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Lithium dosing strategies during pregnancy and the postpartum period
Abstract
Background
Lithium is challenging to dose during pregnancy.AimsTo provide guidance for dosing lithium during pregnancy.Method
Retrospective observational cohort study. Data on lithium blood level measurements (n= 1101), the daily lithium dose, dosing alterations/frequency and creatinine blood levels were obtained from 113 pregnancies of women receiving lithium treatment during pregnancy and the postpartum period.ResultsLithium blood levels decreased in the first trimester (-24%, 95% CI -15 to -35), reached a nadir in the second trimester (-36%, 95% CI -27 to -47), increased in the third trimester (-21%, 95% CI -13 to -30) and were still slightly increased postpartum (+9%, 95% CI +2 to +15). Delivery itself was not associated with an acute change in lithium and creatinine blood levels.Conclusions
We recommend close monitoring of lithium blood levels until 34 weeks of pregnancy, then weekly until delivery and twice weekly for the first 2 weeks postpartum. We suggest creatinine blood levels are measured to monitor renal clearance.
... As a result, lithium concentrations in both mothers and fetuses attain equilibrium, suggesting that it may contribute to neurodevelopmental health. In addition, during breastfeeding, the lithium concentration in milk decreases to approximately half of the maternal serum levels [46,50]. The control of lithium levels is particularly challenging during pregnancy due to normal physiological changes, especially in renal function. ...
... As a result, clinicians often increase the lithium dose during pregnancy. However, later in pregnancy and during the early postpartum period, when glomerular filtration rate returns to preconception levels, the increased dosage may lead to toxic blood lithium levels [50]. Wesseloo et al. [50] showed that lithium initiated during pregnancy, either as treatment for an episode or as an alternative to a mood stabilizer, reduced the risk of teratogenicity when started before conception and continued throughout pregnancy and the postpartum period. ...
... However, later in pregnancy and during the early postpartum period, when glomerular filtration rate returns to preconception levels, the increased dosage may lead to toxic blood lithium levels [50]. Wesseloo et al. [50] showed that lithium initiated during pregnancy, either as treatment for an episode or as an alternative to a mood stabilizer, reduced the risk of teratogenicity when started before conception and continued throughout pregnancy and the postpartum period. The lowest blood lithium levels occurred during the second trimester; in the third trimester and postpartum period, lithium levels progressively returned to preconception levels, highlighting the importance of controlling lithium during this critical gestational period [50]. ...
Lithium was introduced into psychiatric practice in the late nineteenth century and has since become a standard treatment for severe psychiatric disorders, particularly those characterized by psychotic agitation. It remains the most effective agent for managing acute mania and preventing relapses in bipolar disorder. Despite potential adverse effects, lithium’s use should be carefully considered relative to other treatment options, as these alternatives may present distinct safety and tolerability profiles. The World Health Organization classifies lithium salts as ‘essential’ medications for inclusion in global healthcare systems. Over the past two decades, the growing recognition of lithium’s efficacy—extending beyond mood stabilization to include reducing suicide risk and inducing neuroprotection—has led to its incorporation into clinical practice guidelines. Current research, particularly from translational models, suggests that lithium’s pleiotropic effects benefit not only mental and brain health but also other organs and systems. This supports its potential as a therapeutic candidate for neurological conditions, particularly those associated with neurodegenerative processes. This article will discuss the historical background, discovery, and early experimentation of lithium in psychiatry. We will also review its mechanisms of action and discuss its potential in the treatment and prevention of neurodegenerative disorders, focusing on Alzheimer’s disease.
... The administration of lithium poses challenges in dosing due to the physiological changes in renal function that occur during pregnancy. Throughout the first and second trimesters, lithium blood levels progressively decline, and in the third trimester, they return to preconception levels [90][91][92]. ...
... Hence, it is recommended to frequently monitor lithium blood levels during pregnancy and adjust the dosage to maintain levels between the therapeutic range from 0.5 mmol/L to 1.2 mmol/L [93,94]. Prenatal screening, with fetal echocardiography and high-resolution ultrasound around 16-18 weeks of gestation, is recommended for patients on lithium therapy [91]. ...
... Exposure to valproic acid during the first trimester of pregnancy is associated with significantly augmented risks of major and minor congenital malformations. These include a 20 fold increase in neural tube defects (NTDs), mainly with lumbosacral meningomyelocele, cleft lip or palate, midface hypoplasia, cardiovascular anomalies, genitourinary defects, skeletal and limb malformations, endocrine disorders, developmental delay, growth retardation and microcephaly [91,101]. Additionally, it has been associated with developmental neurocognitive deficiencies, lower IQ, impaired cognition, and increased risks of autism and attention deficit disorders in childhood [102][103][104]. ...
Prenatal depression carries substantial risks for maternal and fetal health and increases susceptibility to postpartum depression. Untreated depression in pregnancy is correlated with adverse outcomes such as an increased risk of suicidal ideation, miscarriage and neonatal growth problems. Notwithstanding concerns about the use of antidepressants, the available treatment options emphasize the importance of specialized medical supervision during gestation. The purpose of this paper is to conduct a brief literature review on the main antidepressant drugs and their effects on pregnancy, assessing their risks and benefits. The analysis of the literature shows that it is essential that pregnancy be followed by specialized doctors and multidisciplinary teams (obstetricians, psychiatrists and psychologists) who attend to the woman’s needs. Depression can now be treated safely during pregnancy by choosing drugs that have no teratogenic effects and fewer side effects for both mother and child. Comprehensive strategies involving increased awareness, early diagnosis, clear guidelines and effective treatment are essential to mitigate the impact of perinatal depression.
... 7 Lithium blood levels decrease gradually in the first and second trimester, returning to their preconception level in the third trimester. 8,9 As a consequence, there is a risk of subtherapeutic lithium levels in the first and second trimester, which might lead to an increase in the dose by clinicians. This, in turn, could lead to an increased risk of lithium intoxication in the third trimester and the postpartum period. ...
... Frequent monitoring of lithium blood levels during pregnancy is therefore recommended and dosage should be adjusted in order to remain within the therapeutic window (0.5 mmol/L to 1.2 mmol/L). 4,8,10,11 Several reviews and guidelines have provided clinical advice on dosing strategy during pregnancy and the postpartum, including strategies for dosing around delivery to minimize the risk of both maternal and neonatal complications. Some suggest dose reduction by 30%-50% upon first signs of labor or immediately after delivery, 9,[12][13][14][15] and others recommend to stop lithium prior to delivery. ...
... This retrospective observational cohort study was part of a larger study for which all women referred to the psychiatric and obstetric out-patient clinics of Erasmus Medical Center and Leiden University Medical Center between January 2003 and May 2018 were eligible.8 Women were included in the current study if they used lithium during pregnancy and at least one lithium blood level measurement was obtained during the final week of pregnancy and the first postpartum week (aim 1). ...
... Para las mujeres que logran la eutimia exclusivamente con litio, la reducción cuidadosa de la dosis -tanto en el primer trimestre como en el peripartopuede ser una estrategia terapéutica siempre y cuando estos ajustes no impliquen riesgos significativos de desestabilización de la enfermedad . Además, el litio puede presentar variaciones plasmáticas significativas a lo largo del embarazo (Molenaar et al., 2021;Wesseloo et al., 2017). De acuerdo con la evidencia actual, los investigadores sugieren: a) controles con frecuencia mensual hasta la semana 33 de gestación; y b) controles con frecuencia semanal a partir de la semana 34 (Wesseloo et al., 2017). ...
... Además, el litio puede presentar variaciones plasmáticas significativas a lo largo del embarazo (Molenaar et al., 2021;Wesseloo et al., 2017). De acuerdo con la evidencia actual, los investigadores sugieren: a) controles con frecuencia mensual hasta la semana 33 de gestación; y b) controles con frecuencia semanal a partir de la semana 34 (Wesseloo et al., 2017). Luego del nacimiento, se recomienda el reajuste a las dosis previas al embarazo y litemias de control con una frecuencia semanal en las primeras dos semanas posparto (Clark et al., 2022). ...
... A su vez, se planificarán los estudios complementarios prenatales recomendados. Fármacos como el litio, la lamotrigina, la quetiapina y el aripiprazol (Clark et al., 2013;Wesseloo et al., 2017;Westin et al., 2018) han mostrado variaciones plasmáticas por cambios fisiológicos del embarazo. Por lo anterior, es importante el monitoreo de aparición de síntomas secundarios a los cambios plasmáticos del tratamiento (por ejemplo, de las concentraciones plasmáticas de litio y lamotrigina). ...
Este documento constituye la tercera y última parte del Tercer Consenso Argentino sobre el Manejo de los Trastornos Bipolares llevada a cabo por la Asociación Argentina de Psiquiatría Biológica (AAPB). Siguiendo con el objetivo propuesto por el comité de expertos, en la actual versión del Consenso sobre el manejo de los trastornos bipolares, esta sección está enfocada al abordaje de los Trastornos Bipolares en situaciones especiales. Esto configura una revisión exhaustiva de la evidencia científica sobre: a) el manejo de los trastornos bipolares en pacientes resistentes al tratamiento, b) el manejo de los trastornos bipolares en la mujer en el período perinatal, c) el manejo del trastorno bipolar en la etapa infantojuvenil y d) el manejo de los trastornos bipolares en los adultos mayores.
... Lithium is the first-choice treatment for bipolar disorder. It reduces manic and depressive relapse, and suicide risk [8,9]. Also during pregnancy and the postpartum period, lithium is proven effective, and is often used (albeit cautiously) as maintenance therapy, or to prevent postpartum psychosis [9][10][11]. ...
... According to the literature, neonates with in utero exposure to lithium during the second and third trimesters could possibly present with lithium (adverse) effects. Neonatal lithium-related complications documented in case reports are, for example, thyroid dysfunction, cardiac arrhythmia, hepatic abnormalities, and hypoglycemia [8,9,14,18]. Adverse lithium effects can also present as 'floppy infant syndrome' [24]. ...
... Clark et al. reported that a lithium cord level exceeding 0.64 mEq/L has already been associated with several neonatal complications such as respiratory distress and neurological symptoms [31]. According to these findings, the delivery of a neonate with in utero exposure to lithium should be well-planned, preferably in a centre with a dedicated multidisciplinary perinatal psychosocial team with prenatal counselling, carefully monitored maternal lithium TDM, and experience in neonates with this condition [7][8][9]. Some guidelines suggest interrupting lithium therapy at the onset of labour or 24 to 48 h before induction of labour or caesarian section, to lower lithium TDM at birth to prevent neonatal adverse effects [6,31,32]. ...
Knowledge of the impact of in utero exposure to lithium during the postnatal period is limited. Besides a possible teratogenic effect during the first trimester, exposure during the second and third trimesters might lead to neonatal effects. Uniform guidelines for postnatal management of these neonates are lacking. The aim was to retrospectively describe all neonates admitted to the University Hospitals Leuven after in utero exposure to lithium (January 2010 to April 2020), and to propose a postnatal care protocol. Descriptive statistics were performed. For continuous parameters with serial measurements, median population values were calculated. In total, 10 mother-neonate pairs were included. The median gestational age was 37 (interquartile range, IQR, 36–39) weeks. Neonatal plasma lithium concentration at birth was 0.65 (IQR 0.56–0.83) mmol/L with a median neonate/mother ratio of 1.02 (IQR 0.87–1.08). Three neonates needed respiratory support, 7/10 started full enteral (formula) feeding on day 1. The median length of neonatal stay was 8.5 (IQR 8–12) days. One neonate developed nephrogenic diabetes insipidus. This study reported in detail the postnatal characteristics and short-term neonatal outcomes. A postnatal care protocol was proposed, to enhance the quality of care for future neonates, and to guide parental counselling. Future prospective protocol evaluation is needed.
... Data from retrospective observational studies show that serum lithium concentrations decline across pregnancy. 9,10 In 1 study, investigators found that serum lithium concentrations increase slightly in the third trimester. 9 Characterization of the trajectory of lithium elimination clearance across pregnancy and after birth is necessary to inform monitoring and dose adjustments. ...
... 9,10 In 1 study, investigators found that serum lithium concentrations increase slightly in the third trimester. 9 Characterization of the trajectory of lithium elimination clearance across pregnancy and after birth is necessary to inform monitoring and dose adjustments. The timing and magnitude of dose increases required to prevent bipolar disorder symptom recurrence while minimizing adverse effects across the perinatal period has not been determined. ...
... At each protocol visit, thirteen 3-mL serial blood samples were drawn from an indwelling peripheral intravenous catheter into a tube that contained no anticoagulant or other additive before dosing and 1, 2, 3, 4, 5, 6,7,8,9,10,11, and 12 hours after dosing for participants dosed twice daily, and before dosing and 2, 4, 6,8,10,12,14,16,18,20,22, and 24 hours after dosing for participants dosed once daily. Blood samples were immediately processed, and serum was frozen in a -80°C freezer for 10 to 12 days before analysis. ...
The pharmacokinetics of lithium, the gold standard for the treatment of bipolar disorder, are well described in nonpregnant patients. Because lithium is commonly prescribed to women of childbearing age, more data are essential to characterize lithium pharmacokinetics during the perinatal period. Lithium is primarily eliminated by the kidney. As a result, shifts in lithium elimination clearance parallel pregnancy‐related changes in glomerular filtration rate. Lithium's narrow therapeutic window increases the risk for therapeutic failure and toxicity when lithium elimination clearance is altered. To characterize the pharmacokinetics of lithium in pregnancy and postpartum, 3 women treated with lithium for bipolar disorder completed serial blood sampling protocols during each trimester of pregnancy and at least once postpartum. The trajectory of lithium elimination clearance, creatinine clearance, and serum lithium concentrations were determined. Manic, depressive, and anxiety symptoms were also assessed at each study visit. Compared to the nonpregnant state, lithium elimination clearance increased an average of 63.5% by the third trimester. Lithium elimination clearance was inversely related to changes in serum lithium concentration. Mood symptoms worsened with declines in serum lithium concentration. Lithium elimination clearance returned to baseline at 4 to 9 weeks postpartum. To maintain lithium effectiveness during pregnancy and prevent toxicity postpartum, lithium therapeutic drug monitoring and dose adjustments are warranted.
... However, recent studies could show a much lower risk of cardiac or general malformation than previously thought [4,5]. Additionally, the teratogenic risk seems to be positively correlated with lithium concentration during pregnancy [6]. Furthermore, there is data from a small study showing no negative long-term effect in lithium-exposed children of up to 15 years [7]. ...
... Secondly, it is of interest, whether medication during pregnancy is associated with pregnancy and birth complication. Here, data are scarcer; however, systematic reviews and meta-analysis report a higher risk that the infant needs to be admitted in neonatal care unit [6], but no significant associations with spontaneous abortion, preterm birth, low birth weight, or small for gestational age [5,19] were shown. Our three cases did not show any severe pregnancy or birth complication. ...
... As a result of an increased renal function in the first and second trimester, lithium levels in pregnancy decreased and slowly increased in third trimester and showed a more rapid increase after birth. Wesseloo et al., therefore, propose a monthly monitoring of lithium serum levels until 34th gestational weeks and a weekly monitoring thereafter until birth [6]. In our cases, we measured lithium levels every 4 weeks but did not measure weekly after the 34th week which was partly due to organizational issues. ...
Lithium salts are the first-line prophylaxis treatment for bipolar disorder in most guidelines. The majority of bipolar women are treated with mood stabilizers at the time they wish to get pregnant. One reason for this is the rising average age at first childbirth, at least in the high-income countries, which increases in general the likelihood of a medication with psychotropic drugs. Previously, lithium exposition during pregnancy was thought to strongly increase the risk of severe cardiac malformation. However, recent studies only point to a low teratogenic risk, so nowadays an increasing number of women are getting pregnant with ongoing lithium treatment. Regarding lithium medication during breastfeeding, there is evidence that lithium transfers to the breastmilk and can also be detected in the infants’ serum. The influence on the infant is still a largely understudied topic. Regular monitoring of the infants’ renal clearance, thyroid function, and lithium levels is warranted when breastfeeding under lithium exposure. In this case series, we present three case reports of bipolar mothers who were treated with lithium during pregnancy and breastfeeding to add to the scarce literature on this important topic. In short, we strengthen the importance of therapeutic drug monitoring due to fluctuating plasma levels during pregnancy and after birth, and we can report the birth and development of three healthy infants despite lithium medication during pregnancy and breastfeeding.
... Many women on lithium who learn they are pregnant discontinue lithium, despite a dearth of evidence as to the benefit of the discontinuation [50]. Although most experts agree to the need for continuous administration of lithium during pregnancy lest perilous recurrences occur [51][52][53], some patients find it difficult to obtain a prescription even after their second trimester [50]; doctors tend to prescribe it more intensely with the progression of pregnancy [54], probably because they know that pregnancy in itself reduces lithium levels [55,56]. Therefore, it appears that both patients and doctors share some responsibility for the reduction in prescribing lithium during pregnancy, although many physicians tend to increase doses with pregnancy [54]. ...
... Turning to another effective drug and switching lithium is similarly dangerous, as alternatives like valproate and carbamazepine carry more teratogenic potential than lithium itself. Dose adjustments may be useful, but not in the reduction direction, as pregnancy tends to lower lithium levels [55,56]; increasing the dose would be appropriate but should follow regular examinations of lithium levels. ...
Background/Objectives: Lithium taken during pregnancy was linked in the past with increased risk for foetal/newborn malformations, but clinicians believe that it is worse for newborn children not to treat the mothers’ underlying psychiatric illness. We set to review the available evidence of adverse foetal outcomes in women who received lithium treatment for some time during their pregnancy. Methods: We searched four databases and a register to seek papers reporting neonatal outcomes of women who took lithium during their pregnancy by using the appropriate terms. We adopted the PRISMA statement and used Delphi rounds among all the authors to assess eligibility and the Cochrane Risk-of-Bias tool to evaluate the RoB of the included studies. Results: We found 28 eligible studies, 10 of which met the criteria for inclusion in the meta-analysis. The studies regarded 1402 newborn babies and 2595 women exposed to lithium. Overall, the systematic review found slightly increased adverse pregnancy outcomes for women taking lithium for both the first trimester only and any time during pregnancy, while the meta-analysis found increased odds for cardiac or other malformations, preterm birth, and a large size for gestational age with lithium at any time during pregnancy. Conclusions: Women with BD planning a pregnancy should consider discontinuing lithium when euthymic; lithium use during the first trimester and at any time during pregnancy increases the odds for some adverse pregnancy outcomes. Once the pregnancy has started, there is no reason for discontinuing lithium; close foetal monitoring and regular blood lithium levels may obviate some disadvantages of lithium administration during pregnancy.
... This retrospective observational cohort study was part of the NP3 study (National postpartum psychosis prevention offspring study), that included women with a history of bipolar spectrum disorder or postpartum psychosis that were referred to a psychiatric and obstetric outpatient clinic from 2003 to 2019. 23 Most women were included at Erasmus Medical Center or Leiden University Medical Center and a small number of women were included at other Dutch clinics. Data were collected during clinical visits as part of the regular treatment and were later retrieved from the medical records. ...
... We considered actual serum level to be a more accurate predictor for the effects of lithium than the daily dosage, because of its known therapeutic window and due to the physiological changes of renal function during pregnancy. 23 By focusing on a dose response relationship, the risk of confounding by maternal psychiatric disorder was substantially smaller than in studies comparing exposure versus non-exposure. To account for any remaining confounding factors, we adjusted for the occurrence of a mood episode and the use of additional psychotropic medication during pregnancy. ...
Introduction
Lithium use during pregnancy reduces the risk of mood episodes in the perinatal period for women with bipolar disorder. Some previous studies found deleterious effects of intrauterine lithium exposure on birth outcomes, yet little is known about a dose response relationship. The current study investigated the influence of maternal lithium serum levels on birth outcomes.
Methods
This retrospective observational cohort study included women with a bipolar spectrum disorder who were referred to a specialized psychiatric and obstetric outpatient clinic from 2003 to 2019 and used lithium during the entire pregnancy. For 101 pregnancies at least one lithium level during pregnancy was available. A weighted average lithium level was calculated for the entire pregnancy, as well as for each trimester. Detailed information on maternal, obstetric and neonatal outcomes were retrieved from the medical records. Linear and logistic regression models were used to investigate the association between weighted average lithium level and pregnancy duration, birth weight percentiles, preterm birth and large for gestational age births (LGA). In subsequent exploratory analyses, we studied the role of thyroid‐stimulating hormone (TSH) and thyroxine (T4) as a mediator in the found associations.
Results
The weighted average lithium serum level during pregnancy was negatively associated with pregnancy duration and positively with preterm birth, but not with birth weight percentile or LGA. In exploratory analyses, TSH and T4 did not mediate the association between average lithium serum level and pregnancy duration.
Conclusion
The results of this cohort study during pregnancy indicate a dose response relationship between maternal lithium serum levels and pregnancy duration.
... Anatomic and physiological changes during pregnancy may progressively alter the pharmacokinetics of lithium over the course of the three trimesters (Feghali et al., 2015;Westin et al., 2017;Allegaert, 2020;). In the third trimester, lithium clearance has been found to rise by 30-50%, which may require an adjustment of the dose guided by therapeutical drug monitoring (Granjean and Aubry, 2009;Wesseloo et al., 2017). Lithium has complete placental passage, with an ion equilibration across placental barrier that is remarkably uniform across a wide range of maternal concentrations (0.2-2.6 mEq/L) (Newport et al., 2005). ...
... A systematic review and meta-analysis showed a relapse rate during postpartum in women with bipolar disorder of 37% (Wesseloo et al., 2016). In the first month postpartum, the recommended therapeutical range is ≥0.80 mEq/L (Wesseloo et al., 2017). In our sample of bipolar disorder patients under lithium monotherapy during lactation, only two patients out of 24 (fewer than 10%) relapsed during follow-up (at 36 and 45 days postpartum respectively): one with a subtherapeutic serum lithium concentration, and the other within the therapeutic range. ...
Purpose: Women who take lithium during pregnancy and continue after delivery may choose to breastfeed, formula feed, or mix these options. The aim of the study was to evaluate the neonatal lithium serum concentrations based on these three feeding trajectories.
Methods: We followed 24 women with bipolar disorder treated with lithium monotherapy during late pregnancy and postpartum (8 per trajectory). Lithium serum concentrations were determined by an AVL 9180 electrolyte analyser with a 0.10 mEq/L detection limit and a 0.20 mEq/L limit of quantification (LoQ).
Results: There was complete lithium placental passage at delivery, with a mean ratio of lithium concentration in the umbilical cord to maternal serum of 1.12 ± 0.17. The median times to LoQ were 6–8, 7–8, and 53–60 days for formula, mixed, and exclusive breastfeeding respectively. The generalized log-rank testing indicated that the median times to LoQ differ according to feeding trajectory (p = 0.037). According to the multivariate analysis-adjusted lithium serum concentrations at birth, times to LoQ are, on average, longer under exclusive breastfeeding (formula, p = 0.015; mixed, p = 0.012). No lithium accumulation was observed in infants under either exclusive or mixed breastfeeding. During the lactation follow-up, there was no acute growth or developmental delays in any neonate or infant. Indeed, lithium concentrations in the three trajectories declined in all cases. However, the time needed to reach the LoQ was much longer for those breastfeeding exclusively.
Conclusions: In breastfeed infant no sustained accumulation of lithium and no adverse effects on development or growth were observed.
... For example, physiological renal changes during pregnancy 17 may alter the pharmacokinetics of lithium, and its serum concentrations will decline throughout pregnancy. This necessitates preferably weekly monitoring in the third trimester with does adjustment to maintain therapeutic levels 18 . Lithium also has a complete placental passage and equilibrates between the maternal and fetal circulation across a wide range of maternal concentrations (0.2-2.6 mEq/L) 19 . ...
... Postpartum, serum lithium concentrations in the mother gradually return to their preconception levels, and this presents a risk for lithium intoxication if women have had their dose increased during pregnancy. Lithium serum concentration should be measured twice weekly for the first 2 weeks after delivery and monthly thereafter for the next 3-6 months 18 . ...
... Pregnancy results in alterations in physiological and pharmacokinetic parameters resulting from altered glomerular filtration rates and expansion of plasma volume. These changes, in turn, affect the distribution, absorption, metabolism, and excretion of drugs [12,13]. This necessitates the use of medications with shorter half-lives so that they may not accumulate in maternal and fetal tissues [14]. ...
Background
The presence of psychiatric symptoms in pregnancy is a common occurrence that requires swift and effective management to avoid harm to self, caregivers, staff, and, above all, the reliant fetus. However, there is a dearth of knowledge, practical guidelines, and research in the context of managing agitated states of antenatal patients. To bridge this critical knowledge gap, this research endeavors to illuminate the practices surrounding the management of agitated pregnant women with respect to psychiatric emergencies in a tertiary care hospital.
Aims and objectives
This study aims to study the pattern of psychotropic drugs used to manage agitation in antenatal patients in a tertiary care institute.
Methods
This retrospective record-based study was conducted in a tertiary care center in Central India to assess psychiatric referrals for the management of acute agitation in the department of obstetrics and gynecology. The consultation-liaison (CL) records of interdepartmental psychiatric referrals were assessed for a duration of one year between September 2022 and August 2023.
Results
The most frequently used treatment was intramuscular promethazine 25 mg, given to 32.20% of the participants. This was followed by intramuscular haloperidol 1.25 mg (14.69%) and tablet olanzapine 5 mg (10.17%). Tablet haloperidol 2.5 mg and intramuscular haloperidol 5 mg combined with promethazine 25 mg were each administered to 6.78% of the participants. Other treatments included tablet lorazepam 2 mg (6.21%), intramuscular lorazepam 2 mg (6.21%), intramuscular haloperidol 2.5 mg (9.60%), intravenous lorazepam 2 mg (2.26%), and tablet quetiapine 50 mg (1.13%). Verbal de-escalation was employed for 3.95% of the participants. None of the patients had to be restrained physically.
Conclusion
This study on antenatal agitation found promethazine followed by haloperidol as the most common treatment, used intramuscularly in low doses. Benzodiazepines like lorazepam were used sparingly, while verbal de-escalation proved effective in some cases.
... Lithium is primarily cleared via the kidneys and the blood concentrations of lithium is expected to decrease during pregnancy (24). Throughout the pregnancy lithium blood concentrations have been shown to decrease by 13 to 47% (25). The FDA recommends to avoid sodium restriction and diuretics to maintain lithium's therapeutic window (26). ...
Background and objective
Published works have discussed the pharmacokinetic interactions of drugs with pregnancy, but none comprehensively identify all the approved United States Food and Drug Administration (FDA) and European Medicines Administration (EMA) drugs that have a pregnancy-related intervention. The objective of this systematic review is to comprehensively identify medications that have clinically meaningful interventions due to pharmacokinetic reasons.
Methods
An in-depth search of clinical data using the PDR3D: Reed Tech Navigator™ for Drug Labels was conducted from 1 June to 12 August 2022. The PDR3D was analyzed using the search terms “pregnant” and “pregnancy” within the proper label section. Regarding the US labels, the terms were searched under the “dosage and administration” section, whereas with the EU labels, the terms were searched within the “posology and method of administration” section. If a finding was discovered within the search, the rest of the label was analyzed for further information. Clinical relevance was based on whether an intervention was needed.
Results
Using the search strategy, 139 US and 20 EU medications were found to have clinically meaningful interventions in pregnancy. The most common explanations for clinical relevance included hepatic metabolism, protein binding, renal elimination, and P-gp influence. Of the US labels: 40 were found to undergo hepatic metabolism, 11 were found to be influenced by renal elimination, 12 were found to be influenced by protein binding, 7 were found to be influenced by P-gp, and the remaining drugs required further research. Of the EU labels: 11 were found to undergo hepatic metabolism, 3 were found to be influenced by renal elimination, 3 were found to be influenced by protein binding, 1 was found to be influenced by P-gp, and the remaining drugs required further research.
Conclusion
This comprehensive review of clinically relevant interventions in pregnancy will potentially aid in the treatment of pregnant females when they are undergoing therapy, provide intervention and dosing guidance for physicians, and save time for prescribers and pharmacists. Advances in non-clinical predictions for pregnancy dosing may guide the need for a future clinical evaluation.
... Although previous reviews separately considered the use of lithium in paediatric age (Duffy et al. 2018;Amerio et al. 2018), during the peripartum period (Wesseloo et al. 2017) and in geriatric populations (Cooper et al. 2011), no study to date has synthesised the evidence on lithium efficacy and safety in these three special clinical conditions. An umbrella review can therefore overcome this shortcoming and comprehensively evaluate the benefits of lithium use across lifespan. ...
Background
Lithium is one of the most consistently effective treatment for mood disorders. However, patients may show a high level of heterogeneity in treatment response across the lifespan. In particular, the benefits of lithium use may vary in special clinical conditions. The aim of this study was to test this hypothesis by conducting an umbrella review on the efficacy and safety of lithium in childhood and adolescence, peripartum and old age.
Methods
We applied the Preferred Reporting Items for Systematic Reviews and Meta-analyses criteria (PRISMA) to identify systematic reviews/meta-analyses on the efficacy and/or safety of lithium in mood disorders in special clinical conditions: (i) childhood and adolescence; (ii) peripartum (pregnancy, postpartum and lactation); (iii) old age. The Risk of Bias Assessment Tool for Systematic Reviews (ROBIS) tool was used to assess the risk of bias. Overlap in primary studies across systematic reviews was calculated through the Corrected Covered Area (CCA).
Results
We included 20 independent studies, for a total of 8209 individuals treated with lithium. Regarding paediatric age, efficacy and safety results suggested that lithium may be superior to placebo in bipolar disorders (BD) and not associated with serious adverse events. Nevertheless, primary available data are very limited. Efficacy in paediatric major depressive disorder (MDD) is not clear. During peripartum, lithium use was superior to non-lithium in preventing mood episodes and it was associated with low risk of congenital anomalies and with normal child neurodevelopment. Regarding old age, limited evidence supported lithium as an effective treatment in BD and resistant MDD; low doses should be used in this population. Systematic reviews on paediatric age showed the lowest risk of bias (80% of the studies at low risk). The CCA range of included studies was 13–47%.
Conclusions
This umbrella review supports the use of lithium across the lifespan, including special clinical condition. Nevertheless, more studies with increased methodological homogeneity are needed.
... Pregnancy is associated with physiological changes such as weight gain, plasma volume expansion, and increased renal clearance, which can reduce serum drug concentrations of medications. Wesseloo et al. [62] in a retrospective cohort of 113 pregnancies found an increase in lithium elimination clearance during the irst two trimesters, and a decline during the third trimester and postpartum. The activity of CYP450 isoenzymes might vary during pregnancy, but the precise characterization is complicated due to their genetic polymorphisms and multiple metabolic pathways. ...
Pregnancy in women with bipolar disorder (BD) can be considered a high-risk pregnancy in view of several clinical and pharmacotherapeutic considerations. Pharmacological treatment during pregnancy requires a careful weighing of psychotropic drug exposure against the risk of BD relapse. An untreated bipolar illness can negatively affect the health of mother as well as unborn child in the event of a relapse. Availability of well balanced, latest information on safety of prophylactic drugs for BD is crucial for making informed decisions. The review provides an evidence-based update (2015-2021) on the drug safety considerations involved in providing care for women with BD who are either pregnant or planning to conceive in near future. Literature review based on systematic reviews, meta-analyses, and data available from studies based on large-scale cohorts and birth registries has been synthesized and presented along with clinically relevant recommendations.
... In pregnant women, it is necessary to monitor lithium serum levels on a monthly basis, while in the last trimester, the monitoring should be weekly [124,125]. Moreover, recent observational real-world studies have found that it is not necessary to decrease or stop lithium treatment before delivery, but it should be sufficient to assess serum levels twice weekly, at least for the first two weeks after delivery [125,126]. ...
Introduction
Lithium treatment is considered the gold standard for the long-term management of bipolar disorder and recurrent unipolar depression. It is also extremely effective in other psychiatric conditions characterized by impulsivity and aggression, and for the prevention of suicidal behviours.
Areas covered
This paper provides a review and expert commentary regarding the use of lithium in adult patients. Available information about efficacy, tolerability, dosing, and switching is analysed, and the strategies that may be most useful in real-world clinical settings are highlighted.
Expert opinion
Lithium is effective on different domains of bipolar disorder, including the long-term prevention of recurrences of affective episodes, management of acute mania as well as in the prophylaxis of all affective episodes. Lithium has been defined a “forgotten drug”, since its use in routine clinical practice has been declined over the last 20 or 30 years. Reasons for this trend include lack of adequate training on the management of lithium side effects. Considering its efficacy, use of lithium in ordinary clinical practice should be promoted. Several strategies can be easily implemented in order to minimize lithium side effects and improve its tolerability profile.
... Changing of medication during pregnancy and postpartum should be avoided when possible (Hermann et al. 2019). An increase in the GFR and an expansion of the blood volume occurring during pregnancy can cause a decrease in lithium levels during the first and second trimesters (Wesseloo et al. 2017). Therefore, the lithium dosage may have to be increased in order to ensure sufficient lithium levels. ...
... An association has been observed between high infant lithium concentrations (>0.64 mEq/L), lower 1-min Apgar scores, longer hospital stays, and higher rates of central nervous system and neuromuscular complications (Newport et al., 2005). The regular measurements of the serum lithium concentration are needed perinatally to ensure that it remains within the therapeutic range, and to minimize the risk of both maternal and neonatal complications (Malhi et al., 2017;Wesseloo et al., 2017;Westin et al., 2017). Women are advised to suspend lithium treatment at the onset of labor or for 24-48 h before a scheduled cesarean section (Newport et al., 2005). ...
Background: Most guidelines advise that women taking lithium should not breastfeed. The variation in transfer is just one reason behind this advice.
Objectives: To present clinical and pharmacokinetic data of nine mother–infant pairs exposed to lithium monotherapy during late pregnancy and exclusive breastfeeding at the Perinatal Psychiatric Unit (2006–2018).
Methods: We obtained sociodemographic data, medical risk factors, obstetric variables, and family and personal psychiatric history by semi-structured interview, and assessed maternal psychopathology with the Hamilton Depression Rating Scale and Young Mania Rating Scale. A senior neonatologist reviewed neonatal outcomes at birth using the Peripartum Events Scale. Paired maternal and cord blood and infant venous blood samples were collected. During the breastfeeding period, we monitored serum lithium and creatinine concentrations in mother–infant pairs at delivery, and at days 1–5, 7–11, 30, and 60 postpartum, and monthly until 6-months.
Results: Lithium equilibrated completely across the placenta [1.13 (0.10), range (1.02–1.30)]. No women presented symptoms of postpartum lithium intoxication, two of the neonates presented transient hypotonia (22%). Lithium exposure was significantly less during breastfeeding than during late pregnancy, and serum lithium concentrations decreased up to 44% overtime from delivery to the first-month, and up to 60% to the third-month postpartum. There was no growth or developmental delay in the follow-up period. One woman had a manic episode with psychotic features at 45 days postpartum.
Conclusions: In carefully selected women with bipolar disorder, lithium therapy when breastfeeding can be an appropriate option if coupled with close monitoring of the mother-infant pair.
... 6 Increased glomerular filtration rate in pregnancy also increases elimination of renally cleared drugs; a classic example of this effect is lithium. 13 Changes in hepatic enzyme activity in pregnancy, including upregulation of cytochrome P450 and glucuronidation, are another cause of increased metabolism and elimination of drugs. 14 Increased phase 2 metabolism of lamotrigine by glucuronidation results in lower drug levels in pregnancy, and this can be further affected by polymorphism of UDP-glucuronosyltransferases. ...
A practical handbook providing a succinct overview of the different aspects of mental health disorders, facilitating a solid base knowledge of the field of psychiatry. Offering a systematic, straightforward approach, the book covers the importance and relevance of mental health disorders, their causes, presentation, and the best approaches for their treatment. Written by mental health professionals with a high level of expertise and practical experience in the treatment of patients with mental health issues, the book includes numerous clinical vignettes, bulleted lists, tables, diagrams, and algorithms to facilitate understanding. It covers the important topics across psychiatry, including the psychiatric interview; psychosocial theories and their implications for psychiatry; neurostimulation treatments; the suicidal patient; and dementias, as well as full coverage of the depressive, bipolar, anxiety, and psychotic disorders. Essential reading for medical students, trainees in psychiatry, and other healthcare professionals interested in expanding their knowledge of psychiatry and mental health.
Pharmacists are highly accessible health-care professionals who play a critical role in providing comprehensive medication management and person-centered care to patients. They are now an important part of interdisciplinary teams in various hospital and clinic settings and are well positioned to address social determinants of health in their practice. With these principles, pharmacists can assist in the intersection of women’s health and mental health, particularly in the areas of comprehensive medication management. This chapter will discuss pharmacists’ practice settings outside of dispensing roles, treatment considerations for opioid use disorder in pregnancy, psychotropic medications and risks to women, and advocacy considerations for mental health in women. A women’s health checklist from a pharmacist’s perspective is provided for the readers.
The 2017 International Society for Bipolar Disorders (ISBD) Task Force report on pediatric bipolar disorder (BD) cemented the concept that BD can have onset before the age 18, and that establishing the diagnosis should be based on symptoms of mania or hypomania, while chronic irritability by itself is not sufficient to establish a BD diagnosis [1, 2]. A 2010 study of 1566 patients from six international sites documented that approximately 5% of BD-1 and 5% of BD-2 cases had onset before the age of 20 (Figure 7.1), although the authors noted that only 34.1% of patients were evaluated at onset of their BD, so investigators had to rely on patient recall for two-thirds of the sample.
Worldwide efforts to promote greater lithium use for mood disorders have increased the need for evidence-based guidance addressing key questions related to initiation, monitoring and adverse effect management. This practical handbook provides clinicians with a detailed explanation of lithium's renal journey, how this informs our understanding of polyuria pathogenesis and how medications or hyponatremia can alter lithium clearance. Covering efficacy, pharmacokinetics, toxicity, discontinuation, and use in special patient groups including pregnant and breastfeeding women, older or younger patients, each section also provides a detailed background for its suggested logical approach to managing lithium's renal and other adverse effects. Using the latest data, the book outlines rationales for specific management decisions, and prioritizes options to provide clinical guidance on the best course of action. Colour-coded lists and tables, bulleted text, and diagrams illustrate important points throughout, helping to make information accessible and easy-to-digest. An essential resource for mental health professionals worldwide.
Background
Bipolar disorder is one of the most burdensome severe mental disorders, characterized by high levels of personal and social disability. Patients often need an integrated pharmacological and non-pharmacological approach. Lithium is one of the most effective treatments available not only in psychiatry, but in the whole medicine, and its clinical efficacy is superior to that of other mood stabilizers. However, a declining trend on lithium prescriptions has been observed worldwide in the last 20 years, supporting the notion that lithium is a ‘forgotten drug’ and highlighting that the majority of patients with bipolar disorder are missing out the best available pharmacological option.
Based on such premises, a narrative review has been carried out on the most common “misconceptions” and “stereotypes” associated with lithium treatment; we also provide a list of “good reasons” for using lithium in ordinary clinical practice to overcome those false myths.
Main text
A narrative search of the available literature has been performed entering the following keywords: “bipolar disorder”, “lithium”, “myth”, “mythology”, “pharmacological treatment”, and “misunderstanding”. The most common false myths have been critically revised and the following statements have been proposed: (1) Lithium should represent the first choice for the treatment of patients with bipolar disorder; (2) lithium treatment is effective in different patients’ groups suffering from bipolar disorder; (3) Drug–drug interaction risk can be easily managed during lithium treatment; (4) The optimal management of lithium treatment includes periodical laboratory tests; (5) Slow-release lithium formulation has advantages compared to immediate release formulation; (6) Lithium treatment has antisuicidal properties; (7) Lithium can be carefully managed during pregnancy.
Conclusions
In recent years, a discrepancy between evidence-based recommendations and clinical practice in using lithium treatment for patients with bipolar disorder has been highlighted.
It is time to disseminate clear and unbiased information on the clinical efficacy, effectiveness, tolerability and easiness to use of lithium treatment in patients with bipolar disorder. It is necessary to reinvigorate the clinical and academic discussion about the efficacy of lithium, to counteract the decreasing prescription trend of one of the most effective drugs available in the whole medicine.
Many women with bipolar disorder experience episodes of illness or relapses over the perinatal period, especially in the immediate postpartum period. Risks associated with treated/untreated psychopathologies and fetal exposure to bipolar medications make the management of bipolar disorder during these periods challenging for clinicians and patients. In light of the available effectiveness and reproductive safety data, the current clinical update based on the opinions of a group of international perinatal psychiatry authors recommends general considerations and specific management strategies for each possible clinical scenario, including mixed features, predominant polarity, diagnosis of subtypes of bipolar disorder, severity of previous episodes, and risk of recurrence of mood episodes.
Background:
Postpartum psychosis (PPP) is a psychiatric emergency that generally warrants acute inpatient care. PPP is marked by the sudden onset of affective and psychotic symptoms with a rapid deterioration in mental state. Evidence suggests that PPP is a discrete disorder on the bipolar disorder spectrum with a distinct treatment profile and prognosis.
Methods:
We conducted a PubMed database search for various terms involving PPP and its treatment and included peer-reviewed articles published in English.
Objective:
To provide a treatment algorithm for the management of PPP based on available evidence.
Results:
Pharmacological therapy is the mainstay of PPP management in the acute phase. Evidence points to a combination of antipsychotics and lithium in the acute treatment of PPP. Electroconvulsive therapy can offer a rapid treatment response where required. Lithium appears to have the best evidence for relapse prevention and prophylaxis in PPP. Psychoeducation is essential and psychosocial interventions used in bipolar disorder may be effective in PPP.
Conclusion:
Early detection and prompt treatment with antipsychotics and lithium, followed by maintenance treatment with lithium, is associated with a favourable prognosis in PPP.
Perinatal psychopharmacology is an emerging specialty that is gradually developing alongside perinatal psychiatry. The management of psychiatric disorders during the perinatal period is a challenge for perinatal practitioners due to the multiple changes occurring during this crucial period. This little-known specialty still suffers from inappropriate considerations on the impact of psychotropic treatments on the mother and the infant during pregnancy and postpartum, which can promote a deficiency in perinatal psychic care. However, the risks associated with insufficient management of mental health are major, impacting both the mental and physical health of the mother and the infant. In this paper, we propose a perinatal psychopharmacology prescription guide based on available scientific evidence and international and national recommendations. We thus propose a decision-making process formalized on simple heuristics in order to help the clinician to prescribe psychotropic drugs during the perinatal period.
Affektive Erkrankungen in Schwangerschaft und Postpartalzeit sind häufig und können, insbesondere wenn sie nicht ausreichend gut behandelt werden, negative Folgen für die ganze Familie inklusive der Entwicklung der exponierten Kinder haben. Therapierefraktäre oder schwierig zu behandelnde uni- oder bipolare Depressionen in dieser besonderen Zeit scheinen etwas weniger häufig zu sein als in anderen Lebensphasen, sind aber bisher auch deutlich weniger beforscht. Bei der Behandlung der Mutter müssen in der Schwangerschaft immer potenziell embryo- und/oder fetotoxische Effekte der pharmakologischen oder nichtpharmakologischen Therapien mitbedacht und in der Stillzeit insbesondere bei Medikamenten der Übergang in die Muttermilch beachtet werden. Hier mangelt es aus ethischen Gründen an randomisiert-kontrollierten Studien. Dennoch gibt es ausreichend Daten aus Register- und Beobachtungsstudien sowie Fallserien, um erste Empfehlungen für eine therapierefraktäre uni- bzw. bipolare Depression in Schwangerschaft und Stillzeit herleiten zu können.
Objetivo: Analisar o desfecho materno-fetal do uso do Lítio durante a gravidez. Métodos: A pesquisa de revisão integrativa seguiu etapas, no qual realizou-se uma busca em bases de dados e bibliotecas virtuais: U.S National Library of Medicine (PubMed), Biblioteca Virtual de Saúde (BVS) Scientific Eletronic Library Online (SciELO) e Literatura Latino-Americana e do Caribe em ciências da Saúde (LILACS), com o cruzamento dos descritores “Gravidez” & “Lítio”. Sete artigos foram selecionados para a pesquisa, e todos se encontravam em língua inglesa e na base de dados BVS. Resultados: Todos os autores utilizaram o público gestante e/ou seus filhos com a intervenção do lítio. Observou-se que apenas 28,57% (n=2) associaram o uso do medicamento com desfechos negativos para a população materno-fetal, e um deles associa ao transtorno bipolar, independente do uso da medicação. Já 71,42% (n=5) dos estudos validaram os seus efeitos proveitosos quando relacionado ao risco-benefício do uso do lítio. Considerações finais: Apesar dos dados apresentarem divergências, a maioria relata que a escolha para a terapêutica deve ser direcionada, dando importância a individualização do caso e mostrando segurança na terapêutica com o lítio. Além disso, confirma-se a escassez de estudos claros sobre o tratamento, necessitando de pesquisas mais aprofundadas.
Lithium has a clinical history for nearly 70 years. It is the first choice in the maintenance treatment of bipolar disorder (BD), as an augmentation agent in treatment-resistant unipolar depression, and has the unique property of proven anti-suicidal effects. Here we review the current state of evidence for lithium in the treatment of psychiatric disorders, especially in BD and unipolar depression. We also focus on specific treatment situations as rapid cycling, pregnancy, or age-associated circumstances. We will also discuss lithium’s proposed suicide-preventive effects, the risks of rapid discontinuation, and lithium’s adverse effects.
Mood-stabilizing medication is widely used in treating bipolar disorder. However, not for every phase of bipolar disorder, there is sufficient and recent evidence supporting the use of mood-stabilizing medication. Especially in bipolar depression and mixed episodes, published studies are still sparse. The same is true for potential treatment differences between bipolar I and bipolar II subtypes. We reviewed the most recent available guidelines on the treatment of bipolar disorder as well as the published clinical studies and report the evidence that is at hand for several mood stabilizers in the treatment of different phases and subtypes of bipolar disorder. Additionally, more women suffering from bipolar disorders wish to become pregnant and breastfeed their children. As in this area, there are no randomized controlled trials for ethical reasons; we shortly summarized the evidence that is at hand with a focus on risk for malformation and lactation from register and cohort studies, case series, and a few controlled studies.
Decision-making about pharmacotherapy of mental disorders during pregnancy and lactation is a source of uncertainty in clinical practice. Potentially deleterious effects of drugs on the fetus and the infant are much feared; but at the same time, negative impact of untreated mental disorder have to be taken into account. Discontinuation of long-term medication increases greatly the risk of a relapse, may worsen the course of illness, and results in poor overall outcome. Drug pharmacokinetics is markedly changed throughout the pregnancy and postpartum; thus, the dosage has to be adjusted appropriately. It should be emphasized that mental disorders alone have been associated with numerous pre-, peri-, and postnatal complications and adverse effects on the fetus and the infant. Therefore, not all negative outcomes can be attributed to the medication. All psychotropic drugs cross placental barrierPlacental barrier and pass into the maternal milk. The risk associated with drug treatment in pregnancy depends primarily on the period of exposure, gestational age. Teratogenic potentialTeratogenic potential is greatest during the first trimester, neurobehavioral effectsNeurobehavioral effects during the exposure in the last trimester, and withdrawal and intoxicationIntoxication with administration prior to the delivery. The chapter reviews available data on the risks and safety of antipsychotics, antidepressants, mood stabilizers, anxiolytics, hypnotics, and other psychopharmacological agents in pregnancy and nursing.
Both pregnancy and the postpartum period influence the course of bipolar disorder. Discontinuation of mood stabilizers is associated with increased risk of recurrences in pregnancy; however, there is also evidence that pregnancy has a positive effect on the course of bipolar disorder. During the postpartum period, women are at risk of recurrence as well as first onset of bipolar mood episodes. Management of bipolar disorder during these periods requires understanding of the course of treated and untreated illness, as well as the risks associated with the use of psychotropic drugs for the mother and the fetus or neonate. Peripartum management is further complicated by issues including diagnostic challenges, paucity of controlled pharmacologic or psychotherapeutic data, and concerns about the safety of psychotropic drugs during lactation.KeywordsPregnancyPostpartumPeripartumDepressionBipolarHypomaniaManiaPsychotropicDrugsPharmacotherapy
Background:
Lithium use during peripartum requires careful consideration due to a risk of teratogenic effects, adverse side effects and risk of neonatal complications. However, given the effectiveness of lithium, use during the peripartum period may be indicated.
Aim:
To provide an overview of the current evidence regarding the clinical use of lithium during peripartum, including risk of relapse in case of (dis)continuation and evolution of lithium levels.
Method:
A review was performed in the Medline and ScienceDirect database.
Results:
Ten studies were included. Six studies concerned the risk of relapse in case of (dis)continuation of lithium during the peripartum. Four studies concerned the evolution of lithium levels throughout the peripartum. Lithium discontinuation during pregnancy leads to an increased risk of relapse during pregnancy and postpartum. At the same dose, lithium levels are lower than preconceptual in all trimesters.
Conclusion:
Risk and benefits of lithium use during the peripartum should be carefully considered, if possible prior to conception. Close monitoring of maternal lithium levels and renal function is necessary due to significant fluctuations during peripartum.
Achtergrond: Lithiumgebruik tijdens het peripartum vergt een zorgvuldige afweging wegens het risico op teratogene effecten, het ongunstige bijwerkingenprofiel en het risico op neonatale complicaties. Gezien de effectiviteit van lithium kan het gebruik tijdens het peripartum evenwel geïndiceerd zijn. Doel: Overzicht bieden van de huidige evidentie betreffende het klinisch gebruik van lithium tijdens het peripartum, inclusief terugvalrisico in geval van (dis)continuatie en over het verloop van lithiumspiegels. Methode: Een literatuuronderzoek in de Medline-en ScienceDirect-database. Resultaten: Tien studies werden geïncludeerd. Zes studies betroffen het terugvalrisico in geval van (dis)continuatie van lithium tijdens het peripartum. Vier studies betroffen het verloop van lithiumspiegels gedurende het peripartum. Stoppen met lithium tijdens de zwangerschap leidt tot een verhoogd terugvalrisico tijdens zwangerschap en post partum. Bij eenzelfde dosis zijn de lithiumspiegels in alle trimesters lager dan preconceptioneel. Conclusie: Voor-en nadelen van lithiumgebruik tijdens het peripartum dient men nauwgezet te overwegen, indien mogelijk preconceptioneel. Nauwgezette controle van maternale lithiumspiegels en nierfunctie is noodzakelijk wegens belangrijke fluctuaties tijdens het peripartum.
Treatment of perinatal mood and anxiety disorders (PMADs) requires an individualized approach that considers the health and well-being of the mother, the infant, and the mother-infant relationship. The known risks of untreated illness are weighed against the potential risks and benefits of treatment. There are important pharmacologic considerations during pregnancy and lactation. This chapter will review use of medications, including sleep medications, selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), other antidepressants, benzodiazepines and other anti-anxiety medications, mood stabilizers, antipsychotics, and hormones for the treatment of PMADs. Other treatment modalities including repetitive trans-cranial magnetic stimulation (rTMS), electroconvulsive therapy (ECT), and the novel therapeutic agent, brexanolone, will also be discussed for PMADs. The benefits and risks of treatments during pregnancy and lactation as well as potential long-term effects will be addressed. Specifically, evidence regarding risks of teratogenicity, obstetric and neonatal complications, and long-term developmental outcomes will be reviewed. General lactation guidelines will also be included. Lastly, other treatment and diagnostic considerations will be reviewed, and a general treatment algorithm will be presented.
Perinatal mental illness is common, affecting up to 20% of women, but remains under‐recognised and under‐diagnosed. It may have adverse effects on pregnancy and neonatal outcomes, and mental disorder remains one of the leading causes of maternal death in the UK. Women with mental ill health face difficult decisions in balancing risks and benefits of treatment. Stigma related to mental disorder may lead to non‐engagement with maternity care. Some disorders bring specific challenges for anaesthetists working in maternity settings and it is vital that anaesthetists have knowledge of these disorders so they may offer care which is sensitive and appropriate.
Background
Lithium is especially taken as a maintenance medication for Bipolar Disorder. In women with bipolar disorder, lithium is often effective during postpartum period, but breast‐feeding for medicated mothers is controversial because of harmful effects for her child. At present, the biological mechanisms of lithium are not well understood, affecting its usage and overall health implications.
Procedure
We developed a rat lithium and breast‐feeding model at human therapeutic levels to study the effects of lithium exposure through breast‐milk on pups’ thyroid function. Novel laser analytical spectroscopy, along with traditional blood and immunohistochemical tests, were applied to further investigate the mechanisms behind the thyroid dysfunction. Maternal iodine supplementation was evaluated as a therapeutic method to address the pups’ thyroid dysfunction.
Results
Pups exposed to lithium via breastmilk, even with the dam on a sub‐therapeutic level, experienced weight gain, reduced blood thyroxine (T4), and elevated blood urea nitrogen, indicating effects on thyroid and kidney function. We show that lithium inhibited iodine uptake by thyroid follicles, initiating a mechanism that reduced iodination of tyrosine, thyroglobulin cleavage, and thyroid hormone production. Importantly, infant thyroid function can be significantly improved by administering supplementary iodine to the medicated dam’s diet during breast‐feeding.
Conclusion
These results elucidate the mechanisms of lithium in thyroid function, provide valuable information on use postpartum, and suggest a clinically‐applicable remedy to side‐effects. The results are particularly important for patients (and their infants) who respond well to lithium and need, or choose, to breast‐feed.
Objective:
Women with a history of bipolar disorder, postpartum psychosis, or both are at high risk for postpartum relapse. The aim of this meta-analysis was to estimate the risk of postpartum relapse in these three patient groups.
Method:
A systematic literature search was conducted in all public medical electronic databases, adhering to the PRISMA guidelines. Studies were included if they reported postpartum relapse in patients diagnosed with bipolar disorder and/or a history of postpartum psychosis or mania according to DSM or ICD criteria or the Research Diagnostic Criteria.
Results:
Thirty-seven articles describing 5,700 deliveries in 4,023 patients were included in the quantitative analyses. The overall postpartum relapse risk was 35% (95% CI=29, 41). Patients with bipolar disorder were significantly less likely to experience severe episodes postpartum (17%, 95% CI=13, 21) than patients with a history of postpartum psychosis (29%, 95% CI=20, 41). Insufficient information was available to determine relapse rates for patients with bipolar disorder and a history of postpartum episodes. In women with bipolar disorder, postpartum relapse rates were significantly higher among those who were medication free during pregnancy (66%, 95% CI=57, 75) than those who used prophylactic medication (23%, 95% CI=14, 37).
Conclusions:
One-third of women at high risk experience a postpartum relapse. In women with bipolar disorder, continuation of prophylactic medication during pregnancy appears highly protective for maintaining mood stability postpartum. In women with a history of isolated postpartum psychosis, initiation of prophylaxis immediately after delivery offers the opportunity to minimize the risk of relapse while avoiding in utero medication exposure.
Pharmacotherapy for mood disorders during pregnancy is often complicated by pregnancy-related pharmacokinetic changes and the need for dose adjustments. The objectives of this review are to summarize the evidence for change in perinatal pharmacokinetics of commonly used pharmacotherapies for mood disorders, discuss the implications for clinical and therapeutic drug monitoring (TDM), and make clinical recommendations.
The English-language literature indexed on MEDLINE/PubMed was searched for original observational studies (controlled and uncontrolled, prospective and retrospective), case reports, and case series that evaluated or described pharmacokinetic changes or TDM during pregnancy or the postpartum period.
Pregnancy-associated changes in absorption, distribution, metabolism, and elimination may result in lowered psychotropic drug levels and possible treatment effects, particularly in late pregnancy. Mechanisms include changes in both phase 1 hepatic cytochrome P450 and phase 2 uridine diphosphate glucuronosyltransferase enzyme activities, changes in hepatic and renal blood flow, and glomerular filtration rate. Therapeutic drug monitoring, in combination with clinical monitoring, is indicated for tricyclic antidepressants and mood stabilizers during the perinatal period.
Substantial pharmacokinetic changes can occur during pregnancy in a number of commonly used antidepressants and mood stabilizers. Dose increases may be indicated for antidepressants including citalopram, clomipramine, imipramine, fluoxetine, fluvoxamine, nortriptyline, paroxetine, and sertraline, especially late in pregnancy. Antenatal dose increases may also be needed for lithium, lamotrigine, and valproic acid because of perinatal changes in metabolism. Close clinical monitoring of perinatal mood disorders and TDM of tricyclic antidepressants and mood stabilizers are recommended.
To investigate the risks of adverse pregnancy and birth outcomes for treated and untreated bipolar disorder during pregnancy.
Population based cohort study using data from national health registers.
Sweden.
332 137 women with a last menstrual period anytime after 1 July 2005 and giving birth anytime before the end of 31 December 2009. Women with a record of at least two bipolar diagnoses were identified and grouped as treated (n=320)-those who had filled a prescription for mood stabilisers (lithium, antipsychotics, or anticonvulsants) during pregnancy-or untreated (n=554). Both groups were compared with all other women giving birth (n=331 263).
Preterm birth, mode of labour initiation, gestational diabetes, infants born small or large for gestational age, neonatal morbidity, and congenital malformations.
Of the untreated women, 30.9% (n=171) were induced or had a planned caesarean delivery compared with 20.7% (n=68 533) without bipolar disorder (odds ratio 1.57, 95% confidence interval 1.30 to 1.90). The corresponding values for the treated women were 37.5% (n=120) (2.12, 1.68 to 2.67). The risks of preterm birth in both treated and untreated women were increased by 50%. Of the untreated women, 3.9% (n=542) had a microcephalic infant compared with 2.3% (324 844) of the women without bipolar disorder (1.68, 1.07 to 2.62). The corresponding values for the treated women were 3.3% (n=311) (1.26, 0.67 to 2.37). Similar trends were observed for risks of infants being small for gestational age infants for weight and length. Among infants of untreated women, 4.3% (n=24) had neonatal hypoglycaemia compared with 2.5% (n=8302) among infants of women without bipolar disorder (1.51, 1.04 to 2.43), and 3.4% (n=11) of the treated women (1.18, 0.64 to 2.16). The analyses of variation in outcomes did not support any significant differences between treated and untreated women.
Bipolar disorder in women during pregnancy, whether treated or not, was associated with increased risks of adverse pregnancy outcomes.
Treatment of bipolar disorder with lithium therapy during pregnancy is a medical challenge. Bipolar disorder is more prevalent in women and its onset is often concurrent with peak reproductive age. Treatment typically involves administration of the element lithium, which has been classified as a class D drug (legal to use during pregnancy, but may cause birth defects) and is one of only thirty known teratogenic drugs. There is no clear recommendation in the literature on the maximum acceptable dosage regimen for pregnant, bipolar women. We recommend a maximum dosage regimen based on a physiologically based pharmacokinetic (PBPK) model. The model simulates the concentration of lithium in the organs and tissues of a pregnant woman and her fetus. First, we modeled time-dependent lithium concentration profiles resulting from lithium therapy known to have caused birth defects. Next, we identified maximum and average fetal lithium concentrations during treatment. Then, we developed a lithium therapy regimen to maximize the concentration of lithium in the mother's brain, while maintaining the fetal concentration low enough to reduce the risk of birth defects. This maximum dosage regimen suggested by the model was 400 mg lithium three times per day.
Introduction:
Untreated bipolar disorder during pregnancy leads to detrimental repercussions on the mother-infant pair's health. Despite different drugs having been proposed as mood stabilizers, lithium remains the first-choice agent for preventing mood changes.
Areas covered:
Analyzing up-to-date information on the reproductive safety of lithium and providing practice guidelines to optimize its use during pregnancy.
Expert opinion:
Findings from prospective and case-control studies confirm an increased, specific risk of Ebstein's anomaly (4.45-7.6/1000 live births), although lower than that previously reported. A potential increase in the risk of neural tube defects should also be taken into consideration. Moreover, several perinatal complications may occur, and even in the presence of relatively low infant serum levels, in the case of drug exposure during late pregnancy. Despite such concerns, lithium should still be considered the first-choice agent for treating bipolar disorder in pregnancy. Indeed, the U.S. FDA recently issued a new warning regarding the reproductive safety of antipsychotics. Moreover, the risk of fetal valproate/carbamazepine syndrome (and the confirmed neurodevelopmental teratogenicity of valproate) contraindicates the use of both medications, whereas the use of lamotrigine is limited by efficacy concerns. However, women who need lithium treatment during pregnancy should be carefully monitored: a strict gynecologic and psychiatric surveillance and, probably, preconception folate supplementation is highly advisable. Moreover, delivery should be programmed in Neonatal Intensive Care Units to ensure optimal management of potential iatrogenic perinatal complications.
The British Association for Psychopharmacology guidelines specify the scope and target of treatment for bipolar disorder. The second version, like the first, is based explicitly on the available evidence and presented, like previous Clinical Practice guidelines, as recommendations to aid clinical decision making for practitioners: they may also serve as a source of information for patients and carers. The recommendations are presented together with a more detailed but selective qualitative review of the available evidence. A consensus meeting, involving experts in bipolar disorder and its treatment, reviewed key areas and considered the strength of evidence and clinical implications. The guidelines were drawn up after extensive feedback from participants and interested parties. The strength of supporting evidence was rated. The guidelines cover the diagnosis of bipolar disorder, clinical management, and strategies for the use of medicines in treatment of episodes, relapse prevention and stopping treatment.
Pre-eclampsia is characterized by hypertension, proteinuria and edema. Simultaneous studies of kidney function and structure have not been reported. We wished to explore the degree and nature of glomerular dysfunction in pre-eclampsia.
Physiologic techniques were used to estimate glomerular filtration rate (GFR), renal plasma flow and afferent oncotic pressure immediately after delivery in consecutive patients with pre-eclampsia (PET; N = 13). Healthy mothers completing an uncomplicated pregnancy served as functional controls (N = 12). A morphometric analysis of glomeruli obtained by biopsy and mathematical modeling were used to estimate the glomerular ultrafiltration coefficient (Kf). Glomeruli from healthy female kidney transplant donors served as structural controls (N = 8).
The GFR in PET was depressed below the control level, 91 +/- 23 versus 149 +/- 34 ml/min/1.73 m2, respectively (P < 0.0001). In contrast, renal plasma flow and oncotic pressure were similar in the two groups (P = NS). A reduction in the density and size of endothelial fenestrae and subendothelial accumulation of fibrinoid deposits lowered glomerular hydraulic permeability in PET compared to controls, 1.81 versus 2.58 x 10(-9) m/sec/PA. Mesangial cell interposition also curtailed effective filtration surface area. Together, these changes lowered the computed single nephron Kf in PET below control, 4.26 versus 6.78 nl/min x mm Hg, respectively.
The proportionate (approximately 40%) depression of Kf for single nephrons and GFR suggests that hypofiltration in PET does not have a hemodynamic basis, but is a consequence of structural changes that lead to impairment of intrinsic glomerular ultrafiltration capacity.
Bipolar disorder affects 0.5%-1.5% of individuals in the United States. The typical age at onset is late adolescence or early adulthood, placing women at risk for episodes throughout their reproductive years. General guidelines for the treatment of bipolar disorder are available from the American Psychiatric Association, but additional issues arise when these guidelines are applied in the treatment of peripartum women. The authors summarize knowledge regarding the management of bipolar disorder during pregnancy and the postpartum period, with a focus on managing mania, hypomania, and the psychotic components of the illness.
An expert panel reviewed articles that address the management of bipolar disorder and the consequences of the use of mood stabilizers during pregnancy, and a consensus document was generated.
The treatment of bipolar disorder in pregnant women involves significant challenges. Some mood stabilizers, e.g., sodium valproate and carbamazepine, are human teratogens. On the other hand, the teratogenicity associated with lithium may have been overestimated in the past.
Since treatment can be managed most effectively if pregnancy is planned, clinicians should discuss the issue of pregnancy and its management with every bipolar disorder patient who has childbearing potential, regardless of future reproductive plans. Additional research should address the risks of disturbed sleep to pregnant and postpartum women with bipolar disorder, as well as structural and behavioral consequences to offspring when mood stabilizers are used during pregnancy. Longitudinal and cohort studies can promote these efforts. Given the rate of bipolar disorder in the general population, research efforts will need to be broad based and include multiple collaborating centers.
Much biomedical research is observational. The reporting of such research is often inadequate, which hampers the assessment of its strengths and weaknesses and of a study's generalisability. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Initiative developed recommendations on what should be included in an accurate and complete report of an observational study. We defined the scope of the recommendations to cover three main study designs: cohort, case–control and cross-sectional studies. We convened a 2-day workshop in September 2004, with methodologists, researchers, and journal editors to draft a checklist of items. This list was subsequently revised during several meetings of the coordinating group and in e-mail discussions with the larger group of STROBE contributors, taking into account empirical evidence and methodological considerations. The workshop and the subsequent iterative process of consultation and revision resulted in a checklist of 22 items (the STROBE Statement) that relate to the title, abstract, introduction, methods, results, and discussion sections of articles. 18 items are common to all three study designs and four are specific for cohort, case–control, or cross-sectional studies. A detailed Explanation and Elaboration document is published separately and is freely available on the websites of PLoS Medicine, Annals of Internal Medicine and Epidemiology. We hope that the STROBE Statement will contribute to improving the quality of reporting of observational studies.
Background: The Royal Australian and New Zealand College of Psychiatrists is co-ordinating the development of clinical practice guidelines (CPGs) in psychiatry, funded under the National Mental Health Strategy (Australia) and the New Zealand Health Funding Authority. Method: For these guidelines, the CPG team reviewed the treatment outcome literature (including meta-analyses) and consulted with practitioners and consumers. Treatment recommendations: This guideline provides evidence-based recommendations for the management of bipolar disorder by phase of illness, that is acute mania, mixed episodes and bipolar depression, and the prophylaxis of such episodes. It specifies the roles of various mood-stabilizing medications and of psychological treatments such as cognitive therapy and psycho-education.
Much biomedical research is observational. The reporting of such research is often inadequate, which hampers the assessment of its strengths and weaknesses and of a study's generalizability. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Initiative developed recommendations on what should be included in an accurate and complete report of an observational study. We defined the scope of the recommendations to cover 3 main study designs: cohort, case-control, and cross-sectional studies. We convened a 2-day workshop in September 2004, with methodologists, researchers, and journal editors, to draft a checklist of items. This list was subsequently revised during several meetings of the coordinating group and in e-mail discussions with the larger group of STROBE contributors, taking into account empirical evidence and methodological considerations. The workshop and the subsequent iterative process of consultation and revision resulted in a checklist of 22 items (the STROBE Statement) that relate to the title, abstract, introduction, methods, results, and discussion sections of articles. Eighteen items are common to all 3 study designs and 4 are specific for cohort, case-control, or cross-sectional studies. A detailed Explanation and Elaboration document is published separately and is freely available at www.annals.org and on the Web sites of PLoS Medicine and Epidemiology. We hope that the STROBE Statement will contribute to improving the quality of reporting of observational studies.
We review recent developments in the acute and long-term treatment of bipolar disorder and identify promising future routes to therapeutic innovation. Overall, advances in drug treatment remain quite modest. Antipsychotic drugs are effective in the acute treatment of mania; their efficacy in the treatment of depression is variable with the clearest evidence for quetiapine. Despite their widespread use, considerable uncertainty and controversy remains about the use of antidepressant drugs in the management of depressive episodes. Lithium has the strongest evidence for long-term relapse prevention; the evidence for anticonvulsants such as divalproex and lamotrigine is less robust and there is much uncertainty about the longer term benefits of antipsychotics. Substantial progress has been made in the development and assessment of adjunctive psychosocial interventions. Long-term maintenance and possibly acute stabilisation of depression can be enhanced by the combination of psychosocial treatments with drugs. The development of future treatments should consider both the neurobiological and psychosocial mechanisms underlying the disorder. We should continue to repurpose treatments and to recognise the role of serendipity. We should also investigate optimum combinations of pharmacological and psychotherapeutic treatments at different stages of the illness. Clarification of the mechanisms by which different treatments affect sleep and circadian rhythms and their relation with daily mood fluctuations is likely to help with the treatment selection for individual patients. To be economically viable, existing psychotherapy protocols need to be made briefer and more efficient for improved scalability and sustainability in widespread implementation.
Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Beaulieu S, Alda M, O’Donovan C, MacQueen G, McIntyre RS, Sharma V, Ravindran A, Young LT, Milev R, Bond DJ, Frey BN, Goldstein BI, Lafer B, Birmaher B, Ha K, Nolen WA, Berk M.
Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013.
Bipolar Disord 2012: 00: 000–000. © 2012 John Wiley & Sons A/S.Published by Blackwell Publishing Ltd.
The Canadian Network for Mood and Anxiety Treatments published guidelines for the management of bipolar disorder in 2005, with updates in 2007 and 2009. This third update, in conjunction with the International Society for Bipolar Disorders, reviews new evidence and is designed to be used in conjunction with the previous publications.The recommendations for the management of acute mania remain largely unchanged. Lithium, valproate, and several atypical antipsychotic agents continue to be first‐line treatments for acute mania. Monotherapy with asenapine, paliperidone extended release (ER), and divalproex ER, as well as adjunctive asenapine, have been added as first‐line options.For the management of bipolar depression, lithium, lamotrigine, and quetiapine monotherapy, as well as olanzapine plus selective serotonin reuptake inhibitor (SSRI), and lithium or divalproex plus SSRI/bupropion remain first‐line options. Lurasidone monotherapy and the combination of lurasidone or lamotrigine plus lithium or divalproex have been added as a second‐line options. Ziprasidone alone or as adjunctive therapy, and adjunctive levetiracetam have been added as not‐recommended options for the treatment of bipolar depression. Lithium, lamotrigine, valproate, olanzapine, quetiapine, aripiprazole, risperidone long‐acting injection, and adjunctive ziprasidone continue to be first‐line options for maintenance treatment of bipolar disorder. Asenapine alone or as adjunctive therapy have been added as third‐line options.
Lithium is a widely used and effective treatment for mood disorders. There has been concern about its safety but no adequate synthesis of the evidence for adverse effects. We aimed to undertake a clinically informative, systematic toxicity profile of lithium.
We undertook a systematic review and meta-analysis of randomised controlled trials and observational studies. We searched electronic databases, specialist journals, reference lists, textbooks, and conference abstracts. We used a hierarchy of evidence which considered randomised controlled trials, cohort studies, case-control studies, and case reports that included patients with mood disorders given lithium. Outcome measures were renal, thyroid, and parathyroid function; weight change; skin disorders; hair disorders; and teratogenicity.
We screened 5988 abstracts for eligibility and included 385 studies in the analysis. On average, glomerular filtration rate was reduced by -6·22 mL/min (95% CI -14·65 to 2·20, p=0·148) and urinary concentrating ability by 15% of normal maximum (weighted mean difference -158·43 mOsm/kg, 95% CI -229·78 to -87·07, p<0·0001). Lithium might increase risk of renal failure, but the absolute risk was small (18 of 3369 [0·5%] patients received renal replacement therapy). The prevalence of clinical hypothyroidism was increased in patients taking lithium compared with those given placebo (odds ratio [OR] 5·78, 95% CI 2·00-16·67; p=0·001), and thyroid stimulating hormone was increased on average by 4·00 iU/mL (95% CI 3·90-4·10, p<0·0001). Lithium treatment was associated with increased blood calcium (+0·09 mmol/L, 95% CI 0·02-0·17, p=0·009), and parathyroid hormone (+7·32 pg/mL, 3·42-11·23, p<0·0001). Patients receiving lithium gained more weight than did those receiving placebo (OR 1·89, 1·27-2·82, p=0·002), but not those receiving olanzapine (0·32, 0·21-0·49, p<0·0001). We recorded no significant increased risk of congenital malformations, alopecia, or skin disorders.
Lithium is associated with increased risk of reduced urinary concentrating ability, hypothyroidism, hyperparathyroidism, and weight gain. There is little evidence for a clinically significant reduction in renal function in most patients, and the risk of end-stage renal failure is low. The risk of congenital malformations is uncertain; the balance of risks should be considered before lithium is withdrawn during pregnancy. Because of the consistent finding of a high prevalence of hyperparathyroidism, calcium concentrations should be checked before and during treatment.
National Institute for Health Research Programme Grant for Applied Research.
Women with a history of bipolar disorder or postpartum psychosis are at extremely high risk of relapse postpartum. Although lithium prophylaxis has demonstrated efficacy in reducing postpartum relapse, the timing of prophylaxis remains controversial given the balance of risks and benefits for the mother and fetus. The authors compared lithium use during pregnancy to its initiation postpartum in women at high risk for postpartum psychosis.
Between 2003 and 2010, 70 pregnant women at high risk for postpartum psychosis were referred to the authors' psychiatric outpatient clinic. Women who were initially medication free were advised to start lithium prophylaxis immediately postpartum. Women already taking maintenance lithium during pregnancy were advised to continue treatment.
All women with a history of psychosis limited to the postpartum period (N=29) remained stable throughout pregnancy despite being medication free. Of the women with bipolar disorder (N=41), 24.4% relapsed during pregnancy, despite prophylaxis use by the majority throughout pregnancy. The postpartum relapse rate was highest in women with bipolar disorder who experienced mood episodes during pregnancy (60.0%). In contrast, none of the 20 women with a history of postpartum psychosis only who used postpartum prophylaxis relapsed, compared to 44.4% of patients with postpartum psychosis only who declined prophylaxis.
The authors recommend initiating prophylactic treatment immediately postpartum in women with a history of psychosis limited to the postpartum period, to avoid in utero fetal exposure to medication. Patients with bipolar disorder require continuous prophylaxis throughout pregnancy and the postpartum period to reduce peripartum relapse risk.
To undertake a systematic review of the effects of exposure to mood stabilizer medication in pregnancy, evaluating teratogenicity and other outcomes for mother and child. This was one of three concurrent systematic reviews of psychotropic medication exposure in pregnancy.
A systematic search was carried out of electronic databases, reference books and other sources for original research studies which examined the effects of commonly used mood stabilizers (sodium valproate, carbamazepine, lamotrigine and lithium carbonate) on pregnancy outcomes. These included malformations, pregnancy complications, neonatal complications and longer term developmental outcomes for children exposed.
All mood stabilizers were found to be associated with a risk of malformation and perinatal complications. Studies which examined longer term neurodevelopmental outcomes found poorer outcomes for those children exposed to sodium valproate or polytherapy in pregnancy than for other individual AEDs. The data available for longer term child outcomes with lithium exposure is too limited to draw any conclusions.
This review found that exposure in pregnancy to all four commonly used mood stabilizers may be teratogenic, and is associated with increased rates of pregnancy and neonatal complications. There was also more limited information that sodium valproate may be associated with poorer longer term child developmental outcomes. These findings must be balanced with the risk of relapse and poor pregnancy and child outcomes with untreated maternal bipolar disorder. The information obtained from these reviews of psychotropic medications will assist clinicians in managing women with mental illness in pregnancy.
The 143 cases of lithium use during pregnancy collected by the Register of Lithium Babies show that infants exposed to lithium appear to have a higher than expected ratio of cardiovascular anomalies to all anomalies and may have an increased risk of congenital heart disease. The authors believe that these findings justify a conservative policy on the use of lithium with fertile and pregnant women.
In recent years, lower serum levels have been recommended for maintenance therapy with lithium. We studied 94 patients with bipolar disorder in a randomized, double-blind, prospective trial of two different doses of lithium for maintenance therapy: the "standard" dose, adjusted to achieve a serum lithium concentration of 0.8 to 1.0 mmol per liter, and a "low" dose, resulting in a serum concentration of 0.4 to 0.6 mmol per liter. The group medians of the patients' average serum lithium levels were 0.83 mmol per liter for the patients in the standard-range group and 0.54 mmol per liter for those in the low-range group. Six of 47 patients (13 percent) assigned to receive lithium doses that would produce serum levels in the standard range had relapses while on protocol, as compared with 18 of 47 (38 percent) assigned to the low-dose range. The risk of relapse was 2.6 times higher (95 percent confidence interval, 1.3 to 5.2) among patients in the low-range group than among those in the standard-range group. Side effects, including tremor, diarrhea, urinary frequency, weight gain, and a metallic taste in the mouth, were more frequent in the standard-range group. We conclude that doses resulting in serum lithium levels from 0.8 to 1.0 mmol per liter are more effective in treating bipolar disorder than those that result in lower serum lithium concentrations, although the higher doses are associated with a higher incidence of side effects. Recent findings about the limited nephrotoxicity of lithium, along with our observations, suggest that physicians should attempt to maintain serum lithium levels between 0.8 and 1.0 mmol per liter in most patients with bipolar disorder and that they should attempt to enhance patients' understanding of and compliance with this regimen.
The side-effect profiles of daily vs. alternate-day lithium carbonate dosing schedule were compared in a double-blind study of 50 manic-depressive patients. Following a 3-month period on daily lithium maintenance treatment the patients were randomly allocated to daily or alternate-day lithium dosing aiming at maintaining the same 12-h serum concentration as prior to allocation (median 0.7 mmol/l). The daily and alternate-day median lithium doses were 700 mg and 1200 mg, respectively. There was no significant correlation between changes in the side-effect scores on the UKU side-effect rating scale and lithium dosing schedule (ordinal logistic regression), although analysis revealed a trend in favour of alternate-day dosing with respect to polyuria/polydipsia and diarrhoea (loose stool). The study thus lends no support to the hypothesis that lithium-related side-effects can be diminished by extending the interval between lithium doses from 1 to 2 days.
Lithium has been used during pregnancy for more than four decades, but quantification of fetal lithium exposure and clinical correlations of such exposure are limited. The study objectives were to 1) quantify the rate of lithium placental passage, 2) assess any association between plasma concentration of lithium at delivery and adverse perinatal events, and 3) determine whether lithium concentrations can be reduced by briefly suspending therapy proximate to delivery.
Maternal blood and umbilical cord blood were obtained at delivery for assay of lithium concentrations, and obstetrical outcome data were collected prospectively for 10 participants. These data were combined with results from MEDLINE and PsycINFO searches that identified 32 cases in which maternal lithium was administered throughout delivery. Statistical analysis of the pooled data was conducted.
The ratio of lithium concentrations in umbilical cord blood to maternal blood (mean=1.05, SD=0.13) was uniform across a wide range of maternal concentrations (0.2-2.6 meq/liter). Significantly lower Apgar scores, longer hospital stays, and higher rates of CNS and neuromuscular complications were observed in infants with higher lithium concentrations (>0.64 meq/liter) at delivery. Withholding lithium therapy for 24-48 hours before delivery resulted in a 0.28 meq/liter reduction in maternal lithium concentration.
Lithium completely equilibrates across the placenta. Higher lithium concentrations at delivery are associated with more perinatal complications, and lithium concentrations can be reduced by brief suspension of therapy proximate to delivery. Treatment guidelines are proposed to improve neonatal well-being when lithium use is indicated in late pregnancy.
Lithium, carbamazepine and valproate are established human teratogens. Women of childbearing potential who are prescribed these drugs should be informed of their teratogenic potential and advised of the need for adequate contraception and the protective role of folate. We reviewed the clinical records of all women of childbearing age in long-term contact with one specialist mental health Trust providing services for a total population of 750,000. One hundred and thirty eight (16%) of 837 women of childbearing age were prescribed one or more of these drugs. There was documented evidence that 29 (21%) of these women had been informed about teratogenicity and that 33 (24%) had been advised about contraception. Fourteen women (10%) had a confirmed pregnancy while taking lithium, carbamazepine or valproate; eight had a complication of pregnancy. If prescribing practice in this large mental health Trust were typical of the UK, between 7000 and 11 000 women of childbearing potential would be prescribed lithium, carbamazepine or valproate by psychiatrists without documented discussion of the risks.
There is substantial uncertainty about the most efficacious serum lithium level for the long-term treatment of bipolar disorder (BD). This review focuses on the available evidence taking into consideration the effects of previous lithium history, changes in lithium level and polarity of relapse or recurrence.
We conducted a MEDLINE search, using the MeSH Terms 'bipolar disorder' and 'lithium' together with 'randomized controlled trial' or 'controlled clinical trial' covering the time span from 1966 to March 2006. We only included studies reporting on the long-term treatment of mood disorders where patients with BD were examined as a separate group and were assigned to precisely specified target ranges of lithium level.
The minimum efficacious serum lithium level in the long-term treatment of bipolar disorder was 0.4 mmol/L with optimal response achieved at serum levels between 0.6-0.75 mmol/L. Lithium levels >0.75 mmol/L may not confer additional protection against overall morbidity but may further improve control of inter-episode manic symptoms. Abrupt reduction of serum levels of more than 0.2 mmol/L was associated with increased risk of relapse.
In the long-term treatment of bipolar disorder clinicians should initially aim for serum lithium levels of 0.6-0.75 mmol/L, while higher levels may benefit patients with predominantly manic symptoms.
A 39-year-old gravida 8, para 6 woman at 34 weeks of a twin gestation was admitted to the antenatal ward with severe agitation and restlessness. She had a history of unstable bipolar disorder for which she was treated with lithium. Before admission she had been under close supervision by psychiatric and obstetric teams and lithium levels had been stable. However, an acute deterioration in renal function secondary to ureteric obstruction resulted in toxic plasma lithium levels and associated clinical features. An emergency caesarean section was carried out under general anaesthesia. We provide a review of the current literature including: the pharmacology of lithium, the effects of lithium on fetus and mother, and the current guidelines for management of lithium treatment during pregnancy. Lithium is prescribed relatively rarely during pregnancy. We aim to increase awareness about the issues involved in the management of women receiving lithium during pregnancy.
Lithium dosing strategies during pregnancy and the postpartum period
- Data
- Wesseloo
Data supplement to Wesseloo et al. Lithium dosing strategies during pregnancy
and the postpartum period. Br J Psychiatry doi: 10.1192/bjp.bp.116.192799
10.1192/bjp.bp.116.192799