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Purpose: We aimed to investigate the awareness of oral retinoid teratogenicity and the adherence to the pregnancy prevention program (PPP) related to oral retinoid use by physicians, pharmacists, and patients in Denmark., Methods: As part of the multi-country survey, web-based questionnaires were distributed among Danish dermatologists, general practitioners, community pharmacists, and women of childbearing age, who were using or had used oral retinoids within the past 5 years., Results: A total of 62 physicians, 96 pharmacists, and 50 oral retinoid using women responded; 95%, 100%, and 98%, respectively, were aware of the teratogenic risks of oral retinoids. For physicians, the most applied PPP measures were the usage of the patient (44%) and the healthcare professional (19%) guides, while the least applied measure was signing medication risk awareness form (3%). Among the pharmacists, the warning sign on the outer medication package was the most used measure (45%). Among the women, a majority (90%) had read the patient information leaflet included in the medication package and 72% discussed the use of contraception with their healthcare provider, while risk awareness forms and patient cards were seen by only few., Conclusions: In Denmark, physicians, pharmacists, and medicine users were aware about the teratogenic effects of oral retinoids. Adherence to pregnancy prevention measures varied, suggesting unwillingness to use the measures that require patients' signatures among physicians and a lack of awareness of pharmacy targeting measures. Accessibility of the latter measures need to be optimized to improve the safety of oral retinoid use., (© 2024 The Author(s). Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Curcumin, a natural polyphenol found in the turmeric plant, has been shown to have anti-inflammatory and antioxidant properties. It has been widely studied for its potential protective effect against various health conditions, including ethanol-induced malformation. Ethanol exposure during pregnancy can lead to various developmental abnormalities, known as fetal alcohol syndrome (FAS) and fetal alcohol spectrum disorders (FASD). Due to the high prevalence of FASD and FAS and no effective treatment, it is essential to develop preventive strategies. Recent studies have investigated the potential protective effect of curcumin against ethanol-induced malformation in animal models. This study aimed to examine whether curcumin can reduce the toxic effects of ethanol in zebrafish embryos. The present study showed that pure curcumin applied together with 1.5 % ethanol (v/v) did not lead to a protective effect on ethanol-induced malformations such as disturbances of body length and width or pericardia oedema in growing zebrafish embryos. Moreover, curcumin extract showed a pro-oxidant effect in the Fenton reaction in the presence of ethanol., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Aims: Current guidelines advise against the use of lipid-lowering drugs during pregnancy. This is based only on previous observational evidence demonstrating an association between statin use and congenital malformations, which is increasingly controversial. In the absence of clinical trial data, we aimed to use drug-target Mendelian randomization to model the potential impact of fetal LDL-lowering, overall and through PCSK9 drug targets, on congenital malformations., Methods and Results: Instrumental variants influencing LDL levels overall and through PCSK9-inhibitor drug targets were extracted from genome-wide association study (GWAS) summary data for LDL on 1 320 016 individuals. Instrumental variants influencing circulating PCSK9 levels (pQTLs) and liver PCSK9 gene expression levels (eQTLs) were extracted, respectively, from a GWAS on 10 186 individuals and from the genotype-tissue expression project. Gene-outcome association data was extracted from the 7th release of GWAS summary data on the FinnGen cohort (n = 342 499) for eight categories of congenital malformations affecting multiple systems. Genetically proxied LDL-lowering through PCSK9 was associated with higher odds of malformations affecting multiple systems [OR 2.70, 95% confidence interval (CI) 1.30-5.63, P = 0.018], the skin (OR 2.23, 95% CI 1.33-3.75, P = 0.007), and the vertebral, anorectal, cardiovascular, tracheo-esophageal, renal, and limb association (VACTERL) (OR 1.51, 95% CI 1.16-1.96, P = 0.007). An association was also found with obstructive defects of the renal pelvis and ureter, but this association was suggestive of horizontal pleiotropy. Lower PCSK9 pQTLs were associated with the same congenital malformations., Conclusion: These data provide genetic evidence supporting current manufacturer advice to avoid the use of PCSK9 inhibitors during pregnancy., Competing Interests: Conflict of interest: C.W. is a consultant for Mirum Pharmaceuticals and GlaxoSmithKline. M.C.H. has received consulting fees from CRISPR Therapeutics, reports advisory board service for Miga Health, and receives research support from Genentech, all unrelated to this work. All authors have no conflicts of interest to report., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

This practice guideline provides updated evidence-based conclusions and recommendations regarding the effects of antiseizure medications (ASMs) and folic acid supplementation on the prevalence of major congenital malformations (MCMs), adverse perinatal outcomes, and neurodevelopmental outcomes in children born to people with epilepsy of childbearing potential (PWECP). A multidisciplinary panel conducted a systematic review and developed practice recommendations following the process outlined in the 2017 edition of the American Academy of Neurology Clinical Practice Guideline Process Manual. The systematic review includes studies through August 2022. Recommendations are supported by structured rationales that integrate evidence from the systematic review, related evidence, principles of care, and inferences from evidence. The following are some of the major recommendations. When treating PWECP, clinicians should recommend ASMs and doses that optimize both seizure control and fetal outcomes should pregnancy occur, at the earliest possible opportunity preconceptionally. Clinicians must minimize the occurrence of convulsive seizures in PWECP during pregnancy to minimize potential risks to the birth parent and to the fetus. Once a PWECP is already pregnant, clinicians should exercise caution in attempting to remove or replace an ASM that is effective in controlling generalized tonic-clonic or focal-to-bilateral tonic-clonic seizures. Clinicians must consider using lamotrigine, levetiracetam, or oxcarbazepine in PWECP when appropriate based on the patient's epilepsy syndrome, likelihood of achieving seizure control, and comorbidities, to minimize the risk of MCMs. Clinicians must avoid the use of valproic acid in PWECP to minimize the risk of MCMs or neural tube defects (NTDs), if clinically feasible. Clinicians should avoid the use of valproic acid or topiramate in PWECP to minimize the risk of offspring being born small for gestational age, if clinically feasible. To reduce the risk of poor neurodevelopmental outcomes, including autism spectrum disorder and lower IQ, in children born to PWECP, clinicians must avoid the use of valproic acid in PWECP, if clinically feasible. Clinicians should prescribe at least 0.4 mg of folic acid supplementation daily preconceptionally and during pregnancy to any PWECP treated with an ASM to decrease the risk of NTDs and possibly improve neurodevelopmental outcomes in the offspring.

Objectives: Anti-tuberculosis drugs rifampicin and pyrazinamide combination in pregnancy can cause morphological, visceral and skeletal damage. Several studies showed that propolis improves pregnancy outcomes. This study aims to determine the fetal protective effect of propolis in BALB/c mice given the anti-tuberculosis drug combination rifampicin and pyrazinamide., Methods: A total of 21 pregnant mice were randomly divided into three groups: the normal group (N) was given distilled water as a vehicle, the positive control group (RP) were given rifampicin 15 mg/kg BW, pyrazinamide 35 mg/kg BW and the treatment group (IP) were given rifampicin 15 mg/kg BB, pyrazinamide 35 mg/kg BW and propolis 400 mg/kg BW. The treatment was given during the period of organogenesis, from day 6 to day 15. Laparotomy was performed on the 18th day of pregnancy. Maternal and fetal body weight, fetal length, number of fetuses, and skeletal defects of fetuses were used as parameters to identify the teratogenic effect. All data were analyzed using the ANOVA., Results: All groups significantly differed between maternal and fetal body weights (p<0.05). The administration of rifampicin-pyrazinamide and propolis during pregnancy did not significantly affect the number of fetuses (p>0.05). The administration of propolis protects the fetus from skeletal abnormalities. While in the RP and IP groups, we can find resorption sites and haemorrhagic., Conclusions: This study may suggest the protective effects of propolis against rifampicin pyrazinamide-induced impaired pregnancy., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Background: Prevention of prenatal exposures to teratogenic drugs is a significant clinical and public health concern. With the enactment of the US Food and Drug Administration Amendments Act in 2007, the US Food and Drug Administration has begun to require manufacturers to implement Risk Evaluation and Mitigation Strategies to prevent prenatal exposures. Among 12 risk evaluation and mitigation strategy drugs, several had predecessor risk mitigation plans (eg, isotretinoin) and some were newly required (eg, mycophenolate). Only a small proportion of teratogenic drugs are currently subject to Risk Evaluation and Mitigation Strategies, and the extent of prenatal exposure to the universe of teratogenic drugs compared with drugs subject to Risk Evaluation and Mitigation Strategies is unknown. Moreover, the effectiveness of such advanced risk mitigation programs in preventing prenatal exposure is not clear., Objective: This study aimed to characterize the epidemiology of prenatal exposures to definite and potential teratogens during the risk evaluation and mitigation strategy era., Study Design: We constructed a time-series of pregnancies identified from a national private insurance claims database (IBM MarketScan) to estimate prenatal exposures to teratogenic drugs (2006-2017). Pregnancy outcomes, gestational age, and the onset of pregnancy were determined with previously validated algorithms. The Teratology Information Service and Clinical Pharmacology databases were used to identify drugs with definite (n=141) or potential (n=65) teratogenic effects, and drugs with debatable risks such as benzodiazepines, statins, tetracyclines, sex hormones, infertility treatments, and gonadotropin-releasing hormone analogs were excluded. We defined prenatal exposure as ≥1 prescription fill or medical encounter involving administration of drugs with a definite teratogenic risk (including 12 for which there is a "current or discontinued" risk evaluation and mitigation strategy) or a potential teratogenic risk. We evaluated secular trends and modeled the effects of age, preconception exposure, and state healthcare quality rankings on prenatal exposure, adjusting for demographic factors and clinical conditions., Results: The cohort included 3,445,612 pregnancies (2,532,444 live deliveries). Prenatal exposures to definite teratogens decreased slightly during the study years from 1.86 to 1.24 per 100 pregnancies between 2006 and 2017, whereas exposure increased for potential teratogens from 3.40% to 5.33%. Prenatal exposure prevalences were higher during the first trimester and for pregnancies that ended in nonlive outcomes. Drugs subject to Risk Evaluation and Mitigation Strategies had low background utilization and contributed to a small proportion of prenatal exposures (15.1 per 100,000 pregnancies). We also observed fewer prenatal exposures to risk evaluation and mitigation strategy drugs among women of childbearing age who used these treatments (0.14% vs 0.36% for any definite teratogen). Age extremes and low state-level healthcare quality rankings were independent predictors of prenatal exposure., Conclusion: Fetuses in more than 1 in 16 pregnancies continued to be exposed to teratogenic drugs during the past decade. Drugs with Risk Evaluation and Mitigation Strategies imposed a small burden of prenatal exposure because of the low background utilization rates and lower pregnancy prevalence among women of childbearing age who used these drugs. Although the declining exposure rates to teratogenic drugs with definite risk are encouraging, the rising prenatal exposure to drugs with potential risk calls for more assessments. Future research is needed to elucidate the health outcomes of fetuses exposed to potential risk drugs, understand the effectiveness of risk evaluation and mitigation strategy programs, and prioritize teratogenic drugs for advanced risk mitigation., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Spirulina (Arthrospira maxima) has been recognized as a superfood and nutraceutical by its high nutritional value and the benefits of its consumption; it is an important source of lipids, proteins, vitamins, minerals, and antioxidants. It is known that spirulina has positive effects on the toxicity induced by pharmaceuticals and metals. Heavy metals such as cadmium, frequently used in industrial activities, are continuously detected in water bodies and can generate adverse effects on aquatic organisms even at low concentrations. This study aimed to evaluate the protective effect of spirulina (Arthrospira maxima) against the toxic effects induced by cadmium in the early life stages of Xenopus laevis. Twenty Xenopus laevis embryos were exposed to five different treatments on triplicate, control, cadmium (CdCl 2 24.5 μg L -1 ) and three spirulina mixtures Cd + S 1 (24.5 μg L -1 CdCl 2  + 2 mg L -1 spirulina), Cd + S 2 (24.5 μg L -1 CdCl 2  + 2 mg L -1 spirulina), Cd + S 3 (24.5 μg L -1 CdCl 2  + 10 mg L -1 spirulina); after 96 h of exposure: Malformations, mortality and length were evaluated; also, after 192 h, lipid peroxidation (LPX), superoxide dismutase (SOD) and catalase (CAT) were determined. All spirulina treatments decreased mortality from 34 to 50% and reduced malformations on incidence from 36 to 68%. Treatment Cd + S 3 decreased growth inhibition significantly. Spirulina treatment Cd + S 2 decreased lipidic peroxidation and antioxidant activity; these results suggest that spirulina (Arthrospira maxima) can decrease the mortality, frequency of malformations, the severity of malformations, growth inhibition, and oxidative damage induced by cadmium in Xenopus laevis embryos., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: To establish awareness, knowledge, use and experience in practice of a sodium valproate pregnancy prevention program (PPP) in Ireland ("prevent") among three healthcare professional (HCP) groups., Methods: A cross-sectional study using anonymous online surveys was conducted among general practitioners (GPs), pharmacists, and specialist consultants. Descriptive analyses are presented., Results: HCP response rates were 5.8% for GPs (90/1544), 10.7% for pharmacists (219/2052), and 7.6% for specialists (17/224). Across HCP groups, there was high awareness (>90%) for specialist referral when female valproate patients are planning pregnancy, or become pregnant, but less awareness to refer annually for specialist review. While awareness of a possible teratogenic effect at any stage of pregnancy was high (>80%), most GPs (62.2%, 95% CI: 51.3, 71.9%) and community pharmacists (53.1%, 95% CI: 43.2, 62.8%) were unsure of the magnitude of risk for developmental disorders, while most specialists under-estimated this risk (46.7%, 95% CI: 24.8, 69.9%). Although >70% of the respondents identified valproate to be contraindicated in any woman of childbearing potential unless the conditions of the PPP are fulfilled, experience implementing key elements in practice varied., Conclusions: Our findings suggest continued effort is needed to ensure optimal implementation of "prevent" into clinical practice in Ireland.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. In recent years, many disease-modifying therapies (DMT) have been approved for MS treatment. For this reason, a profound knowledge of the characteristics and indications of the available compounds is required to tailor the therapeutic strategy to the individual patient characteristics. This should include the mechanism of action and pharmacokinetic of the drug, the safety and efficacy profile provided by clinical trials, as well as the understanding of possible side effects. Moreover, the evolving knowledge of the disease is paving the way to new and innovative therapeutic approaches, as well as the development of new biomarkers to monitor the therapeutic response and to guide the clinician's therapeutic choices. In this review we provide a comprehensive overview on currently approved therapies in MS and the emerging evidence-based strategies to adopt for initiating, monitoring, and eventually adapting a therapeutic regimen with DMT., (Copyright © 2021 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Since its approval in 1982, oral isotretinoin has revolutionized acne therapy. However, oral isotretinoin use has long been associated with challenges of variable bioavailability and food dependence. It is recommended to ingest oral isotretinoin with a high-fat meal in order to maximize absorption, but many patients fail to adhere to this recommendation. This may lead to inadequate isotretinoin absorption levels. Patients who fail to achieve isotretinoin target cumulative dose are more likely to experience symptom relapse. To address the challenge of traditional isotretinoin variable bioavailability, subsequent isotretinoin formulations have attempted to improve its absorption abilities. In 2014, an isotretinoin formulation utilizing Lidose technology, known as Absorica, showed significant improvements in absorption levels compared to traditional oral isotretinoin in the fasted state. In 2019, isotretinoin absorption levels were further advanced in a new formulation approved by the FDA known as Absorica LD. Utilizing advanced micronization technology that physically reduces the size of the drug molecule, Absorica LD exhibits twice the absorption levels of Absorica under fasting conditions. In the fed state, Absorica LD achieves similar plasma levels to Absorica with a 20 percent lower dose. Absorica LD also produces consistent serum isotretinoin levels irrespective of gastrointestinal contents. By eliminating the &ldquo;food effect&rdquo; seen in traditional oral isotretinoin, Absorica LD has the potential to improve patient adherence and long-term patient outcomes. J Drugs Dermatol. 20:5(Suppl):s5-11.

The study is aimed to investigate the protective role of Moringa oleifera extracts against sodium arsenate induced embryo toxicity in albino mice. Forty four pregnant mice were divided into 11groups (A-K). Group A was control while B and C were sodium arsenate treated groups with dose, A (0.00), B (6.00, 0.00), C (12.00, 0.00). Group D to G were of sodium arsenate+Moringa oleifera flower extract treated groups with doses D (6.00, 150.00), E (6.00, 300.00), F (12.00, 150.00), G (12.00, 300.00) and groups H to K were sodium arsenate+Moringa oleifera leaf extract treated groups H (6.00, 150.00), I (6.00, 300.00), J (12.00, 150.00) and K (12.00, 300.00) mg/kg B.W. Moringa oleifera leaf extract treated groups showed significant (p<0.05) amelioration against sodium arsenate induced histopathological changes as malformed heart, spina bifida, enlarged ventricles, poorly developed kidneys, anopthalmia and cavitation in brain. Significant (p<0.05) increased in malondialdehyde 36±0.81 and decreased glutathione 8.25±0.95 values in sodium arsenate treated groups were observed as compared to control 22.5±0.57 and 19±0.81.Whereas Moringa oleifera leaf extract at dose of 300mg/kg B.W normalizesd the malondialdehyde 23±0.81 and glutathione 17.75±3.20 values. So concluded that Moringa oleifera leaf extract has ameliorative effects against sodium arsenate induced embryotoxicity.

All malaria infections are harmful to both the pregnant mother and the developing fetus. One in ten maternal deaths in malaria endemic countries are estimated to result from Plasmodium falciparum infection. Malaria is associated with a 3-4 times increased risk of miscarriage and a substantially increased risk of stillbirth. Current treatment and prevention strategies reduce, but do not eliminate, malaria's damaging effects on pregnancy outcomes. Reviewing evidence generated from meta-analyses, systematic reviews, and observational data, the first paper in this Series aims to summarise the adverse effects of malaria in pregnancy on the fetus and how the current drug treatment and prevention strategies can alleviate these effects. Although evidence supports the safety and treatment efficacy of artemisinin-based combination therapies in the first trimester, these therapies have not been recommended by WHO for the treatment of malaria at this stage of pregnancy. Intermittent preventive treatment of malaria in pregnancy with sulfadoxine-pyrimethamine is contraindicated in the first trimester and provides imperfect chemoprevention because of inadequate dosing, poor (few and late) antenatal clinic attendance, increasing antimalarial drug resistance, and decreasing naturally acquired maternal immunity due to the decreased incidence of malaria. Alternative strategies to prevent malaria in pregnancy are needed. The prevention of all malaria infections by providing sustained exposure to effective concentrations of antimalarial drugs is key to reducing the adverse effects of malaria in pregnancy., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: Treatment of coronavirus disease 2019 is mostly symptomatic, but a wide range of medications are under investigation against severe acute respiratory syndrome coronavirus 2. Although pregnant women are excluded from clinical trials, they will inevitably receive therapies whenever they seem effective in nonpregnant patients and even under compassionate use., Methods: We conducted a review of the literature on placental transfer and pregnancy safety data of drugs under current investigation for coronavirus disease 2019., Results: Regarding remdesivir, there are no data in pregnant women. Several other candidates already have safety data in pregnant women, because they are repurposed drugs already used for their established indications. Thus, they may be used in pregnancy, although their safety in the context of coronavirus disease 2019 may differ from conventional use. These include HIV protease inhibitors such as lopinavir/ritonavir that have low placental transfer, interferon that does not cross the placental barrier, and hydroxychloroquine or chloroquine that has high placental transfer. There are also pregnancy safety and placental transfer data for colchicine, steroids, oseltamivir, azithromycin, and some monoclonal antibodies. However, some drugs are strictly prohibited in pregnancy because of known teratogenicity (thalidomide) or fetal toxicities (renin-angiotensin system blockers). Other candidates including tocilizumab, other interleukin 6 inhibitors, umifenovir, and favipiravir have insufficient data on pregnancy outcomes., Conclusion: In life-threatening cases of coronavirus disease 2019, the potential risks of therapy to the fetus may be more than offset by the benefit of curing the mother. Although preclinical and placental transfer studies are required for a number of potential anti-severe acute respiratory syndrome coronavirus 2 drugs, several medications can already be used in pregnant women., (© 2020 Elsevier Inc. All rights reserved.)

Introduction: The use of cytostatic drugs such as Mitomycin C and 5-Fluorouracil is well-known in glaucoma filtering surgery, as well as the management of its complications. However, there is a lack of information regarding the preventive measures to be taken by the professional that handles these types of substances., Objective: Raise awareness among professionals of the risks associated with the use of cytostatic drugs without adequate prevention measures., Results: Review of the available literature and legislation on preventive measures in the management of cytostatic drugs in the medical and ophthalmological field., Conclusions: The prevention and awareness of the risks of the qualified professionals that handle these substances is the most important measure to prevent the possible risks. Coordination is necessary with the Occupational Health teams of the Hospital, as well as the professionals and staff involved in the different phases of the process, from the preparation in Hospital Pharmacy to its elimination., (Copyright © 2020 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: For persons of childbearing potential prescribed isotretinoin, the iPLEDGE program requires use of 2 simultaneous methods of contraception or commitment to abstinence., Objective: To model the relative effectiveness of a variety of contraception strategies for patients taking isotretinoin, including those that are acceptable according to iPLEDGE., Methods: We performed a decision analysis modeling the estimated rate of pregnancy with various contraception strategies during a typical 6-month course of isotretinoin., Results: Tier 1 contraception options (eg, subdermal hormonal implant, intrauterine devices) each had effectiveness of >99.5% alone. When combined with a secondary form of contraception, tier 2 contraception options (eg, depot medroxyprogesterone injections, combined oral contraceptives) each had effectiveness >99%., Limitations: Sensitivity analyses were conducted to evaluate the impact of uncertain parameters on the results., Conclusion: There may be opportunities to simplify iPLEDGE by recognizing the high effectiveness of tier 1 contraception options and increasing use of secondary forms of contraception among those using tier 2 contraception options as their primary form of contraception. Future studies are needed to understand the most effective strategies in clinical practice to prevent unintended pregnancy for patients taking isotretinoin to improve outcomes and provide patient-centered care., (Copyright © 2020 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Genetic or idiopathic generalized epilepsies (IGEs) account for 15-20% of all epilepsies. These syndromes have always been considered as good prognosis forms of epilepsy over time; however, for some patients, there is a need to maintain antiseizure drugs (ASD) for a long-time. Drug resistance is not uncommon (7-15%). Lifestyle remains essential and is an integral part of the treatment. Comorbidities such as obstructive sleep apnea syndrome must be considered and treated. A highly underestimated condition is the risk of sudden unexpected death in epilepsy (SUDEP). Very few data are available about the prevalence of SUDEP in IGE, but patients with generalized tonic-clonic seizures (GTCS) are exposed to this risk. IGEs are also characterized by a specific pharmalogical sensisitivity but may be aggravated by ASDs. Historically, the treatment of IGEs has relied mostly on valproate but this drug should be avoided in women of childbearing potential. Women with IGE not treated with valproate are more likely to have unsatisfactory seizure control. Female gender appears now as a new risk factor for drug-resistance. Finally, aside from the typical forms, there are epilepsies that fulfill most of the criteria of IGE, but that have an unusual history with GTCS, absences, falls, and drug resistance. Patients do not have psychomotor regression, brain magnetic resonance imaging is normal. EEG shows generalized fast rhythms during NREM sleep. These patients with refractory generalized epilepsy with sleep-related fast activities do not belong to a well-established syndromic category. These cases are considered "intermediary" between IGE and epileptic encephalopathies., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Acne vulgaris is the most common skin disease treated by dermatologists. It can be severe and result in permanent scars. Isotretinoin is the most effective treatment for acne and has the potential for long-term clearance. Prescribing and monitoring protocols can vary widely among prescribers. Recent studies, reports, and consensus statements help shed light on optimizing the use of isotretinoin for acne. A recent literature review is summarized in this article to help the practitioner optimize isotretinoin use for acne. The article outlines the advantages and disadvantages of standard, high-dose, and low-dose isotretinoin regimens; discusses the current status of controversies surrounding isotretinoin (including depression/suicide, pregnancy, and inflammatory bowel disease); reviews monitoring recommendations and treatment for hypertriglyceridemia and elevated transaminase levels; and discusses common adverse effects seen with isotretinoin, along with their treatment and prevention.

Nonobstetric surgery during pregnancy occurs in 1% to 2% of pregnant women. Physiologic changes during pregnancy may have an impact when anesthesia is needed. Anesthetic agents commonly used during pregnancy are not associated with teratogenic effects in clinical doses. Surgery-related risks of miscarriage and prematurity need to be elucidated with well-designed studies. Recommended practices include individualized use of intraoperative fetal monitoring and multidisciplinary planning to address the timing and type of surgery, anesthetic technique, pain management, and thromboprophylaxis. Emergency procedures should be performed immediately and elective surgery should be deferred during pregnancy.

Although most teenagers experience acne, for sexual and gender minority teenagers, acne could be more challenging and require specific psychosocial considerations. Acne may be more strongly associated with mental health issues in sexual and gender minority adolescents. Acne development during puberty may trigger gender dysphoria in transgender patients. Transgender and gender nonbinary patients receiving testosterone therapy may experience new or worsening acne. Comprehensive care for moderate to severe acne in sexual and gender minority adolescents should include culturally competent discussions about sexual behaviors, contraception, and/or gender-affirmation treatment plans., Competing Interests: Disclosure Dr H. Yeung was supported in part by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR002378 and KL2TR002381. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Dr H. Yeung has received honorarium from Syneos (InVentiv) Health. All other authors disclosed no financial conflicts of interest., (Published by Elsevier Inc.)

Introduction: Non-nutritive sweeteners (NNS) are food additives that have been used as a possible tool to reduce energy and sugar intake. There is a scientific debate around the real benefits of their use. NNS are substances widely evaluated in the scientific literature. Their safety is reviewed by international regulatory health agencies. Health professionals and consumers often lack education and objective information about food additives based on the best scientific evidence. NNS have been used as a substitute for sucrose, especially by people with diabetes mellitus and obesity. However, concerns related to their possible association with preterm birth have been raised, and also with their use during pregnancy and lactation because of the possibility of metabolic or other consequences in both the mother and offspring. This analysis of the evidence in gynecology and obstetrics presents a review of the most commonly asked questions regarding this matter by health professionals and their patients. This document evaluates a diversity of scientific publications under the sieve of evidence-based medicine and the regulatory framework for food additives to elucidate whether the use of NNS in women in these critical stages of pregnancy and breastfeeding represents a potential risk.

Objective: Current guidelines and regulations strongly discourage the use of valproic acid (VPA) in women of childbearing age because of the risk of congenital malformations and neurodevelopmental disability in children exposed to VPA in utero. Our goal was to establish the reasons for continued use of VPA in a cohort of women with epilepsy (WWE) and to characterize the subgroup of WWE who do not consent to withdraw VPA despite potential risks., Material and Methods: The study included consecutive adult premenopausal WWE who visited an outpatient epilepsy clinic between April 2017 and March 2018. Data on demographics (age, age at onset of epilepsy), characteristics of epilepsy (types and frequency of seizures), and its treatment were collected from medical records and seizure diaries. All WWE taking VPA were regularly informed about VPA-related risks and had the opportunity to discuss the withdrawal of VPA., Results: The study involved 353 WWE (mean age: 31.7 years). Focal epilepsy was diagnosed in 244 (69.1%) patients; 180 (51.0%) women had no seizures during last 12 months before the study visit, and 228 patients (64.6%) were on monotherapy. A total of 146 (41.3%) patients used VPA in the past, and 98 (27.8%) never used VPA. Of women who were currently on VPA (n = 109, 30.9%), 30 had concurrent severe disabilities that would make future pregnancy extremely unlikely, in further 15 patients, VPA was recommenced because of failure of alternative treatment and 64 women did not accept the plan of VPA withdrawal. Women currently on VPA were more likely to have genetic generalized epilepsy and to be on monotherapy (both p ≪ 0.001). Among 64 WWE who decided to continue therapy with VPA, 35 (55.5%) had generalized epilepsy and 35 (55.5%) were in remission, 27 (42.2%) had at least one child, 9 (14.1%) planned to have a child in the near future but only 15 (23.4%) used effective contraception., Conclusion: Treatment with VPA is unavoidable in many WWE of childbearing age despite recent regulations. About 60% of WWE currently treated with VPA do not consent to withdraw VPA treatment after thorough consideration of potential risks and other 40% use VPA because pregnancy is highly unlikely and/or other treatments failed., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: During pregnancy, women may be exposed to teratogenic medications resulting in a risk of complications and poor maternal-fetal outcomes. The objective of this study was to evaluate the prescription of teratogenic medications in women of childbearing age and the associated prescription of contraception in the primary care setting., Methods: The use of high-risk, potentially teratogenic, medications was retrospectively evaluated in women of childbearing age (13 to 45 years old) at 2 family medicine practices. Charts were reviewed for medication use and whether patients received a form of birth control (medication, sterilization, or postmenopausal) with the teratogenic medications. A multivariable logistic regression model was used to estimate the age-adjusted association between receiving a teratogenic medication and contraception. A subgroup analysis excluding ondansetron was also performed., Results: A total of 3,956 nonpregnant women were included with 988 (25%) prescribed at least 1 high-risk medication. The most commonly prescribed high-risk medications were ondansetron (n = 724, 73%) and lisinopril (n = 195, 20%). More than half (55%) of the women prescribed a high-risk medication were without a form of birth control. When ondansetron was excluded, 10% of the population was prescribed at least 1 high-risk medication with 62% also without a form of birth control. Women less than 25 years of age had decreased odds of receiving contraception when prescribed a teratogenic medication (adjusted odds ratio, 0.47; 95% confidence interval, 0.34-0.66)., Conclusion: In a family medicine setting, 25% of women of childbearing age were prescribed a high-risk medication with over half not having evidence of contraception management. Interestingly, younger age women had lower odds of receiving contraceptive management when prescribed high-risk medications. Prescribers should be aware of and counsel on the risks of teratogenic medications and regularly evaluate reproductive plans for patients., Competing Interests: Conflict of interest: none declared., (© Copyright 2019 by the American Board of Family Medicine.)

Many conditions that require frequent medication use are common during pregnancy. The purpose of this article is to list some of the most common of these disorders and to discuss the risk to the developing fetus of the medications used most frequently to treat them. Included are drugs used for the treatment of asthma, nausea and vomiting, hyperthyroidism, pain and fever, and depression during pregnancy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Hyperthyroidism is relatively uncommon during pregnancy. However, those caring for pregnant patients should be versed in the evaluation and management of hyperthyroidism, as there are potential maternal and fetal implications that are related to the disease and to treatment. The differential diagnosis of hyperthyroidism includes clinical and subclinical entities, as well as transient laboratory findings that are related to the pregnancy itself. The clinical management, including the indications for the use of thioamide or antithyroid medications, will be discussed in the context of pregnancy. Finally, considerations for the management of the postpartum and/or breastfeeding patient with hyperthyroidism will be reviewed.

Background: Congenital abnormalities and pregnancy losses due to the teratogenic effects of warfarin are prevalent among the South African population. These are potentially preventable if the challenges and barriers faced by at-risk women are understood and addressed effectively., Objectives: To determine the practice, knowledge and attitudes regarding the teratogenic risks experienced by women administered warfarin., Methods: A descriptive study was performed. Quantitative data were collected through a researcher-administered questionnaire. The target population comprised 101 women of reproductive age who received warfarin treatment and attended a single tertiary-level anticoagulation clinic., Results: Patient-related challenges identified in this study are: language barriers, poor understanding of basic terminology and mathematics, poor contraceptive and family planning practices, lack of knowledge regarding the risks of warfarin in pregnancy and passive attitudes towards information attainment., Conclusions: Interventions are necessary to address the challenges in such settings. These include increased awareness of the teratogenic potential of specific chronic medications among healthcare providers, patients and the public. Standardised management protocols for women of reproductive age initiated on teratogenic medications should be implemented, including contraceptive and family planning discussions at follow-up visits. Improvement of the counselling skills of healthcare providers and the availability of translators or healthcare providers fluent in local languages could assist in risk reduction.

This study aimed to investigate the protective effects of two citrus flavonoids, hesperidin and naringin, on alcohol-induced thigmotaxis behavioural and developmental defects in zebrafish. The results of behavioural assays indicated that acute exposure to 1% alcohol could induce thigmotaxis behaviour in zebrafish larvae at 3 and 5 days post-fertilization (dpf), whereas hesperidin and naringin could inhibit the thigmotaxis behaviour in zebrafish larvae. Moreover, developmental administration of hesperidin and naringin reduced the levels of morphological defects and apoptosis induced by developmental alcohol exposure. In conclusion, this study suggests that the citrus flavonoids hesperidin and naringin could reduce the effects of alcohol damage on embryonic development and neurobehaviour in zebrafish larvae, which would provide useful knowledge for assessing the underlying mechanism of citrus flavonoids and their protective effects., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: Although teratogenic medications are commonly used to treat rheumatic disease, no standard model currently exists for educating adolescent patients about teratogenic risk or performing routine pregnancy screening. We performed a quality improvement project to increase education and pregnancy screening in girls and women of childbearing age prescribed teratogenic medications in our pediatric rheumatology clinic., Methods: Eligible participants included female patients age 10 and older prescribed teratogenic medications in a single-center tertiary care pediatric rheumatology clinic. Seven plan-do-study-act cycles were completed to test the following interventions: visible project reminders, physician and nurse education, progress updates, previsit planning, and development of an electronic health record education template. Chart reviews were performed, and control charts were created for each aim to analyze improvement over time., Results: At baseline, 57 of 231 (24.7%) clinic encounters of female patients age 10 years and older taking teratogenic medications had education documented within the last 12 months, and 47 of 231 (20.3%) had pregnancy screening performed at the visit. Implementation of our interventions resulted in improvement in documentation of annual teratogen education (904 of 1135; 79.6%) and routine pregnancy screening (940 of 1135; 82.8%), both of which were statistically significant ( P < .0001). Control charts revealed special cause with sustained improvement over >1 year., Conclusions: The interventions made through this quality improvement project increased the frequency of both teratogen education and urine pregnancy screening in patients taking teratogenic medications. Development of a standardized education template in the electronic health record played a key role in sustaining these improvements over time., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2019 by the American Academy of Pediatrics.)

Juvenile myoclonic epilepsy (JME) is both a frequent and a very characteristic epileptic syndrome with female preponderance. Treatment of JME in women of childbearing potential must consider multiple factors such as desire for pregnancy, use of contraception, seizure control and previously used antiepileptic drugs (AEDs). Approximately 85% of cases are well controlled with valproate, which remains the reference AED in JME but is nowadays considered unsafe for the expecting mother and her fetus. The prescription of valproate is now severely restricted in women of childbearing potential but may still be considered, at the lowest possible dose and when pregnancies can be reliably planned, with temporary alternatives to valproate prescribed before fertilization. Alternatives have emerged, especially lamotrigine and levetiracetam, but also topiramate, zonisamide, and recently perampanel, but none of these AEDs can be considered fully safe in the context of pregnancy. In special settings, benzodiazepines and barbiturates may be useful. In some cases, combination therapy, especially lamotrigine and levetiracetam, may be useful or even required. However, lamotrigine may have the potential to aggravate JME, with promyoclonic effects. Carbamazepine, oxcarbazepine and phenytoin must be avoided. Valproate, levetiracetam, zonisamide, topiramate if the daily dose is ≤ 200 mg and perampanel if the daily dose is ≤ 10 mg do not affect combined hormonal contraception. Lamotrigine ≥ 300 mg/day has been shown to decrease levonorgestrel levels by 20% but does not compromise combined hormonal contraception. Patients with JME taking oral contraceptive should be counselled on the fact that the estrogenic component can reduce concentrations of lamotrigine by over 50%, putting patients at risk of increased seizures. Pregnancy is a therapeutic challenge, and the risk/benefit ratio for the mother and fetus must be considered when choosing the appropriate drug. Lamotrigine (< 325 mg daily in the European Registry of Antiepileptic Drugs in Pregnancy) and levetiracetam seem to be comparatively safer in pregnancy than other AEDs, especially topiramate and valproate. Plasma concentration of lamotrigine and levetiracetam decreases significantly during pregnancy, and dosage adjustments may be necessary. With persisting generalized tonic-clonic seizures, the combination of lamotrigine and levetiracetam offer the chance of seizure control and lesser risks of major congenital malformations. The risk of malformation increases when valproate or topiramate are included in the drug combination. In one study, the relative risk of autism and autism spectrum disorders (ASD) in children born to women with epilepsy (WWE) treated with valproate were, respectively, 5.2 for autism and 2.9 for ASD versus 2.12 for autism and 1.6 for ASD in WWE not treated with valproate. More studies are needed to assess the risk of autism with AEDs other than valproate. The current knowledge is that the risk appears to be double that in the general population. In patients with JME, valproate remains an essential and life-changing agent. The consequences of a lifetime of poorly controlled epilepsy need to be balanced against the teratogenic risks of valproate during limited times in a woman's life. The management of JME in WWE should include lifestyle interventions, with avoidance of sleep deprivation, and planned pregnancy.

Background:: Medication use during pregnancy and lactation can be unavoidable, but knowledge on safety for the fetus or breastfed infant is limited among patients and healthcare providers., Research Aim:: This study aimed to determine (a) the prevalence of medication use in pregnant and lactating women in a tertiary academic center, (b) the types and safety of these medicines, and (c) the influence of medication use on initiation of breastfeeding., Methods:: This study used a cross-sectional survey among women ( N = 292) who underwent high-risk or low-risk deliveries. Data about their use of prescribed, over-the-counter, and homeopathic medication during pregnancy were obtained through a structured interview, followed by a questionnaire during lactation. Safety was classified according to the risk classification system from the Dutch Teratological Information Service., Results:: Overall, 95.5% of participants used medication. One third of participants used at least one medicine with an unknown risk for the fetus. Teratogenic medication was used by 6.5% of participants, whereas 29.5% used medication with a (suspected) pharmacological effect on the fetus. Lactation was initiated by 258 (88.7%) participants, of which 84.2% used medication while breastfeeding. In 3.8% of participants, this medication was classified unsafe, but none used medication with an unknown risk. One-third of the nonlactating participants decided not to initiate breastfeeding because of medication use. In 70% of participants, this decision was appropriate., Conclusion:: The prevalence of overall use of medication in Dutch pregnant and lactating women admitted to a tertiary center was high. There is an urgent need for pharmacometric studies for determination of the safe use of the most frequently used medicines during pregnancy or lactation.

Competing Interests: Competing interests: None declared.

Schizophrenic or schizoaffective disorders often occur in early adulthood and thus affect women of childbearing age. For paliperidone information about reproductive safety is wanting. Therefore, we evaluated data from the German Embryotox pharmacovigilance institute regarding paliperidone therapy during pregnancy. The German Embryotox pharmacovigilance institute offers risk assessment on drug use in pregnancy and documents the outcome of more than 3500 drug-exposed pregnancies per year. In our study, we analyze the outcome of all pregnancies with paliperidone exposure, which have been assessed by our institute between January 2007 and June 2016. Of the 17 prospectively assessed pregnancies, 14 resulted in 15 live-born children (including one pair of twins). None of the infants presented with major congenital malformations. There were two spontaneous abortions at gestational weeks 6 and 11, respectively, and one elective termination due to personal reasons. Sixty-five percent of the pregnant women smoked cigarettes throughout pregnancy, 17% consumed alcohol. Five children were born prematurely (< 37 gestational weeks) and four were small for gestational age, each group including the twins. The results of our study suggest that paliperidone may be administered during pregnancy. The increased rate of prematurity and small for gestational age children can at least partially be explained by other risk factors. Psychiatric and obstetric close monitoring as well as additional medical and social support are recommended to ensure a healthy pregnancy course in patients with a severe mental illness.

Introduction : This review provides a guide for the rational use of prescription drugs in patients of reproductive age. Areas covered : A comprehensive retrieval of the labels of FDA-approved drugs was performed to identify drugs where the label recommends contraceptive use during and/or after treatment. The acquired data were analyzed and organized into a table. Contraception was recommended or mandated for 268 single-ingredient drugs. These could be divided into four main categories, with many having effects across several categories: 177 drugs required contraception because they were associated with pregnancy loss or stillbirth, 177 drugs were associated with teratogenesis, 136 were associated with non-teratogenic adverse peri- or postnatal effects on the fetus (e.g. low birth weight), and 44 were associated with decreased efficacy of contraception or a change in ovulatory cycle. We also discuss the period of time contraception is required, as well as the known or hypothesized reasons for the reproductive toxicity of these agents. Expert opinion : We have provided a comprehensive overview of the FDA-approved drugs where the warning labels currently stipulate that contraception should be used. Although other references are available for clinicians, this review provides a useful source of information regarding the single-ingredient prescription drugs that may affect the outcome of pregnancy. This information is particularly relevant for researchers, as it provides an overview of the different drugs with reproductive toxicity, and because it highlights the specific needs for future research. In particular, more work (especially epidemiological studies) is needed to clarify the clinical relevance of these findings, most of which were obtained through animal studies.

Purpose: To explore trends in use of maternal medication 3 months prior to, during and 3 months after pregnancy., Methods: Data on births from the Medical Birth Registry of Norway were linked to the Norwegian Prescription Database, identifying women's use of medications around pregnancy. All women giving birth in Norway during 2005 to 2015 (638 532 singleton births to 414 567 women) were included. Proportions of pregnant women using different medications in association with pregnancy, and annual relative change in medication use during 2005 to 2015, were calculated., Results: In Norway, 60% of pregnant women used prescription medications during pregnancy (2005-15), increasing from 57% in 2005 to 62% in 2015. The annual relative increase was 0.9% (95% CI: 0.8-1.0). In the first trimester, approximately 17% of the women used medications regarded as potentially teratogenic during 2005 to 2015, increasing from 15% to 19%. Overall, this proportion was higher in the first than in the second (8.9%) and third (8.0%) trimesters, and higher than in the 3 months after pregnancy (14%). The annual relative increase of medications regarded as potentially teratogenic in the first trimester was 2.5% (95% CI: 2.3-2.7)., Conclusions: The proportion of women using potentially teratogenic medications in the first trimester of pregnancy have increased during the last decade. Clinicians need to be aware of the possibility of pregnancy when prescribing potentially teratogenic medication to women of fertile age and focus this in the consultations. The increasing trends call for the need of routine surveillance of adverse birth outcomes linked to medication use in pregnancy., (© 2018 John Wiley & Sons, Ltd.)

We discuss the possibilities to prevent the post-exposure teratogenic effects of several teratogens: valproic acid (VPA), diabetes and alcohol. Co-administration of folic acid with VPA reduced the rate of Neural Tube Defects (NTD) and other anomalies in rodents, but apparently not in pregnant women. Antioxidants or the methyl donor S-adenosyl methionine prevented Autism Spectrum Disorder (ASD) like behavior in mice and rats. In vivo and in vitro studies demonstrated that antioxidants, arachidonic acid, myoinositol and nutritional agents may prevent diabetes-embryopathy. Prevention of alcohol-induced embryonic and fetal injuries and neurodevelopmental deficits was achieved by supplementation of zinc, choline, vasoactive intestinal proteins (VIP related peptides), antioxidants and folic acid. While the animal research described in this review is indicative of possible preventions of the different teratogenic effects, this is not yet the focus in human research. Future research should promote further knowledge where our current understanding is the vaguest, human prevention., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Isotretinoin has revolutionized the treatment of severe acne vulgaris, a condition which if left untreated may result in significant socio-psychological implications for those affected. Timely access to isotretinoin therapy is important to avoid the risks of potential physical and emotional scarring. However, due to its high risks of teratogenicity, isotretinoin must be used with care in females of childbearing potential. Since isotretinoin's introduction, numerous risk management programs have been implemented across the world in an attempt to prevent isotretinoin use in pregnancy. This paper aims to provide an evidence-based review of the risk management programs for isotretinoin in Australia, Europe, Singapore, New Zealand, and the United States of America. The effectiveness of these programs and the factors leading to isotretinoin exposure in pregnancy are critically analyzed in an effort to inform the future direction with respect to designing the ideal regulatory program. Stringent risk management programs, such as the iPLEDGE in the US and Pregnancy Prevention Program (PPP) in Europe, may not be effective in reducing the risks of fetal exposure to isotretinoin when used alone. There is evidence that such strenuous regulation results in increased fear of teratogenic risks but does not translate into a reduced rate of pregnancies exposed to isotretinoin. A successful program must prioritize education about effective contraception, while minimizing any extraneous requirements, to ensure that women are not inadvertently undertreated for acne., (© 2018 The International Society of Dermatology.)

The study assessed knowledge, attitudes, and medication use of a random sample of pregnant women attending outpatient Gynecology and Obstetrics clinics at randomly selected public General and Teaching hospitals in Naples, Italy. A total of 503 women participated. Those more likely to know that a pregnant woman with chronic condition must discuss whether or not to take a medication with the physician were Italian, aged 31-40 years, employed, with no history of abortion, having had a medical problem within the previous year, with a better self-perceived health status, who knew how to use medications during pregnancy, and who needed information on medications. The knowledge of the potential risk of using non-prescribed medications during pregnancy was significantly higher in employed women, who received information from physicians, who knew how to use medications during pregnancy, and who knew the possible damages related to medications use. More than half had used at least one medication. Those aged 26-35 years, Italian, non-graduated, in the third trimester, having had a medical problem within the previous year, with a risky pregnancy, and with a knowledge that women with chronic condition must discuss whether or not to take a medication with the physician were more likely to use medication. Less than half had used medication without a physician's advice. Those who were more likely to self-medicate were older, Italian, multiparous, with no history of abortion, who knew that women with chronic condition must discuss whether or not to take a medication with the physician, who did not know the potential risk of using non-prescribed medication during pregnancy, who had used prescribed medication during pregnancy, and who needed information about medications. Educational programs for women about medication use are important to increase their knowledge of the potential risks to the pregnant women and the unborn child in order to reduce self-medication., Competing Interests: The authors have declared that no competing interests exist.

Purpose: To evaluate awareness of and compliance in Belgium by French-speaking health care professionals and patients with the isotretinoin safety recommendations regarding its teratogenic risk., Method: Survey using online questionnaires, delivered from December 2014 to March 2015 for patients, pharmacists, dermatologists, and GPs and delivered again from September 2015 to October 2015 for GPs., Results: Questionnaires were completed by 24 dermatologists, 24 GPs, 58 pharmacists, and 33 female patients. The pregnancy prevention programme was poorly known by health care professionals (23.6%) and patients (15.2%). Health care professionals informed women of childbearing age in depth about the teratogenic risk (98.3% of pharmacists and 100.0% of GPs and dermatologists) and the importance of an effective contraceptive method (87.9% and 100.0%, respectively). Patients were less informed about the pregnancy test (25.9% and 14.6%) and the need to use a second contraceptive method (29.3% and 27.1%). The low compliance with the last 2 recommendations was due to a lack of adoption by health care professionals regarding the need for these recommendations if female patients have an effective contraceptive method and the pregnancy risk is discussed in detail with them., Conclusion: The effectiveness of the pregnancy prevention programme recommendations should be reconsidered by an expert committee. Justifications should be added to effective recommendations to increase their adoption by health care professionals and patients., (Copyright © 2018 John Wiley & Sons, Ltd.)

Estimates suggest that nearly 30% of patients diagnosed with chronic myeloid leukemia (CML) are aged <49 years, with approximately half being women. For many of these women, childbearing concerns are a major factor as they initiate treatment with tyrosine kinase inhibitors, which are known to be teratogenic. During her presentation at the NCCN 23rd Annual Conference, Dr. Berman identified the challenges in helping women undergoing treatment for CML who want to have children, and emphasized the importance of an individualized and multidisciplinary approach to management. In addition, she encouraged NCCN to create a pregnancy registry of this patient population to enable clinicians to collect firm data to guide clinical decision-making., (Copyright © 2018 by the National Comprehensive Cancer Network.)