Background: Bipolar disorder is a brain disorder that can cause abnormal changes in a person's mood, cognitive function, and quality of life. Patients who are diagnosed with bipolar disorder often have intense emotional states that are characterized by either manic or depressive episodes. There is a strong correlation between women of child bearing age and the initial age of onset of the disease. Mood stabilizing drugs have been the mainstay of treatment for many decades; however, there is strong data supporting the teratogenic effects of these drugs on the fetus in pregnant and lactating women.

Methods: Review articles, clinical trials, and practice guidelines were located using online databases PubMed, CINAHL, IDIS, and Medline. Search terms included at least one of the following: “bipolar disorder”, “breast-feeding”, “carbamazepine”, “epilepsy”, “lactation”, “lamotrigine”, “lithium”, “mood stabilizers”, “pregnancy”, “valproate”, and “valproic acid”. Online clinical databases Clinical Pharmacology and Lexi-Comp were also used in the study.

Results: All mood stabilizer drugs are found to cause malformations in fetal development if given during the first trimester of pregnancy, thus use should be avoided if possible. Lamotrigine was found to cause lowest risk of adverse effects in both the mother and fetus during pregnancy; however, it should be avoided in breastfeeding women as it readily passes into breast milk. Lithium use during pregnancy and lactation has been associated with severe malformations and should only be used if maternal benefit outweighs fetal risk. Valproate is considered harmful to both the mother and fetus during pregnancy, but may be a compatible option for breastfeeding. Carbamazepine is found to cause serious malformations with the developing fetus as well as metabolic effects with the mother; however, it is found to cause little effects in breastfed infants as it does not readily pass through breast milk.

Conclusion: The use of medications in pregnant and breastfeeding women suffering from bipolar disorder must be carefully considered for impacts on fetal development as well as risks to the mother. Mood stabilizers are readily marketed as first line treatment options for bipolar disorder; however, their use in pregnant and lactating women may cause limitations as preferred therapy. Studies show that though lamotrigine has not been as well studied as the other agents, it may be the best recommendation during pregnancy, for both fetal and maternal health concerns. For breastfeeding women, carbamazepine has been shown to be the better option, as it carries the lowest risk of adverse events to the infant.

Bipolar disorder, also referred to as manic-depressive illness, is a brain disorder that can cause abnormal changes in mood, energy, activity levels, and the ability to perform daily tasks. Patients who have bipolar disorder experience abnormally intense emotional states that occur in periods called “mood episodes”. The exact etiology of bipolar disorder is not completely understood but there are multiple neurochemical theories that propose there is a decrease of serotonin (5-HT) in both manic and depressive disorders. There are also theories that an increased amount of dopamine (DA) and norepinephrine (NE) are found in hyperactive psychosis states, possibly caused from lack of inhibitory neurotransmitter γ-aminobutyric acid (GABA), while there is a deficiency in DA and NE in depressive states.1 Bipolar disorders are often diagnosed into two main classifications, bipolar I and bipolar II. According to the Diagnostic and Statistical Manual of Mental Disorders, text revision (DSM-IV-TR),2 bipolar I can be described as manic or mixed episodes that are experienced for a duration of at least one week or manic symptoms that require immediate hospitalization due to the severity of symptoms. Bipolar II can be differentiated by the lack of severe manic or mixed episodes but similar in the fact these patients often develop depressive episodes that fluctuate with hypomanic episodes.2 

A nationwide survey published in a 2007 article by Merikangas and colleagues found that the United States holds a 1% lifetime prevalence rate of bipolar I disorder and a 1.1% for bipolar II disorder.3 However, the true prevalence of bipolar disorders is uncertain which is likely due to missed diagnoses. Recent data indicate bipolar I disorder equally affects men and women, whereas bipolar II disorder is more common in women.4 A valuable finding shows that the typical age of onset for bipolar disorder in most individuals diagnosed is between the ages of 15–30 years.5 This is of great importance as this age range often identifies the most common age that females are likely to become pregnant.

An issue that remains unclear lies with the possibility that women may experience fewer mood episodes than usual during pregnancy. According to three separate studies, women were found to have relatively fewer episodes during their pregnancy and the few months following delivery.6,7,8 In contrast, multiple reports made by Viguera and colleagues were supported by findings in 2002 that concluded women often experienced the same if not increased reoccurrence of bipolar symptoms during pregnancy.9,10 These disputed findings demonstrate a lack of supportive evidence that women should discontinue treatment for bipolar disorder during their pregnancy. A 2007 article states that the risk of relapse was 85.5% in women who discontinued pharmacological interventions while a continuation of therapy decreased the risk to 37%.11 Findings published in a 2000 article identify a higher than normal risk of relapse if the particular agents dismissed from therapy are mood stabilizers.6 In addition to increases in relapse, other consequences of discontinuing mood stabilizer treatment include increased suicide attempts and suicide completion, increased hospitalizations, and substance abuse.1,5 

A cure has not yet been established, and the practice guidelines published by the American Psychiatric Association (APA) indicate the treatment of bipolar disorder relieves symptoms, prevents recurrence and relapses, improves quality of life, and decreases mortality associated with acute episodes.12 ,Table 1 summarizes the treatment of acute manic and mixed episodes in bipolar disorder. Table 2 summarizes the treatment of acute depressive episodes in bipolar disorder. Maintenance treatment with medication should continue following a single manic episode and should be strongly considered in patients with bipolar II disorder.12 Due to the high dependence of mood stabilizers in the treatment of bipolar disorder and the correlation with bipolar disorder affecting those of childbearing age, the purpose of this review is to determine which mood stabilizers should be considered regarding the safety profile in pregnancy and lactation.

Table 1:

Summary of treatment for acute manic or mixed episodes in bipolar disorder (Adapted from APA)12 

Summary of treatment for acute manic or mixed episodes in bipolar disorder (Adapted from APA)12
Summary of treatment for acute manic or mixed episodes in bipolar disorder (Adapted from APA)12
Table 2:

Summary of treatment for acute depressive episodes in bipolar disorder (Adapted from APA)12 

Summary of treatment for acute depressive episodes in bipolar disorder (Adapted from APA)12
Summary of treatment for acute depressive episodes in bipolar disorder (Adapted from APA)12

A search using electronic databases PubMed, CINAHL, IDIS, and Medline was conducted limiting date ranges to 1980–April 2013. Search terms included at least one of the following: “bipolar disorder”, “breast-feeding”, “carbamazepine”, “epilepsy”, “lactation”, “lamotrigine”, “lithium”, “mood stabilizers”, “pregnancy”, “valproate”, and “valproic acid”. Published research, clinical trials, and other review articles were reviewed to ensure validity and remove potential bias when appropriate. Practical guidelines from the American Psychiatric Association (APA), National Institute of Health (NIH), and Veterans Affairs (VA) were also included to demonstrate relevance of the study. Online clinical databases Clinical Pharmacology and Lexi-Comp were also referenced to identify the mechanism of action and recommended doses for each of the drugs of interest.

As guidelines suggest, mood stabilizers are the initial drug class of choice for treatment of both bipolar I and II disorders.12,13,14,15 When determining treatment options of bipolar disorder in pregnant and breast feeding women, multiple considerations must be taken into account. The use of mood stabilizers in pregnant and breast feeding women is associated with an increased risk of complications.16,17 Some of these risks can include premature births, low birth weights, increased rate of fetal and neonatal death, congenital malformations, developmental delay, behavioral deficits, altered neurochemistry, and cognitive deficits.18,19 Pharmacokinetic issues are some of the most important considerations to keep in mind when treatment is being considered. Data suggest that women naturally have lower hepatic metabolism than that of men and this metabolic rate can be altered by reproductive hormones,20 suggesting fluctuations in plasma drug levels which may be of great importance. Other studies have shown that during pregnancy there is an increase in renal blood flow of the mother as well as an increased glomerular filtration rate21 further proving the need for careful drug monitoring to avoid toxicity in both mother and fetus. Many of the drugs used to treat bipolar disorder are lipophilic enough to pass through the placenta resulting in potential detrimental effects to the fetus as well as through breast milk that may lead to further teratogenic effects of the child. Table 3 summarizes dosing, pregnancy and lactation recommendations for mood stabilizers used in bipolar disorder.

Table 3:

Dosing, pregnancy and lactation risks for mood stabilizers in bipolar disorder.16,17 

Dosing, pregnancy and lactation risks for mood stabilizers in bipolar disorder.1617
Dosing, pregnancy and lactation risks for mood stabilizers in bipolar disorder.1617

Category CM: Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus as recommended by the manufacturer.

Category D: There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective) (DM-recommended by the manufacturer).

Compatible “Either the drug is not excreted in clinically significant amounts into human breast milk or its use during lactation does not, or is not expected to, cause toxicity in a nursing infant” Limited human data-potential toxicity: Either there is no human data or the human data are limited. The characteristics of the drug suggest that it could represent a clinically significant risk to a nursing infant. Breastfeeding is not recommended.

Lithium

Lithium was the first mood stabilizing drug approved in the 1970s for the treatment of mania by the US Food and Drug Administration (FDA)16. Lithium is used in the treatment of both classifications of acute episodes as well as prophylaxis therapy. The exact mechanism in which lithium works in bipolar disorder is not completely understood, but it is known that lithium blocks potassium channels and disrupts monoamine neurotransmitter action in the brain. Lithium is also known to increase serotonin (5-HT) synthesis and release from the CNS.22 

Lithium is associated with a high number of reported adverse effects in the general population. Some of the most common effects seen are bradycardia, tremor, arrhythmia, seizure, confusion, fatigue, thyroid dysfunction, and gastrointestinal and genitourinary system issues.13 The primary concern with lithium use during pregnancy, is teratogenicity reported by several studies. Lithium plasma levels are commonly monitored in all patients throughout treatment, but careful monitoring is especially important during pregnancy to avoid lithium toxicity in both the mother and fetus.

Since lithium has been the initial drug of choice for bipolar disorder for decades, a vast majority of patients will be taking it either alone or in combination with other anticonvulsant or antidepressant medications. Studies have shown that women receiving lithium therapy are at an increased risk of developing hypothyroidism, weight gain, and significant hair loss.23 Long-term lithium treatment has been associated with mild cognitive and memory impairment.24 Women who become pregnant while on lithium therapy should be counseled on the potential fetal development issues that have been reported, especially during the first trimester. Data suggest that lithium use in the first trimester should be avoided completely if possible, but may be considered during the second and third trimesters if maternal benefit is greater than fetal risk.23,25 A five-fold decrease in relapse of severe episodes after delivery has been reported when lithium was used during the later stages of pregnancy (e.g., 36 weeks gestation).23 Comparable findings were reported in another study showing an approximate three-fold increase of recurrence of bipolar episodes post-partum upon lithium discontinuation during pregnancy.26 

Studies have shown that the major changes in the hemodynamic state of the mother during labor and delivery causes a dramatic decrease in renal clearance of the drug, increasing the risk of lithium toxicity.26 Researchers suggest that lithium be discontinued 48–72 hours before expected delivery to avoid the possibility of lithium toxicity in the mother and to decrease the levels passed through the placenta resulting in better fetal outcomes; yet, lithium should be reinitiated immediately post-partum to decrease the risk of relapse.27 If the decision to discontinue lithium therapy is made, it is essential to instruct the patient on the need to taper the medication slowly over two to four weeks to avoid significant rebound episodes.24 As lithium clearance is increased during pregnancy it is very important to monitor plasma lithium levels periodically throughout all stages of gestation28 as well as regular thyroid and electrolyte monitoring.24 

Fetal malformation risk is found to be associated with lithium use during the first trimester of pregnancy. These risks include malformations in the heart (Ebstein's anomaly), arrhythmias, neonatal hypothyroidism, diabetes insipidus, and “floppy baby syndrome” (hypotonicity and cyanosis).23,29,30 Other significant reports of low muscle tone, hepatic abnormalities, decreased respiratory development, overall lethargy of the neonate, polyhydramnious, and possible lithium toxicity with long-term lithium use by the mother.29,30 Lithium toxicity in a neonate is noted as muscle twitching, cyanosis, hypothermia, restlessness, and abnormal electrocardiogram (ECG).23 Multiple studies have also found a significant risk of premature delivery increased birth weight and perinatal death.26,29,30 Due to the severity of heart abnormalities seen in neonates exposed to lithium, careful fetal heart monitoring is recommended starting at 16-week gestation as well as anatomical survey conducted at weeks 18–23 gestation. Plasma drug concentrations should be monitored weekly after 36 weeks gestation due to high risk of lithium toxicity in both mother and fetus around time of delivery.29 

Lithium is a positively charged ion that is known to readily pass through breast milk. Studies have indicated as much as 30–50% of maternal plasma lithium levels are transferred through breast milk and ingested by the infant.31 This high level of transfer in combination with immature renal function of the neonate has put these infants at a greater risk for lithium toxicity.31 In breastfeeding women with a high rate of relapse, the continued use of lithium may be warranted due to greater benefits to the mother compared to harm of the infant, though these infants should be closely monitored for any changes in cardiac, respiratory, thyroid, and hepatic function.23  Table 4 summarizes the adverse effects of lithium use to both mother and fetus during pregnancy and to the infant during lactation.

Table 4:

Comparison of adverse events of mood stabilizers for bipolar disorder during pregnancy and lactation.

Comparison of adverse events of mood stabilizers for bipolar disorder during pregnancy and lactation.
Comparison of adverse events of mood stabilizers for bipolar disorder during pregnancy and lactation.

Valproate

Valproate or valproic acid was the second drug approved by the FDA for the treatment of bipolar disorder. Valproate received approval for use in 1995 and is used in both treatment and prophylactic therapy. Valproate's complete mechanism of action is not fully known, but the believed mechanism for its effect in mania is due to the increased concentrations of the inhibitory neurotransmitter GABA. It is thought that valproate inhibits the enzymes that catabolize GABA leading to an increase in GABA concentrations in the brain, and inhibiting sodium channels that cause a decrease in the firing of neurons.22 

Valproate is an anticonvulsant that is often considered an alternative first line agent in the treatment of bipolar disorder. The APA guidelines recommend valproate as a potentially better option, over lithium, for mixed episodes associated with bipolar I disorder.12 Patients with bipolar disorder treated with valproate have an increase chance of developing adverse events such as headache, somnolence, thrombocytopenia, tremor, flu-like syndrome, vision and gastrointestinal disturbances when compared to placebo.22 Valproate use during pregnancy has been an area of great concern as it is a well-studied teratogen that can cause detrimental effects to maternal and fetal well-being.23 

Valproate is a common treatment option for bipolar I disorder as well as in epileptic patients. This high level of use makes recognition of the risk versus benefit ratio of extreme importance, especially in pregnant patients. Previous studies have reported women taking valproate have experienced an increase in androgen levels, hyperinsulinemia, and polycystic ovarian syndrome.23 Another study found women were also at a greater risk for fluid retention, weight gain, and alopecia.23 Due to the potential of fluid retention and the interference of hepatic metabolism, researchers suggest that plasma drug concentrations are monitored regularly during each trimester, as well as regular liver function tests.24,29 Through a mechanism, which is not fully understood, valproate has been found by many to interfere with folate metabolism.29,32 Due to this folate deficiency, it is recommended that women should supplement 4–5mg of folic acid at least one month prior to conception, which should be continued throughout the duration of the pregnancy to avoid neural tube defects.12,29,32 

Valproate has been found to readily cross the placenta at higher levels compared to other mood stabilizers.33 This causes a greater risk for adverse drug events in the developing fetus, as proven by multiple studies. One of these, published in 2007, showed an increased risk of 20.29% of cases with serious adverse outcomes.18 As previously mentioned, all mood stabilizers are considered harmful during the first trimester. Use of valproate in the first trimester has been associated with the greatest risk of spina bifida, atrial septal defects, cleft palate and other craniofacial defects.23,34 Other noted serious birth defects such as hypospadias, ancephaly, cardiac abnorfmalities, limb reduction and other anatomical malformations were also seen when valproate was used during the first trimester.18,23,34,35 Valproate use during the third trimester of pregnancy has been known to cause behavioral effects in children later in life and is associated with an increased risk of autistic spectrum disorders and infant neurodevelopmental delay.18,19,36 Results from a 2001 study concluded that children exposed to valproate in utero were at an increased risk of educational needs as compared to those exposed to carbamazepine.37 Similar reports were made in other studies that showed children exposed to valproate were at higher risk of developing attention-deficit/hyperactivity disorder (ADHD) and parents noticed lower social skills in children exposed to higher doses (>1000 mg/day) during later stages of pregnancy.19 Few reports have been associated with neonatal anemia and thrombocytopenia, withdrawal, hypoglycemia, hepatotoxicity, and “fetal valproate syndrome”23,29. The currently available evidence supporting teratogenic effects during pregnancy warrants close monitoring of the fetus for cardiac and structural abnormalities. Researchers suggest ultrasounds at 11–13 weeks of gestation to monitor fetal development.29 

Valproate is considered beneficial relative to its pharmacokinetic property of being highly protein bound. With valproate being highly bound to albumin, it causes low levels of free drug to pass through breast milk.33,38 Approximately 0.68% of maternal plasma levels penetrate breast milk, making it a relatively safe option for breastfeeding mothers. 31 Even though low levels are ingested, it is highly recommended in those breastfed infants, regular monitoring for white blood cell count, liver enzymes, and bilirubin should occur to ensure higher than expected levels are not transferred through breast milk. 23  Table 4 summarizes the adverse effects of valproic acid use to both mother and fetus during pregnancy and to the infant during lactation.

Lamotrigine

Lamotrigine gained FDA approval in 2003 for its use in bipolar I disorder. The anticonvulsant properties of this drug are not exactly known, however findings have identified lamotrigine to stabilize neuronal membranes via blockade of sodium channels. Lamotrigine is thought to have minimal effects on DA, NE, and GABA release.22 Lamotrigine is an anticonvulsant medication that has been considered to generally have a safe drug profile in most patients. Some of the most commonly reported adverse events associated with its use are gastrointestinal, insomnia, irritability, rash, and minimal cardiovascular events.16 The relatively new indication for lamotrigine resulted in limited available data on its use during pregnancy.

It has been known for years that many women can suffer from post-partum depression. One benefit in the use of lamotrigine during pregnancy and post-partum is its ability to lower depressive states,32 so many consider it the drug of choice for bipolar disorder treatment with predominant depressive episodes in pregnant women. There have been no significant additional adverse events reported in women taking lamotrigine in comparison to the general population. One study did indicate the possibility that serum drug concentrations (total and free) would be lower than expected during the 3rd trimester as drug clearance increases throughout pregnancy.23,39 This study emphasized the importance of monthly serum drug concentration monitoring throughout pregnancy, as drug levels are known to fluctuate.40 

There have also been few reported adverse events associated with fetal development when lamotrigine has been used during pregnancy. A report in 2007 compared adverse outcomes of lamotrigine, carbamazepine, and valproate, and concluded that lamotrigine is the safest mood stabilizer to use during pregnancy as it was only associated with a 1.02% increase in adverse events.18 Another study states that lamotrigine use during the first trimester only caused a 1.8% increased chance of major fetal malformations.41 The only significant damage to the fetus was found to be neonatal hepatotoxicity with few reports of cleft lip/palate.18,29 There is an insufficient amount of data to determine the extent in which maternal drug levels are passed to the fetus via the placenta, though some consider it to be only a moderate possibility.42 

There has been positive identification in drug levels penetrating into breast milk, so careful consideration should be taken when lamotrigine is used during lactation. Lamotrigine is metabolized in the liver via glucuronidation, which is reduced in neonates, causing an extended half-life resulting in accumulation of conjugates, thus increasing risk of toxicity.42 If lamotrigine use is desired during lactation, the infant should be closely monitored for breathing disturbances, lethargy, rash, and decreased ability to feed.34,42  Table 4 summarizes the adverse effects of lamotrigine use to both mother and fetus during pregnancy and to the infant during lactation.

Carbamazepine

Carbamazepine was FDA approved in 2004 for the treatment of acute manic and mixed episodes of bipolar I disorder.43 This anticonvulsant medication has known ability to block sodium channels in the brain causing a reduction in neuronal firing. Carbamazepine also causes a decrease in norepinephrine release although the exact mechanism is not completely understood. Carbamazepine is unique in that it is one of the few drugs that can induce its own metabolism (auto-induction) via CYP3A4.22 As this drug has been used in practice for many years for epilepsy, there have been several adverse drug events related to its use. These events include central nervous system dysfunction, gastrointestinal upset, renal and hepatic impairment, and various metabolic disorders.13 The unique auto-induction described with carbamazepine has been associated with multiple adverse events, caused in part by its active metabolite, as well as multiple drug interactions through induction of CYP3A4. This unusual pharmacokinetic characteristic makes carbamazepine's use in pregnancy questionable.

Carbamazepine use in women has been controversial for years, mostly due to the induction of CYP3A4 causing rapid metabolism of many oral contraceptives.23 This can lead to decreased therapeutic levels of oral contraceptives, increasing the risk of becoming pregnant. One study discovered constant decline in drug concentrations throughout pregnancy, as drug clearance is increased during progression of the pregnancy.44 These alterations in drug levels can result in lower than desired therapeutic levels causing potential flare-up of bipolar episodes if doses are not adjusted appropriately. With these findings, it is important to monitor serum drug concentrations throughout the pregnancy to ensure levels are maintained.40 Carbamazepine use in women has also been linked to higher risk of diminished white blood cell counts, and liver and hematologic dysfunction.24 Another important consideration during carbamazepine therapy is its ability to induce the metabolism of folate and vitamin K.29,45 To avoid risk of neural tube defects associated with folate deficiency, it is recommended for the mother to initiate 5 mg of folic acid daily, starting one month before pregnancy, and continued throughout all trimesters.29 The accelerated metabolism of vitamin K can lead to an increased risk of neonatal hemorrhage thus necessitating the use of vitamin K 10 mg supplementation daily during the final month of pregnancy.46 

Carbamazepine has been found to cross the placenta in significant amounts.47 This ability for substantial amounts of drug to reach the developing fetus has resulted in numerous reports of neural tube defects and decreased motor and behavioral development later in the child's life. Some of the neural tube defects include spina bifida, craniofacial defects (cleft lip/palate), cardiac abnormalities, and growth retardation.23 These defects can be due to low folate levels or carbamazepine use during the first trimester. Studies have shown that carbamazepine has a lower risk of causing spina bifida when compared to valproate48 but a greater risk of causing cleft palate when compared to lamotrigine.18 Neonatal hepatotoxicity and direct hyperbilirubinemia has been seen when carbamazepine is used in the later stages of pregnancy.23,29 Children exposed to high doses of carbamazepine in utero are at a greater risk of developing decreased motor function and poor adaptive performance when compared to other antiepileptic drugs.19 

The highly protein bound nature of carbamazepine limits its penetration into breast milk.49 Approximately 4.3% of the maternal plasma drug level is excreted in breast milk, making this one of the most preferred treatment options during lactation.31 Due to the fact that most adverse effects of carbamazepine are associated with high doses, this low level of penetration into breast milk is found to cause few effects to the infant. It is still important to monitor the breastfed infant's liver enzymes, bilirubin, serum carbamazepine levels, and white blood cell count to determine if there are excess amounts of maternal drug being passed through the breast milk.23  Table 4 summarizes the adverse effects of carbamazepine use to both mother and fetus during pregnancy and to the infant during lactation.

Mood stabilizers have been the mainstay of therapy in the treatment of bipolar disorder for decades, and they have shown superiority over other drug classes in the treatment and prophylaxis of manic and depressive episodes. Mood stabilizers are linked to teratogenic effects on the fetus. Multiple studies over the years have identified some of the most commonly reported adverse effects seen with the use of these drugs during pregnancy and lactation. Reviews of several of these studies have identified which mood stabilizer(s) should be avoided during certain trimesters of pregnancy as well as post-partum if considering breastfeeding. Lamotrigine has been recognized as the overall safest mood stabilizer when both maternal and fetal complications are reviewed. Lamotrigine has been proven to pass through breast milk, negating its use during lactation. Carbamazepine has been found, by many studies, to cause neural tube defects, liver dysfunction, as well as decreased motor and adaptive function. This high risk of fetal malformations discounts the use of carbamazepine during pregnancy. Though this medication should be avoided during pregnancy, it has been identified as the drug of choice during lactation as minimal amounts penetrate breast milk, therefore causing the lowest level of infant risk during lactation.

Lithium use during pregnancy is often based on maternal benefits versus fetal risks. Discontinuing lithium during pregnancy can cause increased risk of relapse after delivery. Multiple studies show the extreme teratogenic effects if lithium is used during the first trimester; however, due to maternal benefits, it is found to be a better option than carbamazepine and valproate during the later stages of pregnancy. Lithium has been proven to cross through breast milk at extremely high levels, resulting in limited use during lactation. Valproate has been associated with the highest level of fetal anatomical and behavioral abnormalities as compared to all other mood stabilizers. Valproate has also been found to cause a significantly higher level of disturbances in pregnant women, thus making valproate the last line option for bipolar treatment in pregnant women. If therapy with valproate is necessary, one must consider significantly lower doses to avoid toxicity. Valproate has been shown to be one of the more compatible options during lactation as there are only minute amounts that pass through breast milk.

In general, all mood stabilizers may be associated with teratogenic effects to some extent and should be avoided if possible during the first trimester. There is a greater risk of toxicities and other adverse effects when multiple agents are used concomitantly as compared to monotherapy. Nevertheless, the potential teratogenic risks associated with mood stabilizer treatment should be balanced against the potential risks of no treatment, including mood episode recurrence and increased consumption of alcohol and other drugs during a manic episode, posing additional dangers to the fetus.12 Options include continuing medication throughout pregnancy, discontinuing medications before conception or at the beginning of pregnancy, and discontinuing the medication during the first trimester only.12 When mood stabilizers are needed during pregnancy and/or lactation, not only is careful monitoring of serum medication levels important, but fetal development and maternal effects should also be noted.

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