Expert advice on the management of valproate in women with bipolar disorder at childbearing age

IntroductionThe perinatal period is associated with up to 2/3 relapses in untreated bipolar disorder (BD), with important consequences on the clinical BD outcome and on fetal and child development. Valproate (VPA), one of the most effective treatments in BD, is associated with the highest risk of serious neurodevelopmental disorders in exposed children. This has brought to tightened restrictions to its use by regulatory agencies and clinical guidelines.MethodsA panel of experts on the pharmacological treatment of BD conducted a non-systematic review of the scientific literature and clinical guidelines until March 2019, and provided specific evidence-based and experience-based clinical recommendations for VPA switching/discontinuation in BD women of childbearing potential.ResultsAfter the review of the evidence in a face-to-face meeting, the panel concluded that several clinical criteria need to be considered to make a clinical decision about VPA discontinuation and switch. The plateau cross-taper switch may be preferred. Abrupt switching may bear augmented risk of relapseConclusionsBD childbearing women treated with VPA must be managed on a personalized basis according to the clinical situation. It is mandatory to stop VPA during pregnancy. The duration of the discontinuation/switch process depends on different clinical variables. Lithium, lamotrigine, quetiapine, olanzapine or aripiprazole are good options for switch in stable BD patients in planned/unplanned pregnancy. In unstable BD patients planning pregnancy, stability is paramount. Prevention of post-partum episodes requires reinstatement of effective treatment before or after birth (in the case of VPA). VPA is still an option in the post-partum period and beyond.     

Safety of therapeutic options for treating asthma in pregnancy

Introduction: Pregnancy may be complicated by new onset or preexisting asthma. Asthma is one of the most common potentially serious medical problems to complicate pregnancy, and it may adversely affect both maternal quality of life and perinatal outcomes. Optimal management of asthma during pregnancy is thus important for both mother and baby.

Areas covered: This article reviews the recognition and management of asthma during pregnancy, paying close attention to the general principles of asthma medication use during pregnancy. Further, the article reviews the safety of asthma medications commonly used during pregnancy. In this article, the most pertinent recent publications are reported. Electronic databases, such as PUBMED, were searched for terms pregnan* or perinat* or obstet* and asthma or wheeze and treatment.

Expert opinion: Because pregnant women are generally excluded from clinical trials, there is a lack of adequate safety information for most medications taken during pregnancy. One of the most important requirements for the future is the availability of further safety information for asthma medications used during pregnancy that can also account for asthma control.     

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.     

Pharmacological difficulties in the treatment of asthma in pregnant women

Introduction: This is a review of the diagnosis and management of asthma in the pregnant patient. Asthma may adversely affect both maternal quality of life and, perinatal outcomes. Optimal management of asthma is thus important for both mother and baby.

Areas covered: Special attention is paid to the challenges in diagnosis and management of asthma during pregnancy.

Expert commentary: This article reviews the safety of asthma medications commonly used during pregnancy.     

Current challenges in the pharmacological management of thyroid dysfunction in pregnancy

Introduction: Thyroid dysfunction is common in pregnancy and has adverse fetal and maternal health consequences. A number of challenges in the management of gestational thyroid dysfunction remain unresolved including uncertainties in optimal thresholds for correction of hypothyroidism and strategies for pharmacological management of hyperthyroidism.

Areas covered: We addressed key challenges and areas of uncertainty in the management of thyroid dysfunction in pregnancy.

Expert commentary: Gestational thyroid hormone reference intervals vary according to population ethnicity, iodine nutrition, and assay method and each population should derive trimester specific reference intervals for use in pregnancy. Subclinical hypothyroidism and isolated hypothyroxinaemia are common in pregnancy but there is no consensus on the benefits of correcting these conditions. Although observational studies show potential benefits of levothyroxine on child neurocognitive function these benefits are have not been supported by two controlled trials. Carbimazole should be avoided in the first trimester of pregnancy due to risk of congenital anomalies but recent studies would suggest that this risk is present to a lesser magnitude with propylthiouracil. Current international guidelines recommend the use of propylthiouracil in the first trimester and switching to carbimazole for the remainder of pregnancy but the benefits and practicalities of this approach is unproven.     

Treating diabetes during pregnancy

Introduction: Gestational diabetes mellitus (GDM), defined as glucose intolerance with first recognition or onset during pregnancy, is steadily rising in prevalence. GDM affects ～ 3 – 5% of pregnancies in the US and is associated with significant adverse perinatal and maternal outcomes. Diagnosing and treating GDM early in pregnancy is of utmost importance as it can prevent poor outcomes such as macrosomia, shoulder dystocia and obstetric complications.

Areas covered: This review describes the importance of treating GDM and the various available interventions for glycemic control in women with GDM, including the latest evidence regarding pharmacological treatments and specifically anti-hyperglycemic agents. It deals with timing of pharmacological treatments, recommended doses and what pharmacological agent should be used.

Expert opinion: Unless diagnosed late during pregnancy, a stepwise approach is the best way to treat GDM, beginning with diet and exercise and proceeding to pharmacological interventions if failure occurred. Although insulin is the dominant treatment, the use of anti-hyperglycemic agents such as glyburide and metformin in treating GDM has gained popularity and consideration should be made using these agents as first-line pharmacological treatment. Anti-hyperglycemic agents do not require frequent monitoring or injections and may therefore appeal more to patients. Further studies are needed regarding long-acting insulin and other anti-hyperglycemic agents such as thiazolidinediones, as well as identifying treatment options more specific to an individual based on risk factors and other variables predicting treatment outcomes in GDM.     

Migraine therapy during pregnancy and lactation

Importance of the field: Migraine affects about 25% of women during childbearing years but few data are available about the risks connected with most antimigraine drugs during pregnancy.

Areas covered in this review: In this report, we review the available data, mainly obtained from published studies, toxicology databases and clinical guidelines, on migraine treatment during pregnancy and lactation.

What the reader will gain: The following drugs should be preferred for the treatment of acute migraine attacks in pregnant women: paracetamol, NSAIDs and sumatriptan. Migraine prophylaxis should be undertaken when patients experience at least three prolonged severe attacks a month that are particularly incapacitating or unresponsive to symptomatic therapy and likely to result in complications. Non-pharmacologic approaches should be preferred, but if they are not effective, preventive treatment should include low doses of β-blockers and amitriptyline.

Take home message: Migraine treatment is often necessary because maternal and fetal risks related to acute attacks may be more harmful than the therapy itself, especially if they are frequent, severe and associated with nausea, anorexia, vomiting, hypotension or dehydration. If non-pharmacologic treatments do not alleviate migraine symptoms, only few drugs can be used during pregnancy and lactation.     

Pharmacotherapy options to treat asthma during pregnancy

Introduction: Pregnancy may be complicated by new onset or pre-existing asthma. This article reviews the recognition and management of asthma during pregnancy, paying close attention to the general principles of asthma medication use during pregnancy. Asthma is one of the most common potentially serious medical problems to complicate pregnancy, and asthma may adversely affect both maternal quality of life and perinatal outcomes. Therefore, optimal management of asthma during pregnancy is important for both mother and baby. This article reviews asthma pharmacotherapy during pregnancy, with an emphasis on gestational safety of commonly used medications.

Areas covered: In this review of asthma pharmacotherapy during pregnancy, the most pertinent recent publications are reported. Electronic databases such as PubMed were searched for terms pregnan* or perinat* or obstet* and asthma or wheeze and treatment.

Expert opinion: Although retrospective data have been reassuring, since pregnant women are generally excluded from clinical trials, there is a lack of adequate safety information for most medications taken during pregnancy. One of the most important needs for the future is the availability of further safety information for asthma medications used during pregnancy that can also account for asthma control.     

Synthetic therapeutics for the treatment of hepatitis B during pregnancy

ABSTRACT

Introduction: Hepatitis B infection in pregnancy mandates careful monitoring and specialized management according to the phase of hepatitis B infection. Perinatal transmission may be prevented by antiviral therapy in mothers with high viral load and timely immunoprophylaxis of the infant.

Areas covered: This review focuses on the current first-line therapies for treating hepatitis B in pregnancy, timing of therapy, and prevention of perinatal transmission. Strategies to manage disease at the various phases and potential emerging therapies in phase III of development are also covered. Medline/PubMed and Cochrane databases were searched systematically from 1990 to April 2018 with the relevant articles selected for the review.

Expert opinion Universal antenatal screening for hepatitis B and strict immunoprophylaxis for infants form the cornerstones to prevent hepatitis B virus (HBV) perinatal transmission. Tenofovir is the preferred drug for treatment in pregnancy in view of its good efficacy and high barrier to resistance. Most of the data on antivirals are from cohort studies which are prone to bias and more randomized controlled trials (RCTs) are needed to establish the benefits and safety of these drugs in pregnancy. Various novel drugs are in the pipeline which may pave the way for a cure in the near future.     

Two consecutive singleton pregnancies versus one twins pregnancy as preferred outcome of in vitro fertilization for mothers and infants: a retrospective case–control study

Objective Many infertile couples request a multiple embryo transfer because they desire more than one child. Based on this consideration, the current study aimed to compare the reproductive and perinatal outcomes of two consecutive singleton pregnancies versus one twin pregnancy in a large cohort of in vitro fertilization (IVF) patients.

Research design and methods Retrospective analysis of data from patients with clinical twin pregnancy after IVF fresh cycles and from patients with two consecutive IVF fresh cycles and clinical singleton pregnancy.

Main outcome measures Miscarriage rate, delivery rate, gestational age at birth, neonatal birth weight, and perinatal complications. A sub-analysis of data according to vanishing twin syndrome (VTS) was also performed.

Results A total of 18,703 autologous fresh cycles were analyzed. One hundred seven patients had two consecutive singleton clinical pregnancies, whereas one clinical twin pregnancy occurred in 641 women. In patients who had two consecutive singleton clinical pregnancies the rates of overall pregnancies lost (odds ratio [OR] 4.9, 95% confidence interval [CI] 3.4, 6.9) and live births (OR 0.2, 95% CI 0.1, 0.3) were, respectively, higher and lower when compared to patients who had one clinical twin pregnancy. That data did not change after sub-analysis for VTS. The overall risk of perinatal complications was significantly higher in patients who had one twin delivery rather than patients who had two consecutive singleton deliveries (OR 31.8, 95% CI 14.1, 71.5). No difference between groups was detected in terms of intrauterine/neonatal deaths, perinatal mortality and neonatal intensive care unit admission. Data did not change after adjusting for confounders.

Conclusions When compared with two consecutive singleton pregnancies, twin pregnancies are characterized by higher success rates but worse perinatal outcomes irrespectively of VTS. Well designed prospective controlled studies are needed to confirm or rebut current retrospective findings.     

Selective serotonin reuptake inhibitor use in pregnant women; pharmacogenetics,drug-drug interactions and adverse effects

Introduction: Possible negative effects of selective serotonin reuptake inhibitors (SSRIs) in pregnancy relate to congenital anomalies, negative perinatal events and neurodevelopmental outcome. Many studies are confounded by the underlying maternal disease and by pharmacogenetic and pharmacokinetic differences of these drugs.

Areas covered: The possible interactions of SSRIs and serotonin and norepinephrine reuptake inhibitors with other drugs and the known effects of SSRIs on congenital anomalies, perinatal and neurodevelopmental outcome.

Expert opinion: SSRIs should be given with caution when combined with other drugs that are metabolized by cytochrome P450 enzymes. SSRIs apparently increase the rate of severe cardiac malformations, induce neonatal adaptation problems in up to 30% of the offspring, increase the rate of persistent pulmonary hypertension of the newborn and possibly slightly increase the rate of prematurity and low birth weight. Most neurodevelopmental follow up studies did not find significant cognitive impairments except some transient gross motor delay, slight impairment of language abilities and possibly behavioral changes. The literature on the possible association of SSRIs with autism spectrum disorder is inconsistent; if an association exists, it is apparently throughout pregnancy. The risk associated with treatment discontinuation seems to outweigh the risk of treatment, as severe maternal depression may negatively affect the child’s development. If needed, treatment should continue in pregnancy with the minimal effective dose.     

Current knowledge and challenges of antimalarial drugs for treatment and prevention in pregnancy

Importance of the field: Malaria infection during pregnancy is a major public health problem worldwide, with 50 million pregnancies exposed to the infection every year. Approximately 25,000 maternal deaths and between 75,000 and 200,000 infant deaths could be prevented each year by effective malaria control in pregnancy. Antimalarial drug treatment and prevention has been hampered by the appearance of drug resistance, which has been a particular problem in pregnancy due to the inherent safety issues.

Areas covered in this review: New antimalarial drugs and combinations are being studied but there is not yet sufficient information on their efficacy or, more importantly, on their safety in pregnancy. This article provides an overview of the relevance of the topic and reviews the current antimalarial drugs recommended for pregnancy, as well as the guidelines for both treatment and prevention in women living in endemic areas and for travellers.

What the reader will gain: Updated information on the drugs currently used for malaria treatment and prevention in pregnancy, including new drugs under development, is provided. The gaps on efficacy and safety information for use during pregnancy are also discussed.

Take home message: Prevention and case management of malaria during pregnancy is based on risk–benefit criteria and poses one of the greatest challenges to current malaria control.     

Peripartum mental health and the role of the pharmacist: A scoping review

BackgroundThe global prevalence of peripartum mental illness is 20%, though estimates have increased since the start of the COVID-19 pandemic. Chronic illnesses affect one in five pregnancies and may be associated with higher rates of peripartum mental illness. Though pharmacists are well-positioned to facilitate appropriate and timely care of co-occurring mental and physical health conditions during this period, little is understood regarding their potential roles.ObjectivesTo understand the current evidence examining the role of pharmacists to improve the outcomes of women with peripartum mental illness, with and without chronic illness.MethodsA scoping review was performed with assistance from an interdisciplinary team following the Joanna Briggs Institute framework. MEDLINE, Embase, PsychNet and International Pharmaceutical Abstracts databases were searched. English-language articles (published up to May 30, 2022) were screened and assessed for eligibility, and data were charted to collate results, by dual independent reviewers.ResultsThe search strategy produced 922 articles. After screening, 12 articles were included (5 narrative reviews, 7 primary research). There was limited discussion or empirical data regarding specific interventions (screening, counseling), opportunities (accessibility, managing stigma, forming trusting relationships and building rapport with patients) or barriers (lack of privacy, time constraints, adequate remuneration, training) associated with an expanded role of pharmacists in peripartum mental health care. The clinical complexity arising from co-occurring mental health and chronic illnesses was not explored, other than a small pilot study involving pharmacists screening for depression among pregnant women with diabetes.ConclusionsThis review highlights the limited evidence available on the explicit role of pharmacists in supporting women with peripartum mental illness, including those with comorbidity. More research, including pharmacists as study participants, is required to fully understand the potential roles, barriers, and facilitators of integrating pharmacists into peripartum mental healthcare to improve the outcomes of women in the peripartum period.     

Emerging drugs for bipolar disorder

Importance of the field: Bipolar disorder (BD) is a chronic mental illness characterized by the alternation of abnormal mood episodes with periods of remission. It results in important functional and psychosocial disability, as well as high rates of suicide. For many patients with BD, existing treatments do not provide sufficient management, and high rates of relapse and lingering residual symptoms are common.

Areas covered in this review: The present article is a comprehensive literature review focusing on novel pharmacological treatments for BD. The database PubMed (1990 – 2010) was searched, using the MeSH terms ‘bipolar disorder’ and ‘therapeutics’. In addition, a manual search of bibliographical cross-referencing was performed. The papers obtained through the search strategy described above were manually screened for original articles, reviews and case reports emphasizing novel treatments for BD.

What the reader will gain: New pharmacological approaches are discussed here in detail, highlighting their possible mechanisms of action, their potential use in the different phases of the disease and their effect on specific symptoms, such as cognitive impairment.

Take home message: Most of the emergent drugs for BD seem to be particularly promising in the treatment of bipolar depression, and there is a trend in the identification of drugs targeting less explored pathophysiological mechanisms found in BD. However, results regarding most of them are still preliminary, and additional studies are necessary to clarify their real role in the clinical management of BD.     

Challenges and treatment options for rheumatoid arthritis during pregnancy

Introduction: Rheumatoid arthritis (RA) can spontaneously improve during pregnancy. However, a considerable proportion of patients can experience a flare and high disease activity has been associated with an increased risk of adverse pregnancy outcome. Thus, the treatment of RA in pregnant women should be selected taking into account both the potential harmful effects of the treatment and the risk associated with discontinuation.

Areas covered: Recent publications regarding safety of the most important disease modifying anti-rheumatic drugs (DMARDs) during pregnancy has been reviewed. A systematic literature search of MEDLINE was conducted using pregnancy, teratogenicity, adverse effects, embryo/foetal-toxicity as key search terms for each DMARD.

Expert opinion: A great body of evidence suggest that hydroxychloroquine, sulfasalazine, and non-fluorinated steroids can be continued throughout pregnancy, while methotrexate and leflunomide should be discontinued 3 months before pregnancy. Continuation of TNFi during the first part of pregnancy should be considered when benefits outweigh the potential risk of teratogenicity. Data regarding other biologics are scant and, at present, they should be stopped before pregnancy.     

Cost-effectiveness of insulin aspart compared to human insulin in pregnant women with type 1 diabetes in the UK

ABSTRACT

Objectives: In women with type 1 diabetes, poor glycaemic control during pregnancy is associated with high risk of pre-term delivery, perinatal mortality and morbidity. This economic analysis utilises clinical effectiveness data from the Insulin Aspart Pregnancy Study Group Trial to assess costs and outcomes associated with insulin aspart (IAsp) and human insulin (HI) as part of a basal-bolus insulin regimen in pregnant women with type 1 diabetes in the UK.

Research design and methods: Women with type 1 diabetes were enrolled if ≤?10 weeks pregnant or planning to become pregnant, and had HbA_1c ≤?8% at confirmation of pregnancy. Subjects were randomised to treatment with IAsp or HI in a basal-bolus regimen with NPH insulin, with doses titrated according to American Diabetes Association guidelines. An effectiveness endpoint, retrospectively defined for this analysis, was the percentage of women with a live birth at term (≥37 weeks’ gestation). We considered costs of insulin, adverse events, delivery, and neonatal care for pre-term infants. Expected need for neonatal care was estimated from gestational age, using data from the literature and a large UK hospital. Costs were calculated from the perspective of the UK National Health Service.

Results: A total of 322 pregnant women were enrolled in the study and the outcome of pregnancy was known for 302, 151 in each arm. More women experienced a live birth at term with IAsp (72.8%) than with HI (60.9%), difference 11.9% (95% CI 2.0%, 22.5%, p?=?0.028). Mean cost per woman was £3222 for IAsp and £3539 for HI, difference ?£318 (95% CI ?£1353, £576; p?=?0.49).

Conclusions: Compared with HI, the use of IAsp in pregnant women with type 1 diabetes resulted in more live births at term, without increasing total costs of treatment. A prospectively defined study is required to confirm these conclusions.     

基质细胞衍生因子-1与N末端脑钠肽原对围生期心肌病的评估价值

目的 探讨基质细胞衍生因子-1（SDF-1）与N末端脑钠肽原（NT-proBNP）对围生期心肌病的评估价值。方法 选择2012年2月-2017年1月在南阳市第二人民医院产科诊治的围生期心肌病患者60例作为观察组,同期选择在该院进行体检的围生期妇女60例作为对照组,两组都进行SDF-1与NT-proBNP检测,同时进行超声观察与判断。结果 观察组的左房内径和室间隔厚度都明显高于对照组,差异有统计学意义（P < 0.05）;两组右室内径与左心室射血分数对比差异无统计学意义。观察组与对照组的血清NT-proBNP浓度分别为（2.22±0.33）pg/mL和（1.13±0.24）pg/mL,观察组明显高于对照组,差异有统计学意义（P < 0.05）。观察组的SDF-1 3''A基因型频率为41.7%（25/60）,对照组为20.0%（12/60）,观察组明显高于对照组,差异有统计学意义（P < 0.05）。logistic回归分析显示NT-proBNP、SDF-1 3''A基因型、左心室射血分数都为导致围生期心肌病发生的主要独立危险因素（P < 0.05）。结论 SDF-1与NT-proBNP对围生期心肌病有很好的评估价值,能有效判断疾病状况,也是围生期心肌病发生的独立危险因素。     

Augmenting pharmacotherapy with neuromodulation techniques for the treatment of bipolar disorder: a focus on the effects of mood stabilizers on cortical excitability

ABSTRACT

Introduction: Mood stabilizers and antipsychotics have been demonstrated to be effective in Bipolar Disorder, with lithium as the gold standard. However, the presence of adverse events and treatment-resistance is still a relevant issue. To this respect, the use of brain stimulation techniques may be considered as an augmentation strategy, with both Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS) having shown some level of efficacy in bipolar patients although clinical trials are still not sufficient to draw any conclusion.

Areas covered: The authors have conducted a systematic review of the literature, in order to evaluate the role of mood stabilizers on neural activity and cortical excitability. Furthermore, the article reviews neuromodulation techniques and highlights the potential of integrating pharmacological first-line therapies with these techniques to treat BD patients.

Expert opinion: The combination of neuromodulation techniques and available pharmacotherapies is a valuable opportunity which is not undermined by specific effects on cortical excitability and could improve BD patient outcome. Neurostimulation techniques may be considered safer than antidepressant treatments in BD, with a lower level of manic switches and may represent a new treatment strategy in BD depressive episodes.     

The use of insulin detemir during pregnancy: a safety evaluation

Introduction: Diabetes during pregnancy causes both fetal and maternal complications. Insulin is the most effective pharmacological treatment for controlling hyperglycemia during gestation and can limit adverse outcomes. Insulin detemir (IDet), a novel basal insulin, has already been used for this indication for several years. It was reclassified in 2012 by the FDA from category C to category B for the treatment of pregnant women with diabetes.

Areas covered: This article reviews published data regarding the use of IDet during pregnancy. We discuss pharmacokinetic and pharmacodynamic qualities of IDet and potential advantages for its use during pregnancy.

Expert opinion: IDet is a viable option for the management of diabetes during pregnancy. Though data is limited, its safety and efficacy is probably comparable to human insulin, and in some aspects superior to it. More data, specifically for IDet in pregnancies complicated by gestational diabetes (GDM) or type 2 diabetes, is needed.     

Use of anticancer agents in gynecological oncology during pregnancy: a systematic review of maternal pharmacokinetics and transplacental transfer

Introduction: Cancer affects one in a thousand pregnant women and gynecological cancers are one of the most frequent malignancies. Chemotherapy remains the cornerstone treatment for gynecological cancer. Although all chemotherapeutic agents can cross the placental barrier, the extent of placental transfer varies considerably. Furthermore, the significant physiological variations observed in pregnant women may have an impact on pharmacokinetic parameters. Given the complexity of predicting placental transfer, in vivo and ex vivo studies are essential in this context. In view of the paucity of data on chemotherapy during pregnancy, the objective of the present study was to summarize all the available data on the transplacental transfer of anticancer drugs used to treat gynecological cancers.

Areas covered: In order to evaluate the in vivo and ex vivo transplacental transfer of the anticancer drugs most frequently used in gynecological malignancies, we carried out a comprehensive review of the literature published from 1967 to 2015. Lastly, we summarized recent clinical guidelines on the treatment of gynecological cancers in pregnant patients.

Expert opinion: The preclinical and scarce clinical data must now be extrapolated to define the maternofetal toxicity/efficacy profile and thus guide the physicians to choose anticancer drugs more efficiently in this complex situation.