Bipolar Disorder and Pregnancy: Maintaining Psychiatric Stability in the Real World of Obstetric and Psychiatric Complications

"Ms. M" was a 29-year-old Caucasian married woman, gravida 0, with a history of bipolar disorder diagnosed at age 18 and a history of polycystic ovary syndrome and hypothyroidism diagnosed in her early twenties. She was referred by her primary psychiatrist (W.S.R.), who had treated her for more than a decade, to the Women's Life Center, Department of Psychiatry, UCLA–Geffen School of Medicine for advice about becoming pregnant and carrying a baby to full term while remaining emotionally stable. On presentation for the initial perinatal assessment, Ms. M was euthymic and taking 400 mg/day of clozapine, 900 mg/day of lithium, and 75 mg/day of lamotrigine, as well as levothyroxine for hypothyroidism and Demulin (ethinyl estradiol and ethynodiol diacetate) for birth control. She was happily married and enjoyed her life as an advanced graduate student working on the final draft of her doctoral dissertation. She had the full support of her parents, who had devoted a great deal of time to helping her in her recovery efforts. However, Ms. M had been hospitalized psychiatrically six times during the first 2 years of her illness. After working closely with her psychiatrist and undergoing multiple medication trials over a 5-year period, she was eventually stabilized, and she had been stable for 5 years.

Ms. M and her husband, a physician, were well educated about bipolar disorder. Ms. M had excellent insight into her illness and the emotional toll it took on her family when she was severely ill. Both Ms. M and her husband, despite their desire to conceive, carry, and deliver a biological child, were deeply concerned about Ms. M's psychiatric stability during pregnancy and the effects each of the psychiatric medications she was taking might have on the safety of a developing fetus. Ms. M was also very concerned about her risk of decompensating in the postpartum period.

Ms. M's formal psychiatric history began when she was a college freshman. After an episode of bulimia nervosa with bingeing, vomiting, and laxative use, she experienced a severe and progressive depression. Treatment with fluoxetine was begun, but after several weeks she developed a mixed manic episode with distressing intrusive thoughts of cutting herself with knives and razors. She was unable to function at school and returned home. She was initially treated as an outpatient with beta-blockers and a benzodiazepine to address presumptive fluoxetine-induced agitation and akathisia. As her symptoms worsened, she underwent the first of multiple psychiatric hospitalizations at UCLA. A family history of bipolar disorder was obtained, and she was definitively diagnosed as having bipolar disorder, mixed state. Ms. M underwent five subsequent hospitalizations within 2 years, with major depressive episodes, severe mixed psychotic states, and serious suicide gestures and attempts, including episodes of cutting and medication overdoses. She transferred to a college closer to her family, where she began treatment with her current primary psychiatrist for both medication management and psychotherapy.

During her multiple hospitalizations, numerous medication trials were made in an effort to stabilize Ms. M's condition, including lithium, carbamazepine, sodium valproate, lamotrigine, clonazepam, fluoxetine, sertraline, citalopram, bupropion, venlafaxine, risperidone, and thiothixene. Various combinations of these medications proved to be ineffective or were associated with intolerable side effects, including flushing and eosinophilia (carba­mazepine), stimulation or akathisia (fluoxetine, venlafaxine, sertraline), weight gain (most of the mood stabilizers), tremor (valproic acid and lithium), and lithium-induced hypothyroidism. During Ms. M's fifth hospitalization, ECT was administered, which brought minimal, brief improvement in her symptoms.

Because of the refractory nature of Ms. M's condition, clozapine was initiated in sequential trials of combinations with other psychiatric medications (sodium valproate, temazepam, lithium, and topiramate, as well as metformin for weight gain, stimulants for refractory depression, clomipramine for intrusive thoughts, and lamotrigine for depression). Significant and troubling side effects included weight gain of more than 20 pounds, persistent daytime sedation, and hypersomnia. Clozapine and lithium remained at the core of Ms. M's medication regimen, as these were the most effective in keeping her emotionally well.

Despite her relative stability at the time of her consultation and her strong support system, Ms. M admitted to about 12 days of moderate depression per month and occasional episodic agitation with premenstrual exacerbation. There was no history of panic disorder, substance abuse or dependence, or psychotic signs in the absence of mood symptoms.

A perinatal psychiatric consultant (V.K.B.) suggested the option of surrogacy, so that Ms. M might remain on her complicated but effective medication regimen without jeopardizing the health and well-being of her fetus. Ms. M rejected this option, and instead wanted to become pregnant with the safest medications possible. The treatment plan therefore included working closely with her primary psychiatrist to ensure that any changes in her condition would be noted quickly and addressed promptly and consulting with the perinatal psychiatrist monthly during the prepregnancy period and throughout pregnancy and the postpartum period. Psychosocial interventions were emphasized to ensure adequate rest, nutrition, and health maintenance. Permission was granted at the initial perinatal consultation to allow full dialogue with Ms. M's husband. This was essential because past history suggested that when Ms. M decompensated, she sometimes failed to alert her caregivers promptly. Because women with bipolar disorder are vulnerable to postpartum decompensation, recommendations included obtaining additional help after delivery to avoid sleep deprivation and formula feeding to ensure adequate sleep and administration of needed stabilizing medications without exposing the baby to medications through breast milk (2, 8–10).

Prior to attempting pregnancy, recommended medication changes included psychotropic agents that were thought to be safer for a fetus than were Ms. M's current medications. Because there is a relative dearth of data on clozapine in pregnancy and because clozapine has been associated with risks that include agranulocytosis, diabetes, seizures, leukopenia, and neonatal hypotonicity, it was recommended that olanzapine be cross-tapered with clozapine. At the time of Ms. M's presentation, the available literature suggested that olanzapine (an agent with which she had never been treated) was a reasonable choice for severely ill bipolar pregnant women; the literature on alternative agents, such as quetiapine and risperidone, was even more limited than that for olanzapine (2, 3, 11–13). Despite the increased risk of diabetes, the decision was made to use olanzapine to maximize mood stability (3). Because of concerns about cardiac teratogenicity with lithium, Ms. M wanted to discontinue this agent during pregnancy. Therefore, although we emphasized the severity of her illness in the early years and our concern about possible relapse, since she had done well over recent years, an attempt would be made to discontinue lithium for the first trimester of pregnancy (2, 4). After a successful cross-taper of clozapine with olanzapine, lithium would be slowly tapered and discontinued over approximately 3 months. Although the goal was for Ms. M to remain off lithium during at least the first trimester, when the fetal heart is formed, Ms. M and her husband were aware that since the absolute risk for fetal cardiac anomalies was small (approximately 1/1000), if lithium were needed to maintain psychiatric stability, it would be reintroduced (2, 4). A high-resolution ultrasound at 18 weeks' gestation and, if needed, a fetal echocardiogram, were recommended to screen for possible anomalies. Lamotrigine would be continued before, during, and after pregnancy. Folate supplementation was recommended both before and during pregnancy to reduce the risk of neural tube defects (1, 2). Assuming a successful cross-taper of clozapine with olanzapine and discontinuation of lithium followed by a 3-month period of psychiatric stability, Ms. M and her husband would then proceed to address fertility concerns posed by polycystic ovary syndrome and lithium-induced hypothyroidism under the care of a reproductive endocrinologist. They would then move forward to attempt conception.

Over the course of the first year, Ms. M's infant daughter was noted to have hypotonic muscle tone. She was able to sit at 6 months, but by 1 year was unable to crawl and demonstrated continued immature muscle tone and control. Physical therapy was instituted. At 18 months, the baby was not able to walk, and evaluation by a developmental pediatrician found that gross motor skills were at the level of a 9-1/2-month-old baby. Fine motor skills and adaptive and cognitive skills were at the appropriate age level, and speech and language skills were advanced at a 20-month level with scatter to 26 months. Ms. M, her husband, and the treatment team were again faced with a complication with no clear etiology. Because a review of collateral family history revealed a history on both parental sides of delayed ambulation and problems with gross motor coordination, this was felt to be a more likely cause of motor delay than in utero exposure to medications. Continued intensive physical therapy and implementation of ankle and foot orthoses and a truncal support vest were prescribed to increase leg and core strength and coordination. The child was walking independently by 22 months, and now, at 29 months, is running and jumping. She continues to receive physical therapy, and orthotics are still used to promote further strength and coordination. It is expected that the child will fully develop, motorically, over time.

At 29 months, the child is developing steadily and is a happy, articulate, emotionally stable, responsive, and cognitively bright toddler. Ms. M continues to require careful psychiatric monitoring and episodically endorses symptoms of irritable depression and occasional hypomania. Nevertheless, she is a loving, intuitive, empathic, and patient mother. Ms. M and her husband have begun to think about having another baby and have sought counsel from their perinatal psychiatrist about the wisdom and feasibility of another pregnancy. Given the serious obstetric and psychiatric perinatal complications, the couple has decided that if they do have a second biological child, it will be via surrogacy, using Ms. M's egg and her husband's sperm.