Psychopharmacology of the mother–child unit.
The indications and cautions about drug prescription for women who suffer from mental illnesses will be addressed in sequential periods, from the preconception stage through to the parenting stage.
Preconception
The impact of psychopharmaceuticals on the person receiving them and, potentially, on future children, starts even prior to conception. The aim of prescribing drugs is to alleviate symptoms and restore function in the patient. But when the patient is a woman who may want to bear children in the future, effects on her future ability to conceive need to be taken into account.
Antipsychotic medication is an example of a class of drugs that increases prolactin levels and, via this mechanism, makes conception more difficult (La Torre and Falorni, 2007). This is especially problematic when these drugs are taken in conjunction with other psychoactive drugs, many of which (such as SSRIs, monoamine oxidase inhibitors (MAO-Is), and some tricyclic antidepressants) also increase prolactin levels. Before prescribing drugs, the physician needs to inquire about a woman’s intention to become pregnant and to warn her that prolactin-elevating drugs may hinder (though not totally inhibit) her fertility.
It has been estimated that, in general, approximately 50% of pregnancies are unplanned and that many women do not realize that they are pregnant until the end of the first trimester or later. And yet, few mental health professionals discuss family planning with their patients. Given the possibility of an unplanned pregnancy, the consideration and discussion of risks of medications prescribed to women of childbearing age needs to become standard practice, as do contraceptive practices.
It needs to be kept in mind that some psychopharmaceutical agents lower the efficacy of oral contraceptives. This is true for mood stabilizers such as carbamazepine and topiramate, herbs such as St. John’s wort, and the psychostimulant, modafinil (Oesterheld et al., 2008). On the other hand, oral contraceptives increase the clearance of some benzodiazepines and mood stabilizers such as lamotrigine and valproic acid (necessitating higher doses to maintain the same effect). Paradoxically, contraceptives reduce the clearance of other benzodiazepines, as well as of the antipsychotic medications chlorpromazine and clozapine, and of the antidepressants amitriptyline and bupropion (e.g., the required doses of these drugs need to be lowered to prevent side effects) (Oesterheld et al., 2008).
The reader is referred to Seeman and Ross (2011) for a discussion of recommended contraception for women with mental illness.
Pregnancy
Pregnancy is associated with physiological changes that influence drug absorption, distribution, metabolism, protein binding, and excretion. During pregnancy, there is an increase in gastric pH and a reduction in intestinal motility. Cardiac output and glomerular filtration rate are increased whereas the plasma albumin concentration is reduced (Isoherranen and Thummel, 2013). This leads to a decrease in absorption, an increase in excretion, and a reduction in protein binding. The volume of distribution of a drug is increased as pregnancy proceeds and the pregnant woman becomes larger.
Pregnancy also alters the function of drug-metabolizing enzymes and drug transporters in a gestational-stage and tissue-specific manner. Although the placenta is a barrier, most drugs pass through it and are subjected to a new set of placental metabolizing enzymes that are modified, to some extent, by the sex of the fetus (Clifton, 2010; Graves, 2010).
In general, the activity of several hepatic cytochrome P450 enzymes, such as CYP2D6 and CYP3A4, is increased during pregnancy, whereas the activity of others, such as CYP1A2, is decreased. That means that psychotropic drugs that are metabolized by the first two groups of enzymes (which accounts for most drugs used in psychiatry) will be more extensively metabolized during pregnancy than normally and that their dose, therefore, will need to be increased during pregnancy in order to maintain efficacy. The dose of some drugs, such as olanzapine and clozapine that are metabolized by CYP1A2, will need, on the other hand, to be reduced in order to prevent side effects (Malek and Mattison, 2010).
It is usually recommended that women not take any drugs during the first trimester of pregnancy when fetal organs are developing, but (1) many women do not know they are pregnant until well into the first trimester, and (2) many women suffer from illnesses for which pharmacological treatment is necessary. It has been estimated that 10% of pregnant women suffer from some form of mental illness that may require medication (Yonkers et al., 2011).
Although, for many women with chronic or recurrent mental illness, pregnancy is a time of relative well-being, the stress of pregnancy or the altered pharmacokinetics associated with pregnancy may temporarily require increased doses of drugs.
Schizophrenia
Schizophrenia is probably the most serious of the psychiatric illnesses from which pregnant women can suffer. It is an illness that almost always requires maintenance drugs in order to keep symptoms at bay and to allow adequate functioning. The majority of women with schizophrenia report deterioration in their mental health during pregnancy (McNeil et al., 1984), although over 25% report improvement. It is not clear from the literature whether reported deterioration refers to psychotic symptoms or to nonspecific discomfort such as physical malaise, domestic stress, or anxiety about the future.
If psychotic symptoms do increase during pregnancy, they can pose a danger to both mother and fetus; they need to be immediately and vigorously addressed, usually with drugs. At the same time, there are possible risks to the fetus from exposure to antipsychotic medication via placental transfer (Einarson and Boskovic, 2009; Gentile, 2010; Wichman, 2009). In this circumstance, the health of the mother needs to take precedence because an untreated mother with psychosis puts not only herself but also her fetus and, potentially, others in danger; a conservative approach to antipsychotic treatment during pregnancy (low doses; avoidance of polytherapy) is indicated.
The potential of antipsychotic medication to cause neonatal complications is a matter of controversy because randomized, controlled trials cannot be conducted. The only study separating risk of drug from risk of illness is that by Lin et al. (2010). They compared the exposed (to first-generation antipsychotics (FGAs)) and unexposed offspring of mothers with schizophrenia. The infants exposed to FGAs in early pregnancy (n = 242) were more likely to be born prematurely, but their birth weight was within the normal range. Important potential confounders, such as smoking, maternal weight, and alcohol and substance use, were not controlled for in this study.
Although prematurity and birth weight are concerns, the major worry is teratogenicity (for which there is little overall evidence in association with antipsychotic medication). In addition, there is concern about potential complications of pregnancy such as gestational diabetes (for which there is substantial evidence, especially with regard to olanzapine and clozapine (Bodén et al., 2012), neonatal toxicity and withdrawal effects (which can be avoided by judicial management), and long-term neurodevelopmental effects (the evidence for which remains uncertain).
Teratogenicity
In 2011, the US Food and Drug Administration (FDA) updated the pregnancy section of drug labels for the entire class of antipsychotic drugs (US FDA, 2011). The good news is that women taking second-generation antipsychotics (e.g., quetiapine, risperidone, olanzapine) show essentially the same risk of bearing an infant with a congenital malformation (0.9%–4.1%) as does the general population (McKean, 2013).
Infant extrapyramidal effects
When the mother takes antipsychotic drugs during the third trimester, the neonate may, for a period of hours to days, show agitation, abnormal muscle tone, tremor, sleepiness, difficulty in breathing, and difficulty in feeding. Because of this, whenever clinically feasible, the dose of antipsychotic drugs should be lowered in the month prior to the due date. Patients should not, however, do this without consulting their psychiatrist.
Maternal effects
Though suspected in the past, there does not seem to be any linkage between use of antipsychotic drugs and risk of venous thrombosis and embolism in pregnant women (Jensen et al., 2013). Gestational diabetes, however, is a recognized problem for women on antipsychotic drugs, especially when the drugs (clozapine and olanzapine, for instance) induce weight gain (Bodén, 2012). Gestational diabetes increases the risk of eclampsia and obesity, and Type 2 diabetes later in life (Buchanan and Xiang, 2005). Glucose tolerance tests are recommended at 14–16 weeks and again at 28 weeks of gestation. Attention to diet is important. Gestational diabetes may also lead to problems for the baby: birth complications, preterm birth, respiratory distress syndrome, and hypoglycemic seizures after delivery.
Recommendations for antipsychotics during pregnancy
Frequent therapeutic drug monitoring is indicated during pregnancy. Because birth weight may be affected, extra fetal growth surveillance is required during the second half of pregnancy for all mothers taking antipsychotic drugs (Bodén, 2012). Polytherapy increases all risks and should be avoided whenever possible (Sadowski et al., 2013). Well-designed observational pharmacoepidemiology is probably the only way to specify accurately the risks of individual drugs and to help with clinical decision-making (Abel, 2013).
Bipolar disorder
As with schizophrenia, the concerns with respect to bipolar disorder medications are also teratogenicity (in this case, cardiac malformations, neural tube defects, and facial deformity), pregnancy complications (gestational diabetes, polyhydramnios, and fetal macrosomia), neonatal complications (neonatal toxicity and withdrawal effects, neonatal hypothyroidism, and hypotonia), and long-term adverse neurodevelopmental effects (Galbally et al., 2010).
For women with bipolar disorder, the relapse risk from discontinuing medication during pregnancy is even greater than that for women with schizophrenia. Women with bipolar disorder who stop a mood stabilizer are more than twice as likely to relapse in pregnancy, and they stay ill five times longer than those who stay on their medication (Galbally et al., 2010). Changes in body weight, drug absorption, metabolism, and excretion during pregnancy mean that relapse is a concern even for those who stay on their prepregnancy dose of mood stabilizers. For instance, plasma levels of medications such as lithium carbonate, which are excreted by the kidneys and depend for their dispersal on the volume of fluid in the body, are significantly reduced during the third trimester of pregnancy due to the increased volume of distribution.
Teratogenicity
Drugs used to treat bipolar disorder, such as lithium carbonate, carbamazepine, and sodium valproate, are all potential teratogens (Galbally et al., 2010; Morrow et al., 2006; Yonkers et al., 2004). Valproate has the highest rate of congenital malformations (8.7%), with larger doses entailing greater risk (Galbally et al., 2010). Carbamazepine and lamotrigine have lower risks. Lithium is associated with an increased risk of Ebstein’s anomaly, but the risk is relatively low (0.05–0.1%), much lower than once believed. The majority of the congenital malformations that have been reported are central nervous system anomalies, particularly neural tube defects, though cardiac, facial, and urogenital malformations are not rare (Vemuri and Williams, 2011).
Complications for the infant
Lithium has been associated with neonatal complications including floppy baby syndrome, cardiac dysfunction, diabetes insipidus, hypothyroidism, low muscle tone, lethargy, hepatic abnormalities, and respiratory difficulties. Sodium valproate can induce a withdrawal syndrome, hepatic toxicity, and hypoglycemia. Neonatal hepatic toxicity has been attributed to both carbamazepine and lamotrigine. Cognitive development of children whose mothers take mood stabilizers during pregnancy may also suffer, but the jury is still out on this important issue (Galbally et al., 2010).
Recommendations
Carbamazepine and sodium valproate are known to interfere with folate metabolism; therefore, to minimize teratogenic risk, 5 mg of folic acid is recommended 1 month prior to and during pregnancy for women on these drugs. The recommendation for lithium is a monthly serum lithium level test throughout pregnancy, increasing to weekly at 36 weeks. Monthly lamotrigine levels are also recommended. Lithium should be stopped 24–48 hours prior to delivery. The maintenance of adequate hydration is critical, and all neonates of mothers on mood stabilizers should be thoroughly checked by the pediatrician. As in schizophrenia, there is a need for increased fetal growth surveillance in women being treated with mood stabilizers (Vemuri et al., 2011; Yonkers et al., 2004).
Antidepressants
There are conflicting data on the use of SSRIs (selective serotonin reuptake inhibitors) during pregnancy (Byatt et al., 2013).
Teratogenicity, in the sense of a consistent risk and pattern of malformation, has not been demonstrated for SSRIs, although one SSRI, paroxetine, has been associated with atrial and ventricular septal defects. Even this association has not been confirmed in large databases. The reproductive safety of serotonin-norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine, and of the antidepressants trazodone, mirtazapine, and bupropion is also controversial (Byatt et al., 2013). Bupropion has a second use in smoking cessation and has been reported to be safer than nicotine-replacement therapy during pregnancy (Le Houezec and Aubin, 2013). Most reports do not control for the potential hazards of the underlying psychiatric condition and other possibly relevant variables. When these are taken into account, the absolute risk of teratogenicity appears small.
All SSRIs and SNRIs can theoretically increase serotonin concentrations in the developing fetus and affect fetal cardiovascular, respiratory, and neurological development. Neonate serum levels of serotonin have been found to be elevated when mothers take these drugs during pregnancy, and this may be a problem for premature infants. Discontinuation syndromes have also been reported, but there is no evidence that tapering the dose during the last trimester results in better infant outcomes (Byatt et al., 2013).
When treating depression during pregnancy, nonpharmacological treatment should be attempted first, if possible. Where drugs are deemed necessary, SSRIs are generally to be considered first. More than one antidepressant should be avoided and the lowest effective dose used (Byatt et al., 2013).
Antianxiety agents
For pregnant women with generalized anxiety disorder, panic disorder, or obsessive-compulsive disorder, nonpharmacological treatments should be tried first. If drugs are needed, SSRIs can be tried or buspirone, which is classified as a FDA category B drug (no evidence of risk in humans).
Benzodiazepines are not advised. They are classified as category D (evidence of risk in humans but the benefits from use in pregnant women may be acceptable despite the risk) or category X (contraindicated in pregnancy). If a woman is already on a benzodiazepine when she becomes pregnant, tapering the drug is better than stopping it abruptly, because the latter can lead to seizures (Bellantuono et al., 2013; McKean, 2013).
Postpartum
The postpartum period is a vulnerable one for women. Postpartum mental illness is frequent, and it is often treated as “depression.” It can, in fact, be differentiated into postpartum depression/anxiety, postpartum panic disorder, postpartum obsessive-compulsive disorder, postpartum post-traumatic stress disorder, and postpartum psychosis. Appropriate treatment will depend on symptoms and presentation. Approximately 27% of women with past psychosis have a recurrence of psychosis, and 38% develop a nonpsychotic depression in the first postpartum year, but especially in the first 3 months after delivery (Howard et al., 2004). The concern for drugs administered postpartum is whether they are so sedating that they prevent the mother from bonding with her infant. To a large extent, this will depend on the dose used. A second concern, dealt with in the next section, is how much of the drug will enter the milk of breastfeeding mothers.
Generally, it is not difficult to ensure that antipsychotics, antidepressants, mood stabilizers, or antianxiety agents during the postpartum period are given at doses and schedules that are both effective and side-effect-free. However, during the immediate period after delivery, while drug kinetics is still in flux, the patient is often unable to come to the psychiatrist’s office. This means that home-visiting teams are necessary both to support the patient and family and to carefully monitor medication doses. Ensuring sleep is critical for the postpartum mother.
Related posts:
Thinking about children of parents with mental illnesses as a form of intergenerational dialog and practice
Mothers with eating disorders and their children
Enhancing depressed mothers’ sensitivity
E-learning professional development resources for families where a parent has a mental illness
Preventing unnecessary loss of child custody
Parental psychiatric disorder: translating The Family Model into practice change
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