(1) For women with a history of psychosis who are still taking antipsychotics, planning a pregnancy should be discussed as early as possible.
(2) It should be noted that drug-induced hyperprolactinemia can lead to infertility. Switching to another medication should be considered in this case.
(3) For women with a history of psychosis, especially recurrent episodes, it is best to maintain antipsychotic medication during pregnancy to avoid the possibility of needing to increase the dosage or combination of medications in the event of a relapse, thereby reducing fetal exposure to medications.
(4) There is more experience with the use of chlorpromazine (which can cause constipation and sedation), trifluoperazine, haloperidol, olanzapine, and clozapine (both of these SGAs may cause gestational diabetes). If the patient is taking other medications, the latest dosing guidelines should be used as a basis and it may be neither necessary nor wise to change treatment regimens easily.
(5) NICE recommends against the use of long-acting agents and anticholinergic drugs in pregnant women.
(6) A few experts recommend stopping antipsychotics 5-10 days before delivery, however, this may cause withdrawal symptoms in both mother and baby. A mixed feeding regimen (breast/milk) may reduce withdrawal symptoms in the infant. If the patient is taking second-generation antipsychotics, it is not necessary to discontinue the medication.
IV. Depression during pregnancy and postpartum
Numerous studies have shown that about 10% of pregnant women suffer from depressive disorders, 16% have self-limiting depression-like reactions, and most postpartum depression develops before delivery. There is a significant increase in the number of new psychiatric disorders in the first three months after delivery, at least 80% of which are mood disorders (mainly depressive episodes). Those with a previous history of depressive episodes are at significantly higher risk of having an episode during pregnancy or the postpartum period, and the risk of recurrence is highest for bipolar disorder. In fact, antidepressants are commonly taken during pregnancy. In the Netherlands, up to 2% of pregnant women take antidepressants in early pregnancy (first trimester) (Ververs et al., 2006); in the United States, about 10% of pregnant women take antidepressants during pregnancy and this percentage is increasing (Alwan et al., 2011), with the most widely used being the SSRIs class. Relapse rates after discontinuation are high in depressed patients, and Cohen et al. (2006) found that women who were well treated with antidepressants had relapse rates of 68% and 26% for those who stopped taking them during pregnancy versus those who did not.
Some studies have suggested that antidepressants may increase the risk of spontaneous abortion (although these studies failed to control for other confounding factors). Also, antidepressants may increase the risk of preterm delivery, neonatal respiratory distress, low Apgar scores at birth, and admission to the neonatal intensive care unit. Some antidepressants may be associated with certain specific congenital malformations, but are very rare and most of these findings have not been replicated. The effects of the duration of antidepressant use on the fetus show conflicting results, and the effects of antidepressants on neurological development have been reported in few studies to date.
1. Tricyclic antidepressants (TCAs)
(1) Most studies have found that TCAs are not significantly harmful to the fetus and are therefore widely used during pregnancy.
(2) Limited data suggest that the use of TCAs during pregnancy has no effect on their future growth.
(3) Some studies have reported that administration of TCAs during pregnancy may increase the risk of preterm delivery; administration during late pregnancy can cause neonatal withdrawal reactions, but symptoms are generally mild and self-limiting.
(4) Some experts recommend the use of nortriptyline and nortriptyline, which have weaker anticholinergic and antihypertensive effects.
2.Selective 5-hydroxytryptamine reuptake inhibitors (SSRIs)
Some evidence suggests that the SSRIs class does not appear to cause significant teratogenicity. While most studies suggest that fluoxetine is safe, Thormahlen et al. (2006) reported that paroxetine may cause cardiac malformations. Subsequently, Berard et al. (2007) also found a greater risk after high doses of paroxetine in early pregnancy (725 μg/day). However, this result could only be replicated by subsequent studies. Taken together, SSRIs may cause the following problems: they may lead to shortened gestation (mean reduction of one week), spontaneous abortion and low birth weight (mean weight loss of 175 g); the longer the fetus is exposed to drugs in utero, the greater the probability of producing a low birth weight baby and respiratory distress; three groups of symptoms are seen in newborns when SSRIs are taken late in pregnancy: those related to serotonin toxicity, those related to antidepressant withdrawal and those related to preterm birth. Sertraline in late pregnancy may cause low Apgar scores in newborns, and paroxetine may cause neonatal complications, presumably related to rapid withdrawal; other SSRIs have similar, but milder, effects.
Nulman et al. (2002) suggest that the adverse effects of depression itself on fetal growth and development may be greater than the effects of drugs.
3. Other antidepressant treatments
Limited data suggest that venlafaxine is not potentially teratogenic but may lead to neonatal withdrawal reactions, and that venlafaxine taken in mid-gestation may result in preterm births; bupropion and mirtazapine may increase the rate of spontaneous abortion; and fetal bupropion exposure may increase the risk of attention deficit hyperactivity disorder in childhood. Because there is little information on the safety of these drugs in pregnant women and fetuses, they are not recommended for use in pregnant women at this time. Monoamine oxidase inhibitors should be avoided during pregnancy because they may increase the risk of congenital malformations and hypertensive crises. Although general anesthesia still carries some risk to the pregnant woman and fetus, there is no evidence that electroconvulsive therapy (ECT) during pregnancy is harmful to the mother or fetus. Therefore, for refractory depression, NICE recommends the use of ECT before or instead of combination medication. omega-3 fatty acids can be used as a therapeutic agent, although there is insufficient research information on their effectiveness and safety.
4. Summary of antidepressant treatment recommendations during pregnancy
(1) For patients who are taking antidepressants and are at high risk of relapse, it is best to maintain medication before and after pregnancy.
(2) For patients with moderate or severe depression during pregnancy, antidepressants should be used for treatment.
(3) There is more experience with the use of amitriptyline, mipramine and fluoxetine. Of these, amitriptyline and mipramine can both cause constipation and sedation and may also lead to withdrawal syndrome; fluoxetine can increase the risk of preterm delivery and low birth weight babies. If a pregnant woman is already taking other antidepressants, she should look for the latest dosing recommendations. As experience with other medications is increasing, it may be unnecessary and unwise to change treatment regimens. Paroxetine may have a poorer safety profile than other SSRIs.
(4) The remission of withdrawal symptoms in newborns may be an option to maintain breastfeeding first and then move to mixed feeding.
(5) The use of SSRIs in late pregnancy may increase the risk of persistent pulmonary hypertension in newborns.
V. Bipolar disorder during pregnancy and postpartum
Numerous studies of patients with bipolar disorder have shown that: (1) the risk of relapse is increased if mood stabilizers are discontinued during pregnancy, and the duration of illness at the time of relapse is prolonged. (ii) The risk of relapse increases after delivery, with an 8-fold increase in the relapse rate within one month after delivery. ③Mother’s mental status can affect the health of the fetus, the birth situation and the growth and development of the newborn. ④The mother’s unstable state of mind can impair her ability to care for herself, lack of obstetric care and self-injury; at the same time, it may lead to consequences such as neglect of the baby or even infanticide.
1.Lithium salt treatment
(1) Although the risk of congenital malformations due to lithium exposure during fetal life may be currently overestimated, lithium salts should be avoided during pregnancy, and it is best to gradually reduce the dosage of lithium and eventually discontinue it before pregnancy, as abrupt discontinuation may lead to relapse. Lithium discontinuation before pregnancy has been associated with a postpartum recurrence rate of up to 70%. If discontinuation during pregnancy is unsuccessful, the medication should be reintroduced.
(2) Lithium administration during pregnancy can lead to cardiac tricuspid valve malformation (Ebstein’s syndrome, Ebstein’s anomaly) (relative risk 10 to 20 times that of controls, but absolute risk 1:1000) (Cohen et al., 1994). The period when lithium is most harmful to the fetus is 2 to 6 weeks after pregnancy, when many women may not be aware that they are pregnant. In addition, there may be an increased risk of atrial and ventricular septal defects as a result of taking lithium salts.
(3) Continued lithium therapy during pregnancy should be followed by high-resolution ultrasound and echocardiography at weeks 6 and 18 of pregnancy.
(4) Later in pregnancy, due to the increase in total body fluids, increased lithium doses are required at this time to maintain blood lithium levels, but lithium requirements return to pre-pregnancy levels immediately after delivery. Therefore, blood lithium concentrations should be monitored every month during pregnancy. Pregnant women taking lithium should deliver in a hospital, as the hospital can monitor and maintain the fluid and electrolyte balance of the pregnant woman in a timely manner.
(5) Treatment with lithium salts may also result in neonatal goiter, hypotonia, drowsiness, and cardiac arrhythmias.
2.Anti-epileptic drugs
Most of the information on carbamazepine and valproate comes from studies on epilepsy, which itself may lead to congenital malformations in newborns; therefore, they may not all be applicable in the treatment of psychiatric disorders.
(1) Both carbamazepine and valproate have been clearly causally associated with various fetal malformations, especially spina bifida. Therefore, both drugs should be avoided whenever possible and can be replaced with antipsychotics. Valproate has a greater teratogenic effect than carbamazepine.
(2) Treatment with valproate alone may also increase the relative but relatively low absolute risk of fetal atrial defect, cleft palate, hypospadias, polydactyly, and congenital premature closure of the cranial suture.
(3) For those who must take valproate or carbamazepine, low-dose monotherapy is recommended because the teratogenic effects of these two drugs may be dose-related. nice recommends that the daily dose of valproate should be less than 1000 mg.
(4) The susceptibility of newborns to neural tube malformation due to valproate may be determined by the gene encoding folic acid metabolism. It is advisable for all parents to take at least one month of folic acid (5mg/d) before preparing for pregnancy (perhaps to reduce this risk). However, some experts recommend taking lower doses because folic acid increases the risk of twin pregnancies.
(5) Vitamin K must be taken by those taking carbamazepine in late pregnancy.
(6) Lamotrigine alone has a low teratogenic effect on the fetus, but an increased risk of cleft palate has been reported. nice recommends that lamotrigine should not be routinely prescribed to pregnant women.
3. Summary of treatment recommendations for bipolar disorder in pregnancy
(1) For long-term stable non-relapsing patients, a switch to a safer antipsychotic or complete discontinuation of the drug should be considered before pregnancy or at least in the first trimester of pregnancy.
(2) Abrupt discontinuation of medication is associated with a high risk of prenatal and postnatal relapse, and therefore should not be discontinued abruptly.
(3) For those with severe disease or known rapid relapse with discontinuation of medication, maintenance medication should be recommended after discussion of the risks.
(4) No mood stabilizer is absolutely safe. For those taking lithium, 2D ultrasound should be performed at weeks 6 and 18 of pregnancy to rule out fetal Ebstein’s syndrome. Those taking valproate and carbamazepine should take folic acid prophylactically to reduce the risk of fetal neural tube abnormality and should undergo prenatal screening.
(5) If carbamazepine has been taken, vitamin K should be administered prophylactically to both the mother and the newborn after delivery.
(6) Pregnant women should avoid valproate (the most teratogenic) and should also avoid co-administration of mood stabilizers.
(7) Lamotrigine may cause cleft palate.
(8) NICE recommends replacing mood stabilizers with antipsychotics that have mood stabilizing effects.
(9) Sudden onset of acute mania during pregnancy may be treated with antipsychotics; if ineffective, consider ECT treatment.
(10) Bipolar disorder depressive phase occurs during pregnancy, cognitive behavioral therapy (CBT) is available for moderate depressive episodes, and SSRIs are available for severe episodes.
(6) Use of sedatives during pregnancy
Anxiety disorders and insomnia are common during pregnancy and are best managed with CBT and sleep hygiene care. For those for whom the above treatment is ineffective, sedative and anxiolytic treatment may be required.
Benzodiazepines: They are likely to cause low birth weight and preterm delivery when taken during pregnancy and are usually associated with neonatal syndrome (soft baby syndrome) when taken late in pregnancy. In addition, exposure to benzodiazepines in early pregnancy has been reported to increase the risk of cleft lip and palate and to cause pyloric obstruction and gastrointestinal atresia, but these results need further confirmation.
Other medications: promethazine is commonly used for severe vomiting in pregnancy and does not appear to cause malformations, but there is limited research.
VII. Summary of recommendations for psychotropic medication in pregnancy
In summary, the recommendations for the treatment of psychotropic drugs in pregnancy and the postpartum period can be summarized as follows.
1. Antidepressants
There is more evidence for the relative safety of nortriptyline, amitriptyline, mipramine and fluoxetine.
2.Antipsychotics
FGAs are the most used, although their safety has not been fully confirmed. The most experience with chlorpromazine, haloperidol, and trifluoperazine is available. there is less information on studies of SGAs (other than olanzapine and clozapine), but there is no clear evidence that any of the SGAs are significant teratogens (major teratogen), and their use needs to be screened for adverse metabolic effects.
3. Mood stabilizers
Consider replacing antiepileptic drugs with antipsychotics. Antiepileptics should be avoided unless the risk of recurrence and consequences are more severe than teratogenicity. Women of gestational age already taking carbamazepine or valproate should take folic acid prophylactically. Avoid carbamazepine and valproate if possible.
4. Sedatives
There are no preferred drugs available. Benzodiazepines may not be teratogenic, but should be avoided in late pregnancy. Promethazine is widely used, but there is little information to support its safety.