Systemic isotretinoin treatment and pregnancy: A comparative study of two groups of women: A retrospective analysis of 569 women

Piotr Brzezinski1,2, Katarzyna Borowska3, Anca Chiriac4,5, Janusz Smigielski6

1Institute of Biology and Environmental Protection, Pomeranian Academy, ul. Arciszewskiego 22A, 76-200 Slupsk, Poland, 2Department of Dermatology, Provincial Specialist Hospital in Slupsk, ul. Mickiewicza 12, 76-270 Ustka, Poland, 3Department of Histology and Embryology with Experimental Cytology Unit, Medical University of Lublin, Radziwiłowska, Lublin, Poland, 4Department of Dermato-Physiology, Apollonia University Iasi, Strada Muzicii nr 2, Iasi-700399, Romania, 5Institute of Macromolecular Chemistry, Apollonia University, Nicolina Medical Center "Petru Poni", Iasi, Romania, 6State Higher Vocational School, Konin, Poland

 

Corresponding author: Piotr Brzezinski, MD PhD, E-mail: brzezoo77@yahoo.com

 

Submission: 10.09.2017; Acceptance: 15.10.2017

How to cite this article: Brzezinski P, Borowska K, Chiriac A, Smigielski J. Systemic isotretinoin treatment and pregnancy: A comparative study of two groups of women: A retrospective analysis of 569 women. Our Dermatol Online. 2017;9(4e):e2.


ABSTRACT

Background: Oral isotretinoin is the only drug which promotes prolonged remission or cure of severe acne. The aim of our study was to estimate the isotretinoin exposure and to evaluate the effectiveness of the Polish and Romanian pregnancy prevention. This is a comparative study of two groups of women. Methods: A retrospective, comparative study of 569 women with acne vulgaris. The study included two groups of randomly selected women during treatment and follow-up. Group I with rigorous prevention of pregnancy; Group II without this rigor. Results: We did not register any pregnancies. 1.93% used oral contraceptives, 92.79% used a condom during sex, and 7.21% of women abstained from sex. The analysis showed significant differences (p <0.0001) total dose applied depending on the method of treatment. No statistically significant correlations were found between patients' age, duration of disease, location, and type of acne. Average length of therapy was 8.81 months. Isotretinoin therapy was interrupted for 27 patients from group I. Conclusion: The isotretinoin pregnancy prevention in Poland and Romania was very good during our study. Every woman in the fertile phase of life should use contraception while taking isotretinoin. The most important thing is the awareness of the patient.

Key words: isotretinoin; pregnancy prevention programme; side effects; teratogenicity.

 


INTRODUCTION

Isotretinoin (13-cis-retinoic acid) is an effective treatment for of severe and persistent acne vulgaris. However, one of the most important adverse effects of this drug is human teratogenicity [1]. The teratogenic effects of isotretinoin are preventable, and there have been numerous attempts to minimize the risk of pregnancy during this treatment. In 2002, the Food and Drug Administration (FDA) launched an integrated risk management program known as iPLEDGE for all isotretinoin products. As part of this  program one must register, complete an informed consent form and receive counselling about the risks associated with the drug, and women must comply with required pregnancy testing (Table 1). Although the risks of pregnancy during isotretinoin therapy are well recognized, there are doubts about the level of adherence with the pregnancy prevention in Poland and Romania. The objective of our study was to estimate isotretinoin exposure and evaluate the effectiveness of the Polish and Romanian pregnancy prevention. In this study we compared two groups of women.

Table 1: Elements of the European Union isotretinoin pregnancy prevention programme.

 

MATERIAL AND METHODS

This is a retrospective, comparative study of 569 women with acne vulgaris. The study included two groups of randomly selected women during treatment and follow-up from July 2013 to October 2014. The first patient began treatment in July 2013 and ended in March 2014 and was observed to May 2014. The last patient started treatment in November 2013, ended in September 2014 and was observed to October 2014. The study was conducted in the Department of Dermatology, 6th Military Support Unit, Ustka, Poland and in the Department of Dermato-Physiology, Apollonia University Iasi, Romania. The women were treated with oral isotretinoin, in a dose dependent on body weight, the severity of lesions and age. The age of patients was between 14 and 25 years old. Isotretinoin at a dose of 20 mg was taken by 123 women (21.62%), at a dose of 30mg by 340 women (59.75%) and a dose of 40mg by 106 women (18.63%). Skin lesions in the course of acne were located on the face, back, chest, and arms. All patients had chronic moderate to severe acne with a tendency to cause scarring. Before treatment was initiated; age, weight, and anatomic location of lesions were recorded. The women were divided into 2 groups. Group I was counting 113 patients (19.86%). Group II was counting 456 patients (80.14%). The women in group II were divided into two subgroups: A and B. 
Group I – Women received oral information about the teratogenic effects of the drug. They signed a special statement. Women were ordered to visit a gynaecologist and bring monthly pregnancy test results. 
Group II A – Women received oral information about the teratogenic effects of the drug and signed a special statement. They were not ordered to do a pregnancy test during the isotretinoin therapy.
Group II B – Women received only verbal information on the teratogenic potential of the drug. Were not ordered to do a pregnancy test during treatment with isotretinoin or sign any statement.
All women were verbally advised to use two reliable simultaneous forms of contraception during treatment and for 3 months after the termination of treatment. The treatment regimen consisted of fixed, daily amounts of isotretinoin, for a duration of treatment based on the weight of patient, until a total cumulative dose of 120 mg/kg of body weight is achieved. Liver function tests serum transaminases, and lipid profiles (total cholesterol, low-density lipoprotein, high-density lipoprotein, triglyceride) were evaluated for all patients, before the initiation of treatment and again after the 2nd month of treatment. Thereafter, 6 monthly testing was indicated only if an abnormal value was not found on previous tests. The evaluations were done at 1-month intervals. The observation was carried out for two months after treatment with isotretinoin ended. 

Ethics
This study was performed on human subjects; thus, all patients were aware of the presence of the study and they were fully informed about the drug and its side-effects.

Statistics
Non-normal distributions were verified with a Shapiro-Wilk test. U-Mann-Whitney and Kruskal-Wallis tests were used to compare the differences between the two groups. P < 0.05 was considered statistically significant. All data analyzed by STATISTICA 10. 

RESULTS

The mean age range of patients was 23.78 (± 2.90). 189 (33.21%) of patients were younger than 16 years old and 380 (66.79%) of patients were 17 years or older. Acne clearing rate had no relation with the age of patients. The most common site of involvement was the face (569 patients (100%)), then the back (412 patients (72.41%)). Acne clearing rate had no relation with the anatomical location of lesions. Average length of therapy was 8.81 (standard deviation – SDpy. 1.47) months. The longest duration of treatment was 12 months and the shortest duration was 2 months. Patients' weight ranged from 35 to 105 kg (mean, 59.89; SD 12.12). The side-effects were observed during the study. The most common side-effects were mild cheilitis in 569 patients (100%), retinoid dermatitis in 109 patients (19.16%), facial erythema in 33 patients (5.90%), epistaxis in 23 patients (4.04%),  itching of the skin in 11 patients (1.93%), myalgias in 10 patients (1.75%), hair loss in 7 patients (1.23%), mood change in 3 patients (0.53%), arthralgias in 2 patients (0.35%), respectively. In only 5 patients, a slight elevation of liver enzymes and serum lipids was detected. In no patient was the treatment discontinued due to abnormality in laboratory values.
The analysis showed significant differences (p <0.0001) to the total dose applied depending on the method of treatment, i.e. the mean level of 115.89 ± 34.89 dose (median = 130.43) in group I was significantly higher than the average level 133.74 ± 9.66 dose (median = 135.21) and moderate doses 134.10 ± 7.07 (median = 134.10) in group II B (p <0.001) and p <0.01). However, there was no statistically significant difference between the total dose group IIA and IIB group (p> 0.05). Detailed data are presented in Table 2.

Table 2: Analysis of the total dose depending on the method of treatment.


The analysis showed significant differences (p <0.0001) followed total dose depending on the therapy, i.e. the mean dose level 57.30 ± 18.58 (median = 54.54) in group I was significantly lower in women with uninterrupted therapy than the average level of 134.29 ± 6.94 doses (median = 133.33) in women who discontinued therapy. Detailed data are presented in Table 3.

Table 3: Analysis of the total dose, depending on the therapy in the group of women who took the drug for acne.


Isotretinoin therapy was interrupted for 27 patients (4.75%). All the women belonged to Group I, which is 23.90%; one (0.88%) after 2 months, 9 (7.08%) after 3 months, 8 (7.08%) after 4 months, 7 (6.19) after 5 months, 1 (0.88 %) after 6 and 7 months of treatment; despite existing lesions in the course of acne and a failure to achieve a cumulative dose (120-150 mg/kg of body weight).
No women among the 569 observed became pregnant. 11 (1.93%) used oral contraceptives (2 (1.77%) in group I and 9 (7.96%) in group II), 528 (92.79%) used a condom during sex, abstinence from sex 41 women  (7.21%) – (30 (6.58%) in Group I and 11 (9.73%) in Group II).

 

DISCUSSION

There are different opinions about the dose of isotretinoin for treatment of acne vulgaris. The suggested standard dose is 0.5-1 mg/kg/day for 20-24 weeks, with a maximum cumulative dose of 120-150 mg/kg [3,4]. Relapse is reported more frequently following treatment with a lower dose [5,6]. Low dose isotretinoin to treat acne, has been described by Rao or Brzezinski [7,8]. This regimen is known to produce good results; but it causes several dose dependent side-effects [6,9,10]. Isotretinoin is a known human teratogen. The baby of a mother who has taken isotretinoin for even a few days during pregnancy is under an estimated 20%-35% risk of congenital defects including: cardiovascular, craniofacial, thymic and neurologic malformations [11,12]. The most common side-effects in our study were mild for example cheilitis in 93 patients (66.4%), mild xerosis in 569 patients (100%), facial erythema 33 (5.90%), epistaxis in 23 (4.04%), respectively. The observed side-effects were mild. Elevated liver function test results, and increase in serum lipid profiles was mild, and usually returned to normal within 6-8 weeks, despite continuation of treatment.
The women need to prevent pregnancy while taking isotretinoin; contraception (condoms, pills) and abstinence [13]. In our study 11 (1.93%) women used oral contraceptives, 528 (92.79%) used a condom during sex and 41 sexual abstinence (7.21%). Each women should be provided with information about the effects of the drug and the necessity of using contraception.
There are several publications in which the authors describe pregnant patients during treatment with isotretinoin [14,15]. In our study on 569 patients, there were no pregnancies, irrespective of whether the patient was in the rigorous, dermatological control group or in the groups(s) with more “freedom”.
Collins et al. states that approximately 150 women annually become pregnant while taking isotretinoin despite participation in the iPLEDGE programme, and noncompliance with the requirement to be abstinent or use 2 contraceptive methods may be a contributing factor [14]. In this study among 75 participants, 21 (28%) chose abstinence as their primary means of pregnancy prevention, of whom 4 (19%) were sexually active during treatment. The authors conclude that encouraging the use of highly effective, patient-independent contraception and limiting abstinence to women who have never been sexually active may further reduce the rate of isotretinoin-exposed pregnancies. In a Netherlands study of 51 pregnancies, 2.5 per 10 000 pregnancies (between 1 January 1999 and 1 September 2007) [15]. In 60% of isotretinoin exposed pregnancies, women started isotretinoin while already pregnant. In five out of the 51 isotretinoin exposed pregnancies (53 fetuses). In another study (from France) over 4 years, 147 cases of isotretinoin exposure during the teratogenic risk period were spontaneously reported, i.e. ‚conception <1 month after isotretinoin discontinuation' (23%), 'conception during isotretinoin treatment' (61%), and 'patient already pregnant when isotretinoin was started' (16%) [16]. Nineteen percent of the patients did not use any form of contraception. In 23% of the patients, the method of contraception used did not comply with recommendations, while in 86% of the cases, isotretinoin was prescribed by a dermatologist. Among the 44 pregnancies with available data on fetuses or neonates, there were two (4.5%) malformations compatible with the time of exposure and with isotretinoin embryopathy. The iPLEDGE programme has been the subject of some criticism. We know that pregnancies noted through the iPLEDGE programme declined about 15 percent from 2010 to 2011. In 2011, there were 155 reported pregnancies among 129,554 females of child-bearing potential (0.12%) of which 150 were ISO-exposed patients and five were of indeterminate exposure. Of the 2011 pregnancies, 5.8 percent occurred before ISO treatment started, 60.6 percent occurred during the course of treatment [17]. However, we do not know the specialty of doctors who recommend isotretinoin. The greatest awareness and knowledge about this drug, however, is among dermatologists. In Poland, it happens that acne is treated by isotretinoin by a gynecologist or a primary care physician. An interesting case is described in Manders et al. [18]. In this case a 29-year-old woman became pregnant shortly after discontinuing isotretinoin. She wished to continue the pregnancy, she received personal advice on the risk of bearing a child with congenital abnormalities. After an uneventful pregnancy she gave birth to a healthy son. Authors from the Republic of Korea talk about an elevated rate of babies born without evidence of gross malformation or neurofunctional abnormality even though exposure occurred during the teratogenic risk period [19]. In our study of 569 patients, 27 women in group I gave up (i.e. those with the greatest restrictions during treatment). We agree with the authors from Pennsylvania (USA) [20] that the iPLEDGE programme increases anxiety about isotretinoin more than it helps women feel protected from the teratogenic risks of isotretinoin. 

CONCLUSION

The isotretinoin pregnancy prevention program in Poland and Romania was very effective during the16-months period of this study. We did not register any pregnancies. Every woman in the fertile phase of life should use contraception while taking the isotretinoin and every woman should receive information on the teratogenic effects of the drug. The medical practitioners and patients must be constantly reminded of the risks of isotretinoin to the fetus and the most important thing is the awareness of the patients. 

Acknowledgement

Prof. Uwe Wollina from Department of Dermatology and Allergology, Academic Teaching Hospital Dresden-Friedrichstadt, Dresden, Germany.

 

REFERENCES

1. Wolverton SE, Harper JC. Important controversies associated with isotretinoin therapy for acne. Am J Clin Dermatol 2013; 4: 71-6.
2. iPLEDGE: committed to pregnancy prevention [web-based risk management program]. iPLEDGE; 2005. Available: https://www.ipledgeprogram.com
3. Li W, Liu Y, Luo Q, Li X-M, Zhang X-B. Off-label uses of retinoids in dermatology. Our Dermatol Online 2012;3: 259-78.  
4. Brzezinski P, Borowska K, Chiriac A, Smigielski J. Adverse effects of isotretinoin: A large, retrospective review. Dermatol Ther 2017;30. doi: 10.1111/dth.12483. Epub 2017 Mar 14. 
5. Bagatin E, Guadanhim LR, Enokihara MM, Sanudo A, Talarico S, Miot HA. Low-dose oral isotretinoin versus topical retinoic acid for photoaging: a randomized, comparative study. Int J Dermatol 2014;53: 114-22. 
6. Al-Hamamy HR, Salman HA, Abdulsattar NA. Treatment of plane warts with a low-dose oral isotretinoin. ISRN Dermatol 2012;2012: 163929.
7. Rao PK, Bhat RM, Nandakishore B, Dandakeri S, Martis J, Kamath GH. Safety and efficacy of low-dose isotretinoin in the treatment of moderate to severe acne vulgaris. Indian J Dermatol 2014;59: 316.
8. Brzezinski P, Sinjab AT. Low doses isotretinoine in the treatment of acne vulgaris. Dermatol Prakt 2012;3: 51-4.
9. Charakida A, Mouser PE, Chu AC. Safety and side effects of the acne drug, oral isotretinoin. Expert Opin Drug Saf 2004;3: 119–29.
10. Geller AS, Alagia RF. Sacroiliitis after use of oral isotretinoin–association with acne fulminans or adverse effect? An Bras Dermatol 2013;88: 193-6.
11. Alan S, Ünal B, Yildirim A. Premature ventricular contractions associated with isotretinoin use. An Bras Dermatol 2016;91: 820-1.
12. On SC, Zeichner J. Isotretinoin updates. Dermatol Ther 2013;26: 377-89.
13. Choi JS, Koren G, Nulman I. Pregnancy and isotretinoin therapy. CMAJ 2013;185: 411-3.
14. Collins MK, Moreau JF, Opel D, Swan J, Prevost N, Hastings M, et al. Compliance with pregnancy prevention measures during isotretinoin therapy. J Am Acad Dermatol 2014;70: 55-9.
15. Zomerdijk IM, Ruiter R, Houweling LM, Herings RM, Sturkenboom MC, Straus SM, et al. Isotretinoin exposure during pregnancy: a population-based study in The Netherlands. BMJ Open 2014;4: e005602.
16. Autret-Leca E, Kreft-Jais C, Elefant E, Cissoko H, Darrouzain F, Grimaldi-Bensouda L, et al. Isotretinoin exposure during pregnancy: assessment of spontaneous reports in France. Drug Saf 2010;33: 659-65.
17. Leyden JJ, Del Rosso JQ, Baum EW. The use of isotretinoin in the treatment of acne vulgaris: clinical considerations and future directions. J Clin Aesthet Dermatol 2014;7: S3-S21.
18. Manders KC, de Vries LC, Roumen FJ. Pregnancy after isotretinoin use. Ned Tijdschr Geneeskd 2013;157: A6567.
19. Yook JH, Han JY, Choi JS, Ahn HK, Lee SW, Kim MY, et al. Pregnancy outcomes and factors associated with voluntary pregnancy termination in women who had been treated for acne with isotretinoin. Clin Toxicol (Phila) 2012;50: 896-901.
20. Werner CA, Papic MJ, Ferris LK, Lee JK, Borrero S, Prevost N, et al. Women's experiences with isotretinoin risk reduction counseling. JAMA Dermatol 2014;150: 366-71.

 

Notes

Source of Support: Nil,

Conflict of Interest: None declared.


CONTENT

SERVICES

Other Resources

Our Dermatology Online

Home
Current Issue
All Issues
Instruction for authors
Submit Manuscripts
Ethics in Publishing
For Reviewers
Readers
About
Editors & Publishers 
Statistics
Copyright
Contact Us