Epidemiology of isotretinoin exposure during pregnancy.

BACKGROUND: Exposure to isotretinoin during pregnancy is associated with a high risk of major fetal malformations. OBJECTIVE: Our purpose was to determine the reasons for and outcomes of in utero isotretinoin exposure. METHODS: On the basis of 433 spontaneous reports, we describe the likely reasons these exposures occurred and the outcomes of these pregnancies. In our analysis of the outcomes of pregnancy, we separately consider the pregnancies known to us before their outcomes were determined as prospective cases. RESULTS: Timing of conception in relation to initiation of therapy with isotretinoin was known for 396 women. Of these, 130 patients (33%) were already pregnant when they started isotretinoin. An additional 65 patients (16%) became pregnant in the first 3 weeks of isotretinoin use. Pregnancy outcomes were known on 409 pregnancies. Among these, 222 (54%) ended in elective abortion and 29 (7%) in spontaneous or missed abortion. Of 151 births, 72 (48%) were normal, 71 (47%) had congenital malformations, and 8 (5%) had abnormalities other than malformations. Of 94 prospectively ascertained pregnancies that ended in births, 28% had congenital malformations (95% confidence interval 19% to 37%). Exposure to isotretinoin during any time and for as little as one capsule within the first trimester have been associated with congenital malformations. CONCLUSION: The high proportion of exposures in already or recently pregnant women illustrates the importance of obtaining a negative pregnancy test before the initiation of isotretinoin therapy and of delaying the commencement of isotretinoin therapy until the onset of the next menstrual period. Furthermore, the importance of reliable contraceptive methods should be emphasized to patients when isotretinoin is prescribed. Young women seem to be at an especially high risk of pregnancy exposure to isotretinoin. There is a substantial risk of congenital malformation at all therapeutic doses of isotretinoin, even when the duration of exposure is brief.     

Adverse reactions to isotretinoin: A report from the Adverse Drug Reaction Reporting System

Between October 1982 and June 1985 the Adverse Drug Reaction Reporting System received reports of 104 suspected adverse reactions occurring in 93 patients who took isotretinoin. Adverse reactions involving the skin and mucous membranes (29 reports), central nervous system (23), musculoskeletal system (12), pregnancy (11), and eyes (8) were most commonly reported. Severe headache was the most frequently reported adverse reaction (15 reports). In four cases headaches were attributed to pseudotumor cerebri. Some of the reported reactions, for example, a disulfiram (Antabuse)-like reaction and oculogyric crisis, have not been described previously in the literature. Other reports, such as congenital malformations, serve to emphasize sorne of the serious reactions that are known to occur. These spontaneous reports of adverse reactions associated with isotretinoin use, together with the literature we review, may help alert physicians to the diverse spectrum of adverse reactions that may develop in patients taking isotretinoin.     

SURVEY OF AUSTRALIAN ISOTRETINOIN PRESCRIBING

In Australia, dermatologists have been designated as the sole prescribers of isotretinoin and thus we are in a unique position to audit national usage of the drug. Questionnaires were sent by the Australasian College of Dermatologists to all 204 practising Fellows in Australia. The aim was to study the number and type of patients treated with isotretinoin, the manner in which the drug is prescribed, adverse reactions and the number of pregnancies occurring during and after treatment. Judging from the 85% of questionnaires which were returned, isotretinoin is an effective and well-tolerated drug for the treatment of severe nodulocystic acne. In the five years that isotretinoin has been used in Australia, 11 pregnancies while taking the drug were reported. These pregnancies occurred despite exhaustive counselling by dermatologists and the patients being fully aware of the risks to the fetus and the need for adequate contraceptive measures. With one exception, all agreed to have a therapeutic abortion. There were two reports of congenital abnormalities after cessation of treatment, neither of which were thought to be related to isotretinoin. In several regions where a dermatologist is not available, a specialist physician may prescribe isotretinoin according to State Health regulations.     

Are there racial and sex differences in the use of oral isotretinoin for acne management in the United States?

BACKGROUND: Treatment of various diseases has been noted to vary by patient demographics. There is reason to suspect that there may be sex and racial differences in the treatment of severe acne. OBJECTIVE: We sought to determine if treatment of severe acne with oral isotretinoin varied with patient sex, race, or both. METHODS: We analyzed the demographics of patients with acne and patients using oral isotretinoin, minocycline, and tetracycline recorded in the 1990 to 1997 National Ambulatory Medical Care Survey. RESULTS: There were 35 million visits to physicians for the treatment of acne between 1990 and 1997, and isotretinoin was prescribed at 5.8 million (17%) of these visits. Per capita visit rates for acne among whites was 2.3 times that of blacks, and whites were 1.8 times more likely to receive isotretinoin at acne visits. Per capita, women had 1.4 times as many visits for acne as men, but men were 1.7 times more likely than women to receive isotretinoin at an acne visit. Dermatologists managed 83% of all isotretinoin visits. Dermatologists accounted for 100% of isotretinoin visits for which pregnancy prevention education and counseling was reported. CONCLUSIONS: Patients who are black receive less oral isotretinoin than those who are white, and the expense of isotretinoin appears to be one factor in this difference. Women are less likely than men to receive isotretinoin at acne visits. Expense does not appear to be a factor in this difference. Dermatologists have more experience than nondermatologists managing acne, prescribing isotretinoin, and counseling women treated with isotretinoin concerning pregnancy prevention. Pregnancy prevention is an essential component of isotretinoin use in women that must not be ignored.     

Isotretinoin: Still the cause of anxiety for teratogenicity

Isotretinoin is known as a potent teratogenic agent. Pregnancy should be ruled out before isotretinoin is prescribed. In this study, we evaluated the fetal outcomes of pregnant women who had inadvertently been exposed to isotretinoin during or before pregnancy. We collected data of pregnant women who had admitted to the Teratology Information Service due to isotretinoin exposure. Data regarding medications and comorbidities were documented. Outcomes were grouped as: live births, stillbirths, live births with congenital malformations, induced abortions (due to fetal abnormalities), spontaneous abortions, and elective abortions. We found that three women had gone to elective abortions. Three babies were live born without birth defects, of which, maternal exposure periods were between 0 and 3 weeks, 9 and 10 weeks before last menstrual period. One woman, exposed to isotretinoin up to the fourth week of gestation, decided ongoing her pregnancy with no current drug‐related complications. Although many risk management programs worldwide have been used to prevent isotretinoin‐related teratogenicity, the results of the present study showed that women became pregnant during isotretinoin intake and opted for pregnancy termination. Attention should be paid to the risk management programs mandating effective contraceptions, in order to lessen the drug‐related terminations.     

Compliance with pregnancy prevention programmes of isotretinoin in Europe: a systematic review

Most of the publications on isotretinoin, pregnancy and compliance with the pregnancy prevention programme (PPP) originate from North America. Information specific for the European situation is very limited. The aim of this study was to identify publications describing the use of isotretinoin in humans and the compliance with the PPP in Europe, a systematic search in Medline and Embase was conducted using the terms ‘isotretinoin, pregnancy (and Europe)’. Furthermore, a manual search in publications was performed. A total of 17 publications were identified. Publications consisted of case reports of exposed pregnancies, surveys among dermatologists or pharmacists and database studies evaluating compliance with the PPP. The studies and surveys dealt with groups of patients exposed to isotretinoin before or during pregnancy and/or compliance with the isotretinoin PPP. Where the information was provided, in 6–26% of cases isotretinoin was prescribed in full accordance with the PPP. Pregnancy incidence was seen in 0·2–1·0 per 1000 women of childbearing age using isotretinoin. Between 65% and 87% of these pregnancies were terminated. This review of studies in Europe performed to date shows failures in the implementation of the PPP. Therefore, the isotretinoin PPP must be scrutinized to identify whether new measures should be taken or whether the failures in the implementation need to be corrected. New measures should take into account the definition of the ultimate goal of a PPP and the acceptable burden. In the meantime, stakeholders could make a start with adjustments in the implementation of the PPP by taking responsibility and enhancing the performance by explicit instructions, monitoring the performance and adjusting, if necessary.     

妊娠期梅毒临床结局的相关因素分析及临床诊治

目的：分析影响梅毒患者妊娠结局的相关因素,探讨妊娠期梅毒的诊断与治疗方法,最大限度地提高新生儿结局。方法：选择我院2010年1月至2013年3月131例妊娠合并梅毒患者资料进行分析,其中82例孕产妇在产前经血清学筛查确诊后给予驱梅治疗,49例孕产妇于临产经输血前四项指标筛查确诊,未进行驱梅治疗,对两组产妇与新生儿结局进行分析,同时探讨妊娠期梅毒患者的诊治方法。结果：治疗组共发生新生儿先天性梅毒17例,发生率为20．73％;未治疗组共发生先天性梅毒29例,发生率为59．18％。治疗组死胎、早产发生率均低于未治疗组,流产发生率高于未治疗组,早孕组新生儿先天性梅毒发生率、死胎率、不良妊娠发生率明显低于晚孕组,流产、早产发生率高于晚孕组与中孕组,两组比较差异具有显著性（P〈0．05）。剖宫产组新生儿先天性梅毒感染40例,感染率为33．33％;阴道分娩组感染6例,感染率为54．55％,阴道分娩感染率明显高于剖宫产,两种分娩方式感染率比较差异具有显著性（P〈0．05）。结论：妊娠期梅毒是导致新生儿结局不良的危险因素,分娩方式、治疗时间及科学规范的驱梅治疗可提高新生儿结局。     

Outcomes of pregnancies among women and partners of men with a history of exposure to methoxsalen photochemotherapy (PUVA) for the treatment of psoriasis

Because oral methoxsalen and UV-A radiation (PUVA) therapy is mutagenic, concern exists about the potential for teratogenic effects resulting from the use of this therapy at the time of conception and during pregnancy. After 12.8 years of prospective study, we documented the pregnancy outcomes among 1380 patients (892 men and 488 women) who received PUVA treatments. Ninety-four men reported 167 pregnancies in their partners, and 93 women reported 159 pregnancies. For 34% of pregnancies among partners of male patients, the man received PUVA therapy near the time of conception. Nineteen percent of female patients reported exposure to PUVA at the time of conception or during pregnancy. Induced and spontaneous abortions were reported as the outcome of pregnancy more often by female than by male patients (12% vs 30%). Two congenital malformations and two stillbirths occurred, an incidence not significantly different from that expected for the general population. Although the power of our study to detect an increase in the risk of specific defects is limited, our data show no evidence to suggest that PUVA is a potent teratogen. Still, because PUVA is mutagenic, we believe it prudent for patients to avoid PUVA treatment during pregnancy whenever practical.     

Depression and suicidal behavior in acne patients treated with isotretinoin: a systematic review

Isotretinoin (13-cis retinoic acid) is an effective treatment for severe cystic or recalcitrant acne vulgaris; however, concerns have been raised regarding its potential association with depression and suicidal behavior. We sought to explore the proposed relationship between isotretinoin use and the risk of depression and attempted and completed suicide in patients with acne vulgaris by performing a systematic literature search for studies reporting primary data on depression and suicidal behavior in patients treated with isotretinoin for acne vulgaris. Nine studies met the qualifying criteria for our analysis. Rates of depression among isotretinoin users ranged from 1% to 11% across studies, with similar rates in oral antibiotic control groups. Overall, studies comparing depression before and after treatment did not show a statistically significant increase in depression diagnoses or depressive symptoms. Some, in fact, demonstrated a trend toward fewer or less severe depressive symptoms after isotretinoin therapy. This decrease was particularly evident in patients with pretreatment scores in the moderate or clinical depression range. No correlation between isotretinoin use and suicidal behavior was reported, although only one retrospective study presented data on this topic. Although the current literature does not support a causative association between isotretinoin use and depression, there are important limitations to many of the studies. The available data on suicidal behavior during isotretinoin treatment are insufficient to establish a meaningful causative association.     

Depression and suicidal behavior in acne patients treated with isotretinoin: a systematic review

Isotretinoin (13-cis retinoic acid) is an effective treatment for severe cystic or recalcitrant acne vulgaris; however, concerns have been raised regarding its potential association with depression and suicidal behavior. We sought to explore the proposed relationship between isotretinoin use and the risk of depression and attempted and completed suicide in patients with acne vulgaris by performing a systematic literature search for studies reporting primary data on depression and suicidal behavior in patients treated with isotretinoin for acne vulgaris. Nine studies met the qualifying criteria for our analysis. Rates of depression among isotretinoin users ranged from 1% to 11% across studies, with similar rates in oral antibiotic control groups. Overall, studies comparing depression before and after treatment did not show a statistically significant increase in depression diagnoses or depressive symptoms. Some, in fact, demonstrated a trend toward fewer or less severe depressive symptoms after isotretinoin therapy. This decrease was particularly evident in patients with pretreatment scores in the moderate or clinical depression range. No correlation between isotretinoin use and suicidal behavior was reported, although only one retrospective study presented data on this topic. Although the current literature does not support a causative association between isotretinoin use and depression, there are important limitations to many of the studies. The available data on suicidal behavior during isotretinoin treatment are insufficient to establish a meaningful causative association.     

Effects of isotretinoin on serum vitamin E levels in patients with acne

Anecdotal reports suggest that using retinoids with vitamin E leads to improvements of some side effects due to isotretinoin. However, vitamin E blood levels have not been reported previously in patients with acne treated with isotretinoin. We aimed to investigate the serum vitamin E levels before and after isotretinoin therapy in patients with acne. A total of 70 patients treated with isotretinoin for acne in our dermatology department were included in this study. The serum vitamin E levels were measured as baseline before isotretinoin treatment. All patients received 0.6–0.8 mg/kg/d isotretinoin. The treatment was finished within 5–7 months while ensuring that the cumulative dose was 120 mg/kg. Serum vitamin E levels were measured again in the last month of treatment. The mean serum vitamin E levels before and after treatment were compared. Forty‐six patients completed the study. It was detected that the mean serum vitamin E level was 20.22 mg/dl before isotretinoin treatment. In the last month of treatment, the mean serum vitamin E level was 16.24 mg/dl. Serum vitamin E levels decreased in all patients except three. The mean serum vitamin E level after treatment was statistically decreased in comparison with the mean serum vitamin E level before treatment. Our results showed that vitamin E levels decreased during isotretinoin treatment. We considered that some of the side effects due to isotretinoin treatment might be related to this, and supplementation vitamin E may be useful during isotretinoin treatment.     

Comparison of combined azelaic acid cream plus oral minocycline with oral isotretinoin in severe acne.

BACKGROUND/AIMS: The primary aim of the study was to establish the clinical efficacy and safety of a combined treatment consisting of topical 20% azelaic acid (AA) cream and the oral antibiotic minocycline in the therapy of severe inflammatory acne (nodular papulopustular acne and acne conglobata) in a comparison with oral isotretinoin therapy. The secondary aim was to establish the value of AA cream as maintenance therapy in the prevention of recurrent acne. METHODS: This open-label but randomised study involved 85 patients with nodular papulopustular acne or acne conglobata (Leeds grading scale > 4) who were treated for 6 months. In an immediately subsequent 3-month second phase, eligible patients from the initial combination group used the AA cream as maintenance therapy, while the eligible patients from the isotretinoin group served as untreated control. RESULTS: A 6-month course of treatment with topical 20% AA cream plus oral minocycline in 50 patients proved to be effective in nodular forms of acne (median reduction of facial comedones: 70%; of papules and pustules: 88%; of deep inflammatory acne lesions: 100%). Overall, the combined treatment was not quite as effective as treatment with oral isotretinoin (35 patients; reduction of comedones: 83%; of papules and pustules: 97%; of deep inflammatory acne lesions: 100%). In the 3-month maintenance therapy phase, about half of the patients who received AA monotherapy maintained the very good facial result achieved by the end of phase I. A similar rate was found in the patients of the isotretinoin group, who received no further active acne treatment. In the other 50% of patients, differences existed between the groups as regards the degree of deterioration: Marked deterioration occurred more frequently under AA treatment, while only slight deterioration was more frequent in the isotretinoin group. The combination was tolerated much better than isotretinoin. The incidence of local side effects observed under the combination of AA and minocycline (36.5%, mainly transient burning and itching of mild or moderate intensity) was considerably lower than that seen with isotretinoin (65.7%). The rate of local side effects of marked intensity observed under the combination, i.e. 6%, was well within the range of 5-10% previously reported for AA. The incidence of systemic side effects was lower (8%, mainly gastrointestinal symptoms) under the combined therapy than under isotretinoin (14.3%). CONCLUSION: The combination of topical 20% AA cream and oral minocycline is an highly effective treatment in severe forms of acne. It is better tolerated and associated with fewer risks than oral isotretinoin - in particular, there is no risk of teratogenicity. The combination can be regarded as a valuable alternative in patients for whom isotretinoin is not indicated, who do not wish to use or can not tolerate isotretinoin therapy and particularly in female acne patients of child-bearing potential. Topical 20% AA cream can be used successfully as maintenance therapy to prolong the recurrence-free interval.     

Important Controversies Associated with Isotretinoin Therapy for Acne

Isotretinoin is a remarkably effective drug for severe, recalcitrant acne vulgaris. Soon after the drug’s release in the early 1980s, a number of important adverse effects were reported subsequently leading to a variety of medical and medicolegal controversies. Three of these controversies will be highlighted concerning the putative role of isotretinoin in (1) depression and suicide, (2) inflammatory bowel disease, and (3) iPledge and pregnancy prevention programs. It appears that a very small subset of patients receiving isotretinoin for acne are at risk for depression, which is very manageable provided there is adequate patient awareness of the possibility, maximum communication between the patient and physician, and cessation of therapy if clinically important depression occurs (after which the depression rapidly resolves in a week or less). Multiple controlled studies actually suggest a very favorable effect of isotretinoin on depression and anxiety common in the population requiring isotretinoin. With regard to inflammatory bowel disease, in just one study, only ulcerative colitis association with isotretinoin reached statistical significance. The actual incidence of this association is strikingly low. Finally, it is clear that even the most recent pregnancy prevention program (iPledge) is no more successful than prior programs; there will likely always be a small number of female patients becoming pregnant while receiving isotretinoin for acne vulgaris.     

Adverse effects of isotretinoin: A retrospective review of 1743 patients started on isotretinoin

Background/Objectives: Isotretinoin has revolutionized the management of acne vulgaris. However, concerns continue regarding the adverse effect profile of isotretinoin. This study aims to review the adverse effects experienced by patients started on isotretinoin by a single dermatologist. Methods: Retrospective chart review of 1743 patients started on isotretinoin for various dermatological conditions over a 6‐year period. Details of the dose of isotretinoin used, concomitant medications, adverse effects and outcome were recorded. Results: One‐fifth (18.5%) of patients reported no adverse effects during the study period. Cheilitis was the most commonly reported adverse effect, affecting 78% of users, followed by eczema and tiredness, seen in 12% each. However, these were clearly dose‐dependent, as the group treated with doses of isotretinoin under 0.25 mg/kg/day only reported cheilitis in 47%, eczema in 7% and tiredness in 5%, compared with 96%, 16% and 18%, respectively, in those treated with more than 0.75 mg/gm/day. Twenty‐four patients (1.4%) stopped isotretinoin because of adverse effects; a further three patients complained of severe adverse effects on at least one occasion, but continued taking the medication. The adverse effect(s) that led to patients stopping isotretinoin were cheilitis (22 patients), mood change (13), tiredness (12), eczema (6) and pregnancy (2). There were no reported instances of suicidal ideation or attempted suicide. Conclusions: Other than the two oral contraceptive failures, there were no serious adverse events recorded during this review period. Isotretinoin is a very effective medication with a low adverse‐effect profile when used at lower doses.     

A prospective study of the responsiveness of depression and suicidal ideation in acne patients to different phases of isotretinoin therapy

The degree and manner to which isotretinoin affects the mental health of acne patients has not been extensively researched, despite reports of possible associations between isotretinoin and depression. In this study, 33 patients with acne were prescribed a standard 16-week treatment regime with isotretinoin. At the initiation of isotretinoin treatment, week 8 review and termination of treatment, patients completed validated measures of depression, hopelessness and self-rated dermatological severity and were also assessed dermatologically using an acne grading protocol. When the first phase of isotretinoin treatment (week 1 to week 8) was compared to the second phase (week 9 to week 16), patients reported significant improvements in the cognitive-affective features of depression during the first phase of treatment, but not during the second phase. Corresponding improvements in the somatic symptoms of depression and hopelessness were not found. The implications of the research are discussed in relation to methodological design issues in this area.     

Face-to-face: isotretinoin use and pregnancy outcome

Isotretinoin has been used to treat severe acne for more than 40 years. There are no accurate data on the absolute risk of potential teratogenicity to all fetuses exposed to isotretinoin. According to current guidelines, isotretinoin should be discontinued at least 1 month before pregnancy. This study enrolled pregnant women who contacted the Clinical Pharmacology and Toxicology Unit for individual drug risk assessment between 2016 and 2020. Data on maternal characteristics and isotretinoin exposures were obtained at first consultation. After delivery, follow-up calls were conducted using a structured questionnaire. Of 2,323 pregnant women consulted, 1.3% (31/2,323) had systemic isotretinoin exposure during and before pregnancy. Of 31 prospectively followed pregnancies, eight terminated electively. Most elective terminations (7/8) were performed because of the fear of fetal malformation. The majority of continued pregnancies (16/23) resulted in healthy live birth. There were no major birth defects. In six pregnancies, intrauterine deaths (three first trimester, three second trimester) were reported. Cesarean section was performed in 70.5% (12/17) of all deliveries. The median gestational age at birth was 39, and no preterm births were reported. Local isotretinoin treatments in six cases were evaluated and presented additionally, and all babies were born healthy. Based on the results of this study, there was no evidence of major birth defect, mental disorder, or retinoid embryopathy associated with the use of isotretinoin in pregnancy. Not local use, but systemic exposure to isotretinoin is of great concern that results in pregnancy termination.     

Acquired port-wine stains: A report of two cases and review of the literature

Background

Acquired port-wine stains (APWS) are rare vascular malformations that share the same clinical and histological features as their congenital counterparts. Rare cases of AWPS secondary to trauma or in association with medications have been reported in the literature.

Patients and Methods

We report two cases of APWS. One case appeared at the age of 2 months, the earliest reported in the literature and continued to evolve till the age of 3 years presenting with multifocal distribution mainly affecting the lower face. The second case developed during oral isotretinoin intake and persisted after discontinuation of the treatment.

Results and Conclusions

The second patient declined treatment, but the first patient had a remarkable improvement following treatment with the pulsed dye laser, which remains the standard of care for capillary malformations on the face.