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Is lithium a real teratogen? What can we conclude from the prospective versus retrospective studies? A review
Abstract
Lithium is a drug used mainly for the treatment of Bipolar Disorder (BD). Case reports and several retrospective studies have demonstrated possible teratogenicity, but the data in the different studies was inconclusive.
We summarized all published studies in English, including case reports.
We found 24 case reports, of which six infants had congenital anomalies, five having cardiac anomalies, one of them being Ebstein's anomaly. In the retrospective studies there were, in the Lithium Baby Registry, 225 registered cases with 25 anomalies, 18 of them being cardiac, of which six had Ebstein's anomaly. An additional retrospective study on 59 cases found seven anomalies, four of them being cardiac. On the other hand, none of the prospective studies (296 liveborn infants) demonstrated any increase in the rate of congenital anomalies, although two had Ebstein's anomaly. All case control studies regarding Ebstein's anomaly were negative, and among 222 infants with Ebstein's anomaly and 44 with tricuspid atresia none of the mothers had taken lithium during pregnancy.
Considering the serious limitations of the retrospective and case control studies that are also retrospective, lithium does not seem to be a significant teratogen, and hence should be given, if indicated, in pregnancy. It is, however, advisable to perform a fetal echocardiography to exclude the possibility of cardiac anomalies. Lamotrigine seems to be a possible alternative.
... Lityum plasentadan fetüse geçer, ancak fetüsün böbrek gelişimi yeterli olmadığı için annenin serum lityum düzeyleri terapötik düzeyde bile olsa fetal serum lityum düzeyi toksik düzeylere çıkabilir. Doğumdan önceki 36-48 saatte annenin kullandığı lityum dozu en azından yarıya, mümkünse dörtte bire düşürülmediği takdirde ise bebekte lityum entoksikasyonu bulguları gözlenebilir (68). İlk üç ayda lityuma maruz kalan bebeklerdeki olumsuz etkiler, 1968'de "Lityum Bebek Kayıtları" başlığı altında yayınlanmıştır. ...
... İngiltere Ulusal Teratoloji Bilgi Servisi'ne göre lityum tüm konjenital malformasyonları üç kat, kardiyak anomalileri ise sekiz kat arttırmaktadır (70)(71)(72). Bunlara karşılık gebelikte lityum kullanımının teratojenite ile bağlantısını değerlendiren sistematik derlemede ise lityumun majör kardiyak malformasyon görülme riskini arttırmadığı bildirilmiştir (68). ...
... Lityum kullanımının yol açtığı diğer komplikasyonları arasında prematür doğum, yüksek/ düşük doğum kilosu, nefrojenik diabetes insipidus, gevşek bebek sendromu (siyanoz ve hipotoni) ile yenidoğanda geçici nörogelişimsel defektler, reflekslerde azalma, apne ve dispne, bradikardi, tiroid işlev bozuklukları, v.b. sayılabilir (68,69). Newport ve arkadaşları tarafından yapılan ilginç bir çalışmada (73); lityum gebeliğin geç döneminde kullanılırsa, düşük Apgar skorları, uzun süre hastanede kalma ve merkezi sinir sistemi ve nöromüsküler yan etkiler gibi neonatal komplikasyonlar için hatırı sayılır risk bulunmuştur. ...
Pregnancy is a turbulent period, during which hormonal and psychosocial lifestyle changes occur. Hence depression, anxiety disorders, or obsessive-compulsive disorders can be triggered and chronic psychiatric disorders can be exacerbated, particularly, due to limitations on the use of psychotropic drugs. Considering a large percentage of pregnancies are not planned, overcoming these challenges creates difficulties for both the pregnant women and the team providing health care services. There are contradictory findings about the safety of psychotropic drugs and their use in the treatment of psychiatric disorders during pregnancy. The benefits and risks of psychopharmacological treatment during pregnancy should be considered carefully. When psychotropic drugs are given to pregnant women they easily reach fetüs, as there are no barriers between maternal and placental blood. Generally higher serum drug levels are detected in newborns than in maternal serum. Therefore in deciding on psychotropic drug use during pregnancy, the risks of neonatal toxicity, premature and still births, and morphological and behavioral teratogenicity must be taken into account. In addition not only anatomical malformations, but also long-term behavioral teratogenicity of the drugs must be considered while evaluating the safety of drug use during pregnancy. The classical antipsychotics and tricyclic antidepressants (except chlomipramine) are relatively safe for the fetus. Antidepressant use is associated with the risk of anomalies during almost all of the prenatal period; however, the risk appears to be especially increased in fetüses that have been exposed to paroxetine and chlomipramine. There are significant findings that many atypical antipschotics cause an increase in the rate of fetal malformations by provoking gestational diabetes. Therefore, women who wish to become pregnant, who have been on ongoing atypical antipsychotic treatment before pregnancy, should always be switched to conventional antipsychotics upon the beginning of pregnancy. Benzodiazepines used during the first trimester can be teratogenic and can cause withdrawal symptoms in high doses in newborns, hypotonia, and agitation. The mood stabilizers (carbamazepine, valproate, similar anticonvulsants, and lithium) have been known to possess high teratogenic risk for a long time. However, the teratogenicity risk for lithium has recently been decreased. On the other hand, the use of valproate during pregnancy has a strong association with the risk of fetal abnormalities and autism-spectrum disorders. For these reasons, the uses of clomipramine, paroxetine, valproate, and atypical antipsychotics are recommended to be avoided during pregnancy. If there is a need for long-term use of psychotropic drugs during pregnancy, a full assessment should be conducted, polypharmacy and unnecessary medication use should be avoided, and the doses of psychotropic drugs should be kept to a minimum, because there are rarely valid reasons to discontinue medications that are necessary during pregnancy. In this paper, we aimed to update psychotropic drug use during pregnancy, an important and common issue in daily psychiatry practice, in the light of recent data.
... An increased rate of preterm birth, macrosomia [11], and perinatal mortality has been reported among lithium exposed pregnancies [12]. Moreover, an association between perinatal complications and plasma level of lithium at delivery have been reported in literature. ...
... A recent review confirmed what was previously reported, showing an association between lithium exposure and an increased risk for birth complications including preterm birth, hypotonia and respiratory distress [13]. Renal disfunction such as nephrogenic diabetes insipidus and thyroid toxicity have also been reported [11]. In a prospective multicentre study Jacobson and colleagues found that lithium exposed infants weighed a mean of 92 g more than controls at birth (p=0.01), while gestational age did not differ between the groups (p=0.56) ...
... The authors evaluated four case-control studies involving 25, 34, 59 and 89 Ebstein's anomaly affected children finding no history of lithium exposure [18]. Similar findings were reported in two recent reviews [11], [13]. On the other hand, a recent review confirmed the association between lithium exposure during pregnancy and cardiac defect Ebstein's anomaly [17]. ...
The purpose of this review is to give useful information to guide clinicians when treating pregnant women affected by bipolar disorder. This review focuses on mood stabilizers including lithium, sodium valproate, carbamazepine, oxcarbazepine, gabapentin, lamotrigine and topiramate. Data have been extracted from a MEDLINE search. Data from prospective,
retrospective and case-control studies as well as systematic reviews, meta-analysis and data from Pregnancy Registry were included. Major congenital malformations as well as specific
malformations were reported for each drug. Preliminary findings seem to identify lamotrigine as one of the safest antiepileptic drugs to be used in pregnancy. Teratogenity risk of topiramate
is still largely unknown and there are not enough studies to draw even preliminary conclusions. Preliminary studies failed to report an increased risk for major congenital malformations among gabapentin or oxcarbazepine exposed pregnancies. Even if raising less concern when compared to valproate, carbamazepine should be avoided for its documented teratogenity
risk. Valproate seems to be the worst considering major congenital malformations, specific malformations as well as its detrimental effects on neurodevelopment. On the other hand,
lithium might be considered a good option when treating pregnant women affected by bipolar disorder. Given the limited research on mood stabilizers in pregnancy, clinicians need to be very careful when treating child bearing age women. Clinicians have to balance the potential teratogenity risk against that of untreated mental illness considering individual circumstances such as severity of illness and risk of relapse.
... 99 A systematic review of information about the risk of major congenital malformations with in utero exposure to lithium concluded that lithium should not be considered a major human teratogen based on reports published between 1969 and 2005, and that lithium should be administered to pregnant women if indicated. 100 However, the authors also recommended due caution and supported existing recommendations for performing fetal echocardiography to exclude the possibility of cardiac malformations. ...
... Exposure to lithium late in pregnancy has been associated with development of a neonatal adaptation syndrome characterized by hypotonicity, muscle twitching, respiratory and feeding difficulties, cardiac arrhythmias, cyanosis, poor suck, grasp, and Moro reflexes, and lethargy. [100][101][102][103] The syndrome resolves in 1-2 weeks, and usually without further complication; 103 however, intensive neonatal monitoring and longer hospital stays may be required. 103 A small case series of 32 pregnancies during which lithium was administered throughout delivery documented low Apgar scores, longer hospital stays, and higher rates of central nervous system and neuromuscular complications in infants with higher lithium concentrations at delivery (.0.64 mEq/L). ...
... These include reversible hypothyroidism, nontoxic goiter, nephrogenic diabetes insipidus, and hypoglycemia. 100,[104][105][106][107] The potential effects of maternal lithium use on birth weight were investigated in a prospective cohort study of 148 women with first-trimester lithium use, which consulted teratogen information centers in the US and Canada. 95 Compared with matched controls, infant birth weight was significantly higher in lithium-exposed infants than control infants (3,475 g versus 3,383 g) despite identical gestational ages. ...
Treating pregnant women with bipolar disorder is among the most challenging clinical endeavors. Patients and clinicians are faced with difficult choices at every turn, and no approach is without risk. Stopping effective pharmacotherapy during pregnancy exposes the patient and her baby to potential harms related to bipolar relapses and residual mood symptom-related dysfunction. Continuing effective pharmacotherapy during pregnancy may prevent these occurrences for many; however, some of the most effective pharmacotherapies (such as valproate) have been associated with the occurrence of congenital malformations or other adverse neonatal effects in offspring. Very little is known about the reproductive safety profile and clinical effectiveness of atypical antipsychotic drugs when used to treat bipolar disorder during pregnancy. In this paper, we provide a clinically focused review of the available information on potential maternal and fetal risks of untreated or undertreated maternal bipolar disorder during pregnancy, the effectiveness of interventions for bipolar disorder management during pregnancy, and potential obstetric, fetal, and neonatal risks associated with core foundational pharmacotherapies for bipolar disorder.
... Lithium is useful in the treatment of the psychiatric condition of bipolar disorder/manic depression [5]. Lithium salts may also be helpful for related diagnoses, such as schizoaffective disorder and cyclic major depression. ...
... The active part of these salts is the lithium ion Li + [4]. It has been reported that lithium may increase the risk of developing Ebstein's cardiac anomaly in infants born to women who take lithium during the first trimester of pregnancy [5]. The most exciting results for lithium are its reported non--psychiatric medical effects that are centered on the ion's ability to influence the proliferation of stem cells first identified from hematopoietic tissues [6,7]. ...
Lithium (Li) salts have been widely used in psychiatry as mood stabilizing agents for 60 years. Li found in variable amounts in foods, especially grains, vegetables, and in some areas, the drinking water provides a significant source of the element. Therefore, dietary intake in humans depends on location, type of foods consumed, and fluid intake. Traces of Li have been detected in human organs and tissues, leading speculation that the element was responsible for specific functions in the human body. It was not until the 20th century that studies performed in the 1970's and 1990's, primarily in rats and goats, maintained on Li-deficient diets demonstrated higher mortality, altered reproductive and behavioral abnormalities. Such deficiencies have not been detected in humans; however, studies performed on populations living in areas with low Li levels in water supplies have been associated with higher rates of suicides, homicides, and the arrests rate for drug abuse and other crimes. Li appears to play a significant role in early fetal development as evidenced by high Li levels during the early gestational period. Biochemically, the mechanism of Li action involves multifactor and interconnected pathways with enzymes, hormones, vitamins, and growth and transforming factors. This body of evidence now appears sufficient to label Li as an essential element with the recommended RDA for a 70 kg adult of 1000 mg/day. Of extreme importance for the future is the growing body of evidence indicating Li can be used effectively for the treatment of acute brain injuries, e.g., ischemia and chronic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Tauopathies, and Huntington's disease. This conclusion is based upon evidence showing Li as important in neurogenesis as well as protecting neurons from neurotoxicity. Li influences stem cells, both neuronal and marrow derived, thus additional therapeutic implications for this element in clinical medicine to treat disorders associated with the faulty production of blood and nerve cells or as a tool to enhance blood stem cell mobilization for transplantation.
... 28 On the other hand, a relatively recent review mentioned that it would not contribute to the risk of major malformations. 29 In the literature, complications that are uttered to be linked with lithium use during pregnancy are listed as preterm birth, high birth weight, nephrogenic diabetes insipidus, hydramnios, floppy baby syndrome, transient neurodevelopmental defects, poor newborn reflexes, apnea and respiratory distress, feeding difficulties, bradycardia, thyroid dysfunctions, and low birth weight. High-resolution ultrasonography and fetal echocardiography are recommended for expectant mothers using lithium between 16-20 weeks of pregnancy. ...
While psychotherapy is often preferred in treating mild psychiatric disorders, drug and other non-drug options are adopted in treating moderate and severe conditions during pregnancy. In addition, cognitive behavioral therapy (CBT) has become prominent among psychotherapies. Regarding antidepressants, Sertraline, Citalopram, and Escitalopram are recommended as the first choices. Benzodiazepines are not recommended unless necessary; they are prescribed in the minimum dose and duration if highly needed. Mood stabilizers are considered risky and should be carefully used. Moreover, the expectant mother should be required for fetal follow-up more frequently and in detail when such drugs are prescribed. The safest among them is considered Lamotrigine. If antipsychotics are to be prescribed, the expectant mother�s blood glucose, weight, and blood pressure should be followed up frequently. Due to the possible side effects to occur in the infant following delivery, antipsychotics may be considered to be discontinued immediately before birth and restarted after delivery. It is argued that there is no notable difference between the first and second generations. Besides, electroconvulsive therapy (ECT) is recommended in cases of suicidal depression, manic attack, psychotic attack, and catatonia where rapid response is required. Although promising results were previously reported about transcranial magnetic stimulation (TMS) and bright light therapy, their utilization areas are still limited.
... Actualmente se considera que la evidencia que sustentaba la teratogenicidad del litio es débil y se consolidó la noción de que el riesgo fue sobreestimado (Yacobi y Ornoy, 2008;McKnight et al., 2012). Cohen et al (1994) reevaluaron el riesgo teratogénico del litio mediante una revisión de los estudios publicados de exposición al fármaco durante el embarazo. ...
RESUMEN
El trastorno bipolar es un trastorno mental grave y recurrente de carácter crónico que se caracteriza por oscilaciones del estado de ánimo con fases de manía, hipomanía o mixtas alternadas con episodios depresivos. La prevalencia a lo largo de la vida se estima entre el 1 y 3%, siendo la edad media de debut entre los 18 y 20 años. Los factores estresantes psicosociales influyen en el comienzo y en las posteriores recidivas dentro de un modelo de vulnerabilidad genética. Entre los acontecimientos vitales que pueden influir notablemente en el curso de la enfermedad se sitúan el embarazo y el parto. Son periodos de vulnerabilidad en los que puede acontecer un empeoramiento de los síntomas o incluso una recaída a pesar de existir una buena adherencia terapéutica. El riesgo de recurrencias se incrementa cuando los psicofármacos se retiran bruscamente. De hecho, hasta un 81-85’5% de gestantes con trastorno bipolar tienen el riesgo de recaer si dejan de tomar estabilizantes del ánimo. La exposición al litio durante el primer trimestre se ha relacionado con malformaciones cardíacas en el feto, especialmente la anomalía de Ebstein. El ácido valproico y la carbamazepina aumentan el riesgo de defectos en el tubo neural. En cambio, la lamotrigina en monoterapia ha demostrado menor riesgo de malformaciones que otros anticonvulsivantes. Por todo ello, es fundamental valorar el riesgo-beneficio del uso de psicofármacos, siendo necesario el conocimiento de su uso y elaborar un plan de tratamiento individualizado en cada caso.
ABSTRACT
Bipolar disorder is a recurring and chronic severe mental disorder consisting of mood shifts between manic, hypomanic or mixed phases alternated with depressive episodes. Lifetime prevalence is estimated between 1 and 3%, mean age of debut being between 18 and 20 years of age. Psychosocial stressors influence the onset and subsequent relapses within a model of genetic vulnerability. Among the vital events that can significantly influence the course of the disorder are pregnancy and childbirth. They are periods of vulnerability in which there can be a worsening of symptoms or even a relapse despite having a good therapeutic adherence. The risk of recurrence is increased when psychoactive drugs are withdrawn abruptly; in fact up to 81-85.5% of pregnant women with bipolar disorder have the risk of relapse if they stop taking mood stabilizers. Exposure to lithium during the first trimester has been linked to cardiac malformations in the fetus, especially Ebstein’s anomaly. Valproic acid and carbamazepine increase the risk of neural tube defects. Lamotrigine monotherapy has shown a lower risk of malformations than other anticonvulsants. It is essential to assess the risks and benefits of the use of psychotropic drugs, the knowledge of their use is necessary as is the elaboration of an individualized treatment plan in each case.
... Subsequent data suggested that any teratogenic risk is smaller than previously thought, but while the overall risk is low, it is still higher in infants exposed to Li [218][219][220]. A systematic review of information published from 1969 to 2005 on the risk of major congenital malformations with prenatal exposure to Li concluded that lithium should not be considered a "major" human teratogen, and that Li should be administered to pregnant women for treatment of maternal BPD [221]. Concerns are not limited to exposure during the first trimester. ...
This paper reviews the findings from preclinical animal and human clinical research investigating maternal/fetal, neonatal, and child neurodevelopmental outcomes following prenatal exposure to psychotropic drugs. Evidence for the risks associated with prenatal exposure was examined, including teratogenicity, neurodevelopmental effects, neonatal toxicity, and long-term neurobehavioral consequences (i.e., behavioral teratogenicity). We conducted a comprehensive review of the recent results and conclusions of original research and reviews, respectively, which have investigated the short- and long-term impact of drugs commonly prescribed to pregnant women for psychological disorders, including mood, anxiety, and sleep disorders. Because mental illness in the mother is not a benign event, and may itself pose significant risks to both mother and child, simply discontinuing or avoiding medication use during pregnancy may not be possible. Therefore, prenatal exposure to psychotropic drugs is a major public health concern. Decisions regarding drug choice, dose, and duration should be made carefully, by balancing severity, chronicity, and co-morbidity of the mental illness, disorder, or condition against the potential risk for adverse outcomes due to drug exposure. Globally, maternal mental health problems are considered as a major public health challenge, which requires a stronger focus on mental health services that will benefit both mother and child. More preclinical and clinical research is needed in order to make well-informed decisions, understanding the risks associated with the use of psychotropic medications during pregnancy.
... Observational studies in Japan, reported in 2011, suggested that naturally occurring lithium in drinking water might develop Ebstein's cardiac anomaly in infants born to women who take lithium during the first trimester of pregnancy [5]. The most exciting results for lithium are its reported nonpsychiatric medical effects that are centered on the ion's ability to influence the proliferation of stem cells first identified from hematopoietic tissues [6,7]. ...
... Most previous research on lithium use during pregnancy has focused on congenital malformations including Ebstein's anomaly; 13,15,16,28 however, most data come from small retrospective clinical studies, which are prone to over-reporting on malformed infants, and tend to lack confounder control and information on exposed children without adverse out comes. [29][30][31] Adding to the complexities of any interpretation, major cardiac malformations might be associated with maternal mental illness and other associated factors, rather than with exposure to lithium. 29 In our study, comparisons were made with pregnancies among women with mental illness, rather than pregnancies among all women, because at least some adverse outcomes in offspring exposed to lithium during pregnancy could arise from factors other than lithium exposure alone. ...
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.
... Estudios posteriores encontraron tasas de malformaciones generales similares a las del grupo control 24 que llevan a cuestionar la teratogenicidad del litio 25 , aunque mayor riesgo de aborto espontáneo y anomalías cardiovasculares tras la exposición que sin alcanzar significación estadística implican relevancia clínica 26 . En un estudio más amplio y reciente 27 se observó un menor riesgo malformaciones cardiacas, aunque dosis- dependiente (tres veces mayor con dosis superiores a 900 mg/d, frente a las inferiores a 600 mg/d). ...
Resumen
Se revisa el uso de eutimizantes durante el embarazo y la lactancia, analizando su efecto teratógenico, así como los síndromes perinatales descritos y los posibles efectos en el desarrollo del neonato. Los hallazgos de los últimos años sugieren que la lamotrigina es la opción más segura, aunque solo ha demostrado efectividad en la prevención de la depresión bipolar, y que el litio es más seguro que lo clásicamente considerado, mientras que el ácido valproico debe evitarse y no existe suficiente experiencia con carbamazepina. La decisión de tratar o no con un eutimizante dependerá de una cuidadosa valoración de cada caso, con sus antecedentes personales, teniendo en cuenta que el trastorno bipolar por sí mismo se asocia a complicaciones obstétricas y para el feto y que el embarazo y en particular el puerperio son momentos de máximo riesgo de descompensación. En la lactancia el litio parece menos tóxico que lo previamente supuesto y al igual que la lamotrigina puede usarse en casos concretos, mientras que no hay motivos para suspender la carbamazepina o el ácido valproico en niños expuestos a ellos intraútero.
... Lithium ions equilibrate across the placenta and, therefore, the concentrations in maternal and fetal blood are almost equal. This might lead to fetal toxicity, including low Apgar score, hypotonicity, heart failure, and nephrogenic diabetes insipidus (Simard et al., 1989;Zegers and Andriessen, 2003;Yacobi and Ornoy, 2008). ...
Depression is generally treated with antidepressants, but may often need antipsychotics and mood stabilizers. We discuss the updated data regarding the safety in pregnancy of antidepressants and antipsychotics, except selective serotonin reuptake inhibitors, and their possible impact on the long-term development of the offspring. Several earlier studies demonstrated a slight increase in the rate of major anomalies following maternal tricyclic antidepressant treatment, but most current literature shows their relative safety in pregnancy. Data on the development of the offspring are also reassuring. The antipsychotic drugs are also safe for the developing fetus and do not seem to induce developmental delay. Both groups of drugs may cause perinatal withdrawal symptoms and difficulties in neonatal adaptation. The mood stabilizers, lithium, and several anti-epileptic drugs, may adversely affect the developing embryo and fetus. While valproic acid, carbamazepine, and topiramate are teratogenic and may also affect postnatal development, the newer antiepileptic and mood stabilizers, lamotrigine and levetiracetam, seem to be safe in pregnancy and apparently have no long-term neurodevelopmental damage. Lithium may increase the rate of cardiac anomalies, especially of Ebstein's anomaly, and may warrant a mid-trimester fetal echocardiography. Although data on the development of the offspring are reassuring, we should remember that most studies were carried out during early childhood, at a time when inattention, learning difficulties, behavioral and psychiatric problems are not yet identifiable. When considering medical treatment for depression in women at child-bearing age, we have to weigh the severity of the symptoms and their impact on the developing fetus and child. Birth Defects Research 109:933–956, 2017.
... Lamotrigine was chosen for comparison because it is an effective treatment for bipolar disorder, 32 often in combination with other psychotropic medications, and has not been associated with an increased risk of congenital malformations. 9,33 Women who were exposed to lamotrigine were compared with the reference group of unexposed women and were used as the active reference group for women who were exposed to lithium. The former contrast (exposure to lamotrigine vs. no exposure) allows an indirect and stable comparison of lithium and lamotrigine by using a common reference. ...
Background
There has been concern that exposure to lithium early in pregnancy may be associated with a marked increase in the risk of Ebstein’s anomaly (a right ventricular outflow tract obstruction defect) in infants and overall congenital cardiac defects, but data are conflicting and limited.
Methods
We conducted a cohort study involving 1,325,563 pregnancies in women who were enrolled in Medicaid and who delivered a live-born infant between 2000 and 2010. We examined the risk of cardiac malformations among infants exposed to lithium during the first trimester as compared with unexposed infants and, in secondary analyses, with infants exposed to another commonly used mood stabilizer, lamotrigine. Risk ratios and 95% confidence intervals were estimated with control for psychiatric and medical conditions, medications, and other potential confounders.
Results
Cardiac malformations were present in 16 of the 663 infants exposed to lithium (2.41%), 15,251 of the 1,322,955 nonexposed infants (1.15%), and 27 of the 1945 infants exposed to lamotrigine (1.39%). The adjusted risk ratio for cardiac malformations among infants exposed to lithium as compared with unexposed infants was 1.65 (95% confidence interval [CI], 1.02 to 2.68). The risk ratio was 1.11 (95% CI, 0.46 to 2.64) for a daily dose of 600 mg or less, 1.60 (95% CI, 0.67 to 3.80) for 601 to 900 mg, and 3.22 (95% CI, 1.47 to 7.02) for more than 900 mg. The prevalence of right ventricular outflow tract obstruction defects was 0.60% among lithium-exposed infants versus 0.18% among unexposed infants (adjusted risk ratio, 2.66; 95% CI, 1.00 to 7.06). Results were similar when lamotrigine-exposed infants were used as the reference group.
Conclusions
Maternal use of lithium during the first trimester was associated with an increased risk of cardiac malformations, including Ebstein’s anomaly; the magnitude of this effect was smaller than had been previously postulated. (Funded by the National Institute of Mental Health.)
... Incidence of this syndrome appeared to be 10 times higher in infants exposed to lithium than in the general population (1-2 of 1000 children). 64 However, a recent study showed that the rate of major malformations in children who were exposed to lithium in the first quarter of pregnancy did not significantly differ from those of nonexposed children. 65 Other malformations associated with lithium use during pregnancy are CNS and external ear abnormalities, diaphragmatic hernia, and skeletal abnormalities. ...
Importance:
Fifteen percent to 20% of pregnant women suffer from mental disorders, and 86% of them are not treated due to potential teratogenic risks for the fetus. Several drugs seem to be safe during pregnancy but knowledge regarding risks of antenatal exposure to drugs is still limited.
Objective:
The aim of this article is to provide a review of literature, data, and a clinical guideline concerning the treatment and management of mental disorders during pregnancy and lactation.
Evidence acquisition:
Bibliographical research was carried out using Medline and Pubmed (from 2005 until 2015) and articles, books and Websites were consulted.
Results:
Regarding antidepressants, only paroxetine seems to lead to an increased risk of malformations, whereas fluoxetine, fluvoxamine, sertraline, citalopram, escitalopram and venlafaxine do not appear to increase this risk. The use of duloxetine is associated with an increased risk of miscarriage during pregnancy but not with an increased risk of adverse events, such as birth defects. There is no clear evidence of malformation risk associated with the use of antipsychotics, whereas a risk associated with pregnancy and newborn outcome has been detected. All mood stabilizers are associated with risks of birth defects and perinatal complications.
Conclusions and relevance:
Taking psychoactive drugs is possible during pregnancy, but it is important to consider various effects of the drugs. Future research should focus on prospective and longitudinal studies with an adequate evaluation of confounding variables. This should be followed by long-term studies to obtain accurate measures of child development.
... The agents with a known teratogenic effect are lithium, valproate, carbamazepine, and lamotrigine in doses >200 mg/d. Valproate and carbamazepine should be avoided in any case; continuation of lithium treatment might be justified in selected patients with their informed consent as the risk of heart malformations has been overestimated in the past (Burt and Rasgon, 2004;Yacobi and Ornoy, 2008). Atypical antipsychotics and lamotrigine monotherapy in doses <200 mg/d are reasonable choices, although the data on their safety during pregnancy are still limited. ...
Background:
The current paper introduces the actual CINP clinical guidelines for the treatment of Bipolar disorder (BD).
Concept and structure of the guidelines:
The current clinical guidelines are based on evidence based data, but they also intend to be clinically useful, while a rigid algorithm was developed on the basis of firm evidence alone. Monotherapy was prioritised over combination therapy. There are separate recommendations for each of the major phases of BD expressed as a five-step algorithm.
Discussion:
The current CINP clinical guidelines for the treatment of BD are the most up-to-date guidance, and are as evidence based as possible. They also include recommendations concerning the use of psychotherapeutic interventions, again on the basis of available evidence. This adherence of the workgroup to the evidence in a clinically oriented way helped to clarify the role of specific antidepressants and traditional agents like lithium, valproate or carbamazepine. The additional focus on specific clinical characteristics, including predominant polarity, mixed features and rapid cycling is also a novel approach.Many issues need further studies, data are sparse and insufficient and many questions remain unanswered. The most important and still unmet need is to merge all the guidelines which concern different phases of the illness into a single one and in this way consider BD as a single unified disorder, which is the real world fact. However, to date the research data do not permit such a unified approach.
... Based on these results, it should be explained to women that the precise teratogenic risk associated with lithium is uncertain [78], but avoidance of lithium in pregnancy altogether seems unwarranted. Some experts suggest routine fetal echocardiography in women taking lithium during pregnancy, which is reasonable given the lack of clarity on the precise cardiac malformation risk [79]. ...
Introduction: Postpartum depression is a prevalent disorder affecting many women of reproductive age. Despite increasing public awareness, it is frequently underdiagnosed and undertreated leading to significant maternal morbidity and adverse child outcomes. When identified, postpartum depression is usually treated as major depressive disorder. Many studies have identified the postpartum as a period of high risk for first presentations and relapses of bipolar disorder.
Areas Covered: This article reviews the acute and prophylactic treatment of postpartum major depressive disorder, bipolar depression and major depressive disorder with mixed features. The safety of antidepressant and mood stabilizing medications in pregnancy and breastfeeding will also be reviewed.
Expert Commentary: Differentiating postpartum major depressive disorder and postpartum bipolar depression can be difficult given their clinical similarities but accurate identification is vital for initiating proper treatment. Antidepressants are the mainstay of drug treatment for postpartum major depressive disorder, yet randomized controlled trials have shown conflicting results. A paucity of evidence exists for the effectiveness of antidepressant prophylaxis in the prevention of recurrences of major depressive disorder. Mood stabilizing medications reduce the risk of postpartum bipolar depression relapse but no randomized controlled trials have examined their use in the acute or prophylactic treatment of postpartum bipolar depression.
... Of these 53, 35 papers were excluded (Fig. 1). Reasons for exclusion were: drug related issues (21 papers, [14,[18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37]), no focus on the chosen study group (six papers, [38][39][40][41][42][43]), outcomes in women not diagnosed before pregnancy (two papers, [44,45]), mixed groups bipolar disorder and schizophrenia (two papers, [46,47]), discussion paper (two papers, [48,49]), gender mixed groups also including men (one paper, [50]), duplicates (one paper, [15]). Occasionally it was difficult to separate the different diagnoses that were included in the sample; for example, in Doyle et al. [46] it was not possible to find separate data for the three included groups: BD I, BD II and schizoaffective disorders bipolar type. ...
Background
Bipolar Disorder (BD) is a mental disorder usually diagnosed between 18 and 30 years of age; this coincides with the period when many women experience pregnancy and childbirth. As specific problems have been reported in pregnancy and childbirth when the mother has BD, a systematic review was carried out to summarise the outcomes of pregnancy and childbirth, in mother and child, when the mother has BD diagnosed before pregnancy. Methods
An a priori protocol was designed and a systematic search conducted in PubMed, CINAHL, Scopus, PsycINFO and Cochrane databases in March 2015. Studies of all designs were included if they involved women with a diagnosis of bipolar disorder prior to pregnancy, who were pregnant and/or followed up to one year postpartum. All stages of inclusion, quality assessment and data extraction were done by two people. All maternal or infant outcomes were examined, and narrative synthesis was used for most outcomes. Meta-analysis was used to achieve a combined prevalence for some outcomes and, where possible, case and control groups were combined and compared. ResultsThe search identified 2809 papers. After screening and quality assessement (using the EPHPP and AMSTAR tools), nine papers were included. Adverse pregnancy outcomes such as gestational hypertension and antepartum haemorrhage occur more frequently in women with BD. They also have increased rates of induction of labour and caesarean section, and have an increased risk of mood disorders in the postnatal period. Women with BD are more likely to have babies that are severely small for gestational age (<2nd-3rd percentile), and it appears that those women not being treated with mood stabilisers in pregnancy might not have an increased risk of having a baby with congenital abnormalities. DiscussionDue to heterogeneity of data, particularly the use of differing definitions of bipolar disorder, narrative synthesis was used for most outcomes, rather than a meta-analysis. Conclusions
It is evident that adverse outcomes are more common in women with BD and their babies. Large cohort studies examining fetal abnormality outcomes for women with BD who are not on mood stabilisers in pregnancy are required, as are studies on maternal-infant interaction.
... In a meta-analysis by Yacobi and Ornoy ( 2008 ), the authors reviewed all the studies on teratogenic and embryotoxic effects associated with lithium treatment during pregnancy. In the conclusions, the authors stated that lithium therapy throughout pregnancy did not seem to increase the general rate of major anomalies and apparently added only a small risk of cardiovascular defects, notably Ebstein's anomaly. ...
Safety and tolerability of mood stabilisers are major clinical concerns when used in bipolar patients. Side effects of lithium and some antiepileptics have been reviewed in the context of a spontaneous reporting database over the last 10 years (FDA database and published reports). During pregnancy, antiepileptics show great concerns, and adverse events are all related to childbirth, whilst congenital abnormalities are not higher than previously estimated. Cutaneous adverse reactions are the most prevalent in children and adolescent. In adult lithium-treated patients, nephrotoxicity is still a major problem; the combination with carbamazepine and valproate can increase the risk of hypothyroidism. Hyperparathormonemia and hypercalcaemia are unrecognised and underappreciated adverse effects. Acute exacerbation of psoriasis is still a major problem, and the risk of skin reactions with eosinophilia and systemic symptoms is higher when mood stabilisers are used concomitantly; when associated with antipsychotics, the risk of pneumonia is possible (highest risk for olanzapine plus carbamazepine). A decrease in total body water and the decline of glomerular filtration rate represent the main lithium adverse effects in elderly patients. Long-term treatment is associated with impairment in immediate verbal learning and memory and creativity performance. Antiepileptics display significant adverse events (hyponatraemia, cardiac toxicity) and the risk of multiple drug-drug interactions is very high. Cumulative exposure to antipsychotics and mood stabilisers can be associated with vascular stiffness (elevated systolic blood pressure), hypertriglyceridaemia, insulin resistance and low HDL cholesterol. In light of the above considerations, clinicians should continuously and further assess risks and benefits of mood stabilisers when treating bipolar patients.
... Although lithium and valproic acid have a teratogenic effect, in some studies it was seen that these substances did not increase the incidence of major malformations. The negative information previously existing about these drugs was not confirmed by later research (12,13). ...
... Giles e Banningan 2006;Yacobi 2008). Attualmente il rischio assoluto di presentare l'anomalia di Ebstein nei neonati esposti a litio è valutato 0.05% (1 su 2000 nati esposti), che è appena superiore al rischio basale (0.01%, 1/20000 esposti). ...
Una revisione della letteratura e delle linee guida internazionali sulla diagnosi e trattamento del Disturbo Bipolare I
... 4 Variable additional features have been observed, including other central nervous system anomalies (agenesis of the corpus callosum, polymicrogyria, heterotopia and occipital encephalocele), chorioretinal coloboma, retinal dystrophy, cystic renal disease, hepatic fibrosis and polydactyly. [5][6][7][8][9][10][11][12][13][14][15][16] MKS is characterised by a posterior fossa brain malformation (typically occipital encephalocele), cystic renal disease, congenital hepatic fibrosis (eg, ductal plate malformation) and postaxial polydactyly. 17 18 Phenotypic variability is also present, and other characteristics can include microphthalmia, situs inversus, skeletal abnormalities and Dandy-Walker malformation. ...
Background:
Joubert syndrome (JS) is a recessive ciliopathy characterised by a distinctive brain malformation 'the molar tooth sign'. Mutations in >27 genes cause JS, and mutations in 12 of these genes also cause Meckel-Gruber syndrome (MKS). The goals of this work are to describe the clinical features of MKS1-related JS and determine whether disease causing MKS1 mutations affect cellular phenotypes such as cilium number, length and protein content as potential mechanisms underlying JS.
Methods:
We measured cilium number, length and protein content (ARL13B and INPP5E) by immunofluorescence in fibroblasts from individuals with MKS1-related JS and in a three-dimensional (3D) spheroid rescue assay to test the effects of disease-related MKS1 mutations.
Results:
We report MKS1 mutations (eight of them previously unreported) in nine individuals with JS. A minority of the individuals with MKS1-related JS have MKS features. In contrast to the truncating mutations associated with MKS, all of the individuals with MKS1-related JS carry ≥1 non-truncating mutation. Fibroblasts from individuals with MKS1-related JS make normal or fewer cilia than control fibroblasts, their cilia are more variable in length than controls, and show decreased ciliary ARL13B and INPP5E. Additionally, MKS1 mutant alleles have similar effects in 3D spheroids.
Conclusions:
MKS1 functions in the transition zone at the base of the cilium to regulate ciliary INPP5E content, through an ARL13B-dependent mechanism. Mutations in INPP5E also cause JS, so our findings in patient fibroblasts support the notion that loss of INPP5E function, due to either mutation or mislocalisation, is a key mechanism underlying JS, downstream of MKS1 and ARL13B.
... С 1968 г. ведется учет применения препаратов лития во время беременности, так называемый «Lithium Baby Register». Установлено, что они не обладают значительной тератогенностью и могут назначаться в последние 6 мес беременности, а при высоком риске рецидива и в первом триместре под контролем их концентрации в плазме крови [39,64]. ...
The paper reviews the literature on bipolar affective disorder (BAD). It considers the diagnosis, course, and treatment of BAD with emphasis on maintenance pharmacotherapy to prevent disease recurrence and to improve quality of life in patients. Major drug classes both used to prevent recurrent BAD and promising agents whose effect on the course of affective diseases is being just tested are viewed.
O lítio já foi apontado nos anos de 1980 como um forte teratógeno. Uma revisão de estudos posteriores realizada nos anos 1990 estimou que o risco de malformações cardíacas era menor do que o relatado e deveria estar entre 0,9% a 12%. Este artigo revisa os dados destes estudos e assinala possíveis vieses que podem colocar em dúvida as estimativas aceitas na atualidade. Concluiu-se que, considerando as sérias limitações dos estudos retrospectivos, caso-controle e prospectivos sobre este tema, o potencialteratogênico do lítio não deve ser desprezado e, portanto, é uma medicação que deve ser prescrita com muito critério durante a gravidez. Quando houver a exposição, é aconselhável realizar uma ecocardiografia fetal e neonatal para excluir a possibilidade de anomalias cardíacas. Antipsicóticos e lamotrigina podem ser possíveis alternativas para o tratamento do transtorno bipolar durante a gravidez.
A 25-year-old woman has recently been diagnosed with bipolar disorder, 6 years after her symptoms began. She has had no mood stabilizing treatment in that time. According to the kindling model and allostatic load hypothesis, what progressive pattern of illness would you expect this patient to have exhibited over the course of the last 6 years?
The current study aims to find out the reasons for the increase in caesarean sections compared to natural birth in Al-Diwaniyah Governorate
Since the inception of clinical teratology, the vast majority of scientific work has focused on identification of drugs and environmental agents causing malformations in humans as a dichotomous variable (i.e. yes or no), as well as the relative and absolute risks of such occurrences. Generally, the dose dependency of such events has not been investigated. With the establishment of large pregnancy databases, dose-dependence relationships are being uncovered for increasing numbers of medications, including valproic acid, carbamazepine, phenobarbital, lamotrigine, topiramate, and lithium. In this review we discuss newly recognized dose-dependent human teratogens and the implications to counseling and clinical management of pregnant women. The option of limiting the dose below a teratogenic threshold for women who may need these drugs may be important in managing such pregnancies. Similarly, in women that were exposed before they realized they had conceived, this new knowledge may lead to significant improvement in risk assessment. A common denominator of all studies calculating dose-dependent teratogenicity in humans is their use of total daily drug dose. None of these studies have standardized their calculations for women’s body weight. It is quite possible that the teratogenic dose threshold may be below the clinically effective dose levels for specific women, and hence such information needs to be considered and applied individually. With large administrative databases now reporting on drug safety in pregnancy, more accurate data will likely emerge on dose dependency of human teratogens, and these will likely increase the accuracy of risk assessment.
Lithium has been an intriguing treatment option in psychiatry for over a century. While seemingly just a simple elemental compound, it has powerful treatment effects for both depression and bipolar disorder. The evidence base for treatment of pediatric bipolar disorder is relatively small, but, in recent years, additional clinical trial data have enabled lithium to re-emerge as a valuable and, in many cases, preferred treatment. Pharmacologically, lithium is complex, with varied effects at both intracellular and extracellular levels. As a treatment for bipolar disorder in pediatrics, lithium is challenging, given its narrow therapeutic window and myriad of potential side effects. However, the efficacy of lithium continues to match that of newer pharmacologic agents, and its tolerability has been shown to be comparable with more commonly prescribed medications. Lithium is still one of few drugs that have been proven to reduce the risk of suicidality, and it may have utility in illnesses beyond affective disorders. Practically, as a primary agent or as an adjunct, lithium continues to claim a rightful place in the treatment armamentarium of child psychiatry. New dosing paradigms have improved tolerability and reduced potential side effects. Recent evidence affirms that lithium is effective for pediatric bipolar disorder in multiple phases of the illness.
There is an increasing number of women, who plan to become or already are pregnant, and concurrently use psychotropic drugs for mental illness. Most of psychotropic drugs pass through the placenta to developing fetus and thus may affect the embryogenesis. On the other hand, untreated psychiatric disorder represents a risk factor of adverse pregnancy outcome and poor neonatal adaptation of an exposed newborn, as well. We review current published data on the impact of prenatal exposure to untreated bipolar disorder and anxiety disorders, and effects of mood stabilizers and anxiolytics on the fetus development, pregnancy outcome, and neonatal adaptation. Available data suggests that some mood stabilizers have a high teratogenic potential and therefore should not be prescribed during pregnancy. The risks for fetus resulting from untreated bipolar disorder seems to be high. Psychiatrists should prefer safer drugs in pregnancy such as lithium and newer (atypical) antipsychotics for pregnant bipolar patients. There is no solid evidence that anxio-lytics as a group have a significant teratogenic potential. Their use during pregnancy is relatively safe; however, the risks increase with higher daily dose. Administration of benzodiazepine during third trimester of pregnancy increases the risk of poor neonatal adaptation of exposed child. Pharmacotherapy is indicated in severe cases, where the risk of untreated illness outweighs the risk of drug exposure.
Suicidal behaviors and communications are obvious concerns for psychiatrists. Whereas the infrequency of completed suicide makes it hard to study and the alternative construct of “suicidality” is not uniformly defined across studies, associations can be found between treatments in the psychiatrist’s toolbox and possible suicide-protective effects. This review identifies several candidate treatments-psychotherapy, antidepressants, lithium, anticonvulsant agents, electroconvulsive therapy, and clozapine-and weighs their potential suicide-protective effects against their known risks.
Bipolar disorder is associated with high morbidity and mortality. The management of bipolar disorder includes a broad approach involving psychoeducation, psychological therapies and psychotropic medication. The management of bipolar disorder in pregnancy is challenging; there is an increase in the rate of relapse of bipolar disorder in the perinatal period and treatment decisions are complex as clinicians are required to weigh up the risks of untreated illness versus unwanted treatment effects on both the mother and the developing fetus. Whilst depressive relapses are more common, women are also at an increased risk of postpartum psychosis, which is a psychiatric emergency that almost always requires inpatient treatment. This paper discusses the limited evidence base regarding the safety of psychotropic medication in the perinatal period, including challenges in perinatal mental health research and the lack of robust evidence. The general principles of prescribing in pregnancy, the importance of preconception counselling, and the risks and benefits associated with antipsychotics, mood stabilisers and antidepressants are addressed.
Frauen mit phasenhaft verlaufenden psychischen Störungen setzen sich selbst oft sehr differenziert mit der Frage der Familiengründung auseinander. Dabei mischen sich Überlegungen zu Auswirkungen der Medikation auf das Kind und die Sorge einer Verschlechterung der Erkrankung durch Schwangerschaft und Entbindung. In dieser Konfliktsituation benötigen Frauen fachkompetente Beratung und auch die Aussicht auf qualifizierte Unterstützung während der Schwangerschaft und nach der Geburt. Eine fundierte Nutzen-Risiko-Abwägung sollte Entscheidungsbasis sein.
Objective: The authors conducted a prospective , comparative observational study to evaluate the risk of major anomalies following exposure to lithium during pregnancy. Method: A total of 183 lithium-exposed pregnancies of women who contacted the Israeli Teratology Information Service were followed up (90.2% in the first trimester) and compared with 72 disease-matched and 748 nonteratogenic-exposed pregnancies. Results: There were significantly more miscarriages (adjusted odds ratio=1.94, 95% CI=1.08–3.48) and elective terminations of pregnancy (17/183 [9.3%] compared with 15/748 [2.0%]) in the lithium-exposed group compared with the nonteratogenic exposure group. The rate of major congenital anomalies after exclusion of genetic or cytogenetic anomalies was not significantly different between the three groups (lithium-exposed in the first trimester: 8/123 [6.5%]; bipolar: 2/61 [3.3%]; non-teratogenic: 19/711 [2.7%]). Cardiovascular anomalies occurred more frequently in the lithium group exposed during the first trimester when compared with the non-teratogenic exposure group (5/123 [4.1%] compared with 4/711 [0.6%]) but not after excluding anomalies that spontaneously resolved (3/123 [2.4%] compared with 2/711 [0.3%]). Ebstein's anomaly was diagnosed in one lithium-exposed fetus and in two retrospective lithium cases that were not included because contact with the information service was made after the pre-natal diagnosis by ultrasound. The rate of noncardiovascular anomalies was not significantly different between the groups. The rate of preterm deliveries was higher in the lithium group compared with the nonteratogenic exposure group (18/131 [13.7%] compared with 41/683 [6.0%]). Conclusions: Lithium treatment in pregnancy is associated with a higher rate of cardiovascular anomalies. Women who are treated with lithium during organo-genesis should undergo fetal echocardiog-raphy and level-2 ultrasound. (Am J Psychiatry 2014; 171:785–794)
Bei der Behandlung von Frauen im gebärfähigen Alter tauchen nicht selten Fragen zu Risiken und Nutzen einer Psychopharmakotherapie bei Schwangerschaftswunsch, in Schwangerschaft und Stillzeit auf. Bei der Behandlung depressiver Erkrankungen in Schwangerschaft und Stillzeit muss die Option einer medikamentösen Behandlung nicht prinzipiell ausgeschlossen werden. Vielmehr bedarf es einer individuellen Nutzen-Risiko-Abwägung zwischen der Gefährdung von Mutter und Kind durch eine unbehandelte Depression ohne Medikamenteneinnahme und einer gut behandelten Depression unter einer Medikation. Bei einer Medikation muss die potenzielle Gefährdung des Kindes durch fetotoxische Medikamenteneffekte, Schwangerschafts- oder peripartale Komplikationen und mögliche Langzeitfolgen beachtet werden. Es liegen heute Daten für Antidepressiva vor, die eine gute Einschätzung über ihre Eignung in Schwangerschaft und Stillzeit erlauben. Unter Beachtung einiger Regeln und bei geeigneter Auswahl der Antidepressiva kann das Risiko für das Neugeborene in Schwangerschaft und Stillzeit minimiert werden. In der Stillzeit besteht prinzipiell die Möglichkeit des Abstillens. Therapeutisches Drug Monitoring erhöht die Arzneimittelsicherheit für Mutter und Kind
Im Verlauf der intrauterinen Entwicklung durchläuft die Frucht Stadien unterschiedlicher Empfindlichkeit gegenüber äußeren Einflüssen. Während sich die Reaktion auf schädigende Agenzien in den ersten beiden Wochen nach Konzeption weitgehend auf die Alternativen vollständige Heilung des Defekts oder Absterben beschränkt, können Einflüsse von Woche 3–8 nach Konzeption zu Störungen der Organdifferenzierung und damit zu Fehlbildungen führen.
In der Fetalperiode stehen Wachstums- und Funktionsstörungen durch exogene Noxen im Vordergrund.
Seit nach Einnahme von Thalidomid ca. 10.000 Kinder mit schweren Gliedmaßendefekten geboren wurden, herrscht bei pharmazeutischer Industrie, Ärzten und Patientinnen berechtigte Vorsicht gegenüber dem Einsatz von Arzneimitteln in der Schwangerschaft. Ein therapeutischer Nihilismus bei chronisch kranken Schwangeren kann jedoch zu einer dramatischen Verschlechterung der Grunderkrankung und damit zu einer erheblichen Gefährdung der fetalen Entwicklung führen.
Die Behandlung psychisch kranker Frauen in Schwangerschaft und Stillzeit ist eine eher seltene Aufgabe für Psychiater; vielleicht ist das der Grund dafür, dass Unsicherheit vonseiten des Arztes eine typische Reaktion ist. Wir haben alle aufgrund der Contergan-Affäre in den 1960er-Jahren gelernt, welch gravierende Probleme teratogene Substanzen verursachen können. Ein verantwortlicher Umgang mit Psychopharmaka in der Schwangerschaft ist die erfreuliche Konsequenz dieser Erfahrungen. Andererseits aber gibt es auch immer wieder Situationen, in denen vorschnelles Handeln – wie etwa das ungerechtfertigte Absetzen einer bewährten Medikation bei Kinderwunsch oder Feststellung einer Schwangerschaft – eine Patientin psychisch destabilisieren kann. Stattdessen ermöglicht eine qualifizierte Beratung der Patientin und ihres Partners eine informierte Entscheidung der Betroffenen. Die psychiatrische Betreuung im Falle einer Schwangerschaft sollte eine möglichst positive Erfahrung von Schwangerschaft und Entbindung zum Ziel haben. Die Prinzipien der Behandlung von psychisch kranken schwangeren Frauen und Frauen, für die die Familienplanung noch nicht abgeschlossen ist, werden hier dargestellt, ergänzt durch Informationen zum peripartalen Management und zur Stillzeit.
Background
It is not rare that the first manifestation or relapse of an affective disorder occurs during pregnancy. Should a pharmacological treatment be indicated, the selection of a suitable substance should be made on a basis which is as safe as possible. Even when treating women of childbearing age it should be assured that the psychotropic drug selected is safe to use during pregnancy as a high percentage of pregnancies are unplanned.
Objective
When assessing the risks and benefits of psychopharmacotherapy in women who are or wish to get pregnant, not only the exposure of the child to potentially teratogenic drug effects but also potential complications during or after pregnancy and long-term neuropsychological issues need to be addressed.
Methods
This article provides an overview of the currently available literature on the use of antidepressants and mood stabilizers during pregnancy.
Results
A growing body of increasingly reliable data for many antidepressants and mood stabilizers are available, which allow a good prediction of their suitability for use during pregnancy and lactation.
Conclusion
When treating affective disorders during pregnancy an individual assessment of the benefits and risks for mother and child is required. The benefit of an appropriate treatment for the mother by including medication which may be potentially harmful to the child versus the risk of an insufficient treatment for the mother by excluding medication which may be potentially harmful to both the mother and the child need to be weighed up. When a suitable psychopharmacotherapy during pregnancy has been selected, the risk for mother and child can be minimized by incorporation of therapeutic drug monitoring.
Management of bipolar disorder during pregnancy often involves medications with potential adverse effects, including risks to the mother and fetus. Although some specifics are known, many medications continue to have incompletely characterized reproductive safety profiles. Women with bipolar disorder who are planning pregnancy face challenging decisions about their treatment; careful risk-benefit discussions are necessary. With the goal of further informing these discussions, this article reviews the data currently available regarding medication safety in the management of bipolar disorder during pregnancy, with specific attention to lithium, valproic acid, lamotrigine, carbamazepine, and antipsychotic medications.
We developed this clonazepam guideline using drug prescribing information and reviewing the available literature on relevant neuropsychiatric disorders in populations without intellectual disabilities because of the dearth of available literature on the population with intellectual disabilities. This guideline includes indications; contraindications; assessments prior to and during treatment; dosing with particular focus on dosing modifications required by drug–drug interactions, personal characteristics, or genetic variants; and adverse drug reactions. The procedures contained in this guideline may not fully account for all of the possible risks of treatment in this population because of the limited studies available; thus, there will be a need to periodically update this guideline as new information becomes available. Nevertheless, we believe that this guideline provides a useful resource for clinicians who treat epilepsy, anxiety, or catatonia in adult individuals with intellectual disabilities. A clonazepam drug utilization review that summarizes this guideline is described.
Fetal imaging has become standard in prenatal care. Thorough knowledge of not only pathogenesis but also morphological appearances of different anomalies are mandatory for adequate diagnosis. This chapter explains ultrasound and magnetic resonance in prenatal diagnosis of congenital anomalies. Teratogens are agents that cause malformations in a developing embryo. Numerous agents exhibit teratogenic effects. The dose and duration of exposure usually are the main determining factors regarding the severity of the damage and the type of defect. Holoprosencephaly (HPE) is a term used for a group of cerebral anomalies, which are the result of a failure or incomplete cleavage of a primitive forebrain - prosencephalon. Neural tube defects (NTD) and spinal malformations are among the most common congenital malformations. The epidemiology of these anomalies is various - multifactorial inheritance, chromosomal abnormality, teratogens, maternal predisposing factors or they may come as part of a syndrome. Congenital heart disease is a multifactorial disorder and a result of a combined effect of a genetic predisposition and environmental factors in more than 90% of cases. Exomphalos is characterized by herniation of the intra-abdominal contents into the base of the umbilical cord, with a covering amnioperitoneal membrane. The most frequently herniated organs are the liver, bowel and stomach. If abnormalities are found, the parents need as much accurate information as possible in order to make decisions about the future of the pregnancy.
Lithium has long been used as a treatment for bipolar disorder in adults and children and adolescents. Despite the growing evidence of efficacy for second generation antipsychotics in the treatment of manic symptoms in youth, lithium remains an effective and valuable option for treating mania and certain other psychiatric conditions in children and adolescents. We review the phenomenology of bipolar disorder in youth as well as the pharmacology of lithium, evidence for the use of lithium in children and adolescents, and the most recent understanding of potential mechanisms of action. We also describe practical considerations for dosing, drug monitoring, and potential side effects that may arise while using lithium to treat children and adolescents.
Exposures that can cause permanent structural or functional abnormalities in an exposed embryo or fetus are called “teratogenic.” Teratogenicity is a property of an exposure, and agents that are teratogenic exhibit this potential only under certain conditions. Clinical assessment of human teratogenic risk requires the careful interpretation of data obtained from several kinds of studies. Teratogenic exposures may be grouped into four major categories on the basis of the kind of agent involved: infectious agents, physical agents, maternal metabolic factors, and drug and chemical agents.
The main objective of this chapter is to summarize the clinical differences found in the literature between men and women suffering from bipolar disorder. The secondary objective is to analyze the treatment and how there are gender differences in the adherence to medication. Briefly, we could say that in men the manic component predominates, both at onset and throughout their lifetime, and that they usually have comorbid drug abuse. On the other hand, women usually tend to have a predominance of depression; they have a depressive polarity both at onset and during their lifetime and experience more mixed mania episodes. Furthermore, in women onset often occurs at an older age, comorbidity of physical pathological conditions is common, and adherence to medication is greater than in men.
We cannot forget that women can experience two very important periods: pregnancy and postpartum. Both can be critical periods for the disorder, and a relapse or recurrence at either stage can have serious consequences not just for the woman but also for her baby. Because the effect of medication on the fetus still remains unclear, it makes it even more difficult to set the treatment during these periods.
Die medikamentöse Behandlung von psychischen Störungen in Schwangerschaft und Stillzeit stellt eine klinisch besonders komplexe Situation dar, die eine Gratwanderung zwischen klinischen Erfordernissen und den besonderen Risiken für Embryo bzw. Fetus und Neugeborenes bedingt . Die Bedeutung dieses Th emas ergibt sich einerseits aus der hohen Inzidenz psychischer Störungen in Schwangerschaft und Stillzeit (v. a. im Wochenbett), andererseits aus der großen Zahl von Müttern, die Psychopharmaka in diesen vulnerablen Phasen der kindlichen Entwicklung einnehmen (Altshuler et al. 1996). So haben beispielsweise die American Psychiatric Association (APA) zusammen mit dem American College of Obstetricians and Gynecologists (ACOG) aufgrund der Aktualität der Problematik und der in den letzten Jahren deutlichen Zunahme während der Schwangerschaft antidepressiv behandelter Frauen Behandlungsalgorithmen zur antidepressiven Th erapie im Umfeld von Konzeption und Schwangerschaft entwickelt (Yonkers et al. 2009).
Die Behandlung psychisch kranker Frauen in Schwangerschaft und Stillzeit ist eine eher seltene Aufgabe für klinisch tätige oder auch niedergelassene Psychiater; vielleicht liegt darin der Grund, warum Unsicherheit vonseiten des Arztes eine typische Reaktion ist. Natürlich haben wir alle auf dem Hintergrund der Contergan-Affäre in den 1960er Jahren gelernt, welche gravierenden Probleme teratogene Substanzen verursachen können. Ein verantwortlicher Umgang mit Psychopharmaka in der Schwangerschaft ist die erfreuliche Konsequenz dieser Erfahrungen. Andererseits aber gibt es auch immer wieder Situationen, in denen vorschnelle Handlungen – wie etwa das gezielte Absetzen einer bewährten Medikation bei Kinderwunsch oder sogar das abrupte Absetzen der Medikation bei Feststellung einer Schwangerschaft – eine Patientin ohne Not psychisch destabilisieren können. Stattdessen sollte eine qualifizierte Beratung der Patientin und ihres Partners die Fähigkeit zur informierten Entscheidung unterstützen und im Fall einer Schwangerschaft die psychiatrische Betreuung eine möglichst positive Erfahrung von Schwangerschaft und Entbindung zum Ziel haben. Die Prinzipien der Behandlung von Frauen, die eine Schwangerschaft planen oder auch ungeplant schwanger sind, werden im folgenden Kapitel dargestellt, ergänzt durch Informationen zum peripartalen Management und zur Stillzeit.
Bipolar illness can be particularly difficult to manage in pregnancy and during the post-partum period. The risks of mood stabilizing medication on the health of the infant must be considered carefully along with the risks of uncontrolled illness in the mother. Lithium use in pregnancy and lactation has been associated with a number of negative effects in the newborn. This article reviews the latest evidence regarding the risks and benefits of the use of lithium in pregnant or lactating women.
Although some psychotropic drugs are known to be teratogenic no psychotropic drug is of proven safety for treatment of depression during pregnancy. Untreated mood disorders during pregnancy pose significant risks for mother and the newborn. This review focuses on the use of somatic tretments of depression during pregnancy.Electroconvulsive therapy, bright light therapy, transcranial magnetic stimulation and vagal nerve stimulation are relatively safe and effective treatments during pregnancy if steps are taken to decrease potential risks. A clear information related to the somatic treatment should be given to the patient and informed consent should be obtained. [Psikiyatride Guncel Yaklasimlar - Current Approaches in Psychiatry 2015; 7(3.000): 244-254]
This paper presents an overview of the Motherisk Program data on pregnancy outcome and neurodevelopment of children exposed in utero to selected psychoactive drugs. First, the use of cocaine during pregnancy has been associated with increased risk of spontaneous abortions, abruptio placenta, premature labor, and stillbirth. Twenty-three adopted children exposed in utero to cocaine demonstrated an 8-fold increase in risk for microcephaly compared with controls. Global intelligence quotients (IQ) did not differ between the 2 groups, but the cocaine-exposed children achieved significantly lower scores on the Reynell language test. Second, the long-term neurobehavioral effects of fetal alcohol syndrome (FAS) were studied in 384 children to show that alcohol-induced brain insults, which consist of attention and memory deficits together, and poor adaptability and organization are not attenuated with age. Third, the rates of major malformations in children exposed in utero to fluoxetine, tricyclic antidepressants, and nonteratogenic drugs did not differ or exceed the expected rates in the general population. A 2nd phase of this study established the safety of antidepressants during pregnancy by demonstrating that the mean IQ and language scores are comparable in the 3 groups. A level 2 ultrasonography is recommended in cases of in utero exposure to lithium and carbamazepine because of an increased risk of cardiac malformations and spina bifida, respectively.
The purpose of this study was to review the use of lithium in pregnancy and its effects on the neonate. This was a case study and review of the published literature. Lithium is commonly used in the treatment of psychiatric disorders, specifically bipolar depression. Bipolar disorders that require treatment with lithium demand special consideration when the woman becomes pregnant. Reported neonatal problems with maternal lithium therapy include Ebstein's anomaly, poor respiratory effort and cyanosis, rhythm disturbances, nephrogenic diabetes insipidus, thyroid dysfunction, hypoglycemia, hypotonia and lethargy, hyperbilirubinemia, and large-for-gestational-age infants. Lithium can have adverse effects on the fetus and newborn infant, but data suggest normal behavioral patterns in childhood.
ABSTRACT– – By record linkage of a discharge diagnosis registry and a medical birth registry we identified 350 women with manic-depressive disease who had born a child. The total delivery outcome was poorer than expected with a high perinatal death rate and a high malformation rate. Further studies revealed a high rate of perinatal deaths and/or congenital malformations among infants born of women who had used drugs in early pregnancy, and this phenomenon was concentrated to women who had used lithium and to heart defects. The sample is small, however, and there is no statistically significant difference between delivery outcome in women on lithium and in women on other psychotropic drugs. Until better risk estimates are obtained, lithium should not be used in early pregnancy.
Congenital malformations have been previously reported in infants born to women who received lithium carbonate during pregnancy.1 Although this drug has been used in psychiatric therapy since 1949 and has received attention as a possible human teratogen, evidence relative to its teratogenicity on human fetuses is inconclusive. In 1974, Nora et al reported two cases of Ebstein's anomaly of the tricuspid valve in infants whose mothers had received lithium during pregnancy and suggested that the incidence of this rare cardiac defect is strikingly high among such babies.2 The purpose of our report is to describe another patient in support of the contention that lithium is a potent cardiovascular teratogen.
Report of a Case.—A female infant was delivered at term to a 25-year-old primigravida who had taken 1,200 mg of lithium carbonate daily throughout her entire pregnancy for manic-depressive symptoms. The mother denied taking any other medication during
Ebstein's anomaly is a specific structural deformity of the tricuspid valve, and its rarity has hampered etiologic evaluation. Cases of Ebstein's anomaly registered in the Baltimore Washington Infant Study (BWIS), a regional case-control study of cardiovascular malformations (CVM) in infancy, are reviewed. Between 1981 and 1989 a total of 4,390 CVM cases, including 47 Ebstein cases, and 3,572 controls were registered. The prevalence of Ebstein's anomaly was 5.2 per 100,000 livebirths. Additional cardiac anomalies were present in 38.3% of Ebstein cases. Non-cardiac malformations were present in 19.1% of Ebstein cases vs. 25.5% of other CVM, and 1.7% of controls. Case-fatality by 1 year of age was 23.4% in Ebstein vs. 18.1% in other CVM. Interviews of parents of Ebstein cases, other CVM, and controls (n = 44, 3,335, and 3,572, respectively) elicited information on family history of malformations, maternal illnesses, reproductive history, therapeutic drugs, parental lifestyle, and environmental exposures during the periconceptional period. Case-control analyses suggest genetic, reproductive, and environmental risk factors: twins [odds ratio (OR) 8.2, 95% confidence interval (CI) 2.6-25.3]; family history of CVM (OR 6.4, 95% CI 1.8-22.2); white race (OR 2.9 with non-whites as reference, 95% CI 1.2-7.0); previous miscarriages (OR 2.0, 95% CI 1.2-3.3); maternal exposure to benzodiazepines (OR 5.4, 95% CI 1.5-19.1); and varnishing (OR 3.4, 95% CI 1.3-9.1). Additional multicenter investigations are warranted to elucidate the role of genetic, reproductive, and environmental factors in the etiology of this anomaly.
Lithium carbonate is an effective drug for prophylaxis and treatment of major affective disorders. In-utero exposure to lithium during the first trimester of pregnancy might be associated with an increased risk of cardiac malformations, especially the rare Ebstein's anomaly. We prospectively recruited and followed 148 women (mean age 30 years, SD 5 range 15-40) using lithium during the first trimester of pregnancy, who consulted four teratogen information centres in the USA and Canada. Pregnancy outcome was compared with that of controls matched for maternal age. We had complete follow-up of pregnancy outcome in 138 of 148 patients recruited. In the other 10, fetal echocardiograms were available but postnatal follow-up was not done. Mean daily dose of lithium was 927 mg (SD 340). Rates of major congenital malformations did not differ between the lithium (2·8%) and control (2·4%) groups. 1 patient in the lithium group chose to terminate pregnancy after Ebstein's anomaly was detected by a prenatal echocardiogram. There was 1 ventricular septal defect in the controls. Birthweight was significantly higher in the lithium-exposed infants than in the controls despite identical gestational ages (3475 [660] g vs 3383 [566] g, p=0·02). The true difference in birthweight might have been even larger, since significantly more women using lithium than controls were cigarette smokers (31·8% vs 15·5%, p=0·002). These results indicate that lithium is not an important human teratogen. Women with major affective disorders who wish to have children may continue lithium therapy, provided that adequate screening tests, including level II ultrasound and fetal echocardiography, are done.
Reduced serotonin transporter (5-HTT) expression is associated with abnormal affective and anxiety-like symptoms in humans and rodents, but the mechanism of this effect is unknown. Transient inhibition of 5-HTT during early development with fluoxetine, a commonly used serotonin selective reuptake inhibitor, produced abnormal emotional behaviors in adult mice. This effect mimicked the behavioral phenotype of mice genetically deficient in 5-HTT expression. These findings indicate a critical role of serotonin in the maturation of brain systems that modulate emotional function in the adult and suggest a developmental mechanism to explain how low-expressing 5-HTT promoter alleles increase vulnerability to psychiatric disorders.
Psychotropic drugs are used frequently for the treatment of emotional as well as other disorders. With usage so widespread, many pregnant women receive psychotropic drugs. Maternal ingestion of these drugs may produce, in the fetus, side effects including withdrawal symptoms. Withdrawal signs in the fetus as a result of maternal intake of opiates, hypnotics, analgesics, and tricyclic antidepressant drugs have been reported. Fetal side effects can occur by maternal ingestion of nuroleptic medications, lithium, antidepressants, anxiolytic sedatives, anticonvulsants, and bromides. The author feels that even though these drugs are generally safe, they must only be administered to pregnant women when absolutely needed, and then under vigilance.
About 3% of adult patients on a regimen of lithium carbonate develop a clinically visible goiter. Lithium reduces the conjugation of iodotyrosins as well as the secretion of thyroid hormones. Lithium crosses the placental barrier and might be teratogenic. The authors recently observed a prematurely born infant with large goiter whose mother had received lithium treatment throughout 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.
Lithium carbonate is considered to be a first-line drug in the management of manic depressive psychosis. According to Food and Drug Administration figures 0.1% of pregnant women are using this medication.1 During the last 2 decades accumulated data have suggested that lithium carbonate may be teratogenic in humans.2 The Danish registry has accumulated over 200 cases, among which there was a 10% occurrence rate of cardiac malformations.3 This rate appears high when compared to the 0.1% risk for such malformations in the general population.2 In particular, the Danish registry reported 8 cases of the rare Ebstein's anomaly which occurs spontaneously in only 1 of every 20,000 births, suggesting a relative risk of 500-fold above that in the general population.
The data of the Hungarian Case-Control Surveillance of Congenital Anomalies, 1980-1987, were evaluated concerning drug intake during pregnancy in 10,698 index patients, 21,546 negative controls, and 828 positive controls (Down syndrome). Excluding pregnancy supplements, the proportion of no drug use was about 30% and the mean number of drugs used was 2.0 in the negative control group. These figures did not differ significantly from data of study and positive control groups. The analysis of most commonly used drugs indicated an extremely high proportion of hormonal support therapy. The teratogenic effect of several human teratogenic drugs was confirmed. However, their use is relatively rare and their attributable risk within the etiology of congenital anomalies is low, at about 0.3-1.0%. At present the teratogenic risk of drugs in humans is exaggerated and it has several unfortunate consequences: negligence in necessary drug use, unnecessary anxiety in pregnant women, and termination of planned pregnancies without any reasonable cause.
Lithium is widely used in the treatment of bipolar affective disorders, and teratogenic effects include cardiovascular abnormalities, notably Ebstein anomaly. The most common side effect in the patient taking lithium is polyuria, a form of nephrogenic diabetes insipidus. We report the case of a manic-depressive gravida on lithium therapy who developed polyhydramnios in her last trimester. Because lithium crosses the placenta, we postulate that, by a similar mechanism, lithium may cause fetal polyuria which results in polyhydramnios. (Obstet Gynecol 76:517, 1990)
(C) 1990 The American College of Obstetricians and Gynecologists
Severe polyhydramnios, probably due to fetal lithium toxicity, is described. The mother had been treated with lithium because of manic-depressive psychosis. The plasma lithium level during the pregnancy was in or below the therapeutic range. From the 26th week of gestation, polyhydramnios developed. In the 35th week, 11.5 L of amniotic fluid was removed over a period of 12 hours by transabdominal amniocentesis. A cesarean delivery was performed in the 39th week of gestation because of fetal distress. The infant presented with the following symptoms, which in previous reports have been associated with lithium toxicity: asphyxia, apnea, cardiac decompensation, respiratory distress, hypoglycemia, thrombocytopenia, diabetes insipidus, hypotonia, and convulsions. The polyhydramnios was probably caused by fetal diabetes insipidus, possibly combined with cardiac decompensation. Lithium can be toxic to the infant and the fetus even though the mother is not affected and has a normal or low plasma lithium level. Polyhydramnios may be a sign of fetal lithium toxicity.
• Lithium carbonate is a widely used and invaluable drug in the treatment and prevention of manic-depressive illness. However, this medication has a low therapeutic index and, therefore, many attendant side effects. Acute lithium carbonate intoxication affects predominantly the central nervous system and the renal system and is potentially lethal. We studied a case of acute lithium carbonate intoxication characterized by a prolonged comatose state, severe nephrogenic diabetes insipidus, and glucose intolerance. Of interest, the patient's symptoms and signs of toxic reaction developed after normalization of the plasma lithium ion levels. We reviewed the multisystemic toxic effects of lithium carbonate as well as its teratogenic potential and guidelines for its use during pregnancy. The management of acute lithium carbonate intoxication should include hydration with normal saline, intensive care monitoring, and dialysis if indicated.
(Arch Intern Med 1989;149:36-46)
The article deals with Ebstein's anomaly, lithium and their relationship. Some studies suggest that lithium might be involved as a teratogen increasing the incidence of Ebstein's anomaly in the offspring of female patients with manio-depressive psychosis and lithium-administered during pregnancy. The second part of the article contains data on the incidence of Ebstein's anomaly in the Czech Socialist Republic between 1960 and 1985. The results indicate a steady rise in the incidence of this congenital malformation over the above period of time.
Although initially considered safe for the foetus, lithium has been shown to have teratogenic effects if used during the first trimester of pregnancy. Its use is also associated with a higher than expected frequency of still births and perinatal deaths. Our patient, in whom lithium prophylaxis was considered essential for clinical and social reasons, continued to take lithium without medical supervision throughout her pregnancy and had a still birth. We suggest avoiding the use of lithium at least during the first trimester of pregnancy.
The authors present a case in which lithium toxicity in a pregnant patient was avoided. If salt restriction and/or diuretics are necessary during lithium therapy in pregnancy, the authors recommend the careful monitoring of lithium side effects, dosage, and serum levels. Further, lithium therapy should be discontinued twenty-four hours prior to delivery and only restarted after post-delivery levels have been carefully reevaluated.
We have collected information about 118 children born to mothers who were given lithium treatment during the first trimester of pregnancy. The data show that the risk of teratogenic effects is lower than one might have expected from some of the studies carried out on rats and mice; they do not answer the question of whether or not lithium is teratogenic in man. The data were collected retrospectively and therefore overestimate rather than underestimate the risk of teratogenicity.
The use of lithium salts in the treatment of affective neurosis has recently become popular. There have been no reports of neonatal lithium toxicity although it is embryopathic in other species. A newborn whose mother received lithium during the last month of pregnancy is presented. The infant manifested a 10-day course of cyanosis and lethargy with serum lithium levels in the adult toxic range. It is suggested lithium be used with caution during pregnancy.
A manic patient on lithium carbonate treatment was discovered to be in the seventh month of pregnancy. The drug was continued until term with no untoward effects on the infant. During the first 10 days of life, the lithium was completely cleared from the newborn infant's blood in an exponential manner.
By record linkage of a discharge diagnosis registry and a medical birth registry we identified 350 women with manic-depressive disease who had born a child. The total delivery outcome was poorer than expected with a high perinatal death rate and a high malformation rate. Further studies revealed a high rate of perinatal deaths and/or congenital malformations among infants born of women who had used drugs in early pregnancy, and this phenomenon was concentrated to women who had used lithium and to heart defects. The sample is small, however, and there is no statistically significant difference between delivery outcome in women on lithium and in women on other psychotropic drugs. Until better risk estimates are obtained, lithium should not be used in early pregnancy.
• A newborn with massive tricuspid regurgitation, atrial flutter, congestive heart failure, and a high serum lithium level is described. This is the first patient to initially manifest tricuspid regurgitation and atrial flutter, and the 11th described patient with cardiac disease among infants exposed to lithium compounds in the first trimester of pregnancy. Sixty-three percent of these infants had tricuspid valve involvement. Lithium carbonate may be a factor in the increasing incidence of congenital heart disease when taken during early pregnancy. It also causes neurologic depression, cyanosis, and cardiac arrhythmia when consumed prior to delivery.
(Am J Dis Child 1981;135:941-943)
Severe transplacental lithium toxicity in a neonate is described. There were gross functional lesions of the cardiovascular, renal, and neuromuscular systems with no structural abnormalities. At 1 year of age cardiovascular and renal function is normal, but there is developmental delay.
We report a case of isolated atrial flutter in a neonate, attributable to maternal lithium treatment, and suggest that the assessment of all infants born to mothers on lithium treatment during pregnancy should include an electrocardiogram.
A case of lithium intoxication in the newborn is presented. Besides displaying extreme hypotonia and a goitre, the infant developed symptoms of congenital heart disease immediately after birth. Cardiac catheterization and angiocardiography revealed an elevated pulmonary vascular resistance and indicated that the cardiopulmonary symptoms were caused by persistent fetal circulation. Previously, four authors have independently reported cardiopulmonary symptoms in association with lithium intoxication without finding cardiac or pulmonary disease.
The similarity between the present and the four earlier reported cases in regard to the symptoms and the course of illness, raises the question of the connection between lithium intoxication and persistent fetal circulation being more than coincidental. In view of recent investigations it is speculated that lithium intoxication in utero may result in the pulmonary vascular changes responsible for the persistence of fetal circulation.
To reevaluate the risk associated with in utero exposure to lithium.
Data were obtained from all published studies, in multiple languages, referenced in MEDLINE, Toxline, and the Lithium Information Center databases. Unpublished studies were not included. The search terms were lithium, pregnancy, teratogen, abnormalities (drug induced), Ebstein's anomaly, and adverse effects.
In the 1970s a very strong association was suggested between maternal lithium treatment during pregnancy and Ebstein's anomaly of the heart in the offspring. The relative risk for Ebstein's anomaly among such children was estimated to be 400 on the basis of data collected from a registry of voluntarily submitted cases. More recent controlled epidemiologic studies have consistently shown a lower risk. No women who took lithium during pregnancy were found among four case-control studies of Ebstein's anomaly involving 25, 34, 59, and 89 affected children, respectively. In two cohort studies, risk ratios of 3.0 (95% confidence interval [CI], 1.2 to 7.7) and 1.5 (95% CI, 0.4 to 6.8) for all congenital anomalies have been observed. The risk ratios for cardiac malformations in these studies were 7.7 (95% CI, 1.5 to 41.2) and 1.2 (95% CI, 0.1 to 18.3), respectively.
While initial information regarding the teratogenic risk of lithium treatment was derived from biased retrospective reports, more recent epidemiologic data indicate that the teratogenic risk of first-trimester lithium exposure is lower than previously suggested. The clinical management of women with bipolar disorder who have childbearing potential should be modified with this revised risk estimate.
Lithium is widely used and the treatment of choice for patients with manic-depressive illness. For pregnant patients with manic-depressive illness, however, the use of lithium during the first trimester of pregnancy may present an increased risk for fetal maldevelopment. We have recently cared for several large-for-gestational-age, prematurely born infants whose mothers were treated with lithium throughout pregnancy. To determine whether maternal lithium use during pregnancy may predispose to the onset of premature labor and fetal macrosomia, we reviewed records from the International Register of Lithium Babies and from a cohort of manic-depressive pregnant women. More than one third (36%) of infants reported to the International Register were born prematurely, and 37% of the premature infants were large for gestational age; 15% of the term infants were born large for gestational age. In the cohort group, manic-depressive mothers who received lithium during pregnancy had a 2.5-fold higher incidence of premature births than manic-depressive pregnant patients who did not receive lithium treatment. The incidence of large-for-gestational-age births in lithium-treated women in the cohort was not different from that of the general population or from manic-depressive women not treated with lithium. In summary, an association between maternal lithium therapy and premature delivery is reported. We recommend that women receiving lithium therapy during pregnancy be closely monitored for the onset of premature labor.
Pregnancy poses major challenges for the treatment of bipolar disorder, and information to guide clinical care remains very sparse. The authors sought to determine the illness recurrence risk for women with bipolar disorder who discontinue lithium maintenance during pregnancy.
The authors retrospectively compared recurrence rates and survival functions for 101 women with DSM-IV bipolar disorder (68 type I, 33 type II) during pregnancy and postpartum (N=42) or during equivalent periods (weeks 1-40 and 41-64) for age-matched nonpregnant subjects (N=59) after either rapid (1-14 days) or gradual (15-30 days) discontinuation of lithium. Recurrence rates also were obtained for the year before discontinuing lithium.
Rates of recurrence during the first 40 weeks after lithium discontinuation were similar for pregnant (52%) and nonpregnant women (58%) but had been much lower for both in the year before treatment was discontinued (21%). Among subjects who remained stable over the first 40 weeks after lithium discontinuation, postpartum recurrences were 2.9 times more frequent than recurrences in nonpregnant women during weeks 41-64 (70% versus 24%). Depressive or dysphoric-mixed episodes were more prevalent in pregnant than nonpregnant women (63% versus 38% of recurrences). Recurrence risk was greater after rapid than after gradual discontinuation, and for patients with more prior affective episodes, but was similar for diagnostic types I and II.
Rates of recurrence during the first 40 weeks after lithium discontinuation were similar for pregnant and nonpregnant women but then sharply increased postpartum. Risk was much lower during preceding treatment and less with gradual discontinuation. Treatment planning for potentially pregnant women with bipolar disorder should consider the relative risks of fetal exposure to mood stabilizers versus the high recurrence risks after discontinuing lithium.
Critical appraisal techniques are not only useful in evaluating evidence of therapeutic trials. In this final article of the series of evidence-based psychopharmacology, the evidence about the teratogenic effects of lithium carbonate is considered. This exercise highlights the importance of assessing the evidence oneself and not relying on the interpretation others put on it.
The treatment of bipolar disorder has seen greater innovation in the past decade than at any other time since the introduction of lithium and the neuroleptics a half-century ago. The place of lithium in contemporary psychiatric therapeutics has become controversial, calling for the present overview of research findings pertaining to its use in treating patients with bipolar disorder. Lithium, by itself, typically is inadequate for rapid control of acute mania; antipsychotics, divalproex, or potent sedatives are commonly used, with or without lithium, for this purpose. The special usefulness of lithium lies in long-term prevention of recurrences of mania and bipolar depression and in reducing risk of suicidal behavior. Lithium also may be beneficial in recurrent unipolar depression and is an effective adjunct for treatment-resistant depression. Expectations that prolonged untreated bipolar illness, multiple episodes, rapid cycling, or retreatment following discontinuation might routinely lead to lithium nonresponsiveness, and the belief that lithium is too toxic for use during pregnancy, have not been borne out by research. Lithium retains a substantial share of prescriptions for bipolar disorder and is inexpensive. No other treatment has performed as well as lithium in as many aspects of long-term care of bipolar disorder patients, and despite some risks and limitations, lithium remains the standard against which all proposed alternatives are compared.
The purpose of this annual article is to highlight and briefly review new and significant information on agents that may be teratogenic in pregnant women. Various sources of on-line and printed information are given.
The following topics have been discussed: 1) lithium medication: decreased estimate of risk; 2) cigarette smoking and genotype as contributors to oral-facial clefts and clubfoot; 3) trimethoprim; 4) methimazole syndrome?; 5) glucocorticoids and oral-facial clefts; 6) binge drinking; 7) fetal valproate syndrome; and 8) carbamazepine.
We have highlighted several maternal exposures during pregnancy that are associated with small but increased rates of birth defects, generally only a few cases per 1,000 infants. These exposures include cigarette smoking, and treatment with lithium, trimethoprim, methimazole, or corticosteroids. This weak teratogenic effect was usually identified by the linkage of an uncommon treatment with an unusual birth defect outcome. The use of modern epidemiologic techniques, especially prospective multicenter studies that provide increased numbers, has helped to strengthen the evidence for these associations. We discuss how teratogenic risks that are small in comparison to the background risk can be presented to at-risk women and their doctors. We have briefly listed some elements that might be used in prioritizing further studies of suspected teratogenic exposures. Various existing methods for expressing the strength of evidence for human teratogenicity are also given.
Challenges for the clinical management of bipolar disorder (BD) during pregnancy are multiple and complex and include competing risks to mother and offspring.
We reviewed recent research findings on the course of BD during pregnancy and postpartum, as well as reproductive safety data on the major mood stabilizers.
Pregnancy, and especially the postpartum period, are associated with a high risk for recurrence of BD. This risk appears to be limited by mood-stabilizing treatments and markedly increased by the abrupt discontinuation of such treatments. However, drugs used to treat or protect against recurrences of BD vary markedly in teratogenic potential: there are low risks with typical neuroleptics, moderate risks with lithium, higher risks with older anticonvulsants such as valproic acid and carbamazepine, and virtually unknown risks with other newer-generation anticonvulsants and atypical antipsychotics (ATPs).
Clinical management of BD through pregnancy and postpartum calls for balanced assessments of maternal and fetal risks and benefits.
To report a case of neonatal goiter and biological hypothyroidism in a newborn exposed to lithium in utero resulting from therapy given to the mother before and during her pregnancy.
A male neonate, born at 37 weeks' gestation, presented with a goiter without other signs of hypothyroidism. His serum thyroid-stimulating hormone concentration was high and unbound tetrathyroxine concentration was low, indicating that chronic exposure to lithium was present. Oral thyroxine treatment was initiated when the infant was 3 days old and continued for 11 weeks. Treatment was effective in reducing the goiter and hormone concentrations, and allowing normal growth and psychomotor development during the following 3.5 months. Other drugs taken by the mother during pregnancy are not known to induce thyroid abnormalities.
Lithium is used for prophylaxis and treatment of bipolar disorder. Goiter and hypothyroidism in adults have been described in patients treated with lithium; thyroid disorders are reversible if lithium is discontinued. Few cases of goiter and hypothyroidism have been reported in newborns exposed to lithium in utero. In our patient, congenital hypothyroidism required longer thyroxine treatment than lithium-induced thyroid disorders. The delay before improvement seems to be similar to that observed in adults. The Naranjo probability scale indicated that lithium was the probable cause of hypothyroidism resulting from in utero exposure.
Lithium is a well-known goitrogenic agent. Thus, if lithium treatment needs to be continued during pregnancy in women with bipolar disorder, adequate screening for morphology by ultrasonography and systematic hormonal biological control in newborns are recommended.
Lithium medication during pregnancy is uncommon and the problems of a neonate who has been exposed to lithium represents a rare situation in neonatology. The clinical presentation and management of a newborn whose mother received lithium during pregnancy is presented. The newborn manifested a four day course of lethargy with unexplained high lithium levels in the adult toxic range. The infant improved clinically under intravenous hydration therapy, nevertheless lithium serum levels increased again and we did not know for certain if our clinical instinct or the actual figures were correct. Finally we noticed that our confusion had resulted from test tubes containing lithium heparine.