Management of Lithium Dosing Around Delivery: An Observational Study.

Objectives: Recommendations on lithium dosing around delivery vary, with several guidelines suggesting that lithium should be discontinued prior to delivery. We aimed to evaluate the validity of these recommendations by investigating 1) maternal lithium blood level changes following delivery, and 2) the association between neonatal lithium blood levels at delivery and neonatal outcomes. Methods: In this retrospective observational cohort study, we included women with at least one lithium blood level measurement during the final week of pregnancy and the first postpartum week. For aim 2, we included a subcohort of women with neonates for whom neonatal lithium blood levels (obtained from the umbilical cord or a neonatal vein puncture within 24 hours of delivery) were available. Results: There were a total of 233 maternal lithium blood level measurements; 55 (23.6%) in the week before delivery and 178 (76.4%) in the week after. There was no association between time and lithium blood level/dose ratio (Pearson correlation coefficient -0.03, P = .63). Additionally, we included a total of 29 neonates for whom a lithium measurement was performed within 24 hours postpartum. Maternal and neonatal lithium blood levels were strongly correlated. We observed no associations between neonatal lithium blood levels at delivery and neonatal outcomes. Conclusion: Based on our findings, we do not recommend lowering the dosage or discontinuation of lithium prior to delivery. Stable dosing can prevent subtherapeutic lithium serum levels, which is especially important in the postpartum period when relapse risks are highest.Appeared originally in Bipolar Disord 2021; 23:49-54.

Dose response relationship between lithium serum levels during pregnancy and birth outcomes.

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.

Management of lithium dosing around delivery: An observational study.

OBJECTIVES: Recommendations on lithium dosing around delivery vary, with several guidelines suggesting that lithium should be discontinued prior to delivery. We aimed to evaluate the validity of these recommendations by investigating 1) maternal lithium blood level changes following delivery, and 2) the association between neonatal lithium blood levels at delivery and neonatal outcomes. METHODS: In this retrospective observational cohort study, we included women with at least one lithium blood level measurement during the final week of pregnancy and the first postpartum week. For aim 2, we included a subcohort of women with neonates for whom neonatal lithium blood levels (obtained from the umbilical cord or a neonatal vein puncture within 24 hours of delivery) were available. RESULTS: There were a total of 233 maternal lithium blood level measurements; 55 (23.6%) in the week before delivery and 178 (76.4%) in the week after. There was no association between time and lithium blood level/dose ratio (Pearson correlation coefficient -0.03, P = .63). Additionally, we included a total of 29 neonates for whom a lithium measurement was performed within 24 hours postpartum. Maternal and neonatal lithium blood levels were strongly correlated. We observed no associations between neonatal lithium blood levels at delivery and neonatal outcomes. CONCLUSION: Based on our findings, we do not recommend lowering the dosage or discontinuation of lithium prior to delivery. Stable dosing can prevent subtherapeutic lithium serum levels, which is especially important in the postpartum period when relapse risks are highest.

Lithium exposure during pregnancy increases fetal growth.

BACKGROUND: Lithium is an effective treatment in pregnancy and postpartum for the prevention of relapse in bipolar disorder, but there is a lack of knowledge about the potential adverse impact on fetal development. AIMS: To investigate the impact of lithium exposure on early fetal growth. METHODS: In this retrospective observational cohort study, we included all singleton pregnancies of women using lithium and referred for advanced fetal ultrasound scanning between 1994 and 2018 to the University Medical Centers in Leiden and Rotterdam, the Netherlands (n=119). The Generation R study, a population-based cohort, served as a non-exposed control population from the same geographic region (n=8184). Fetal head circumference, abdominal circumference, femur length, and transcerebellar diameter were measured by ultrasound at 18-22 weeks of gestation. RESULTS: Lithium use during pregnancy was associated with an average increase in head circumference of 1.77 mm (95% confidence interval: 0.53, 3.01), in abdominal circumference of 5.54 mm (95% confidence interval: 3.95, 7.12) and in femur length of 0.59 mm (95% confidence interval: 0.22, 0.96) at 18-22 weeks gestation. Furthermore, lithium use during pregnancy was associated with an average increase in birth weight of 142.43 grams (95% confidence interval: 58.01, 226.89), whereas it was associated with an average decrease of 1.41 weeks in gestational duration (95% confidence interval: -1.78, -1.05). CONCLUSIONS: Lithium use during pregnancy was associated with increased fetal growth parameters at 18-22 weeks gestational age and increased birth weight. Further research is needed to evaluate both short- and long-term implications, as well as the mechanisms driving this difference in growth.

Maternal and infant outcomes associated with lithium use in pregnancy: an international collaborative meta-analysis of six cohort studies.

BACKGROUND: Concerns about teratogenicity and maternal and offspring complications restrict the use of lithium during pregnancy for the treatment of mood disorders. We aimed to investigate the association between in-utero lithium exposure and risk of pregnancy complications, delivery outcomes, neonatal morbidity, and congenital malformations. METHODS: In this meta-analysis, primary data from pregnant women and their children from six international cohorts based in the community (Denmark, Sweden, and Ontario, Canada) and in clinics (the Netherlands, UK, and USA) were analysed. Pregnancies were eligible for analysis if the pregnancy resulted in a liveborn singleton between 1997 and 2015, if health-related information was available for both mother and infant, and if the mother had a mood disorder (bipolar disorder or major depressive disorder) or if she had been given lithium during pregnancy (at least two dispensations of lithium during pregnancy that were dispensed any time from 1 month before conception until the delivery, or a single lithium dispensation during pregnancy when there was at least one other lithium dispensation within 6 months before or after this date). Pregnancies during which the mother had been prescribed known teratogenic drugs were excluded. Pregnancies were grouped into a lithium-exposed group and a mood disorder reference group. The main outcome measures were pregnancy complications, delivery outcomes, neonatal readmission to hospital within 28 days of birth, and congenital malformations (major malformations and major cardiac malformations). Analyses were done at each site by use of a shared protocol. Adjusted odds ratios (aORs) and 95% CIs were calculated by use of logistic regression models, and site-specific prevalence rates and ORs were pooled by use of random-effects meta-analytical models. FINDINGS: 22   124 eligible pregnancies were identified across the six cohorts, of which 727 pregnancies were eligible for inclusion in the lithium-exposed group (557 [77%] from register-based cohorts and 170 [23%] from clinical cohorts). Lithium exposure was not associated with any of the predefined pregnancy complications or delivery outcomes. An increased risk for neonatal readmission within 28 days of birth was seen in the lithium-exposed group compared with the reference group (pooled prevalence 27·5% [95% CI 15·8-39·1] vs 14·3% [10·4-18·2]; pooled aOR 1·62, 95% CI 1·12-2·33). Lithium exposure during the first trimester was associated with an increased risk of major malformations (pooled prevalence 7·4% [95% CI 4·0-10·7] vs 4·3% [3·7-4·8]; pooled aOR 1·71, 95% CI 1·07-2·72) but for major cardiac malformations the difference was not significant (2·1% [0·5-3·7] vs 1·6% [1·0-2·1]; pooled aOR 1·54, 95% CI 0·64-3·70). INTERPRETATION: Considering both the effect sizes and the precision of the estimates in this meta-analysis, treatment decisions for pregnant women with mood disorders must weigh the potential for increased risks of lithium during pregnancy-in particular those associated with use of lithium during the first trimester-against its effectiveness at reducing relapse. FUNDING: None.

Thyroid peroxidase antibodies during early gestation and the subsequent risk of first-onset postpartum depression: A prospective cohort study.

BACKGROUND: During the postpartum period, women are at risk for the new onset of both auto-immune thyroid disorders and depression. The presence of thyroid peroxidase antibodies (TPO-ab) during early gestation is predictive for postpartum auto-immune thyroid dysfunction. The aim of this study was to investigate the association between TPO-ab status during early gestation and first-onset postpartum depression. METHODS: Prospective cohort study (n = 1075) with follow-up during pregnancy up to one year postpartum. Thyroid function and TPO-ab status were measured during early gestation. Depressive symptomatology was assessed during each trimester and at four time points postpartum with the Edinburgh Depression Scale (EDS). Women with antenatal depression were not eligible for inclusion. Self-reported postpartum depression was defined with an EDS cut-off of ≥ 13. RESULTS: The cumulative incidence of self-reported first-onset depression in the first postpartum year was 6.3%. A positive TPO-ab status was associated with an increased risk for self-reported first-onset depression at four months postpartum (adjusted OR 3.8; 95% CI 1.3-11.6), but not at other postpartum time points. Prevalence rates of self-reported postpartum depression declined after four months postpartum in the TPO-ab positive group, but remained constant in the TPO-ab negative group. LIMITATIONS: Depression was defined with a self-rating questionnaire (EDS). CONCLUSIONS: Women with an increased TPO-ab titer during early gestation are at increased risk for self-reported first-onset depression. The longitudinal pattern of self-reported postpartum depression in the TPO-ab positive group was similar to the typical course of postpartum TPO-ab titers changes. This suggests overlap in the etiology of first-onset postpartum depression and auto-immune thyroid dysfunction. Thyroid function should be evaluated in women with first-onset postpartum depression.

Phenotypical characteristics of postpartum psychosis: A clinical cohort study.

OBJECTIVES: Postpartum psychosis (PP) is known for its clear onset but its phenotype has never been clearly described in a cohort. The aim of this study was to describe PP symptomatology, and to identify subgroups of patients based on symptom profiles. METHODS: We prospectively assessed a wide range of symptoms in cases of PP in a cohort of women (N=130) admitted to the Mother-Baby inpatient unit. Using a person-centered analytic approach, we distinguished mutually exclusive subgroups of women. Subgroups were related to demographic and clinical characteristics. RESULTS: The most prevalent symptoms of PP were irritability (73%), abnormal thought content (72%), and anxiety (71%). Suicidal and infanticidal ideation was present in 19% and 8% of patients, respectively. Delusions and hallucinations often had a negative content. Latent class analysis revealed three symptom profiles, a manic (34%), depressive (41%) and atypical (25%) profile, respectively. The manic profile is characterized by manic symptoms and agitation, the depressive profile by depressive and anxiety symptoms, and the atypical profile by disturbance of consciousness and disorientation. In women with a depressive profile, treatment was started 2 weeks later (P=.049), and more often voluntarily, than in manic and atypical women (P=.037). CONCLUSIONS: We distinguished subgroups of PP patients with a manic, depressive, and atypical profile. Disturbance of consciousness, disorientation, and depersonalization/derealization were less prevalent than previously suggested in the literature. Instead, the depressive profile was the most prevalent, but the depressive profile can easily remain undetected, which could lead to treatment delay and risk of suicide/infanticide. Within the manic profile, irritability was highly prevalent and occurred more often than elevated mood.

Lithium dosing strategies during pregnancy and the postpartum period.

BackgroundLithium is challenging to dose during pregnancy.AimsTo provide guidance for dosing lithium during pregnancy.MethodRetrospective 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.ConclusionsWe 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.

Risk of postpartum episodes in women with bipolar disorder after lamotrigine or lithium use during pregnancy: A population-based cohort study.

BACKGROUND: Women with bipolar disorder are at high risk for relapse/recurrence postpartum. Among all mood stabilizers, lithium has the largest evidence base for efficacy in the peripartum period, but lamotrigine is increasingly prescribed for bipolar spectrum disorders during pregnancy. The aim of this study was to investigate whether lamotrigine use during pregnancy is as effective as lithium in the prevention of severe episodes postpartum. METHODS: Danish national registries were used to identify pregnancies of women with a diagnosis of bipolar spectrum disorders at the time of conception who used lamotrigine or lithium during pregnancy. We compared the risk of inpatient psychiatric admission within three months postpartum between women who used lamotrigine (N=55) versus lithium (N=59) during pregnancy. A logistic regression model was used to calculate crude and adjusted odds ratios. RESULTS: We did not find a significant difference in the risk of postpartum psychiatric admission between women who used lamotrigine versus lithium during pregnancy (7.3% versus 15.3% respectively, adjusted OR 0.83; 95% CI 0.22-3.14). We adjusted for year of delivery, parity, previous admissions and antidepressant/benzodiazepine use during pregnancy. Other variables did not differ substantially between groups. LIMITATIONS: We used an observational design and therefore patients were not randomized to lamotrigine or lithium. The study has a small sample size. CONCLUSIONS: Lamotrigine was not inferior to lithium in the prevention of severe postpartum episodes. Our findings suggest lamotrigine could be a reasonable alternative treatment option for bipolar disorder during pregnancy in patients with vulnerability for depression and may prevent severe episodes postpartum.

Risk of Postpartum Relapse in Bipolar Disorder and Postpartum Psychosis: A Systematic Review and Meta-Analysis.

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.