A safety evaluation of aripiprazole for treating schizophrenia during pregnancy and puerperium

Introduction: Aripiprazole (ARI) is a second-generation antipsychotic acting as a dopamine-serotonin system stabilizer and partial agonist at D₂ receptors. The drug is indicated in several and severe psychiatric disorders which are particularly frequent in women during the childbearing age.

Area covered: A systematic review of studies investigating the reproductive safety of ARI.

Expert opinion: For first trimester use, reviewed data provide no clear evidence about the safety of the drug for the developing fetus. However, a decline of plasma levels (PLs) throughout the pregnancy compared with PLs before pregnancy was observed. This finding suggests the need to increase the dosage during pregnancy in order to maintain stable PLs. If used during late pregnancy, some signals exist suggesting that ARI may worse neonatal outcomes. Hence, clinicians should consider withdrawing the drug before the last month of pregnancy to reduce the risks of neonatal complications. However, such risks must be weighed against the risks of woman’s symptom deterioration. In any case, parturition should happen in hospitals equipped with well-organized neonatal intensive care units. No information is available on the impact of antenatal exposure to ARI on the main neurodevelopmental milestones. Infant exposure to the drug through maternal milk may increase the risk of insufficient milk production and neonatal somnolence.     

Pregnancy exposure to second-generation antipsychotics and the risk of gestational diabetes

Introduction: Assessment of the metabolic safety of second-generation antipsychotics (SGAs) is mandatory in pregnant women, where the occurrence of metabolic complications and, especially, gestational diabetes mellitus (GDM) may severely impact on pregnancy and fetal outcomes.

Areas covered: The aim of this article is to review published data reporting the occurrence of GDM during SGA treatment, and to establish whether or not this iatrogenic complication is a relevant concern in clinical practice. Medical literature information published in any language since 1996 was identified using MEDLINE/PubMed, EMBASE, Scopus, and The Cochrane Library. All articles reporting metabolic complications in pregnancies exposed to single, specific SGAs were acquired, without methodological or language limitations.

Expert opinion: Among studies assessing the metabolic safety of specific SGAs, we have 18 cases of GDM overall: 5 cases involve clozapine (CLO), 9 olanzapine (OLA) - the SGA agent that shows the highest number of reported cases of pregnancy exposure - and 2 each for quetiapine and risperidone. Four of these cases, 2 involving CLO and 2 OLA, were complicated by serious fetal and/or neonatal consequences. Such reports of SGA-associated GDM, together with preliminary data coming from retrospective and prospective studies, may represent signals of a potential safety issue.     

Antipsychotic use in elderly patients and the risk of pneumonia

Antipsychotics are frequently and increasingly prescribed off-label for the treatment of behavioral and psychological symptoms associated with dementia, despite their modest efficacy. Instead, the safety profile of antipsychotics has been questioned repeatedly in recent years with various concerns, including death. Meta-analyses of randomized controlled trials found that one of the major causes of death associated with atypical antipsychotics use was pneumonia. Only few observational studies, however, have investigated the risk of pneumonia in elderly patients, especially among those receiving conventional antipsychotics. The aim of this editorial is to synthesize the current evidence from observational studies regarding the risk of pneumonia in elderly patients receiving either conventional or atypical antipsychotics. The studies conducted so far document that the risk of pneumonia is two- to threefold increased in a dose-dependent fashion with both classes compared to nonuse, with a possibly higher risk attributable to atypical antipsychotics. The risk seems to peak at the beginning of treatment (e.g., 7 – 30 days), and dissipates over time for both conventional and atypical antipsychotics. The risk–benefit ratio suggests that there will be 1 excess hospitalization for pneumonia for every 2 – 5 patients receiving any clinical improvement in symptoms. Considering the modest improvement in terms of efficacy, the risks associated with antipsychotics in elderly patients may outweigh their benefit.     

Hyperprolactinemia,Clinical Considerations,and Infertility in Women on Antipsychotic Medications

Infertility, the inability to establish a clinical pregnancy after 12 months of regular unprotected sexual intercourse, is caused by a wide variety of both male and female factors. Infertility is estimated to affect between 8–12% of couples trying to conceive globally. Female factor infertility can be subdivided into the following broad categories: ovulatory dysfunction, fallopian tubal disease, uterine causes, and oocyte quality. Hyperprolactinemia causes ovulary dysfunction along with other hormonal abnormalities, such as decreased estrogen, which can lead to infertility. In this regard, antipsychotics are commonly used for both schizophrenia and bipolar disorder. The use of these medications can be associated with hyperprolactinemia and hyperprolactinemia associated infertility. Antipsychotic-induced hyperprolactinemia occurs through blockade of D₂ receptors on lactotroph cells of the anterior pituitary gland. Discontinuation of the hyperprolactinemia-inducing antipsychotic is an option, but this may worsen the patient’s psychosis or mood. If antipsychotics are determined to be the culprit of infertility, the degree of hyperprolactinemia symptoms, length of treatment with the antipsychotic, and risk of relapse should be assessed prior to discontinuation, reduction, or switching of antipsychotic medications. The treatment of a women’s mental health and her desire to have children should always be considered as treatment may influence fertility while on the medication.     

Antipsychotics in clinical practice: guidelines for safe and effective use

Antipsychotic drugs have made a significant contribution to the treatment of schizophrenia but the older drugs in particular have significant side-effects. The newer atypical drugs are effective for the treatment of both positive and negative symptoms and they also have significantly fewer serious side-effects. However, these drugs are considerably more expensive that the older drugs and this has generated intense debate about their cost effectiveness. There is now good evidence that when all factors are taken into consideration the atypical drugs are both cost effective and improve the quality of life of patients with schizophrenia. Despite the importance of these drugs there is widespread variation in their use and a national consensus on this important issue is long overdue.     

The pharmacology of bipolar disorder during pregnancy and breastfeeding

Treating bipolar disorder in women during reproduction presents a significant challenge to the physician. The pharmaceutical agents most commonly used for treating bipolar disorder have been associated with adverse effects when used during pregnancy and breastfeeding. Of particular concern has been the association of lithium with cardiac malformations, and the association of carbamazepine and valproate with neural tube defects including spina bifida. Toxicity in neonates has also been reported for the most commonly used mood-stabilising agents. Treatment options for mood stabilisation are either associated with risks of adverse advents, have been used less frequently and their associated risks are unknown, or may not provide effective prophylaxis against recurrences of bipolar episodes. However, strategies are available that minimise the risk to the fetus and infant whilst still providing effective prophylaxis against bipolar disorder in the mother. Ideally, a treatment regimen tailored to suit the individual should consider both mother and baby and should be planned prior to conception.     

Lithium in pregnancy: the need to treat,the duty to ensure safety

Introduction: Untreated bipolar disorder during pregnancy leads to detrimental repercussions on the mother–infant pair's health. Despite different drugs having been proposed as mood stabilizers, lithium remains the first-choice agent for preventing mood changes.

Areas covered: Analyzing up-to-date information on the reproductive safety of lithium and providing practice guidelines to optimize its use during pregnancy.

Expert opinion: Findings from prospective and case–control studies confirm an increased, specific risk of Ebstein's anomaly (4.45–7.6/1000 live births), although lower than that previously reported. A potential increase in the risk of neural tube defects should also be taken into consideration. Moreover, several perinatal complications may occur, and even in the presence of relatively low infant serum levels, in the case of drug exposure during late pregnancy. Despite such concerns, lithium should still be considered the first-choice agent for treating bipolar disorder in pregnancy. Indeed, the U.S. FDA recently issued a new warning regarding the reproductive safety of antipsychotics. Moreover, the risk of fetal valproate/carbamazepine syndrome (and the confirmed neurodevelopmental teratogenicity of valproate) contraindicates the use of both medications, whereas the use of lamotrigine is limited by efficacy concerns. However, women who need lithium treatment during pregnancy should be carefully monitored: a strict gynecologic and psychiatric surveillance and, probably, preconception folate supplementation is highly advisable. Moreover, delivery should be programmed in Neonatal Intensive Care Units to ensure optimal management of potential iatrogenic perinatal complications.     

Antipsychotic Trials in Schizophrenia from India: A Systematic Review and Meta-analysis

Ethnic and regional variations have been found in the pharmacological treatment response. Though many efficacy studies have been conducted in India for antipsychotic treatment modalities of schizophrenia, there is a lack meta-analytic data of the existing literature from India. This study aimed to conduct a systematic review and meta-analysis of the antipsychotic treatment trials of schizophrenia in the Indian context. All controlled trials from India evaluating the clinical efficacy of antipsychotics in patients with schizophrenia were evaluated and 28 trials were included in the metanalysis. Effect sizes were computed using Cohen''s ‘d’ and risk of bias was evaluated. Meta analysis revealed superiority of first generation antipsychotics over placebo (mean effect size of 1.387, confidence interval of 1.127 to 1.648). Second generation antipsychotics were marginally better than first generation antipsychotics (effect size 0.106, confidence intervals 0.009 to 0.204). There was improvement in the methodology of the trials over time (Kendall tau=0.289, P=0.049), though no statistically significant increase in trial duration and sample size was noted. There is lack of data on long term efficacy of antipsychotic in schizophrenia from India. First generation antipsychotics have demonstrated benefits over placebo in patients with schizophrenia in the Indian context, though marginally lesser than second generation ones.     

抗精神分裂症口服药物门诊应用分析

目的了解门诊抗精神分裂症口服药使用现状,评价该类药物门诊应用的合理性。方法对我院2006~2008年门诊抗精神分裂症药物的用药频度(DDDs)、每日药费(DDDc)、消耗量及销售金额等进行统计分析。结果我院门诊非典型性抗精神分裂症药物应用呈上升趋势,其中以利培酮应用前景看好。DDDs排序前3位为药物费用较低者。结论我院抗精神分裂症口服药物应用基本合理。     

Lamotrigine use in pregnancy

Lamotrigine is a sodium-channel-modulating, antiepileptic drug (AED), which was approved in the USA in 1994 for use in partial-onset seizures. It was ultimately approved for monotherapy in 1998. Lamotrigine has gained widespread use in the USA as both an immediate and an extended-release agent. Lamotrigine is effective against a broad spectrum of seizure types and has a favorable metabolic profile, with few but significant drug interactions. Pregnancy registries in several countries have demonstrated that AED use in women with epilepsy is associated with an increased risk of fetal malformations, if the infant is exposed during the period of organogenesis. In addition, new evidence demonstrates that AEDs may affect the intellectual development of a child, as measured up until the age of 3 years. This information has made the choice of an anticonvulsant for a woman who might become pregnant significantly more important. Pregnancy registries have consistently demonstrated lamotrigine to be among the safest medications for a developing fetus, both in terms of fetal malformations and postpartum cognitive development. These findings make lamotrigine probably the first choice of AED for women wishing to become pregnant and for whom the medication is appropriate.     

妊娠中晚期高危妊娠胎心率电子监护异常分析

目的 评价妊娠中晚期实施胎心监护的临床效果和意义.方法 对福建省妇幼保健院收治的596例实施中晚期胎心监护的高危孕妇其胎心电子监护结果进行分析,并与121例外院转入未实施中晚期胎心监护的高危妊娠孕妇比较其妊娠结局.结果 两组人群基本人群社会资料构成一致,中晚期妊娠胎心率从32周到36周逐渐下降趋势.胎心监护异常的高危妊娠孕妇平均胎心率低于胎心监护正常的高危孕妇(P<0.05).实施中晚期胎心监护的高危妊娠产妇其顺娩率和阴道助产率显著高于未实施中晚期胎心监护者(P<0.05).结论 对高危妊娠产妇实施中晚期胎心监护有积极的意义,能够更好保障高危妊娠孕妇的母婴健康,值得推广.     

First trimester exposure to cefuroxime: a prospective cohort study

AIMS: There are no published studies on the safety of cefuroxime use during pregnancy. We therefore investigated prospectively the possible teratogenic effect of intrauterine exposure to cefuroxime. METHODS: One hundred and six women who received cefuroxime during the first trimester of pregnancy were recruited from three teratogen information centres in Israel. Exposed women were paired for age, smoking habits and alcohol consumption with references being exposed to nonteratogenic antibiotics administered for the same indications. RESULTS: Maternal history, birthweight, gestational age at delivery, rates of live births, spontaneous abortions and fetal distress were comparable among the two groups. Rates of major malformations in the cefuroxime group (3.2%) did not differ from references (2%) (P = 0. 61, relative risk = 1.56, 95% confidence interval 0.27-9.15). There was a significantly higher rate of induced abortions among the cefuroxime exposed women as compared to the references (P = 0.04, relative risk = 3.33, 95% confidence interval 0.94-11.77). CONCLUSIONS: Our data may suggest that exposure to cefuroxime during the first trimester is probably not associated with an increased risk for malformations or spontaneous abortions; however, in light of the small sample size and the broad confidence limits, larger studies are needed to confirm these findings.     

The safety of drugs for the treatment of nausea and vomiting of pregnancy

Nausea and vomiting of pregnancy (NVP) is the most common medical condition of pregnancy, affecting up to 80% of all pregnancies to some degree. In most cases it subsides by the week 16 of pregnancy, although up to 20% of women continue to have symptoms throughout pregnancy. Severe NVP (Hyperemesis gravidarum) affects < 1% of women and in some severe cases can require hospitalization and rehydration of fluids. Women suffer not only physically but also psychologically, which has been documented in a number of studies. In addition, some women have decided to terminate their pregnancy rather than tolerate severe symptoms. Even less severe cases of NVP can have significant adverse effects on the quality of a woman's life, affecting her occupational, social, domestic functioning and general well being. Therefore, it is of great importance to treat this condition effectively to improve the quality of life for these women. In this paper, the authors review different classes of antiemetics used to treat this condition and discuss that some have better safety profiles than others, but most appear to be safe to use in pregnancy. Also included is a treatment algorithm that can assist the healthcare provider in treating this condition in pregnant safely and effectively.     

Newer antidepressants in pregnancy and rates of major malformations: a meta-analysis of prospective comparative studies

BACKGROUND: A substantial number of women of childbearing age suffer from depression. Despite this, relatively little is known about the safety of antidepressant use during pregnancy. PURPOSE: We conducted a meta-analysis of prospective comparative cohort studies to quantify the relationship between maternal exposure to the newer antidepressants and major malformations. METHODS: We searched Medline, Embase and Reprotox from 1996 to the present for studies comparing outcomes in first trimester exposures to citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, reboxetine, venlafaxine, nefazodone, trazodone, mirtazapine and bupropion to those of non-exposed mothers. Data were combined using a random effects model; heterogeneity was tested with chi2, and publication bias with a funnel plot and the Begg-Mazumdar statistic. RESULTS: Twenty-two studies were identified, 15 were rejected (4 reviews, 4 without comparison groups, 2 third trimester exposures, 2 retrospective database studies, 2 case reports and 1 duplicate); 7 studies (n = 1774) met inclusion criteria. Effects were not heterogeneous (chi2 = 2.04, p = 0.92); funnel plot and test (tau = -0.24, p = 0.45) indicated no publication bias. The summary relative risk was 1.01 (95%CI: 0.57-1.80). CONCLUSIONS: As a group, the newer antidepressants are not associated with an increased risk of major malformations above the baseline of 1-3% in the population.