Prevention of Postpartum Psychosis and Mania in Women at High Risk

Between January 2003 and December 2010, a total of 618 referrals to the outpatient clinic of the Peripartum Prevention Program at the Department of Psychiatry, Erasmus Medical Center (Rotterdam, the Netherlands), were evaluated. Requests for evaluation and clinical management during pregnancy and the postpartum period were made by obstetricians, psychiatrists, and general practitioners. This study was approved by the institutional review board of the Erasmus Medical Center.

Psychiatric diagnosis was obtained through a semistructured interview by a psychiatrist and review of clinical records. We included women with bipolar I or bipolar II disorder with only nonpuerperal episodes and those with both puerperal and nonpuerperal episodes. Further, we also included women with a history of postpartum psychosis but without any manic or psychotic symptoms outside the postpartum period. Since “postpartum psychosis” is not described as a separate disease entity in DSM-IV, we defined “postpartum psychosis” as a history of any of the following DSM-IV diagnoses: psychotic disorder not otherwise specified, brief psychotic disorder, or mood disorder (manic, mixed, or major depressive episode) with psychotic features, all requiring the specifier “with postpartum onset” (≤4 weeks after delivery). Women with chronic psychotic disorders such as schizophrenia or schizoaffective disorder were excluded.

In total, 75 pregnant women fulfilled the inclusion criteria. Five women were lost to follow-up during pregnancy (Figure 1). Therefore, in total we included 70 pregnant women at high risk for postpartum psychosis. Of this number, 29 had a history of postpartum psychosis but without any manic or psychotic symptoms outside the postpartum period. Conversely, we included 41 women with a diagnosis of bipolar disorder based on a history of nonpuerperal episodes with or without puerperal episodes. For women who had more than one delivery during the study inclusion period, we included only the most recent pregnancy in the main analysis.

The Peripartum Prevention Program was designed to provide standardized evidence-based clinical care for women at high risk for peripartum relapse (18). Women enrolled in the program received their full obstetric care through the Department of Obstetrics and Gynecology and peripartum psychiatric care through the Department of Psychiatry.

We advised women who were using a mood stabilizer at the time of evaluation to continue pharmacologic treatment during pregnancy. Given that lithium monotherapy has the largest evidence base as an effective mood stabilizer in the peripartum period, this was our primary pharmacological recommendation (2, 19). We also informed women about teratogenic risks of lithium during early pregnancy and the elevated rate of neonatal complications of lithium (20, 21).

We attempted to reduce the incidence of polypharmacy by recommending mood stabilization with a single medication. Further, we advised against the use of valproate during the peripartum period because of high teratogenic risks during pregnancy (22) and the lack of efficacy for postpartum prophylaxis shown in a single study (23). However, given the potential risks of switching medications, our treatment plan discussion always included carbamazepine, lamotrigine, and antipsychotics as important considerations, if patients were clinically stable while taking these medications and had manageable side effects or if they had a history of a favorable response to these medications. It is important to note that the final decision regarding prophylaxis during pregnancy was always made by the patient, following a collaborative discussion to consider the risks and benefits of each pharmacologic treatment option, including the potential for teratogenicity and the risk of relapse.

In the women receiving maintenance lithium treatment, we prescribed doses three times a day during pregnancy to avoid peak lithium levels. After delivery, we reduced the number of doses to one per day (with a target minimum plasma level postpartum of 0.8 mmol/L). High-risk women who were medication free at the time of evaluation were advised to start lithium prophylaxis immediately postpartum. For these women, lithium was started the first evening after delivery and given once daily according to the plasma level (target minimum, 0.8 mmol/L). Plasma lithium levels were monitored twice weekly during the first week postpartum, once per week during weeks 2 and 3, and thereafter as clinically indicated. Lithium levels were individualized according to clinical symptoms and side effects, incorporating the preferences of each patient and her previous history, if any, of lithium therapy.

We particularly emphasized the importance of sufficient sleep during the peripartum period, as sleep loss has been demonstrated to be a modifiable risk factor in bipolar disorder and postpartum psychosis (24–26). Accordingly, all women were advised to spend the first week postpartum in a private room on the inpatient obstetric ward, where nurses performed the overnight newborn feedings to provide mothers with the opportunity to sleep throughout the night. In addition, we recommended standardized treatment with a benzodiazepine (lorazepam, 1 mg at bedtime) during the first week postpartum, during which subjective self-reports of sleep quality were collected daily through clinical interviews. Further, the women were advised against breast-feeding given the current uncertainty regarding breast-feeding during maternal lithium treatment (21, 27).

In summary, a comprehensive individualized perinatal treatment plan was created on the basis of the choices of each woman in collaboration with her clinician regarding the risks and benefits of each treatment option, including prophylaxis, breast-feeding, sleep hygiene, and postpartum inpatient obstetric care. All women received follow-up evaluations every 4–6 weeks throughout the peripartum period. We defined the postpartum period according to the DSM-IV definition of the first 4 weeks postpartum. Therefore, we followed all women for a minimum of 4 weeks postpartum. The mean period of follow-up was 12.6 weeks postpartum (range=4–52 weeks).

Each patient and her partner were encouraged to immediately contact her psychiatrist in case of affective instability, psychotic symptoms, or refractory insomnia. We defined relapse as the occurrence of any psychiatric episode fulfilling the DSM-IV criteria, including hypomanic episodes. During the first week postpartum, all patients were screened daily for prodromal symptoms by a perinatal psychiatric nurse (J.V.) in order to provide the earliest possible intervention.

All analyses were performed by using SAS, version 9 (SAS Institute, Cary, N.C.). For characteristics of the study group, categorical data were evaluated by means of Fisher's exact test and continuous variables were examined with two-sample t tests. Categorical outcomes related to relapse risk were examined by using both Fisher's exact test and odds ratios with corresponding 95% confidence intervals (CIs). All hypotheses were tested with an alpha of 0.05 (two-sided).

The timing of relapse was substantially different between the women with bipolar disorder and those with postpartum psychosis only (Figure 2). Remarkably, despite being medication free throughout the entire pregnancy, none of the 29 women with postpartum psychosis relapsed during pregnancy. Postpartum, four of the 29 (13.8%) relapsed (Table 2). Of these four women with previous postpartum psychosis, the current relapse was manifested as mania for one woman, psychosis for one, a mixed episode for one, and depression for one. Three of these four women required postpartum inpatient admission.

In contrast to the women with a history of postpartum psychosis only, none of whom had a relapse during pregnancy, 24.4% of the women with bipolar disorder (10 of 41) relapsed during pregnancy (p<0.01, Fisher's exact test) (Table 2). Of these 10 women, five had a manic episode, two had a mixed episode, two had a major depressive episode, and one developed hypomania. Those with a manic or mixed episode all required hospitalization. Relapse postpartum occurred in 22.0% of the women with bipolar disorder (nine of 41), the majority of whom (six of nine) had also previously relapsed during pregnancy. Three out of these six women achieved full remission after the relapse during pregnancy but relapsed again postpartum. The other three women experienced a postpartum worsening of an episode beginning in pregnancy (Table 2). Consequently, relapse during pregnancy was a significant risk factor for relapse postpartum (p<0.01, Fisher's exact test; odds ratio=14.0, 95% CI=2.5–80.0). Of all nine women with bipolar disorder and postpartum relapse, three had a manic episode, one had a mixed episode, three had depression, and two had hypomania. Overall, six bipolar women required postpartum inpatient admission (Table 2).

Relapse in the bipolar women, both during pregnancy and postpartum, was especially common in women with a history of puerperal episodes (Table 2). Eight women with bipolar disorder reported a history of both puerperal and nonpuerperal episodes, of whom 50.0% (four of eight) had a peripartum relapse. In contrast, the peripartum relapse rate was 27.3% in the women with bipolar disorder with a history of only nonpuerperal episodes (nine of 33).

All 29 women with postpartum psychosis only were medication free during pregnancy. During this time, none of these women had symptoms of relapse, including any manic, psychotic, or depressive episodes (Table 3).

Of the 29 patients with a history of postpartum psychosis only, 20 began prophylactic treatment within 24 hours of delivery. Of these 20, 17 used lithium and three used antipsychotics. Notably, there were no cases of relapse among the women with postpartum psychosis who initiated postpartum prophylaxis upon delivery. Nine of the 29 patients decided against prophylactic medication, with the majority citing their intention to breast-feed. The relapse rate in the women without postpartum prophylaxis and a history of postpartum psychosis was 44.4% (four of nine). The difference in relapse rates between the patients with and without prophylaxis was significant (p<0.01, Fisher's exact test). No differences were found in demographic variables between these two groups.

One woman had two deliveries during the study inclusion period. She was medication free throughout the first of these pregnancies, used lithium for postpartum prophylaxis, and remained clinically stable throughout the entire peripartum period. During the second pregnancy, she was medication free and clinically stable throughout pregnancy. Unfortunately, however, she relapsed without postpartum prophylaxis.

Of the 41 women with bipolar disorder, 31 (75.6%) received maintenance prophylaxis during pregnancy: 27 women used lithium monotherapy for mood stabilization, two women used lithium plus an antidepressant, one woman used lithium plus an antipsychotic, and one woman used haloperidol monotherapy as prophylaxis. Ten (24.4%) of the 41 bipolar women did not use prophylaxis continuously throughout pregnancy: three discontinued prophylaxis during the first trimester and seven were without prophylaxis during the entire pregnancy. No significant differences in demographic or baseline clinical characteristics were observed between the women with bipolar disorder who received prophylaxis and those who did not.

The relapse rate during the pregnancies of the women with bipolar disorder who used prophylaxis was 19.4% (six of 31), compared to 40.0% (four of 10) in women without prophylaxis. Relapse during pregnancy was treated as clinically necessary, after which mood stabilization was continued throughout pregnancy and the postpartum period. However, despite maintenance mood stabilization, 60.0% (six of 10) of the women who relapsed during pregnancy also experienced a postpartum relapse (p<0.01, Fisher's exact test; odds ratio=14.0, 95% CI=2.5–80.0).

Among the women with bipolar disorder who remained stable throughout pregnancy, 83.9% (26 of 31) used prophylaxis postpartum. Of these women, only 7.7% (two of 26) relapsed postpartum. Further, five of the 31 women who were stable throughout pregnancy declined prophylaxis postpartum, of whom one woman (20.0%) relapsed.

Five bipolar women had two deliveries each during the study inclusion period. Three women declined prophylaxis during both of their pregnancies: two of them were stable during both pregnancies, while the third woman relapsed during both pregnancies. Two women used lithium prophylaxis and were stable during both pregnancies: one woman used lithium continuously during both pregnancies, whereas the other woman used lithium prophylaxis postpartum after her first pregnancy and continuous prophylaxis during her second pregnancy.