Bipolar disorder in women

Abstract

Bipolar affective disorder in women is a challenging disorder to treat. It is unique in its presentation in women and characterized by later age of onset, seasonality, atypical presentation, and a higher degree of mixed episodes. Medical and psychiatric co-morbidity adversely affects recovery from the bipolar disorder (BD) more often in women. Co-morbidity, particularly thyroid disease, migraine, obesity, and anxiety disorders occur more frequently in women while substance use disorders are more common in men. Treatment of women during pregnancy and lactation is challenging. Pregnancy neither protects nor exacerbates BD, and many women require continuation of medication during the pregnancy. The postpartum period is a time of high risk for onset and recurrence of BD in women. Prophylaxis with mood stabilizers might be needed. Individualized risk/benefits assessments of pregnant and postpartum women with BD are required to promote the health of the women and to avoid or limit exposure of the fetus or infant to potential adverse effects of medication.

INTRODUCTION

Bipolar disorder (BD) in women needs unique consideration as it differs from its male counterparts in various aspects. The gender difference in phenomenology, course and outcome of the disorder is reviewed. BD affects the most important period of life that is reproductive period of life in women. Most women in Indian scenario experience many life stressors during this period.[1] The significant impact of the reproductive cycle on disease and the issues posed to the clinician to treat this disorder in preconception, conception, and postconception and lactation period are discussed in detail.

EPIDEMIOLOGY

There is not much difference in the life time prevalence of bipolar affective disorder amongst the genders. There are few clinical characteristics that differentiate men and women with BD. Women experience more depressive episodes in BD as they do in major depressive disorder (MDD) Bipolar I is equally distributed between men and women. The national co-morbidity survey, an American Epidemiological study involving 8098 respondents, found life time prevalence rates of BD in men (0.42%) and women (0.47%). The Bipolar II Epidemiological Catchment Area study using Diagnostic and Statistical Manual of Mental Disorder-III (DSM-III) criteria did not find any difference in gender distribution of Bipolar II (life time prevalence 0.5% vs. 0.4% in women vs. men). Another prevalence study of DSM-III mental disorders indicated the similar rate of hypomania, Bipolar I in females and males (1.7% vs. 1.4%; 1.7% vs. 1.1%). Bipolar II was significantly more common in females as compared to males.[2]

Hendrick et al. reviewed the medical charts of 131 bipolar patients seen at a specialized mood disorder clinic in Los Angeles, and found 48% of their clinic population were women, but women accounted for 60% of Bipolar type II.[3] Khess et al. in a study of first-episode mania found no difference in prevalence among male and female among Indian patients.[4] Most of the hospital-based Indian studies of BD found that the male patients outnumbered female patients, but in Western studies it has been recorded that women with mania require more hospitalization.[5]

CLINICAL PRESENTATION

Age of onset

Women appear to have a later age of onset of BD than men in a study of 69 euthymic outpatients with BD.[6] Women experienced onset of episodes of depression (27.2 years = 1.3 vs. 22.4 years = 1.2) and mania (25.9 = 1.0 vs. 21.8 = 1.0) at a significantly later age than men.[7]

Another more recent study of 360 outpatients with BD also found that women had a significantly later age of onset of BD than men, with women experiencing the onset of illness approximately 3.2 years later than men. The onset of BD during the fifth decade of life is also more common in women than men.[2]

Most of these studies are retrospective, and many a times depressive features are considered as the normative mood in women, which delay the diagnosis of BD in women. However, the concern that women may be more willing to report a prior depressive episode has not received adequate attention.[8]

Phenomenology

BD often starts with depression; onset with the depressive episode is seen in 75% of women and 67% of men with BD.[9] In a study of bipolar adolescents, same findings were observed.[10]

No studies have found any gender differences in the main phenomenological features of mania. In women major depressive episode predominates, whereas in males manic episodes predominate or are equal to depressive episodes.[11] There is no significant difference found between the length of the episodes.

Many female bipolar patients initially present with depressive symptom that is why many a times they are misdiagnosed as unipolar depression. Kupfer et al. found that bipolar women were more likely than bipolar men to receive a diagnosis of depression.[12] This has an important clinical implication as these cases are exposed more to antidepressant medication due to misdiagnosis.

Another finding suggesting a depressive diathesis for female bipolarity is its relationship with suicidality. Women attempt suicide 2–3 times more often than men in general population. Like in general population, bipolar women are all the more likely to attempt suicide than bipolar men.[13]

Women with BD are more prone to Bipolar II disorder which is characterized by episodes of hypomania and depression, with a female:male ratio of 3:2. Bipolar II patients have more frequent depressive episodes as compared to bipolar I patients. Patients with Bipolar II disorders have more frequent mood episodes and are more likely to be rapid cyclers. DSM-IV atypical features were found to be more common in Bipolar II depression than unipolar depression. A significant association was also found between atypical features and female gender.[2]

Many clinical studies have found that bipolar women are more likely than bipolar men to experience mixed mania. However, in a review of 17 studies of mixed mania, five studies reported that mixed mania was more common in women; one reported that men were overrepresented in the mixed mania group, and 11 did not provide information about gender distribution. The discrepant findings were likely attributable to different criteria used to define mixed mania. Mixed mania has been defined in broad, intermediate, and narrow terms: Mania with any depressive symptom (broad); mania with several depressive symptoms (intermediate); and mania with syndromal major depression (narrow). The study found that mixed mania was more common in women than in men when defined by narrow criteria, which required a greater number of depressive symptoms during mania. The gender distribution was similar when the mixed mania was defined by lesser degrees of depression.[13]

Mixed mania is less responsive to treatment with lithium than classic mania.[14,15,16] In contrast, the presence of depressive symptoms during mania is associated with a better response to valproate compared with lithium.[14,16] Treatment of mixed mania with carbamazepine also led to a better treatment response than lithium.[17]

Rapid cycling defined as four or more episodes in 1 year is more common in bipolar women than bipolar men. 2 meta-analysis have supported the association. Tondo and Baldessarini reported 29.6% rapid cyclers in women compared to 16.6% in males.[17] Kupka et al., found 66% rapid cyclers in the female group as compared to nonrapid cyclers (53%).[18] Females have more cyclicity, that is, more intense mood instability or more frequent polarity shifts.

BD in women is unique in its course and presentation due to the impact of the reproductive cycle. Bipolar mood disorder may worsen during certain phases of the female reproductive cycle, particularly postpartum, but also during the premenstrual phase of menstrual cycle, peri-menopause, and menopause.[19] Evidence of the impact of the menstrual cycle on a course of illness of BD remains mixed. Some studies report that women with BD report frequent premenstrual mood disturbances and BD may worsen during the premenstrual phase.[20] Premenstrual depression was reported to occur in one-fourth of women with BD.[21] The use of an antidepressant for the treatment of the bipolar depressive symptom of premenstrual dysphoric disorder may increase the risk of mood cycling.[22,23]

The postpartum period is associated with a high risk of onset and relapse of BD in women. For example, one study found that 36% of bipolar women reported onset of the disorder in the puerperium, with a risk of puerperal relapse of 25–40%.[24]

A survival analysis indicated that the women receiving prophylactic treatment with mood stabilizers maintained well-being significantly longer than the women who did not receive such treatment. Women with BD appear to benefit from puerperal prophylaxis with mood stabilizers.[25,26,27] The findings have implications for the early identification and treatment of subgroups of women at particular risk for puerperal illness.

In another study, one-third of women with BD developed manic episodes temporally related to childbirth.[28] Finally, a retrospective review of the impact of reproductive events on the course of BD in 30 female outpatients with children revealed that 67% experienced postpartum mood episodes, predominately depression, and the rate of recurrent postpartum episodes after subsequent pregnancies were 64%.[29]

Postpartum psychosis is more frequently associated with BD than other psychotic illnesses. The rate of postpartum psychosis is between 20% and 30% in women with BD.[30] Moreover, women who have had a postpartum psychotic episode are at high risk of recurrent affective episodes. Women with BD who have a family history of postpartum psychosis are at higher risk of puerperal episodes than other bipolar women.[31]

Women with BD who are perimenopausal or postmenopausal may experience an increase in mood symptoms. Approximately, 20% of postmenopausal women with BD report worsening of their mood symptoms, mostly depression, following menopause.[32] Women who are not using hormone replacement therapy (HRT) during the peri-menopause and menopause are significantly more likely than those who were using HRT to report worsening of mood, suggesting a protective effect of HRT.[2]

The dose of antipsychotic medication has been reported to be higher in a group of women with BD older than 40 years compared with a younger group of women.[33] This difference might be related to declining estrogen levels in the older women and the subsequent loss of estrogen's purported antidopaminergic effects.

In addition to being more common in women than men, thyroid dysfunction is more common in patients with mood disorders. Both mixed mania and rapid cycling have been associated with elevated rates of overt and sub-threshold thyroid abnormalities. First-episode patients with mixed mania are more likely to have elevated thyroid-stimulating hormone (TSH) than pure mania. Mean TSH was higher than mean T4 lower in patients with the mixed episode. Kupka et al., in a meta-analysis of 20 studies found a significant association between current rapid cycling and sub clinical hypothyroidism.[18] An increased risk of endocrine diseases that can either impact the course of illness or manifest in some treatments in women with BD.[34]

Rapid cycling is strongly associated with Bipolar II disorder and is predominated by depressive episodes.[35,36,37,38] In a study of 919 patients with BD over 1–5 years, patients who developed rapid cycling compared with nonrapid-cycling patients, had a history of more depressive episodes and were more likely to have been taking tricyclic antidepressants or monoamine oxidase inhibitors.[35] There is continued debate about the role of antidepressants in the development of rapid cycling through cycle acceleration. There is some evidence that the risk of rapid cycling is increased by the excessive use of antidepressants and that women are at higher risk of drug-induced rapid cycling than men.[36,37,38] Women with BD might receive antidepressant monotherapy in the course of the disorder because they are frequently misdiagnosed with unipolar depression. The use of antidepressants without mood stabilizers might contribute to rapid cycling in these patients. Rapid cycling is a predictor of nonresponse to most treatments. Dunner and Fieve, who first coined the term “rapid cycling,” found that patients with a rapid cycling course were significantly more likely than other bipolar patients to experience recurrent depression, mania, or hypomania during lithium treatment.

Course and outcome

Females have a later age of onset than male.[6] Onset during the fifth decade is more common in women.[39] Bipolar women are more likely to have an episode pattern of depression followed by mania (DMI Pattern),[40] while bipolar men are either equally likely or more likely to have an episode of mania followed by depression (MDI Pattern). The bimodal peak of psychiatric hospitalizations in spring and fall is observed in female bipolar patients as compared to the unimodal peak in males in spring.[41] Some studies have reported gender difference in the impact and long-term outcome of BD. Women report significantly more disruption in social/leisure life and family life after being surveyed on a mood disorder questionnaire (MDQ). More symptom disruption occurs as a result of the irritability, increased confidence, talkativeness distractibility, and spending money. Women were hospitalized significantly more often than men.[6]

Women with BD experience a seasonal pattern of mood disturbance more often than men. Women have depressive episodes more often in the fall and winter than the spring and summer. Fiedda et al. found that there was a bimodal peak of admissions in the spring and fall for women with BD.[41]

Psychiatric co-morbidity

Except for substance use disorder, women with BD are more prone to medical and psychiatric co-morbidity due to which they are more adversely affected than men.[42] In women, the common co-morbid disorders are medical and psychiatric disorders. The common psychiatric disorders are seen in Axis I: Anxiety, substance use and eating disorders and Axis II: Borderline personality disorder (BPD). Anxiety and eating disorders are more common in women in general. As co-morbidity, these are likely to be more common in females as compared to males suffering from bipolarity.[43,44] Substance abuse disorders as co-morbidity in bipolarity are higher in males than females.[45,46] However compared to males without bipolarity the risk of substance abuse is higher in females with bipolarity, especially alcoholism.[47,48]

The Stanley Foundation Bipolar Network has revealed an interesting finding that the risk of alcoholism is greater for women with bipolarity than for men with bipolarity. Strawoski et al., found that females with mania at first hospitalization had a higher rate of alcohol abuse or dependence than men.[48] These findings suggest that substance abuse in females can be considered as a marker for bipolarity.

Women with BD have 4 times rate of alcohol use and 7 times rate of other substance abuse than other women from a community sample. Complications of substance include increased rate of mixed or rapid cycling, prolonged recovery, higher prevalence of medical disorder including liver disease and more suicide attempts and suicide.[49]

Bulimia nervosa

High rates of BD are found in patients with bulimia nervosa.[50] Life time prevalence of co-morbid bulimia in bipolar patients is 2–15%.[51,52] Patients with mixed mania are more likely to have co-morbid bulimia. Bipolar II patients were seen to have higher rates of bulimia.

Impulse dyscontrol disorder

High rates of co-morbid impulse control disorders are seen in the range of 13–23%.[53,54] Co morbid impulse control disorder is the antecedent of BD in many cases.[55]

Borderline personality disorder

BPD as a comorbid disorder with bipolarity and this has significant implications since these patients have an earlier onset of disease, less favorable outcome and response to treatment is also relatively poor.[56,57]

Nearly 15–29% of patients with BD have a diagnosis of BPD.[56,58] There is considerable overlap between symptoms of BPD and bipolarity which include emotional instability, impulse dyscontrol, and cognitive dysfunction. The use of antidepressant poses a risk in aggravation of bipolarity.[58]

Medical co-morbidity: General medical disorders

Certain medical conditions which frequently co-occur in women with BDs are like migraine,[59] thyroid disease, and obesity.[60,61,62,63] in bipolar women the rates of thyroid disorders and migraine are more common compared bipolar men.[59] The presence of sub-clinical or overt thyroid disease contributes to higher rates of rapid cycling and mixed states in women.[60,61,62,63] Lower thyroid function, in the form of lower free thyroid index and higher TSH, is associated with a delay in treatment response.[64]

Obesity

Women with BD are more likely to be obese compared to males. Obesity has been found to be associated with higher depressive episodes particularly those treated with lithium.[65]

Sexual and physical abuse

Female patients of BD are more likely to report history of sexual abuse, which is associated with a worse course of this disorder, earlier age of onset, greater co-morbidity and a higher rate of suicidal attempts.[66] Chandra et al., reported that Indian women with the psychiatric disorder also face sexual coercion and violence.[1]

MEDICATION-INDUCED DISORDER IN WOMEN WITH BIPOLAR DISORDER

Polycystic ovary syndrome (PCOS) is a serious endocrine disorder that affects women in their reproductive years.[67] PCOS is a syndrome defined by the presence of: (1) Ovulatory dysfunction (2) clinical evidence of hyperandrogenism or hyperandrogenemia (3) and exclusion of other endocrinopathies (i.e. Hyperprolactinaemia, thyroid dysfunction, adrenal hyperplasia or Cushing syndrome).[68] PCOS is the leading cause of anovulatory infertility and hirsutism, and is associated with multiple reproductive, metabolic and general health disorder, including increased risk of miscarriage, insulin resistance, hyperlipidemia, cardiovascular disease, and endometrial cancer. Rasgon et al., conducted a small pilot study in 22 women with BD, receiving lithium monotherapy, valproate monotherapy, or lithium-valproate combination therapy.[69] None of the patients in the study met criteria for PCOS. Subsequently, a larger cross-sectional trial for DSM-IV diagnosis of Bipolar I, II or not otherwise specified (NOS), and who had received long-term treatment with an antimanic through the Stanley Foundation Treatment Network was undertaken. Of the 80 women with complete questionnaire data, 52 (65%) reported current menstrual abnormalities. While only 15 women (38%) reported new menstrual abnormalities since treatment for BD.[70]

EVALUATION OF WOMEN WITH BIPOLAR DISORDER

A complete assessment of women with BD is an integral part of management that includes a psychiatric and medical history, family and social history, and mental status exam with a focus on mood, psychotic features, anxiety, substance use, and eating disorder signs and symptoms.[2]

Because women with BD, particularly Bipolar II disorder, frequently present with depression, it is important to probe carefully for a history of hypomanic or manic symptoms, which may not be recognized as problematic by the patient. In all the women who present as a case of major depression, especially those who have an early age of onset and do not respond well to antidepressant monotherapy, there is the possibility of BD. The most well-known are MDQ;[71] other options include Hypomania checklist.[72]

Using structured clinical interviews, such as the Structured Clinical Interview for DSM-IV,[73] may improve the identification of BD. The diagnosis of Bipolar II disorder, rapid cycling or mixed mania, which is more common in women, have an impact treatment options. The medical evaluation includes physical examination, weight and vital signs, laboratory tests (e.g., thyroid function test, metabolic and lipid screening profiles), and toxicology screen. The assessment also includes the menstrual and reproductive history, and history of menstrual, pregnancy/postpartum, or menopausal-related mood or psychotic symptoms. The history of hormonal treatments and the effects of the treatment of mood are also important.

PHARMACOTHERAPY OF BIPOLARITY IN WOMEN

Women with BD are typically in their teens and early 20s at the onset of the illness, placing them at risk for episodes throughout their reproductive years.[75] Overall, the general approach to the treatment of women with BPD during pregnancy remains one of balancing the risk and benefits of illness versus treatment. Similarly, if pharmacologic treatment is deemed the best option, the clinician has several alternatives to reduce the risks. While planning treatment for the woman and selecting a medication, the stage of the reproductive cycle of the patient should be considered. In adolescent group - avoid medication, which can lead to PCOS. Despite the burgeoning attention, there has been limited focus on the management of BD (BPD) over the course of pregnancy.[76]

Preconception

Treatment planning should ideally begin in the preconception period. The initial discussion between the psychiatrist and client should cover the following aspects.

• Family planning, that is, ways of effective birth control, significance of planned pregnancy, folate supplementation before conception, obstetric complications, teratogenicity of psychotropic medications and risk of relapse during pregnancy and postpartum should be discussed in detail. When women with BD are provided accurate and balanced information about potential risks and benefits they face, 37% choose not to pursue pregnancy.[77] Genetic counseling should be provided to the patient. Regular prenatal visits, encouraging maintenance of a healthy diet and management other risk factors such as smoking, alcoholism, and obesity should be an essential part of a pre conception therapy. The gynecologist's advice regarding the mode of contraception to be adopted should be discussed, as the efficacy of oral contraception can be affected by the use of medication that induce liver enzymes, e.g., carbamezapine. Barrier methods or increasing the dose of oral contraceptive pills may be needed if pregnancy has to be delayed. In case, pregnancy is desired early, and the patient is on antipsychotic medications, medicines with least effect of prolactin should be preferred, as increased prolactin decreases menstrual cyclicity and fertility. The clinician has the daunting task of selecting the appropriate psychotropic medicine keeping in mind risk to the mother and fetus while limiting the morbidity from the active psychiatric illness

• Detailed illness history should be elicited which includes the severity of illness, duration of euthymia while taking not taking medication, time to recover after medication discontinuation and time to recover with the reintroduction of pharmacotherapy. Both clinician and patient need to decide together whether medication should be stopped or continued. The patient's previous response to various medications is a key factor in choosing a medicine

• A stable patient with past history of mild severity may discontinue mood stabilizers before attempting to conceive.[77] A slow tapering is preferred rather than abrupt discontinuation as it allows the clinician to assess the patient's response and plan accordingly. In case, symptoms recur then the difficult choice to continue medication may have to be made.

Women with severe illness are likely to choose to continue medication, but some may await early documentation of pregnancy before discontinuation of mood stabilizer. Teratogenicity is highest with mood stabilizers when it occurs early in pregnancy, hence the need to avoid in this period.[2] While withdrawing the mood stabilizers, adjunctive antipsychotic may be used though the efficacy of this approach is yet to be established.

Pregnancy

All pregnant women reporting to the gynecologist for the 1^st time should be universally screened for BD by enquiring about personal and family history of BD. There is a need for valid screening instruments to detect hypomania/mania as well as depression. Although the course of BD during pregnancy is still unclear, some evidence suggests that pregnancy neither protects nor exacerbate the illness.[74] Many patients prefer to discontinue medication in pregnancy while the best option for some patients is to reintroduce medication only with early signs of relapse. Often patients may opt to reinstitute medication regardless of whether relapse can occur or not. If there is a history of severe illness, with a history of self-harm, protracted recovery, poor insight and lack of good support system, then pharmacological intervention is advisable to reduce the risk to both the mother and fetus. For women who prefer to continue taking medication during the first trimester it is always better to opt for monotherapy. The lowest effective dose should be used, and agents with least teratogenic potential are preferred. However, if an agent has been effective in the past it may be preferred. Older agents with case and cohort data may be a better choice than a newer agent whose reproductive toxicity is not yet assessed.

During pregnancy there are rapid physiological changes in the body like increased total body water, increased body fat store, increased cardiac output and increased glomerular filtration rate which results in altered drug metabolism. So careful drug monitoring is essential. The period of highest teratogenicity is in the first trimester. Perinatal risks are related to later exposure. They include risks for minor malformations, behavioral effects, low birth weight, and preterm delivery. It is difficult to make recommendations as little is known about these risks and whether mood stabilizers affect these risks or not.

Few authors prefer gradual tapering medications before delivery and reinstituting full dose after delivery. It is recommended that women who are on mood stabilizers during pregnancy take 5 mg/day of folate starting 4 weeks before conception and continuing through 12 weeks of pregnancy.[76] They should undergo high-resolution ultrasound and fetal echocardiogram at 18–20 weeks of gestation to rule out cardiac abnormality. An ultrasound at 16–19 weeks should be done to detect the neural tube defect.[2]

Management of acute episodes during pregnancy

The decision of starting medication in a new case that is pregnant is very difficult. As there is a risk of drug exposure and risk associated with the disease itself. The general recommendation for treatment of bipolar women during pregnancy includes minimizing pharmacotherapy if clinically feasible, particularly during the first trimester. If treatment is initiated or continued, use of monotherapy at the minimal effective dose is recommended.

Findings from case–control studies suggest no significant associations between overall maternal selective serotonin reuptake inhibitor (SSRI) use during early pregnancy and risk of birth defects.[77,78] However, data suggest that individual SSRIs many confer increased the risk for some specific defects, but these defects are rare, and the absolute risks are small.

In utero exposure to SSRIs can also have an impact on the neonate, with reports of neonatal abstinence syndrome[79] and persistent pulmonary hypertension of the newborn.[80] Data on the effect of atypical antipsychotic on birth weight are conflicting, with one study reporting significantly higher birth weights among infants exposed to atypical antipsychotic[81] and another reporting a trend toward lower birth weights.[82]

Maintenance therapy during pregnancy

Treatment planning for pregnant women with BD should consider not only the relative risks of fetal exposure to lithium/divalproex, but also the high risk of recurrence and morbidity associated with stopping maintenance treatment.

During a prospective, cohort study involving 89 pregnant women with BD, the overall risk of at least one recurrence in pregnancy was 71%.[83] Among women who discontinued versus continued lithium/divalproex treatment, recurrence risk was 2-fold greater and the median time to first recurrence was more than 4-fold shorter. Time to recurrence was 11-fold shorter with abrupt versus gradual discontinuation of lithium/divalproex. Most recurrences were depressive or mixed, and 47% occurred during the first trimester. Similarly, the risk of recurrence was substantially reduced when lamotrigine therapy was continued compared to discontinuation of lithium/divalproex therapies in a survey of 26 pregnant women with BD.[84] The risk of new illness episodes was 30% with lamotrigine versus 100% after discontinuing lithium/divalproex, and time to recurrence was 12-fold longer.

The previous guidelines suggested that lamotrigine may be considered for maintenance therapy during pregnancy, particularly in patients who primarily suffer depressive relapses, as data from a large pregnancy registry suggested no increased teratogenicity.[85] More recently, the Food and Drug Administration issued an alert stating that preliminary data from the North American Drug Pregnancy Registry suggested a possible link between lamotrigine exposure during the first trimester and the incidence of cleft lip/palate.[86] However, they also stated that other pregnancy registries of similar size have not replicated this observation, and the clinical significance of this report is thus uncertain.

Risks associated with mood-stabilizing agents during pregnancy

The potential risks of medications during pregnancy include malformations, obstetrical, and neonatal complications; and long-term neurobehavioral effects.

Neurobehavioral teratogenicity can result from medication exposure after the first trimester of pregnancy. Unfortunately, there is a dearth of long-term studies of children of women with BD exposed to medications during pregnancy. Maximizing safety requires familiarity with the impact of individual medications across these domains and interventional strategies to reduce risks.

Malformations associated with maternal drug use depend on the properties of the drug and the point of exposure: Up to 32 days postconception can affect neural tube development and closure; days 21–56 after conception may affect normal heart formation; and during days 42–63 may influence development of the lip and palate. Craniofacial anomalies can also occur after the first trimester.

Given that more than 50% of pregnancies are unplanned, by the time women and their clinicians are aware of the pregnancy, the period of susceptibility to these risks would have already occurred. Clinicians should provide maintenance treatments in anticipation of potential pregnancy and be aware of which medications pose the fewest risks.

Lithium

Lithium remains one of the mainstays of acute and maintenance treatment of BD. The International Registry of Lithium Babies, a voluntary physician-reporting database, noted a 400-fold increased rate for cardiovascular malformations, most notably Ebstein's anomaly, associated with lithium exposure in utero. Subsequent investigations identified a risk for Ebstein's anomaly among lithium users at between 1/1000 (0.1%) and 2/1000 (0.2%), or 20–40 times higher than rates in the general population. Thus, the relative risk for Ebstein's anomaly is somewhat increased though the absolute risk remains small.[87,88]

Lithium use is associated with higher-weight babies, and there are numerous reports of neonatal complications in association with lithium treatment in late pregnancy, including: Cardiac dysfunction; diabetes insipidus; hypothyroidism; low muscle tone; lethargy; hepatic abnormalities; and respiratory difficulties.[87,88]

Recognizing lithium's low therapeutic index, it seems plausible that such complications are directly related to the level of lithium exposure proximate to delivery. In a small prospective sample, Newport et al. demonstrated that discontinuation of lithium proximate to delivery and reinstitution immediately after delivery significantly reduced neonatal complications while maintaining maternal euthymia.[88]

Long-term follow-up data are sparse. Sixty children older than 60 months, identified from the International Registry as being exposed to lithium during either the first trimester or throughout pregnancy, did not differ behaviorally from their nonexposed siblings. A second investigation found that attainment of major developmental milestones for 22 lithium-exposed subjects was comparable to that of controls.[88]

Lithium is contraindicated for breastfeeding. High concentrations of the drug are seen in infant serum and breast milk.

Carbamazepine

Carbamazepine is a known human teratogen. The rate for neural tube defects ranges between 0.5% and 1%.[92] The teratogenic potential of carbamazepine is enhanced when it is given with other agents, valproate, in particular, perhaps because the toxic epoxide metabolites are increased. In theory, oxcarbazepine, which does not produce the epoxide metabolite, may be less teratogenic. However, studies have not been performed to confirm this speculation.[89,90,91]

Carbamazepine has been associated with lower birth weight and mean head circumference (standardized for gestational age and sex). Carbamazepine can cause fetal Vitamin K deficiency. Carbamazepine exposure in utero could increase the risk for neonatal bleeding and mid-facial abnormalities because adequate levels of Vitamin K are necessary for normal mid-facial growth and for the functioning of clotting factors. Most experts recommend administering Vitamin K 20 mg by mouth daily throughout pregnancy. Pediatricians should also administer Vitamin K 1 mg intramuscularly to neonates after in utero carbamazepine exposure.[91]

Lamotrigine

Lamotrigine is a potential maintenance therapy option for pregnant women with BD owing to its protective effects against BP depression; general tolerability; and growing reproductive safety information relative to alternative mood stabilizers.

Briefly, the pooled risk for reported major fetal anomalies following exposure to lamotrigine during pregnancy is 2.6% (78 of 2974 first trimester exposures, including a rate of 0.34% (8 of 2372 exposures) for midline cleft formations); these rates are within the range of births not involving drug exposures. A relatively high risk for midline facial clefts (0.89% of 564 exposures) was reported by 1 pregnancy registry, and another reported greater risk for birth defects at higher maternal daily doses (greater than 200 mg/day).[92]

Until date, there are no reports of obstetrical or neonatal complications associated with lamotrigine monotherapy exposure. It has the largest safety database. Gentile suggested that lamotrigine can be used as first-line mood stabilizer during pregnancy.[93]

Valproate

Sodium valproate is a known human teratogen (causing neural tube, cardiovascular, craniofacial defects) with acute and long-term adverse effects on infant development. Exposure during the first trimester is associated with neural tube defect rates of approximately 5–9%. The effect of the drug on neural tube development is related to the use of valproate 17–30 days postconception and the risk is increased with higher maternal daily doses/serum concentrations.[94,95,96,97]

Similar to carbamazepine, transient neonatal symptoms have also been reported, including liver toxicity; hypoglycemia; and withdrawal symptoms of irritability, jitteriness, feeding difficulties, and abnormal muscle tone.

One of the greatest concerns is the burgeoning clinical and preclinical data showing that valproate is a profound neurobehavioral teratogen. Investigations in the mid-1980s utilized in utero exposure to valproate as an animal model for autism.[97] Potential risks include major malformation (first-trimester exposure), neonatal toxicity (third trimester), longer-term neurobehavioral effects and increased risk of physical health problems in adult life.

Atypical antipsychotic medications

The use of atypical antipsychotics has dramatically increased over the past decade in pediatric populations, patients with BPD, and as adjunctive medications for a variety of symptoms, such as depression, sleep, and agitation. Those more commonly used include aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone.

A recent investigation demonstrated that atypical antipsychotics cross the placenta, however, the obstetrical outcome data on these medications are extremely limited. The largest single investigation failed to identify any pattern of defects though sample sizes were limited.[98,99,100]

The obstetrical complication data are limited to case reports on olanzapine of maternal weight gain; insulin resistance; gestational diabetes; and preeclampsia.

There are no published infant/child follow-up studies.

Typical antipsychotic agents

Typical antipsychotic agents continue to have a role in the acute treatment of mania during pregnancy. Some experts consider the risk associated with typical antipsychotic agents, which have been available for decades, to be less than the risk associated with mood stabilizers. One of the largest databases available is for the older, “typical” antipsychotic agents, although even this information is limited. Phenothiazines and butyrophenones historically have been used to treat hyperemesis gravidarum, nausea, and (less commonly) psychotic disorders in pregnant women; they are the drug classes with the largest amount of reproductive information within this broad group of medications.[101]

Electroconvulsive therapy

ECT is a relatively safe and effective treatment during pregnancy if steps are taken to decrease potential risks. Complications associated with ECT during pregnancy, include benign fetal arrhythmias; mild vaginal bleeding; abdominal pain; self-limited uterine contractions increased the likelihood of aspiration, without proper preparation, aortocaval compression, and respiratory alkalosis.

Preparation for ECT during pregnancy should include pelvic examination, discontinuation of nonessential anticholinergic medication, uterine tocodynamometry, intravenous hydration, administration of a non-particulate antacid elevation of the pregnant woman's right hip during ECT, external fetal cardiac monitoring, intubation, and avoidance of excessive hyperventilation. Informed consent for ECT should include the patient's capacity to understand and rationally evaluate risks and benefits to herself and the fetus.[102]

ECT can be used safely in pregnancy but should be reserved for women hospitalized in severe vegetative state or in severe psychotic episode.

Addition of Omega 3 fatty acids may benefit both mother and fetus as they are necessary for optimal fetal and infant brain and nervous system development and docosahexaenoic acid is selectively transferred to developing fetus during pregnancy. Pregnant women achieve only 20-60% of the recommended dose.

POSTPARTUM PERIOD AND LACTATION

The postpartum period is a particularly high-risk period for women with BD. Symptom emergence is often rapid and may occur in late pregnancy or within the first few days to weeks after delivery.[103]

A Danish, population-based, cohort study found a 24-fold increase in the risk of postpartum mental disorders for women who have a first-degree relative with BD compared to a reference group.[104] The diagnosis of BD is frequently missed in women with postpartum depression. Hypomania after childbirth may be misconstrued as the normal joy related to the experience of mother-hood. In a survey of 56 women referred for postpartum depression, over half had a bipolar diathesis.[105] The primary diagnosis were: MDD (46%), BD NOS (29%), BD II (23%), and BD I (2%).

In a retrospective survey of 127 women who developed a bipolar affective puerperal psychosis within 4 weeks of childbirth, there was a high prevalence of early-onset hypomanic symptoms.[105] The onset of symptoms occurred within 3 days of delivery in 73% of women. The most common symptoms were: Feeling excited, elated, or high; not needing or not being able to sleep; feeling active or energetic, and talking more or feeling very chatty. These types of symptoms should be carefully monitored in individuals at high risk of puerperal psychosis episodes.

Postpartum hypomania has been reported in 10–20% of women after childbirth.[106,107] In addition, there was no phase in a woman's life, or for that matter a man's when the point prevalence of hypomania reached the level in the postpartum period.[108] The DSM-IV does not acknowledge hypomania as a postpartum-onset specifier, which means that women with BD II are likely often misdiagnosed as having MDD. The high prevalence of postpartum hypomania immediately after delivery highlights its importance as a window of opportunity to understand the biological underpinnings of BD.

Antidepressants should be used cautiously in women with postpartum depression due to the risk of induction of postpartum psychosis, mania, and rapid cycling. There are case reports of early-onset postpartum depression in which bipolarity manifested following antidepressant treatment.[108] In each case, there was no past history of psychiatric disturbance but there was a family history of BD.

Several authors have reported on the implications of psychotropic medications on breastfeeding.[109,110,111] A systematic review of antidepressant and mood stabilizer use during lactation concluded that SSRIs, tricyclic antidepressants (except doxepin), carbamazepine, sodium valproate, and low doses of short-acting benzodiazepines were relatively safe for the breastfed infant.[112] SSRIs may not be drugs of first choice in the postpartum period, as case reports have described adverse effects with fluoxetine and citalopram in breastfed infants. A case report on the use of carbamazepine and its metabolite oxcarbazepine were acceptable.[112] There are also emerging data about quetiapine during lactation. In a series of six women receiving quetiapine augmentation to antidepressants during lactation,[114] no quetiapine was detected in breast milk in four of the six cases, and in all cases, estimated levels of infant quetiapine exposure were <0.01 mg/kg/day. Four of the six babies showed typical developmental delays. Levels of quetiapine were not detectable in breast milk in the mothers of the two infants showing mild delays.

The American College of Obstetricians and Gynecologists clinical management guidelines categorized the lactation risk of psychiatric medications using the following criteria: L1 = Safest; L2 = Safer; L3 = Moderately safe; L4 = Possibly hazardous; L5 = Contraindicated.[115] The most common bipolar medications were categorized as follows: Lithium (L4), divalproex (L2), carbamazepine (L2), lamotrigine (L3), olanzapine (2), risperidone, aripiprazole, and clozapine (L3), and quetiapine and ziprasidone (L4).[115]

Treatment decisions about medication in this period should be based on mother's clinical status, previous course, regardless of breastfeeding status. Breastfeeding can lead to sleep disruption which should be avoided. Women can explore options to ensure adequate sleep by arranging other adults to feed the infant, expressing milk earlier in the day for night feeding. Mother and partner need to be educated about possible risks of breastfeeding while taking medication and infants should be monitored.

NONPHARMACOLOGICAL TREATMENT OPTIONS DURING PREGNANCY AND LACTATION

Psychosocial interventions

When used adjunctively to pharmacotherapy, psychosocial interventions such as group psycho education, cognitive behavior therapy, and interpersonal and social rhythm therapy have each demonstrated a number of significant benefits, such as decreased relapse rates, mood fluctuations, need for medications, and hospitalizations, as well as increased functioning and medication adherence. Therefore, providing psychoeducation is an especially essential part of the management of patients with BD.[2]

MANAGEMENT OF COMORBID DISORDERS

The basic principle of management of comorbid disorders would be first to achieve mood regulation with the help of mood stabilizers. A mood stabilizer which can take care of both the bipolarity and comorbid disorder should be preferred such as valproate for panic disorder[113] and alcohol dependence or migraine,[114] carbamazepine for alcohol withdrawal,[115] Topiramate in alcohol dependencies,[116] obesity, migraine,[116] binge eating,[117] and gabapentin in social anxiety disorder.[118,119]

Many comorbid psychiatric disorders like anxiety disorder, obsessive compulsive disorder, eating disorder etc., respond to antidepressants, but it would be prudent to use them along with mood stabilizers to avoid the risk of cycle acceleration. In case antidepressants have to be avoided, psychotherapic measures like cognitive behavioral therapy interpersonal therapy may be used.[120,121,122]

CONCLUSION

Treatment of women during pregnancy and lactation is a challenge because available mood stabilizers pose potential risks to the developing fetus and infant. Pregnancy neither protects nor exacerbates BD, and many women require continuation of medication during the pregnancy. The postpartum period is a time of high risk for onset and recurrence of BD in women, and prophylaxis with mood stabilizers might be needed. Individualized risk/benefit assessments of pregnant and postpartum women with BD are required to promote the health of the women and avoid or limit exposure of the fetus or infant to potential adverse effects of medication.