9th Greek Australian Legal and Medical Conference
THE BIOLOGICAL TREATMENT OF BIPOLAR MANIA IN PREGNANCY AND THE POSTPARTUM
Dr. Spiri Katsenos MBBS, MMed, FRANZCP
Women who become pregnant, whether planned or otherwise, face many challenges. Although it can be an exciting time for many, it is also universally anxiety provoking.
The pregnant woman, who suffers from a mental illness such as Bipolar disorder, is faced with a demanding experience, which involves an even greater level of anxiety and uncertainty.
The fear of transmitting the illness to the unborn child, the fear of relapse during pregnancy, the fear of the potential teratogenic effects of prescribed medication on the developing child and the uncertainty associated with breastfeeding whilst taking medication, are all relevant concerns in such women.
These issues are equally challenging for the psychiatrist who manages women with major mental illness, including Bipolar disorder, during pregnancy.
Added to such dilemmas are a host of clinical difficulties that result from the nature of manic illness. A pregnant woman who develops acute mania is less likely to comply with antenatal care, is less likely to plan realistically for her baby and is more vulnerable to the effects of poor judgement (for example engaging in unprotected sex leading to sexually transmitted diseases compromising the delivery of the child). She may be inclined to impulsively use harmful substances or be the perpetrator, or victim, of violence. Delusions related to bodily changes and foetal movements, coupled with impulsivity may result in her risking her own life, as well as that of the unborn child.
Such complicating issues highlight the importance of adequate assessment and treatment of pregnant women with manic illness.
Importance of the Topic
Women will often compromise their own mental health to secure an optimum environment for their developing child. Minimising the risk of foetal exposure to medication, whilst limiting the risk of untreated psychiatric illness, is the clinician's goal. Such decisions are never risk free.
Empirical evidence to date is limited and conflicting. As such the arrival of a clinical decision in the management of these very complicated cases requires further systematic research.
The current study involving a literature review and a psychiatrist survey was thought to be an important step in determining the prescribing patterns of psychiatrists in this complicated area. Comparing the current knowledge with clinicians' prescribing patterns was thought to offer an important preliminary step in stimulating local debate about the need to further refine treatment guidelines.
The Epidemiology of Bipolar Disorder
In 1984, the US National Institute Of Mental Health (NIMH) Epidemiological Catchment Area (ECA) Study  estimated the lifetime prevalence of Bipolar disorder to be 0.8 %. The 1-month prevalence for Bipolar disorder was reported at 0.4%. In 1994, the US National Comorbidity Survey (NCS)  estimated the lifetime prevalence for the disorder at 1.6%.
Bipolar disorder has been postulated to be equally prevalent in men and women  . Certain subtypes are thought to be unequally distributed; with Bipolar I disorder manic type being more prevalent in men  and Bipolar II disorder depressive type being more common in women  . Rapid cycling is also reported to be more common in women  . Given all of these limitations, the life-time risk for developing mania has been estimated at approximately 1% [2, 3] .
The average age of onset was reported at 21 years in the ECA study, coinciding with the childbearing years  .
These statistics highlight the importance of mania in pregnancy, being an important consideration in the use of health resources in the current social climate.
Overview of Mania
Mania can be conceptualised in a variety of ways. Most typically, mania is included as part of Bipolar disorder, however it can also occur secondary to a variety of medical and pharmacological antecedents  .
The DSM IV criteria for mania  are displayed below:
American researchers have considered affective episodes with onset in the post partum as being no different to affective episodes at other times. This is reflected in the DSMIV classification system.
In contrast, some European researchers view post partum disturbances as a distinct group, whose aetiology, clinical presentation and prognosis differ from those of non-puerperal mental illness [8, 9] .
Mania in the post partum period is also viewed as part of the Bipolar spectrum by British researchers such as Brockington [10, 11] .
The course of Bipolar Disorder during Pregnancy
Until recently, it has been a traditional view that pregnancy is a time of emotional well being for women  . The following studies indicate the confusion found within the literature concerning this topic.
Finnerty [13 ] suggests that recurrences of mania and bipolar depression are not as uncommon as previously thought in pregnancy.
Viguera, et al [14 ] report on the risk of recurrence of Bipolar disorder in pregnant and non-pregnant women after discontinuing lithium maintenance therapy. They found that the rates of relapse during the first 40 weeks after lithium discontinuation were similar in pregnant (52%) and non-pregnant (58%) women. Relapse was found to be lower for both groups in the year before the treatment was discontinued.
Among subjects who remained stable over the first 40 weeks following lithium cessation, post partum recurrences were 2.9 times more frequent than recurrences in non-pregnant women.
In contrast to the above findings, Grof et al's  retrospective study indicated that women with Bipolar disorder I experienced significantly fewer and shorter recurrences during pregnancy.
In summary, there is little consensus regarding the course of Bipolar disorder in pregnancy with a significant paucity of rigorously conducted studies.
There is no systematic research estimating the incidence and prevalence of mania during pregnancy.
The course of Bipolar Disorder during the Post partum Period
The literature does suggest a higher rate of relapse in patients with established Bipolar disorder during the Post partum period  . In the absence of lithium prophylaxis, established Bipolar disorder patients are at a particularly high risk of developing mania or depression in the post partum period.
Reich and Winokur, in a group of 20 patients with a diagnosis of Bipolar disorder found that 8 (40%) developed a post partum psychosis  .
Kadrmas et al (1979) reported that women with Bipolar disorder were less likely to have an affective recurrence outside the post partum period  .
Given this, Cohen et al [18, 19 ] recommends that lithium prophylaxis be considered to prevent established patients relapsing in the post partum period. The question of when this should begin remains unanswered.
In summary, the literature does suggest that the postpartum period results in an increased risk of relapse in patients with established Bipolar disorder.
Biological Treatment of Bipolar Mania in Pregnancy And The Postpartum Period
Pharmacological treatments are a critical component in the treatment of patients with mania [20, 21] .
Medications have been shown to be effective in the treatment of the acute episodes, as well as in the prevention of future episodes [22, 23] .
Overview of Critical Issues concerning Medication
The crucial issues that separate the treatment of mania in pregnancy, from mania at other times in women's lives, involve the potential risks of exposure to psychotropic medication including:
Embryo toxicity refers to the 1st trimester effects of medications. Data is only available from animal studies, which show that medications can induce a higher rate of spontaneous abortion [24 , 25] .
The period of conception to day 17 is known as the implantation phase. Women generally will not be aware that they are pregnant until 45 days after the last menses (30 days into the pregnancy)  . This is of importance when considering a rapid versus a gradual tapering of medication, in an attempt to minimise the risk of embryo exposure to medication whilst trying to minimise the risk of relapse for the mother.
Foetotoxicity refers to the 2nd and 3rd trimester effects (day 56 to birth) of medications. Data from animal studies suggest that there is an increased perinatal mortality rate as a result of in utero exposure to medication  .
Teratogenesis is associated with foetal drug exposure during the first twelve weeks of gestation when organ formation occurs  . The baseline incidence of congenital malformations in the United States is 2.0%- 2.5 %  . In Australia, 4% of babies born have a birth defect  .
Most often the cause of an anomaly is unknown. A medication is considered a teratogen when prenatal exposure is associated with a significant increase in the risk of congenital physical deformities over the baseline risk [29, 25] .
Perinatal syndromes refer to a wide range of physical and behavioural symptoms noted shortly after birth. These are presumed to relate to drug use at or near the time of birth, and are typically of limited duration  .
Behavioural teratogenesis refers to the potential for long term neurobehavioural abnormalities in children following in-utero exposure to medication  .
Alterations in noradrenergic, dopaminergic, cholinergic and serotenergic function have been demonstrated in animal studies, but the relevance of these findings to humans is undetermined  .
The risk of long term behavioural difficulties, following exposure to psychotropic medication has not been adequately addressed in the literature  .
Issues related to Breastfeeding
The advantages of breastfeeding have been well documented and recently reviewed by Chaudron in 2000  . There are a number of medical benefits for the mother, including decreased risk of ovarian cancer, breast cancer, and decreased risk of osteoporosis  .
In addition, there are several psychological benefits for the mother including emotional bonding with the infant, and increased self-esteem  .
For the infant, there are a number of advantages given that breast milk contains nutritive and immunological value. Breastfed infants also have lower mortality rates from sudden infant death syndrome and lower rates of necrotizing enterocolitis  .
There is also favourable research concerning the effect of breastfeeding on neurodevelopment and attachment  .
The breastfeeding mother being treated with a mood stabiliser may expose the infant to medication  .
A paucity of data has generally led to a conservative approach, in which clinicians advise against breastfeeding when prescribing psychotropic medication.
Lithium During Pregnancy
In the last three decades, lithium has come under significant scrutiny in its use during pregnancy  .
Questions arose about the safety of lithium in humans emerging mainly from anecdotal case descriptions  .
In 1969 Schou initiated a registry of children of Danish women who had been treated with lithium during at least the first trimester of pregnancy  .
Similar registries were subsequently initiated in the United States and Canada, resulting in the formation of the International Register of Lithium Babies  .
Ebstein's anomaly occurs with an estimated frequency of one in 20,000 live births in the general population. Based on the data from the register, Nora et al estimated that the risk of Ebstein's anomaly among infants treated with lithium during pregnancy was some 400 times greater than expected in the general population  .
The final report  using the international register included data on a total of 225 infants. Congenital anomalies were apparent in 25 (11.1%) of these children, including 18 infants with cardiovascular defects (8.0%) and six with Ebstein's anomaly (2.7%).
Recent risk estimates of Ebstein's anomaly following first trimester exposure to lithium range from 10 to 20 times that noted in the general population. Whilst the relative risk for Ebstein's anomaly is increased, the absolute risk is small  .
Perinatal toxicity in infants exposed to lithium at the time of labour and delivery has also been reported  . This includes "floppy infant syndrome" characterised by hypotonicity and cyanosis  . Other adverse effects reported in the neonate include atrial flutter  , tricuspid incompetence and congestive cardiac failure  . Prematurity and macrosomia have also been reported  .
In contrast, in one naturalistic study of women with Bipolar Disorder maintained on lithium during pregnancy and the puerperium, no direct evidence of neonatal toxicity was observed during pregnancy, or after delivery  .
In a 5 year follow up study of 60 children exposed to lithium in the second and third trimester, Schou et al [44 ] found no significant behavioural problems compared to non lithium exposed siblings.
The above results suggest that the use of lithium in pregnancy carries an increased risk of teratogenesis and of perinatal syndromes.
Lithium During Breastfeeding
In the last 10 years, the use of lithium during breastfeeding has generally been discouraged. The American Academy of Paediatrics Committee on Drugs initially classified lithium as compatible with breast-feeding  , but revised its classification in 1989  . The last revision in 1994  , maintains that lithium is contraindicated. The Australian Drug Evaluation Committee opinion (1999)  is consistent with the American recommendation that breastfeeding should be discouraged in women taking lithium.
The use of lithium during breastfeeding has recently been reviewed by Chaudron  , indicating that the current recommendations are based on a paucity of data.
Recommendations vary throughout the literature concerning breastfeeding. They range from strong statements against breastfeeding to supporting a mothers' informed choice.
Given the paucity of evidence about negative effects of lithium on breastfed infants and given the increasing literature indicating benefit to both mother and infant, the generally accepted contraindication to breastfeeding would seemingly warrant further evaluation.
Valproate During Pregnancy
Animal studies suggest a teratogenic association of valproate when used during pregnancy  . Of most concern is the reporting of neural tube defects such as spina bifida and anenchephaly  .
The first suggestions of an association between valproate and spina bifida in humans were reported in 1982 by Bjerkedal  . It was reported that 9 of 72 infants with neural tube defects in the Rhone-Alpes region of France had been antenatally exposed to valproate. Four had also received other anticonvulsants and in two there was a positive family history of neural tube defects.
In 1986, Lindhout, published a prospective study on antenatal exposure to valproate. The analysis of 2111 pregnancies revealed the risk of neural tube defects to be in the region of 1.5%  .
Cohen et al  , estimated that valproate exposure during the first trimester is associated with spina bifida at a rate of 3%-5%.
The possibility of a specific 'foetal valproate syndrome' was raised by DiLiberti et al 1984, Chitayat 1988, and Winter et al 1987 [52, 53, 54] . The features of this syndrome include epicanthic folds, a flat nasal bridge, a broad nasal base, anteverted nostrils, a shallow philtrum, a thin upper lip and thick lower lip.
The literature suggests that doses of folic acid at 4mg per day be administered in conjunction with valproate to minimise central nervous anomalies such as spina bifida, although there is no substantiative evidence for this  .
Valproate in the first trimester has also been reported to be associated with congenital heart disease  .
As such, based on current knowledge, there is a strong association between major and minor congenital malformations and valproate exposure during pregnancy. It is possible that combination anti convulsant therapy may increase this risk further.
Valproate during breastfeeding
Valproate has been considered compatible with breastfeeding [48, 57] because of consistently low concentrations demonstrated in breastmilk. Breast milk contains concentrations that are between 1% and 10% of the mothers' serum level  . In 2000, it has been reported that there have been cases of fatal hepatotoxicity in children under the age of 2 years when treated with valproate  . Some clinicians advise against breastfeeding whilst on valproate based on this evidence.
Despite valproate being classified as compatible with breastfeeding by the American Academy of Paediatric Committee on Drugs (1994)  and the Australian Drug Evaluation Committee (1999)  , the risk involved in using valproate requires further consideration.
It would appear that the opinion that valproate is relatively safe during breastfeeding is based on inadequate evidence.
Carbamazepine During Pregnancy
Animal studies indicate that carbamazepine use in pregnancy is associated with reports of cleft palate, club foot, cardiovascular anomalies and neural tube defects  .
Rosa et al reviewed a cohort of women with epilepsy receiving carbamazepine which revealed a ten fold increased risk of spina bifida compared to the general population, and an absolute risk of spina bifida of 1%  .
Although initially considered safe in pregnancy, there is now evidence to suggest that infants exposed to carbamazepine antenatally show a number of dysmorphic features including cranio-facial defects, fingernail hypoplasia  .
Carbamazepine, like valproate can cause deficiencies in vitamin K in the latter half of gestation, which can predispose to bleeding in the central nervous system  . Monotherapy is considered less teratogenic than combination therapy  .
More research is needed to determine the risk of major and minor congenital malformations due to carbamazepine exposure in the offspring of women with Bipolar disorder.
Carbamazepine During Breastfeeding
Carbamazepine is found in breast milk in concentrations between 7% and 95% of the maternal serum  . Most reports involve individual case reports.
There is less information concerning serum carbamazepine levels in nursing infants. Data from case reports  show that infant serum levels ranged from 6% to 65% of maternal serum levels.
The American Academy of Paediatrics Committee on Drugs (1994)  considers carbamazepine compatible with breastfeeding. Similar views are reported by the Australian Drug Evaluation Committee  , but the generalizability of the data on carbamazepine and breastfeeding is limited due to the small number of cases and because studies do not adequately address infants' serum levels.
Given that there are only published case reports, further study is required before the risk-benefit profile of carbamazepine is established.
The use of gabapentin in pregnancy is limited to those patients suffering from epilepsy. There are no adequately controlled studies  on humans to determine the gabapentin associated risk to the foetus.
There are no published reports concerning breastfeeding infants exposed to gabapentin.
The use of lamotrigine during pregnancy has been mainly limited to epileptic patients. More than one hundred women have been exposed to lamotrigine in pregnancy with no major adverse event to date  .
Lamotrigine is excreted in considerable amounts in breast milk. It has been reported that no acute adverse events were observed in infants exposed to lamotrigine. Exposure of breastfeeding infants to lamotrigine is of some potential concern because of the increased risk of severe life-threatening rashes in children with epilepsy who are treated with this medication.
In summary, there is a clear need for more accurate information about the risks involved when prescribing anticonvulsants during pregnancy and breastfeeding.
In America and Europe the Antiepileptic Drug Pregnancy Registry has been established to address the above issues  . A similar register has been established in Australia, which is based at St Vincent's hospital in Melbourne  .
Benzodiazepines During Pregnancy
Early reports described an increased risk of oral clefts after first trimester exposure to diazepam  . Later studies did not support this association  .
To date, 14 studies have addressed the relationship between antenatal exposure to benzodiazepines and the risk of congenital malformations  .
One meta-analysis suggests that first trimester exposure to benzodiazepines significantly increases risk of oral cleft palates. The risk of cleft palate was estimated at 0.7 %, following in utero exposure to benzodiazepines, compared to the general population risk at 0.06%  .
Benzodiazepine exposure around the time of delivery has been linked to impaired temperature regulation, apnoea, depressed Apgar scores, muscular hypotonicity and failure to feed  .
The data on neurobehavioural sequelae is conflicting and limited. A meta-analytic review of the literature on 550 infants followed up to a maximum of four years of age, found no increase in neurobehavioural sequelae  .
Benzodiazepines During Breastfeeding
Benzodiazepines are excreted in human breast milk in low concentrations  . It has been reported that the infant may suffer from 'floppy infant syndrome'  . This is characterised by hypotonia, lethargy and reduced suckling in the infant. Problems are more frequently encountered with longer acting benzodiazepines  . Of particular concern are the first few days in the post partum period, especially if the infant has physiological jaundice (given that benzodiazepines are metabolised by the liver).
There is also the potential for respiratory depression in the infant exposed to benzodiazepines. An infant withdrawal syndrome could also occur in the context of chronic use in the mother particularly when breastfeeding is ceased  .
The Australian Therapeutic Guidelines recommend that short acting benzodiazepines be used, preferably in single doses  .
Typical Antipsychotics During Pregnancy
Little is known about the consequences of prenatal exposure to high potency neuroleptics including haloperidol although the current literature does not support a causal relationship between teratogenicity and haloperidol  .
While an early case report describing limb malformations raised concerns regarding first trimester exposure to haloperidol  several subsequent studies have failed to demonstrate increased teratogenic risk with high potency neuroleptics  .
Pooled results of larger retrospective and small prospective controlled studies concerning low dose chlorpromazine given in weeks 4-10 suggest that its use in the first trimester may increase congenital anomalies by 0.4%. This increase was not observed with trifluoperazine  .
Case reports of neonates have demonstrated motor restlessness, tremor, difficulty with oral feeding, hypertonicity, dystonic movements and parkinsonian like effects  .
There is no established data concerning long term neurobehavioural effects following exposure to high or low potency antipsychotic medications. One five-year follow up study showed no abnormalities in infants exposed to chlorpromazine in utero  .
Typical Antipsychotics During Breastfeeding
Chlorpromazine is excreted in breast milk in very low concentrations up to 3 % of the maternal serum level  . Haloperidol is excreted in breast milk in higher concentrations with little evidence of adverse outcome  .
There are case reports suggesting occasional adverse reaction in breastfed infants, such as urinary retention, dystonic reactions and drowsiness  . The Australian Therapeutic Guidelines suggest that dosages of less than 10mg of haloperidol are usually regarded as safe, and that depot medications during breastfeeding are best avoided  .
Atypical Antipsychotics During Pregnancy
There is sparse information available on the reproductive safety of risperidone in pregnancy, with no adequately designed studies to determine teratogenic risk. Animal foetotoxicity has been suggested  .
There is limited information available about the reproductive safety of olanzapine in pregnancy, with no evidence concerning teratogenesis. Animal studies using higher than equivalent recommended human doses showed an increased risk of non-viable foetuses  .
There is limited information on the reproductive safety of quetiapine in pregnancy [30, 25] .
To date there are a number of case reports concerning women having delivered healthy babies whilst taking clozapine  . So far there is no clear evidence of teratogenesis. There is little evidence concerning perinatal syndromes and no data concerning neurobehavioural sequelae.
Atypical Antipsychotics During Breastfeeding
The use of atypical antipsychotics during lactation has received little systematic research. There are a small number of case reports concerning infants exposed to olanzapine and risperidone, showing no adverse outcomes  .
Clozapine is concentrated in breast milk and has been reported to cause sedation, decreased suckling, restlessness and cardiovascular instability in the infant  .
Electroconvulsive Therapy (ECT)
ECT During Pregnancy
As experience with ECT in pregnancy has accumulated in the last few decades, attitudes toward its use have changed dramatically. Initially ECT was considered contraindicated for use in pregnancy.
By the late 1940's pregnancy was no longer considered a contraindication  . Knowledge concerning ECT in pregnancy evolved through published case reports reporting favourable outcomes.
To date, there are no controlled studies concerning the rate of complications with ECT compared to other treatments during pregnancy.
Nevertheless there are real concerns when considering ECT in pregnancy. The following is a summary of the reported complications of ECT during pregnancy:
Risks of ECT During Pregnancy
Miller  reported complications by reviewing 300 cases in the literature. Complications were noted in 28 cases (9.3%). These included:
Current Treatment Guidelines for ECT during Pregnancy
There are no published treatment guidelines in Australia regarding the use of ECT in mania during pregnancy.
The American Psychiatric Association recommends that in high risk situations involving acutely disturbed manic patients during pregnancy, ECT may be appropriate as first line treatment  .
ECT During Breastfeeding
There were no articles found that suggested any reasons specific to the postpartum period, that would act to contraindicate ECT during lactation.
It is well-established clinical practice to use ECT in women with postpartum psychoses  .
Risks Associated with Untreated Mania During Pregnancy
The impact of untreated psychiatric illness on the developing foetus and infant has essentially been ignored in the literature. To date, there are no studies investigating the direct effect of untreated mania on foetal development.
Most human studies in this area have examined links between various types of antenatal psychological distress and obstetric outcome. The most frequent findings are that antenatal stress and anxiety are linked with premature labour, low birth weight, smaller head circumference and poorer results on functional tests in the newborn  .
These findings suggest that the morbidity of untreated mania to the mother and developing foetus may be significant, despite a lack of specific quantitative data.
Studies have demonstrated that infants of untreated depressed mothers look less at their mothers, have greater physiological reactivity, make fewer vocalisations, and of greatest concern perform poorer on developmental tasks at one year of age compared to normal controls  .
These findings are sobering, and highlight the need for research into the possible effects of mania on the offspring of pregnant and postpartum women affected by Bipolar Mania.
Synthesis of the Literature
On the basis of the above literature review, only the following tentative guidelines can be proposed as having some basis in the current (limited) evidence.
Aims of the Survey
The broad aims of the survey included:
Methodology of the Survey
A pilot survey using a convenience sample of psychiatrists was developed, involving 5 public hospitals and 1 private psychiatric hospital, with an anonymous means of return in order to safeguard anonymity.
The survey involved 3 crucial clinical scenarios:
The survey used a 5 point closed response graphic rating scale, a ranked order list of biological treatment options and a categorical response option to collect data. The psychometric properties of the survey were untested, but a thorough process of specialised psychiatric review resulted in the instrument holding adequate face validity.
Results of the Survey
The similarity of the demographic variables of the sample to the RANZCP list of College fellows added a significant amount of representative validity to the results.
Specifically, the age, gender and psychiatrist experience variables were comparable to the College list, enhancing the generalisability of the results to the target population.
A favourable completed response rate of 52.3% further enhanced the representative nature of the results.
Summary of Trends
Responses were widespread across many of the scenarios, consistent with the lack of clarity within the literature. Responses seemed most influenced by concern about the teratogenic effects of medications in the 1st trimester of pregnancy.
There were 2 points of concordance between the survey responses and the literature:
Valproate was preferred over carbamazepine despite a reportedly higher rate of neural tube defects when used in the 1st trimester.
Novel anticonvulsants were avoided during pregnancy and the postpartum period, reflecting a cautious approach, which was likely to be due to concern about insufficient data regarding teratogenic risk.
Lithium was generally avoided during breastfeeding, with a significant increase in respondents' preferences when not breastfeeding (p<0.001).
In summary, the potential teratogenic effects of medications given during pregnancy, and the potential for adverse effects during breastfeeding seem to have been the most prominent concerns of respondents when considering their scenario responses.
The medico-legal implications involved in ignoring known teratogenic risks are also likely to have contributed to this cautious approach.
Such a cautious approach would seem reasonable in light of the paucity of rigorous knowledge currently available. However, the mother's mental state may be compromised in order to reduce the risk on the developing foetus.
These results act as a valuable preliminary step aimed at stimulating the development of awareness and future research in this important area, within the profession.
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