Psychiatric Disorders During Pregnancy
WHEC Practice Bulletin and Clinical Management Guidelines for healthcare providers. Educational grant provided by Women's Health and Education Center (WHEC).
Each woman brings her individual constellation of assets and vulnerability to pregnancy. It is estimated that more than 500,000 pregnancies in the United States each year involve women who have psychiatric illnesses that either predate or emerge during pregnancy, and an estimated one third of all pregnant women are exposed to a psychotropic medication at some point during pregnancy (1). Why certain women develop primary mood disorders as opposed to eating disorders or schizophrenia is an active area of research inquiry. Our discussion of psychiatric disorders includes six major diagnostic categories that occur commonly in women of childbearing age: mood disorders, anxiety disorders, eating disorders, schizophrenia, substance abuse disorders, and personality disorders. Within the lifecycle context, the impact of childbearing on existing disorders or vulnerabilities in the female patient is of primary interest, as well as episodes that are etiologically related to childbearing. Treatment considerations for psychiatric disorders during childbearing invoke special modifications of the risk-benefit decision-making process. Perinatal health can be conceptualized within a model that integrates the complex social, psychological, behavioral, environmental, and biologic forces that shape pregnancy. Biological vulnerability to disease in relation to the life cycle has been described. In each individual, the relative contributions of biologic, psychological, and social factors vary. For pregnant woman, the capacity to function optimally, enjoy relationships, manage the pregnancy, and prepare for infant's birth is critical. Maternal psychiatric illness, if inadequately treated or untreated, may result in poor compliance with prenatal care, inadequate nutrition, exposure to additional medication or herbal remedies, and disruptions within the family environment.
The purpose of this document is to focus discussion and management of anxiety, schizophrenia, psychosis and bipolar disorder during pregnancy and lactation. Mental health is fundamental to health. The effect of pathology in any part of the body affects the entire patient. A synopsis of available literature on the biological factors related to major depressive disorder in perinatal women is reviewed here. The majority of studies relate to investigations of postpartum women, but those that are relevant to pregnant women are included when available. With the limited information available on the risks of psychotropic medications, clinical management must incorporate an appraisal of the clinical consequences of offspring exposure, the potential effect of untreated maternal psychiatric illness, and the available alternative therapies.
Etiopathology of Unipolar Major Depressive Disorders in Pregnant and Postpartum Women
It is likely that biological, psychological, and social factors interact to trigger an episode of unipolar major depressive disorder in pregnant and postpartum women. Known risk factors for major depressive disorder in postpartum women include a previous episode of major depressive disorder, life stress, and lack of social support in the postpartum period (2). The structure and function of various cortical regions such as the prefrontal cortex, anterior cingulated gyrus, and other areas of the limbic system are implicated generally in the etiology of major depressive disorder (3). Researchers also have focused on aberrations in selected neurotransmitter systems, including serotonin, norepinephrine, and dopamine, as well as possible role of stress and the glucocorticoid system. However, the unique timing of major depressive disorder and biology of the perinatal period (particularly the postpartum period) has sparked investigation into whether major depressive disorder that occurs in pregnancy or the postpartum period has unique biological underpinnings relative to non-perinatal major depressive disorder. There is evidence from correlational, familial, and genetic studies that there may be a subgroup of women who are uniquely at risk for unipolar major depressive disorder in pregnancy or increased biological risk continue to be poorly characterized but may be related to abrupt changes in sex steroids and monoamine levels; postnatal failure to achieve optimal regulation of thyroid hormone, immune responses, and the hypothalamic-pituitary-adrenal axis are additional contributors to unipolar mood disorders.
Sex Hormones: The dramatic changes in hormone levels that occur in pregnancy and after delivery have made this a popular area of exploration. Women with a history of postpartum depression compared with those without such a history are more likely to experience depressive symptoms after hormonal withdrawal, which supports biological vulnerability to the disorder given the appropriate hormonal changes. Perhaps one of the stronger pieces of evidence is that postpartum estrogen supplementation, which slows the postpartum decline in estrogen levels, leads to resolution of depressive symptoms (4). However, estrogen has a myriad of effects on neurotransmitter systems that have been implicated in major depressive disorder, and thus its influence may be direct.
Neurotransmitter Systems: Because of the known interplay between hormones and neurotransmitter systems, neurotransmitters implicated in major depressive disorder such as monoamine oxidases (MAOs), i.e., MAO-A and MAO-B, serotonin, and norepinephrine have been specifically studied in perinatal populations. Through the use of positron emission tomography, researchers found that MAO-A levels in the early postpartum period correlate with a decrease in estrogen level (5); this suggests a model in which an acute monoamine-lowering process contributes to the mood change indicative of postpartum blues and postpartum major depressive disorder. Serotonin transporter activity is greater in postpartum women with, as compared with those without, depressive symptoms and serotonin levels in platelets correlate with the severity of blues at 5 days postpartum (6). These results imply that lower synaptic serotonin may lead to depressive symptoms in postpartum women. However, one of these studies found that a metabolite of norepinephrine was elevated after delivery in women with, compared with women without, depressive symptoms (6). The research group hypothesizes that the later finding is a reaction to stress.
Hypothalamic-Pituitary-Adrenal Axis Abnormalities: Major depressive disorder has been associated with hypothalamic-pituitary-adrenal axis dysfunction, and events of pregnancy and parturition may perturb this system. Nonpregnant individuals have an elegant feedback mechanism whereby control cortisol, corticotrophin-releasing hormone (CRH), and adrenocorticotropin (ACTH) autoreceptors decrease hormone production in the hypothalamus, anterior pituitary, and adrenal cortex. In pregnancy, the placenta independently produces a number of hormones (7) (e.g., CRH, ACTH, and cortisol) that are regulated in a feed-forward manner, which leads to down-regulation of autoreceptors in the hypothalamus and anterior pituitary. This process of receptor down-regulation and the transition to a nonpregnant hormonal state has been hypothesized by some to constitute a period of vulnerability for mood disorders (7). Overall elevations in hypothalamic-pituitary-adrenal axis are consistent with work that finds elevated CRH levels at 25 weeks of gestational age and augmented cortisol response to stress in pregnant women who go on to express postpartum depressive symptoms (8).
Immune System: Delivery of a newborn stimulates a pro-inflammatory state presumably attributable to pain, physical exertion, and tissue injury involved in delivery (9). Pro-inflammatory cytokines are also linked to hypothalamic-pituitary-adrenal axis activity and have been associated with mood disorders in nonpregnant individuals (9). Interleukin-1β, a potent pro-inflammatory cytokine released from white blood cells, is elevated in the first month postpartum. In a cross sectional study, serum interferon-γ or interleukin-10 and cortisol levels were measured in postpartum women and were lower in those who had depressive symptoms, suggesting a hypoactive hypothalamic-pituitary-adrenal and mixed pro-inflammatory immune response (10).
Thyroid Function: A relationship between abnormalities in thyroid function and mood disorders is well established. The thyroid axis is also affected by pregnancy via the effects of chorionic gonadotropin on the thyroid gland and may constitute an area of biological vulnerability for depression in pregnancy or after delivery. Thyroid indices have included elevations of thyroid-stimulating hormone (TSH) that would indicate hypothyroidism and elevations of free T4 that would be consistent with sub-clinical hyperthyroidism (11). Some work also shows that elevations in thyroid autoantibodies are a risk factor for depressive symptoms in pregnancy and after delivery, although this finding is not uniform (11). It is reasonable to assess thyroid status in pregnant and postpartum women with depressive mood disorders because this may indicate thyroid dysfunction and may assist in the management of depression.
Melatonin: In some studies it is observed that pregnant women with major depressive disorder had lower melatonin levels and postpartum women with major depressive disorder had higher melatonin levels as compared with their non-depressed counterparts (12). These findings are consistent with earlier work from this group that showed a beneficial effect of critically timed sleep deprivation on mood symptoms in postpartum women with major depressive disorder. Such results need to be replicated before they can be strongly implicated in the pathophysiology of major depressive disorder in pregnancy or after delivery.
Familial Aggregation: In the multicenter Depression Network Study, investigators diagnosed postpartum major depressive disorder in 42% of 31 women with a sister who had experienced major depressive disorder after delivery compared with only 15% of 59 women whose sisters had not experienced postpartum major depressive disorder (13). A report from the Genetics of Recurrent Early-Onset major depressive disorder study revealed that having a sibling with major depressive disorder during pregnancy or after delivery increased the odds of a similar episode in the other sibling by 2.28; a sibling with postpartum major depressive disorder increased the odds of having postpartum major depressive disorder by 4.96 (14).
Genetic Studies: Findings from familial aggregation studies have spurred the search for underlying genetic mechanism. Polymorphisms in the serotonin transporter gene (5HTTLPR) lead to either low or high expression of the serotonin transporter. High expression of the transporter gene is linked with depressive symptoms, particularly when the serotonin precursor, tryptophan, is relatively depleted. The postpartum is a time when tryptophan is relatively depleted and the high expression of polymorphisms is associated with elevated scores at 8 weeks postpartum, although not at 32 weeks postpartum (15). In a prospective cohort study of perinatal women, the low functioning polymorphism of the serotonin transporter was associated with depressive symptoms at 6 weeks postpartum (16). Additionally, the low functioning polymorphisms of two enzymes that degrade neurotransmitters, monoamine oxidase-A and catechol-O-methyl-transferase, were associated with depressive symptoms during the third trimester and 6-week time point after delivery.
Depression During Pregnancy
This subject is discussed in detail in another article in this section of the web site.
Anxiety Disorders During Pregnancy
Anxiety disorders include panic disorder, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), posttraumatic stress disorder (PTSD), social anxiety disorder, and specific phobias. Collectively, anxiety disorders are the most commonly occurring psychiatric disorders, with a prevalence of 18.1% among adults 18 years and older in the United States (17). Anxiety and stress during pregnancy are documented as factors associated with poor obstetric outcomes, including spontaneous abortions, preterm delivery, and delivery complications such as prolonged labor, precipitated labor, clinical fetal distress, and forceps deliveries (18). A direct causal relationship has not been established. Panic disorder is characterized by recurrent panic attacks that arise spontaneously in situations that are not expected to cause anxiety. Most investigators agree that women are at greatest risk for exacerbation of panic disorder during the postpartum period. In a recent study PTSD was reported to be the third most common psychiatric diagnosis among economically disadvantaged pregnant women, with a prevalence of 7.7% (18). Women with PTSD were significantly more likely to have a comorbid condition, principally major depression or GAD. Many reports have documented traumatic obstetric experiences (e.g., emergency delivery, miscarriage, and fetal demise) as precipitants to PTSD-related symptomatology. The incidence of OCD during pregnancy is unknown. Despite limited formal investigation, most clinicians and researchers agree that pregnancy seems to be a potential trigger of OCD symptom onset, with 39% of the women in a specialized OCD clinic experiencing symptom onset during pregnancy (18). It generally is accepted that OCD worsens during the postpartum period.
Safety and efficacy of treatment for anxiety disorder during pregnancy: Use of benzodiazepines does not appear to carry a significant risk of somatic teratogenesis. In early studies of in-utero exposure to diazepam, a benzodiazepine, an increased risk of oral clefts was reported (18). In a subsequent meta-analysis, it was demonstrated that prenatal benzodiazepine exposure increased the risk of oral cleft, although the absolute risk increased by 0.01%, from 6 in 10,000 to 7 in 10,000 (18). If discontinuation of benzodiazepine use is considered during pregnancy, benzodiazepines should not be abruptly withdrawn. The data regarding neonatal toxicity and withdrawal syndromes are well documented, and neonates should be observed closely in the postpartum period. Floppy infant syndrome, characterized by hypothermia, lethargy, poor respiratory effort and feeding difficulties, is associated with maternal use of benzodiazepines shortly before delivery (19). Neonatal withdrawal syndromes, characterized by restlessness, hypertonia, hyperreflexia, tremulousness, apnea, diarrhea, and vomiting, have been described in infants whose mothers were taking alprazolam, chlordiazepoxide, or diazepam (19). These symptoms have been reported to persist for as long as 3 months postpartum.
The long-term neurobehavioral impact of prenatal benzodiazepine exposure is unclear. The existence of a "benzodiazepine-exposure syndrome", including growth restriction, dysmorphism, and both mental and psychomotor retardation, in infants exposed prenatally to benzodiazepines is disputed (20). In one study, no difference in the incidence of behavioral abnormalities at age 8 months or IQ scores at age 4 were found among children exposed to chlordiazepoxide during gestation (20).
Schizophrenia-Spectrum During Pregnancy
Schizophrenia is one of the more challenging and complex psychiatric disorders. It is a chronic disorder of thought, affect, and cognition, and it significantly disturbs the individual's ability to function in society and develop interpersonal relationships. The clinical presentation is extremely varied, and despite attempts to portray a stereotype in the media, the stereotypic schizophrenic individual does not exist. Schizophrenia is a severe and persistent mental illness characterized by psychotic symptoms, negative symptoms, such as flat affect and lack of volition, and significant occupational and social dysfunction. It occurs in approximately 1-2% of women, with the most common age of onset during the childbearing age (21). A variety of adverse pregnancy outcomes in women with schizophrenia have been reported, including preterm delivery, low birth weight infants, small for gestational age fetuses, placental abnormalities and antenatal hemorrhage, increased rates of congenital malformations, especially of cardiovascular system, a higher incidence of postnatal death (18). If left untreated during pregnancy, schizophrenia-spectrum disorders can have devastating effects on both mother and child, with rare reports of maternal self-mutilation, denial of pregnancy resulting in refusal of prenatal care, and infanticide.
Safety and efficacy of treatment for schizophrenia during pregnancy: The atypical antipsychotics generally are better tolerated and possibly are more effective in managing the negative symptoms of schizophrenia. They also are used increasingly for bipolar disorder, OCD, and treatment-resistant depression. The reproductive safety data regarding the use of atypical antipsychotics remains extremely limited. In a prospective comparative study of pregnancy outcomes between groups exposed and unexposed to atypical antipsychotics, outcomes of 151 pregnancies with exposure to olanzapine, risperidone, quetiapine, and clozapine demonstrated a higher rate of low birth weight (10% in the exposed versus 2% in non-exposed group) and therapeutic abortions (22). The typical antipsychotic drugs have a larger reproductive safety profile and include haloperidol, thioridazine, fluphenazine, perphenazine, chlorpromazine, and trifluoperazine. No significant teratogenic effect has been documented with chlorpromazine, haloperidol, and perphenazine (23). In clinical neurobehavioral outcome studies encompassing 203 children exposed to typical antipsychotics during gestation, no considerable differences have been detected in IQ scores at 4 years of age, although relatively low antipsychotic doses were used by many women in these studies. Fetal and neonatal toxicity reported with exposure to the typical antipsychotics includes neuroleptic malignant syndrome, dyskinesia, extrapyramidal side effects manifested by heightened muscle tone and increased rooting and tendon reflexes persisting for several months, neonatal jaundice, and postnatal intestinal obstruction (24). Fetuses and infants also may be exposed to drugs used to manage the extrapyramidal side effects (e.g., diphenhydramine, benztropine, and amantadine).
In summary, typical antipsychotics have been widely used for more than 40 years, and the available data suggest the risks of use these agents are minimal with respect to teratogenic or toxic effects on the fetus. In particular, use of piperazine phenothiazines (e.g. trifluoperazine and perphenazine) may have especially limited teratogenic potential (24). Doses of typical antipsychotics during the peripartum should be kept to a minimum to limit the necessity of utilizing medications to manage extrapyramidal side effects. There is likewise little evidence to suggest that the currently available atypical antipsychotics are associated with elevated risk for neonatal toxicity or somatic teratogenesis. No long-term neurobehavioral studies of exposed children have yet been conducted. Therefore, the routine use of atypical antipsychotics during pregnancy and lactation cannot be recommended. In a woman who is taking an atypical antipsychotic and inadvertently conceives, a comprehensive risk-benefit assessment may indicate that continuing therapy with the atypical antipsychotic (to which the fetus has already been exposed) during gestation is preferable to switching to therapy with a typical antipsychotic (to which the fetus has not yet been exposed).
Psychosis During Pregnancy
Psychosis is a mental disturbance in which there is a loss of contact with reality evidenced by hallucination, delusions, or thought disorganization. Hallucinations -- false sensory perception, usually auditory; delusions -- false beliefs can include persecutory, grandiose, religious, or somatic; thought disorganization -- disruption of logical process of thought, loose associations, nonsensical speech, or bizarre behavior. Psychotic episodes are seen most commonly in patients who suffer from schizophrenia / schizoaffective disorder or psychotic episodes of bipolar disorder and major depression. Although depression during pregnancy is common, new-onset acute psychosis during pregnancy is extremely rare. A classic epidemiologic study found that the risk of developing a severe mental illness in pregnancy is estimated to be 7.1 in 10,000 per year (25). However, women with a preexisting diagnosis of a psychotic disorder may experience progression of disease in pregnancy (particularly if they have discontinued antipsychotic therapy) and thus present with a psychotic episode. Relapse rates are also high for women who have experienced a previous psychosis in pregnancy. New-onset psychosis during pregnancy is very uncommon and should trigger a careful search for an underlying medical or pharmacologic cause (25). Encephalopathy is a ubiquitous term encompassing any extensive alteration in brain function caused by diffuse brain disease. Symptomatic presentation of an encephalopathy can include personality changes, inability to concentrate, lethargy, disorientation, memory loss, and involuntary movements. Wernicke's encephalopathy is caused by thiamine (vitamin B1) deficiency. This encephalopathy presents with a classic triad of symptoms: confusion, oculomotor dysfunction, and gait ataxia. Although Wernicke's encephalopathy is most commonly seen in chronic alcoholism, it is also a rare but known complication of hyperemesis gravidarum.
Recent innovations in antipsychotic therapy might inadvertently increase the risk for unplanned pregnancy among women with chronic psychotic disorders. Whereas the older, so-called typical, antipsychotics commonly produce hyperprolactinemia that can in turn suppress ovulation, the newer atypical antipsychotics (with the exception of risperidone and paliperidone) have comparatively little effect on prolactin physiology. Consequently, concern has been raised that the emergence of atypical antipsychotics will contribute to higher rates of inadvertent conception among women with psychotic disorder, although there are yet no objective data to confirm this suspicion.
The risk factors associated with acute psychosis in pregnancy are:
The workup generally begins by eliminating medical or pharmacological causes. A thorough history and physical examination must be obtained first. A comprehensive neurologic examination is an important component of the evaluation. Basic laboratory studies should be ordered including electrolytes, complete blood count, hepatic and renal function, coagulation panel, arterial blood gas, thyroid function (thyroid-stimulating hormone, T3, free T4), albumin, urinalysis, and serum and urine drug screen. If the physical examination suggests a neurological impairment, MRI should be ordered. Serum / plasma testing also can be useful in the diagnostic work-up of suspected Wernicke's encephalopathy. Three tests are now available, including erythrocyte transketolase activity, thiamine pyrophosphate effect, and thiamine pyrophosphate concentration in plasma or whole blood.
Management during pregnancy: Psychosis during pregnancy or the postpartum period owing to any cause (medical, pharmacologic, or psychiatric) constitutes an emergency. Even when medical or pharmacologic causes have been identified, psychiatric consultation is warranted to ensure the safety of the patient and her offspring. In particular, bizarre ideas about the pregnancy or the neonate should heighten concern for the safety of the patient and her child. Transfer to an inpatient psychiatric unit is recommended. If medical instability dictates that the psychotic patient's care must be managed in the obstetric unit, she should be placed on constant close observation.
Before initiating antipsychotic therapy, it is important to perform a thorough risk / benefit analysis. If the patient presents with acute psychosis, she may pose an imminent risk to herself and her fetus. Consequently, management with antipsychotic medication is virtually always warranted. Acute psychosis in pregnancy is a clinical emergency, and prompt hospitalization is necessary. Haloperidol remains the antipsychotic with the most extensive reproductive safety data, having been used in the management of hyperemesis gravidarum in earlier decades. Therefore, it is typically used to manage new-onset psychosis during pregnancy (26). Lorazepam can be used in conjunction with haloperidol to manage agitation or combativeness during acute psychosis in pregnancy; however, lorazepam does not alleviate psychosis itself, and indiscriminate use of benzodiazepines can exacerbate symptoms of disorganization or disinhibition. Typically, psychosis during pregnancy is not an acute problem but the continuation of a chronic psychotic illness that had arisen long before conception. Consequently, many such patients will have conceived while taking one of the newer, so-called atypical antipsychotics. These are preferred for long-term management owing to reduced risk for tardive dyskinesia and extrapyramidal side effects and arguably greater effectiveness in managing the negative symptoms of schizophrenia (26). Unfortunately, the data remains sparse with regard to the safety and efficacy of atypical antipsychotic drug use in pregnancy. Nevertheless, in a clinical situation wherein a fetus already has been exposed to the atypical antipsychotic, switching to an older, better studied agent such as haloperidol is not recommended. Switching agents after conception only heightens risk by exposing the fetus to yet another psychotropic agent and increases the likelihood of maternal psychiatric decompensation when it is unclear how the patient will respond to the second medication.
Pregnant women who experience a psychiatric episode of a psychiatric illness are by definition at high risk for developing postpartum psychosis. Such patients are also at an increased risk for other psychiatric illness. Pregnant women with psychiatric illness are more likely to smoke, abuse alcohol or drugs, engage in suicidal behavior, and receive inadequate nutrition (27). Several studies have shown that pregnant women with psychosis have an increased risk for preterm delivery as well as for having small for gestational age infants (28). Placental passage rates of four common atypical antipsychotics (olanzapine, haloperidol, risperidone, and quetiapine) parallel transfer rates for antidepressants and anticonvulsants (28). Although it is known that these drugs do indeed cross the placenta, the end effect of fetal outcome remains unclear.
Bipolar Disorder During Pregnancy
Bipolar disorder, historically called manic-depressive disorder, affects between 3.9% and 6.4% of Americans and affects men and women equally (29). Bipolar disorder should always be considered in the differential diagnosis of depression; one quarter of those presenting with depression prove to have bipolar disorder (30). Risk of relapse for bipolar disorder is tightly linked with medication discontinuation, and because a number of agents that are used to treat bipolar disorder are teratogens, many women stop medications during pregnancy. Studies find that between 80% and 100% of women who stop mood stabilizer medication during pregnancy will experience relapse soon after medication discontinuation; these rates are two-fold to three-fold higher than rates found for pregnant women with bipolar illness who continue medication in pregnancy (29). Women who experience relapse appear to be more likely to have relapse into an episode of depression or mixed-mood disorder that is characterized by both manic and depressive symptoms. Rates of postpartum relapse range from 32% to 67% (29). Perinatal episodes of bipolar disorder tend to be depressive, and when experienced with one pregnancy, are more likely to recur with subsequent pregnancies. There are also in an increased risk of postpartum psychosis as high as 46% (31).
Almost 33% of women with bipolar disorder will experience an episode during pregnancy, and about 50% report severe emotional problems. During pregnancy the risks of therapy must be balanced against the risks of untreated bipolar disorder. Concerns about psychotropic medication use in pregnancy include malformations, poor neonatal outcome, and behavioral teratogenesis. The fetus may be exposed before the patient knows she is pregnant. Prenatal screening with α-fetoprotein testing, high-resolution ultrasonography, and other modalities is strongly advised. Physicians should be alert to other pregnancy risks in women with bipolar disorder such as smoking, substance abuse, and victimization. The goal should be control of specific symptoms with lower doses and less polypharmacy.
Safety and efficacy of lithium for treatment of bipolar disorder during pregnancy: Use of lithium in pregnancy may be associated with a small increase in congenital cardiac malformations. The initial retrospective data suggested that fetal exposure to lithium was associated with a 400-fold increase in congenital heart disease, particularly Ebstein's anomaly (18). A subsequent meta-analysis of the available data calculated the risk ratio for cardiac malformations to be 1.2-7.7 and the risk ratio for overall congenital malformations to be 1.5-3 (18). Fetal exposure to lithium later in gestation has been associated with fetal and neonatal cardiac arrhythmias, hypoglycemia, nephrogenic diabetes insipidus function, premature delivery, and floppy infant syndrome similar to seen with benzodiazepine exposure (32). Symptoms of neonatal lithium toxicity include flaccidity, lethargy, and poor suck reflexes, which may persist for more than 7 days. Neurobehavioral sequelae were not documented in a 5-year follow-up of 60 school-aged children exposed to lithium during gestation (18)(31). The physiologic alterations of pregnancy may affect the absorption, distribution, metabolism and elimination of lithium, and close monitoring of lithium levels during pregnancy and postpartum is recommended. The decision to discontinue lithium therapy in pregnancy because of fetal risks should be balanced against the maternal risks of exacerbation of illness. The following guidelines for treatment have been suggested for women with bipolar illness who are treated with lithium and plan to conceiver: 1) in women who experience mild and infrequent episodes of illness, treatment with lithium should be gradually tapered before conception; 2) in women who have more severe episodes but are only at moderate risk for relapse in short term, treatment with lithium should be tapered before conception but reinstituted after organogenesis; 3) in women who have especially severe and frequent episodes of illness, treatment with lithium should be continued throughout gestation and the patient counseled regarding reproductive risks. Fetal assessment with fetal echocardiography should be considered in pregnant women exposed to lithium in the first trimester. For women in whom an unplanned conception occurs while receiving lithium therapy, the decision to continue or discontinue the use of lithium should be in part based on disease severity, course of patient's illness, and the point of gestation at the time of exposure.
Safety and efficacy of antiepileptic drugs for treatment of bipolar disorder during pregnancy: Several anticonvulsants, including valproate, carbamazepine, and lamotrigine, currently are used in the treatment of bipolar disorder. Data regarding fetal effects of these drugs are derived primarily from studies of women with seizures. Prenatal exposure to valproate is associated with a 1-3.8% risk of neural tube defects, with a corresponding dose-response relationship (33). Other congenital malformations associated with valproate use include craniofacial anomalies, limb abnormalities, and cardiovascular anomalies. A "fetal valproate syndrome" has been described with features of fetal growth restriction, facial dysmorphology, and limb and heart defects. Varying degrees of cognitive impairment, including mental development delay, autism, and Asperger's syndrome, have been reported with fetal valproate syndrome. Acute neonatal risks include heptotoxicity, and withdrawal symptoms (34). Carbamazepine exposure in pregnancy is associated with a fetal carbamazepine syndrome manifest by facial dysmorphism and fingernail hypoplasia. It is unclear whether carbamazepine use increases the risk of fetal neural tube defects or development delay. Fetal exposure to lamotrigine has not been documented to increase the risk of major fetal anomalies, although there may be an increased risk of midline facial clefts (0.89% of 564 exposures) as reported by one pregnancy registry (35), possibly related to higher daily maternal doses (greater than 200 mg/day). The reproductive safety of lamotrigine appears to compare favorably with alternative treatments, but lacking are studies of the effectiveness of this antiepileptic drug as a mood stabilizer in pregnancy.
In managing bipolar disorders, the use of valproate and carbamazepine are superior to that of lithium for patients who experience mixed episodes or rapid cycling but exhibit limited efficacy in the treatment of bipolar depression. In contrast, lamotrigine is efficacious in the prevention of the depressed phase of the illness. Lamotrigine is a potential maintenance therapy option for pregnant women with bipolar depression, general tolerability, and growing reproductive safety profile relative to alternative mood stabilizers. Because both valproate and carbamazepine are associated with adverse effects when used in pregnancy, their use, if possible should be avoided especially during first trimester. The effectiveness of folate supplementation of 4 mg/day should be offered preconceptionally and for the first trimester of pregnancy. Whether the use of antiepileptic drugs such as carbamazepine increase the risk of neonatal hemorrhage and whether vitamin K supplementation is effective remains unclear.
Psychiatric Drugs and Breastfeeding
The postpartum phase represents the highest lifetime risk period for women to develop mental illness. Evidence indicates an elevated risk of postpartum psychosis in women with bipolar disorder (36). Postpartum psychosis often constitutes a psychiatric emergency, increasing the risk of both infanticide and suicide (36). Maintenance treatment in the postpartum period may be prophylactic. Treating bipolar postpartum depressive episodes is more complex than treating unipolar depression due to the risk of precipitating manic episodes. In these cases a mood stabilizer should be used, and an antidepressant may also be needed. These women require close monitoring. Communication between treating physicians is critical and infants should be monitored for adverse effects, including with laboratory tests.
Breastfeeding has clear benefits for both mother and infant, and in making the decision to recommend breastfeeding, these benefits should be weighed against the risks to the neonate of medication exposure while breastfeeding. Most medications are transferred through breast milk, although most are found at very low levels and likely are not clinically relevant for the neonate. For women who breastfeed, measuring serum levels in neonates is not recommended. Most clinical laboratory tests lack the sensitivity to detect and measure the low levels present. However, breastfeeding should be stopped immediately if a nursing infant develops abnormal symptoms most likely associated with exposure to the medication. In the management of anxiety disorders, benzodiazepine use exhibits lower milk / plasma ratios than other classes of psychotropics (18). Some investigators concluded that benzodiazepine use at relatively low doses does not present a contraindication to nursing (39). However, infants with an impaired capacity to metabolize benzodiazepines may exhibit sedation and poor feeding even with low maternal doses. Maternal benzodiazepine use shortly before delivery is associated with floppy infant syndrome.
Lithium should be prescribed with caution due to the risk of rapid dehydration (32)(33). The existing data regarding lithium use and lactation shows adverse events including lethargy, hypotonia, hypothermia, cyanosis, and electrocardiogram changes. Lithium is detectable in breast milk and many counsel cautions in its use while breastfeeding, and the American Academy of Pediatrics (AAP) discourages the use of lithium during lactation (39). If used; the infant's lithium levels, hydration status of nursing infants and complete blood count should be monitored. There are no available reports regarding the long-term neurobehavioral sequelae of lithium exposure during lactation. Carbamazepine and valproate are more compatible with breastfeeding (31). Only one adverse event, an infant with thrombocytopenia and anemia, has been reported in studies regarding valproate use and lactation, which includes 41 mother-infant nursing days (39). Studies of the neurobehavioral impact of valproate exposure during lactation have not been concluded. The AAP and the World Health Organization (WHO) Working Group on Drugs and Human Lactation have concluded that use of valproate is compatible with breastfeeding. Reported adverse effects of carbamazepine in breast milk include transient cholestatic hepatitis and hyperbilirubinemia. The WHO Working Group on Drugs and Lactation has concluded that use of carbamazepine with breast feeding is "probably safe". Infants exposed to lamotrigine should be monitored for rash (37). The atypical antipsychotics, such as olazapine, for which we have less information, appear to be like older antipsychotics and can lead to extrapyramidal side effects in the infants (38). No adverse effects from the use of carbamazepine, valproate, or lamotrigine have been reported. However, serum concentrations of lamotrigine were 30% of maternal levels in one study, leading to recommendations that such infants be monitored for rash (40).
Maternal psychiatric illness, if inadequately treated or untreated, may result in poor compliance with prenatal care, inadequate nutrition, exposure to additional medication or herbal remedies, increased alcohol and tobacco use, deficits in mother-infant bonding, and disruptions within the family environment. Mental health is fundamental to health. For the pregnant woman, the capacity to function optimally, enjoy relationships, manage the pregnancy, and prepare for the infant's birth is critical. Perinatal health can be conceptualized within a model that integrates the complex social, psychological, behavioral, environmental, and biologic forces that shape pregnancy. Unipolar and bipolar mood disorders, which are common in pregnant and postpartum women, deserve the attention of obstetric providers. Procedures to identify those at risk should begin in pregnancy if not in the preconceptional period. There is evidence to suggest familiality for perinatal risk among women with unipolar major depressive disorder and bipolar disorder. Use of a single medication at a higher dose is favored over the use of multiple medications for the treatment of psychiatric illness during pregnancy. Psychotherapeutic counseling is beneficial for mild to moderate ill women with unipolar major depressive disorder, but medication is likely required for women with severe major depressive disorder or bipolar disorder. For women who breastfeed, measuring serum levels in the neonate is not recommended. Obstetric management that coordinates care with psychiatric providers is likely to optimize outcomes for mothers and their children. Whenever possible, multidisciplinary management involving the patient's obstetrician, mental health clinician, primary healthcare provider, and pediatrician is recommended to facilitate care.