Use of isotretinoin among girls and women of childbearing age and occurrence of isotretinoin-exposed pregnancies in Germany: A population-based study

Jonas Reinold; Bianca Kollhorst; Nadine Wentzell; Katharina Platzbecker; Ulrike Haug

doi:10.1371/journal.pmed.1004339

. 2024 Jan 25;21(1):e1004339. doi: 10.1371/journal.pmed.1004339

Use of isotretinoin among girls and women of childbearing age and occurrence of isotretinoin-exposed pregnancies in Germany: A population-based study

Jonas Reinold ¹, Bianca Kollhorst ², Nadine Wentzell ¹, Katharina Platzbecker ¹, Ulrike Haug ^1,^3,^¤,^*

PMCID: PMC10810459 PMID: 38271295

Abstract

Background

Exposure to isotretinoin during pregnancy must be avoided due to its teratogenicity, but real-world data on its use are scarce. We aimed to describe (i) isotretinoin use in women of childbearing age in Germany; (ii) the occurrence of isotretinoin-exposed pregnancies; and (iii) malformations among children exposed in utero.

Methods and findings

Using observational data from the German Pharmacoepidemiological Research Database (GePaRD, claims data from approximately 20% of the German population), we conducted annual cross-sectional analyses to determine age-standardized prevalence of isotretinoin use between 2004 and 2019 among girls and women aged 13 to 49 years. In cohort analyses, we estimated the number of exposed pregnancies by assessing whether there was prescription supply overlapping the beginning of pregnancy (estimated supply was varied in sensitivity analyses) or a dispensation within the first 8 weeks of pregnancy. Data of live-born children classified as exposed in a critical period according to these criteria were reviewed to assess the presence of congenital malformations.

The age-standardized prevalence of isotretinoin use per 1,000 girls and women increased from 1.20 (95% confidence interval [CI]: 1.16, 1.24) in 2004 to 1.96 (95% CI: 1.92, 2.01) in 2019. In the base case analysis, we identified 178 pregnancies exposed to isotretinoin, with the number per year doubling during the study period, and at least 45% of exposed pregnancies ended in an induced abortion. In sensitivity analyses, the number of exposed pregnancies ranged between 172 and 375. Among live-born children, 6 had major congenital malformations. The main limitation of this study was the lack of information on the prescribed dose, i.e., the supply had to be estimated based on the dispensed amount of isotretinoin.

Conclusions

Isotretinoin use among girls and women of childbearing age increased in Germany between 2004 and 2019, and there was a considerable number of pregnancies likely exposed to isotretinoin in a critical period. This highlights the importance of monitoring compliance with the existing risk minimization measures for isotretinoin in Germany.

Jonas Reinold and colleagues investigate how isotretinoin use has changed over a 15 year period in Germany and the potential for in-utero exposure.

Author summary

Why was this study done?

Systemic (oral) isotretinoin is used in the treatment of moderate to severe acne.
Given that isotretinoin is one of the strongest human teratogens known today, it is important to monitor the use of isotretinoin in girls and women of childbearing age as well as the occurrence of pregnancies exposed to this drug.
There is a lack of population-based studies addressing these research questions.

What did the researchers do and find?

Using a database covering 20% of the German population, we conducted cross-sectional analyses to assess the prevalence of isotretinoin use between 2004 and 2019 in girls and women of childbearing age.
We found that the age-standardized prevalence of isotretinoin use increased from 1.20 to 1.96 per 1,000 girls/women during this period.
In cohort analyses, we estimated the number of pregnancies likely exposed to isotretinoin in a critical period. In the base case analysis, we identified 178 of such pregnancies.
Sensitivity analyses considering the recommended one-month washout period suggested that there could have been additional pregnancies exposed to isotretinoin because they started before the end of the washout period.

What do these findings mean?

Isotretinoin use among girls and women of childbearing age increased in Germany between 2004 and 2019, and there were a considerable number of pregnancies likely exposed to isotretinoin in a critical period.
This highlights the importance of monitoring compliance with the existing risk minimization measures for isotretinoin in Germany.
It also seems important to increase awareness regarding the component of the pregnancy prevention program that recommends contraception also in the month after treatment cessation.
The main limitation of this study was the lack of information on the prescribed dose of isotretinoin. We therefore estimated the dose based on the dispensed amount of isotretinoin and varied the underlying assumptions.

Introduction

Systemic (oral) treatment with the vitamin A derivative isotretinoin (13-cis-retinoic acid) is indicated in moderate to severe acne (e.g., nodular or conglobate acne or acne at risk of permanent scarring) resistant to therapy with systemic antibiotics and topical anti-acne treatment [1]. Systemic isotretinoin is considered to be the clinically most effective anti-acne therapy, achieving long-term remission or significant improvement in many patients [2,3]. At the same time, isotretinoin is one of the strongest human teratogens known today [4]. Given the age distribution of patients with acne, girls and women of childbearing age are among the patients to whom isotretinoin is prescribed.

In 2003, i.e., 20 years after the EU-market authorization for isotretinoin, uniform pregnancy prevention programs were established in order to avoid isotretinoin exposure during pregnancy. In 2018, these measures were evaluated and updated [5]. Girls and women initiating systemic isotretinoin treatment are required to have monthly pregnancy tests and to use 2 complementary contraceptive methods from 1 month before treatment initiation to 1 month after treatment cessation [5]. The continuation of contraception for 1 month after treatment cessation is recommended due to delayed plasma elimination [3]. Because of this delayed elimination, pregnancies beginning shortly after treatment with isotretinoin may also be exposed to potentially harmful plasma concentrations.

Given the potential harm to the unborn child, it is important to monitor the use of isotretinoin in girls and women of childbearing age as well as the frequency of pregnancies exposed to this drug. However, no such data are available from Germany. Also internationally, population-based studies quantifying the frequency of isotretinoin-exposed pregnancies are only available for few countries, namely the United States, Canada, France, and the Netherlands [6–11], and there are no studies on time trends of isotretinoin use among young women. Furthermore, there is a lack of studies systematically exploring the extent to which conceptions occurring in the month after discontinuation of treatment may contribute to the number of exposed pregnancies.

Therefore, the aims of this study were (i) to describe the utilization of isotretinoin in girls and women of childbearing age in Germany including time trends; (ii) to describe the frequency of pregnancies exposed to isotretinoin, considering also potential exposure due to treatment cessation in the month before pregnancy; and (iii) to explore potential malformations among children exposed to isotretinoin in early pregnancy (not to be mistaken with estimating causal effects).

Methods

Data source

We used the German Pharmacoepidemiological Research Database (GePaRD) which is based on claims data from 4 statutory health insurance providers in Germany and currently includes information on approximately 25 million persons who have been insured with one of the participating providers since 2004 or later. In addition to demographic data, GePaRD contains information on drug dispensations as well as outpatient (i.e., from general practitioners and specialists) and inpatient services and diagnoses. The data is available on an individual level. Per data year, there is information on approximately 20% of the general population and all geographical regions of Germany are represented [12,13]. The German health care system is based on mandatory private or statutory health insurances [14]. About 90% of the general population are covered by statutory health insurances [15]. Core characteristics of the German health insurance system are uniform access to all levels of care and a free choice of providers.

In GePaRD, the Anatomical Therapeutic Chemical (ATC) code is used to identify drugs dispensed in the outpatient setting. Systemic isotretinoin treatment was identified based on the ATC code D10BA01. Diagnoses in GePaRD are coded according to the International Classification of Diseases 10th revision, German modification (ICD-10-GM). For research on drug utilization and safety during pregnancy, algorithms to identify and classify pregnancy outcomes [16,17], to estimate the beginning of pregnancy [18], and to link mothers with their children [19] have been developed for GePaRD. This study follows the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) guidelines (S1 Checklist).

Study design and study population

Prevalent use of isotretinoin among girls and women of childbearing age

To determine prevalent use of isotretinoin over time, we conducted year-wise cross-sectional analyses from 2004 to 2019. For each calendar year, we included all girls and women in the numerator who had at least 1 dispensation of isotretinoin, were aged between 13 and 49 years in the respective year, and were insured on June 30 of that year. In the denominator, we included all girls and women aged between 13 and 49 years in the respective year and insured on June 30 of that year.

Identification of exposed pregnancies

Using the algorithm for pregnancy outcomes, we identified pregnancies ending between 2004 and 2019 and occurring among girls and women aged 13 to 49 years at beginning of pregnancy.

Exposure to isotretinoin during early pregnancy was assumed if the exposure window assigned to the last dispensation before pregnancy overlapped the first day of pregnancy or if there was a dispensation in the first 8 weeks of pregnancy. The latter time period was restricted to 8 weeks rather than 12 weeks because it is then more likely that the dispensed drug was actually used during the first trimester, so this was a conservative approach to avoid overestimating the number of pregnancies exposed during the first trimester. The exposure window assigned to the last dispensation before pregnancy was defined as the dispensation date plus the total number of defined daily doses (DDDs) in the package (1 DDD of isotretinoin is 30 mg). In various sensitivity analyses, we changed the exposure window to take into account (i) delayed elimination (30 days were added to the exposure assigned to the last dispensation); (ii) potential treatment at higher or lower doses (the DDD was multiplied by the factor 0.75, 1.5, and 3.0, respectively, which corresponds to a daily dose of 40 mg, 20 mg, and 10 mg, respectively); and (iii) delayed elimination in combination with treatment at higher or lower doses (the DDD was multiplied by the factor 0.75, 1.5, and 3.0, respectively, and in addition, a 30-day period was added). In addition (iv), we conducted a sensitivity analysis assuming a fixed supply of 30 days after the last dispensation before pregnancy as this is the maximum supply that should be dispensed to girls and women of childbearing age according to the German pregnancy prevention program for isotretinoin [20]. In each of the analyses, we made sure that the pre-observation period of the mothers included in the respective analysis before beginning of pregnancy was sufficiently long to assess the exposure status.

Given that certain incomplete pregnancies in claims data may have no outcome recorded (e.g., miscarriages not requiring medical treatment, induced abortions without medical indication) and would therefore remain undetected when only applying the outcome algorithm, we also searched for this type of incomplete pregnancies. To qualify for this category, there had to be at least a code indicating the expected delivery date and another indicator of a pregnancy (e.g., a pregnancy-related examination) within a plausible time interval after the estimated beginning of pregnancy. The date of the last pregnancy-related examination recorded in the data was assigned as the end of these pregnancies. We determined the exposure status of these pregnancies as described above.

Pregnancies were followed up from the beginning to the end of pregnancy. Pregnancies that could not be followed up until the end due to an interruption in the mother’s health insurance period, the end of the study period or the mother’s death, the pregnancies were not excluded but we classified them as a separate category (“ongoing pregnancies”) given that their outcome could not be determined within the available follow-up. When assessing the distribution of pregnancy outcomes, we only considered non-ongoing pregnancies.

Exploration of potential malformations among exposed children

For exposed pregnancies ending in a live birth, we applied an algorithm linking mothers with their children [19] to explore potential congenital malformations in the children. Among linked children, we identified those with any malformation code (ICD-10-GM: Q00–Q99) occurring up to 1 year after birth. We reviewed all information available on them in GePaRD in order to verify the presence of malformations. The profile review was conducted independently by 2 reviewers (1 physician and 1 epidemiologist, both with expertise in the interpretation of codes in German claims data). Consensus was reached in a subsequent case conference. While reviewers were instructed to consider certain objective criteria confirming the occurrence of malformations, such as the presence of inpatient codes, repeated coding, and treatment or monitoring of the malformations, they were specifically asked to apply their clinical judgment in light of the overall patient history including, e.g., gestational age at birth or chromosomal abnormalities as potential alternative explanations for malformations. In doing so, the primary focus was on malformations categorized as “major” as suggested by EUROCAT, but so-called “minor” malformations were also considered if treatment (e.g., surgical) or other information (e.g., physical impairment, malformation-related complications) indicated a higher level of severity [21].

Data analysis

In the cross-sectional analyses, we determined—for each year—age-specific and age-standardized prevalence of isotretinoin use. For age standardization, we used the age distribution of the German female population on 31 December 2019 as reference. Furthermore, we described the medical specialty of the prescribing physicians. For that purpose, we considered all isotretinoin dispensations in the respective year among included girls and women and assigned the specialty of the prescribing physician based on the information contained in the individual physician number [22]. As for pregnancies, we determined the number of those classified as exposed overall and by calendar year. We described the mothers’ age at the beginning of pregnancy and the pregnancy outcomes.

The distribution of continuous variables was summarized as median (interquartile range [IQR]), while categorical variables were expressed as frequency counts (percentages). We conducted all statistical analyses using the software SAS version 9.4. The analyses were planned beforehand and conducted in an analogous way for other drugs with teratogenic potential [23]. There were no data-driven changes to the analysis plan. Two of the sensitivity analyses were conducted in response to reviewers (assuming a daily dose of 40 mg and a fixed supply of 30 days after the last dispensation before pregnancy, respectively).

Ethics and approvals

In Germany, the utilization of health insurance data for scientific research is regulated by the Code of Social Law. All involved health insurance providers as well as the German Federal Office for Social Security and the Senator for Health, Women and Consumer Protection in Bremen as their responsible authorities approved the use of GePaRD data for this study. Informed consent for studies based on claims data is required by law unless obtaining consent appears unacceptable and would bias results, which was the case in this study. According to the Ethics Committee of the University of Bremen, studies based on GePaRD are exempt from institutional review board review. Specifically, for this study, the Ethics Committee of the University of Bremen was again asked whether a retrospective review might be needed. They judged that the information deducible from the publication is not suited—even in combination—to result in an identification of affected persons. They do thus not believe that there is sufficient risk to the individuals to warrant a retrospective review by an ethics committee. From a public health perspective, the information provided in this paper is very important to increase knowledge on the teratogenic effects of isotretinoin including the number and type of affected organs, all the more so as the use of isotretinoin is further increasing in women of childbearing age.

Results

Prevalence of isotretinoin use among girls and women of childbearing age

Overall, there were 50,936 girls and women with at least 1 prescription of isotretinoin in GePaRD between 2004 and 2019. Across all years, 52% to 67% of users were 16 to 30 years old, and 81% to 90% were ≤40 years old (S1 Table). The overall age-standardized prevalence of isotretinoin use per 1,000 girls and women increased from 1.20 (95% confidence interval [CI]: 1.16, 1.24) in 2004 to 1.96 (95% CI: 1.92, 2.01) in 2019, i.e., by 63% (Fig 1). The prevalences increased particularly among girls and women aged 13 to 30 years. For example, in age group 16 to 20 years they increased by 103% (from 2.07 [95% CI: 1.92, 2.23] to 4.20 [95% CI: 4.00, 4.41] per 1,000) and in age group 21 to 25 years they increased by 96% (from 1.96 [95% CI: 1.82, 2.11] to 3.84 [95% CI: 3.67, 4.02] per 1,000).

Fig 1 — CI, confidence interval; GePaRD, German Pharmacoepidemiological Research Database.

In total, 339,408 prescriptions of isotretinoin were dispensed to girls and women aged 13 to 49 years during the study period (S2 Table). The vast majority of those prescriptions (89%) was issued by dermatologists while general practitioners had a share of 6%.

Exposed pregnancies

In the base case analysis, there were 178 pregnancies classified as exposed to isotretinoin during early pregnancy (Table 1). The number of exposed pregnancies per year increased over the course of the study period. On average, there were 7 pregnancies per year from 2004 to 2011 and 15 pregnancies per year from 2012 to 2019. The majority of the 178 pregnancies (62.9%) occurred in the age group 16 to 30 years (S3 Table).

Table 1. Number of pregnancies exposed to isotretinoin between 2004 and 2019 in GePaRD, mother’s age at pregnancy beginning and type of pregnancy outcome: base case and sensitivity analyses considering delayed elimination (exposure window assigned to the last dispensation before pregnancy was extended by 1 month), a fixed supply of 30 days, and the possibility that lower or higher doses than the DDD for isotretinoin (30 mg) were used.

	Base case analysis	Sensitivity analyses
	Daily dose 30 mg (DDD)	(A) One-month extension	(B) Fixed supply of 30 days	(C) Daily dose 40 mg	(D) Daily dose 40 mg and one-month extension	(E) Daily dose 20 mg	(F) Daily dose 20 mg and one-month extension	(G) Daily dose 10 mg	(H) Daily dose 10 mg and one-month extension
Number of exposed pregnancies	178	233	190	172	224	188	261	283	375
Exposure overlapping pregnancy beginning, n (%)	46 (25.8%)	103 (44.2%)	58 (30.5%)	40 (23.3%)	93 (41.5%)	58 (30.9%)	133 (50.9%)	161 (56.9%)	254 (67.7%)
Dispensation in the first 8 weeks of pregnancy, n (%)	88 (49.4%)	62 (26.6%)	77 (40.5%)	96 (55.8%)	66 (29.5%)	77 (40.9%)	60 (23.0%)	56 (19.8%)	53 (14.1%)
Both, n (%)	44 (24.7%)	68 (29.2%)	55 (28.9%)	36 (20.9%)	65 (29.0%)	53 (28.2%)	68 (26.1%)	66 (23.3%)	68 (18.1%)
Mother’s age
Median (Q1; Q3)	28 (24; 33)	28 (24; 33)	28 (23; 32)	28 (24; 32)	28 (24; 33)	28 (24; 33)	28 (24; 33)	28 (24; 33)	28 (25; 33)
Number of exposed and non-ongoing pregnancies ¹	164¹	213¹	175¹	158¹	205¹	172¹	240¹	259¹	340¹
Pregnancy outcomes
Live birth, n (%)	48 (29.3%)	63 (29.6%)	52 (29.7%)	44 (27.8%)	61 (29.8%)	49 (28.5%)	81 (33.8%)	103 (39.8%)	157 (46.2%)
thereof preterm birth, n (% of live births)	3 (6.3%)	4 (6.3%)	3 (5.8%)	3 (6.8%)	3 (4.9%)	3 (6.1%)	5 (6.2%)	4 (3.9%)	8 (5.1%)
Still birth, n (%)	0 (0%)	1 (0.5%)	0 (0%)	0 (0%)	1 (0.5%)	0 (0%)	1 (0.4%)	2 (0.8%)	2 (0.6%)
Induced abortion, n (%)	74 (45.1%)	90 (42.3%)	79 (45.1%)	74 (46.8%)	86 (42.0%)	79 (45.9%)	94 (39.2%)	89 (34.4%)	96 (28.2%)
Ectopic pregnancy or molar pregnancy, n (%)	5 (3%)	7 (3.3%)	6 (3.4%)	5 (3.2%)	6 (2.9%)	5 (2.9%)	6 (2.5%)	6 (2.3%)	7 (2.1%)
Miscarriage, n (%)	3 (1.8%)	3 (1.4%)	4 (2.3%)	4 (2.5%)	3 (1.5%)	3 (1.7%)	3 (1.3%)	3 (1.2%)	3 (0.9%)
No pregnancy outcome recorded², n (%)	34 (20.7%)	49 (23%)	34 (19.4%)	31 (19.6%)	48 (23.4%)	36 (20.9%)	55 (22.9%)	56 (21.6%)	75 (22.1%)

Open in a new tab

¹This number is lower than the number of all exposed pregnancies in the respective analysis given that some pregnancies were still ongoing at the end of the observation period, so the outcome could not be determined yet. The percentages regarding the different types of pregnancy outcome refer to the number of non-ongoing pregnancies.

²There were clear indicators of a pregnancy but no outcome was recorded. It can be assumed that these pregnancies ended in a miscarriage not requiring medical care or an induced abortion not reimbursed by the health insurance.

DDD, defined daily dose; GePaRD, German Pharmacoepidemiological Research Database.

The mothers’ median age at the beginning of pregnancy was 28 years (IQR 24 to 33 years). About half of these pregnancies were classified as exposed due to a dispensation of isotretinoin within the first 8 weeks of pregnancy, about one quarter because the exposure window assigned to the last dispensation before pregnancy overlapped the beginning of pregnancy and in the remaining, both criteria were fulfilled.

For exposed pregnancies ending during the observation period (n = 164), the distribution of pregnancy outcomes is summarized in Table 1. Overall, 29.3% (n = 48) of exposed pregnancies ended in live birth, thereof 6.3% (n = 3) were preterm births, 45.1% (n = 74) ended in an induced abortion, and 1.8% (n = 3) in a miscarriage. For 20.7% (n = 34) of pregnancies, no outcome was recorded (i.e., they are assumed to also be abortions).

Table 1 also shows the number of pregnancies and the distribution of pregnancy outcomes observed in the sensitivity analyses. When delayed elimination (washout period of 1 month) was considered, the number of exposed pregnancies increased by 31% (from 178 to 233), while the proportion of live births and induced abortions remained at a level similar to the base case analysis. If a fixed supply of 30 days was assumed, there was an increase of exposed pregnancies by 7% (from 178 to 190). If a daily dose of 40 mg was assumed, the number of exposed pregnancies decreased by 3% (from 178 to 172), if a daily dose of 20 mg was assumed, it increased by 6% (from 178 to 188) and if a daily dose of 10 mg was assumed, it increased by 58% (from 178 to 283) compared to the base case analysis. When the one-month washout period was considered for assumed doses of 10 mg, 20 mg, and 40 mg, the increase in the number of exposed pregnancies was 33% (from 283 to 375), 39% (from 188 to 261), and 30% (from 172 to 224), respectively. In all sensitivity analyses, the proportion of live births was below 40% except for those with an assumed daily dose of 10 mg when delayed elimination was considered (46%).

Characterization of exposed children

In 138 out of 157 (87.9%) pregnancies ending in a live birth and classified as exposed in the base case or the sensitivity analyses, the mother’s and child’s data could be linked. Of these, 6 children had at least 1 major congenital malformation according to EUROCAT definitions (Table 2). Five children had malformations classified as minor according to EUROCAT but are reported here as they required surgical or other intense treatment. Two other children had an atrial septal defect that could not be classified into major or minor according to EUROCAT given that the distinction requires information that is not available in German claims data.

Table 2. Malformations observed in live-born children exposed to isotretinoin during pregnancy in GePaRD between 2004 and 2019.

				Exposure classification
				Base case	Sensitivity analyses¹
Child	Q-Code	Description	Classified as “major” according to EUROCAT²	Base case	A	B	C	D	E	F	G	H
1	Q24.9	Congenital malformation of heart, unspecified	Yes	X	X	X	X	X	X	X	X	X
2	Q40.0	Congenital hypertrophic pyloric stenosis³	No	X	X	X	X	X	X	X	X	X
3	Q15.9	Congenital malformation of eye, unspecified	Yes	X	X	X	X	X	X	X	X	X
3	Q10.3	Other congenital malformations of eyelid	No	X	X	X	X	X	X	X	X	X
4	Q02	Microcephaly	Yes	X	X	X	X	X	X	X	X	X
	Q16.5	Congenital malformation of inner ear	Yes
	Q21.0	Ventricular septal defect	Yes
	Q25.6	Stenosis of pulmonary artery⁴	Yes
5	Q40.0	Congenital hypertrophic pyloric stenosis³	No							X	X	X
6	Q53.1	Undescended testicle, unilateral⁵	No								X	X
7	Q21.1	Atrial septal defect⁶	Unclear								X	X
8	Q75.0	Craniosynostosis	Yes									X
8	Q01.0	Frontal encephalocele	Yes									X
9	Q53.1	Undescended testicle, unilateral⁷	No							X	X	X
10	Q75.8	Other specified congenital malformations of skull and face bones	Yes								X	X
10	Q30.1	Agenesis and underdevelopment of nose	Yes								X	X
11	Q66.2	Metatarsus varus⁸	No								X	X
12	Q21.1	Atrial septal defect⁶	Unclear									X
13	Q05.3	Sacral spina bifida with hydrocephalus	Yes							X	X	X

Open in a new tab

¹In the base case analysis, a daily dose of 30 mg was assumed and the exposure window was not extended beyond the supply provided by the last dispensation before pregnancy. In the sensitivity analyses, the estimated daily dose was varied and/or the exposure window was extended to consider delayed plasma elimination. Specifically, the variations were as follows. A: one-month extension of the exposure window, B: a fixed exposure window of 30 days after the last dispensation was assumed, irrespective of the dispensed amount of isotretinoin, C: daily dose 40 mg, D: daily dose 40 mg and one-month extension of the exposure window, E: daily dose 20 mg, F: daily dose 20 mg and one-month extension of the exposure window, G: daily dose 10 mg, H: daily dose 10 mg and one-month extension of the exposure window.

²For those with minor malformation, information on treatment is provided to explain why they are reported here (see also Methods section).

³Hypertrophic pyloric stenosis was surgically treated.

⁴Classified as “major” as child was born on term (EUROCAT classification “minor” if gestational age at birth <37 week).

⁵Undescended testicle was surgically treated.

⁶The subtype of atrial septal defect is not reported in German claims data. “Unclear” in the column regarding EUROCAT classification means that although additional information coded for the child was considered, it was not clear whether the child had the subtype classified as minor according to EUROCAT (ICD-10 Q21.11) or one of the other subtypes classified as major. For child 7, ICD-10-GM Q21.1 was coded repeatedly (also in the inpatient setting) together with codes for cardiology visits and further diagnostics indicating monitoring beyond the first year of life. For child 12, ICD-10-GM Q21.1 was also coded repeatedly together with codes for cardiac murmur (ICD-10-GM R01), cardiology visits and further diagnostics indicating monitoring beyond the first year of life.

⁷Undescended testicle was surgically treated; in addition, there were codes for cardiac malformations (ICD-10-GM Q21.1, Q25.0, Q21.8) that are not listed in the table as the child was born prematurely.

⁸Child received extensive orthopedic treatment and had continuous records of ICD-10-GM R26.8: Other and unspecified abnormalities of gait and mobility.

GePaRD, German Pharmacoepidemiological Research Database.

Of the 6 children with major malformations, 3 were classified as exposed in the base case analyses and 3 were classified as exposed in the sensitivity analyses. The major malformations affected the heart, the eye, the skull, and the nose. Furthermore, 1 child had sacral spina bifida with hydrocephalus and 1 child had multiple major malformations including microcephaly, malformation of the ear and heart. Among children with so-called minor malformations, 2 had congenital hypertrophic pyloric stenosis requiring surgical treatment, 2 had undescended testicles requiring surgical treatment and 1 had metatarsus varus with abnormalities of gait and mobility requiring extensive orthopedic treatment. Four of these 5 children were classified as exposed in the sensitivity analyses only.

Table 2 shows—for each of the 13 children with congenital malformations—in which of the analyses they were classified as exposed. In all of them, the exposure window assigned to the last dispensation before pregnancy overlapped the beginning of pregnancy. In the children classified as exposed in the base case analysis, the mother additionally had a dispensation of isotretinoin within the first 8 weeks of pregnancy, while no such dispensations were observed in the mothers of children classified as exposed in the sensitivity analyses only.

Discussion

In this population-based study covering approximately 20% of the German population, we found that the use of isotretinoin among girls and women of childbearing age increased by 63% between 2004 and 2019, from 1.20 per 1,000 in 2004 to 1.96 per 1,000 in 2019. This increase was particularly pronounced in girls and women up to the age of 30 years. Across the whole study period, more than 80% of users were ≤40 years (between 3,629 of 4,456 and 6,723 of 7,504), i.e., in age groups in which pregnancies typically occur. Even though risk minimization measures are in place, we observed—in the base case analysis—178 pregnancies likely exposed to isotretinoin during a time window most critical for fetal development. In sensitivity analyses varying the assumptions on the dose and considering the recommended one-month washout period, this number ranged between 172 and 375 pregnancies. In the base case analysis, at least 74 exposed pregnancies ended in an induced abortion (sensitivity analyses: 74 to 96). Among live births classified as exposed in the base case or the sensitivity analyses, there were 6 children with major malformations.

Regarding the increase in the prevalence of isotretinoin use among girls and women of childbearing age, there is hardly any data to which we could compare our findings. There is only a single data source reporting—for each year—the total number of DDDs dispensed to all persons with statutory health insurance in Germany (i.e., no denominator/prevalence estimate, and no age or sex-specific findings). Even though comparability is limited, that report supports our finding regarding an increase of oral use of isotretinoin (ATC code D10BA01) between 2004 and 2019 (2004: 5.2 million dispensed DDDs; 2019: 6.0 million dispensed DDDs) [24,25]. The mainstays of acne treatment have remained largely unchanged over recent years [26], so the increase in the prevalence of isotretinoin use cannot be explained by changes in treatment guidelines. Also, there have been no reports on major changes in the disease prevalence during the past 15 years. We can thus only speculate about reasons for this increase. German guidelines, which expired in 2014 without renewal, recommended systemic isotretinoin as second-line therapy after systemic antibiotics and topical anti-acne therapy, while the European guidelines recommend systemic isotretinoin as first-line therapy in moderate as well as severe acne [1]. In view of the effectiveness of systemic isotretinoin in the treatment of acne and the increasing awareness of the mental health burden associated with acne, German dermatologists might have been inclined to follow the European rather than the German guidelines. Another potential reason could be an increased awareness of antibiotic resistance related to the antibiotic stewardship programs launched during the past decade [27]. Considering recommendations from experts, regulatory authorities, and the WHO to shorten and reduce the number of treatment episodes with antibiotics, the threshold to proceed to second-line treatment with systemic isotretinoin might have become lower when treating acne patients [3,28].

In Germany, there is a long-established pregnancy prevention program for isotretinoin in line with EMA recommendations. In addition, prescriptions of isotretinoin must be filled within 7 days of being issued and the supply per prescription is limited to 30 days of treatment [20]. Despite these measures, we found—in the base case analysis—178 pregnancies likely exposed to isotretinoin in the critical time window. As our database covers approximately one fifth of the German population, it can roughly be estimated that at least 980 such pregnancies occurred across Germany between 2004 and 2019. As a matter of concern, the number of exposed pregnancies per year doubled during the study period, i.e., this problem is continuously gaining relevance. Our sensitivity analyses considering delayed plasma elimination and lower-dose treatment showed that the number of exposed pregnancies may even be considerably higher than estimated in the base case analysis. Of note, irrespective of the daily dose we assumed, the number of pregnancies classified as exposed increased by 30% to 39% if the one-month washout period was considered. Since this suggests that pregnancies often occur too soon after the end of isotretinoin treatment, increasing awareness regarding the component of the pregnancy prevention program that recommends contraception also in the month after treatment cessation seems important.

Our study confirms reports from other countries about isotretinoin-exposed pregnancies occurring despite long-standing pregnancy prevention programs [29]. However, there is a lack of studies quantifying the frequency of these pregnancies. Dividing the number of exposed pregnancies by the total number of users in our study yields (roughly) a ratio between 3.5 (base case analysis) and 6.7 (sensitivity analyses) exposed pregnancies per 1,000 isotretinoin users. This is similar to the results of a study from the US based on pregnancy reports from the FDA Adverse Event Reporting System (FAERS) showing between 3.3 and 6.5 exposed pregnancies per 1,000 users between 1997 and 2017 [10]. It is also similar to a study based on Canadian administrative data (data from the provinces British Columbia, Saskatchewan, Manitoba, and Ontario) from 1996 to 2011, in which this ratio varied between 3.1 and 6.2 pregnancies per 1,000 isotretinoin users depending on the exposure definition (high-specificity versus high-sensitivity) [7]. Regarding Europe, population-based studies estimating the frequency of pregnancies per 1,000 users are only available for France where this ratio ranged between 0.32 and 0.95 when combining data from studies conducted between 1987 and 2011 [9]. A population-based study from the Netherlands determined the proportion of isotretinoin-exposed pregnancies among all pregnancies. It reported that between 1999 and 2007 about 2.5 per 10,000 pregnancies were exposed to isotretinoin in the 30 days before or during pregnancy [11].

The number of exposed pregnancies ending in a live birth in our study was 48 of 164 (29%) in the base case analysis and increased to 157 of 340 (46%) in a sensitivity analysis where a dose of only 10 mg and delayed elimination were considered. This illustrates that the proportion of live births is sensitive to the exposure definition, which may hamper comparability between existing studies. Furthermore, it is influenced by the extent to which incomplete pregnancies are captured in the respective database, which may also vary between studies. This may explain variation in the proportion of live births reported in different studies. For example, a German study using data collected in the context of counseling pregnant women and their health care providers reported a proportion of 18 live births of 91 pregnancies (20%) [30], a study from the United States reported proportions of 68 of 138 (49%) [8], while much lower proportions of 118 of 1,473 (8%) were reported by a Canadian study [7] and 85 of 553 (15%) in French studies [9].

While our study was not designed to quantify risks, it was still striking that 13 live-born children classified as exposed to isotretinoin in early pregnancy in the base case or the sensitivity analyses had congenital malformations, 6 of them with major malformations. Many of these malformations involved organ systems known to be affected by the so-called retinoic acid embryopathy. This finding and the fact that at least 45% of exposed pregnancies (74 of 164) in our study ended in an induced abortion—as compared to 4% when all pregnancies in GePaRD are considered [17]—underline the importance of improving adherence to pregnancy prevention programs.

Some limitations should be considered in the interpretation of our results. First, German claims data do not include the dose prescribed by the physician. Consequently, treatment duration has to be estimated based on the DDD. The DDD represents the dose for adults, but lower doses may be used, particularly in girls and adolescents, or sometimes a higher dose might be used. To address this issue, we performed comprehensive sensitivity analyses varying the exposure windows assigned to each dispensation. Second, as in all pharmacoepidemiological studies, there is uncertainty whether patients filling a prescription are actually taking the drug. It is also uncertain whether they always start taking the drug after filling the prescription or whether they may partly start later. Third, while our study was designed to describe prevalence of isotretinoin use and pregnancies occurring under treatment with isotretinoin, our database would not have been suited to assess whether risk minimization measures were followed on an individual level. This would have required comprehensive information on contraceptive measures, which is limited in GePaRD as in most other claims databases [31]. Fourth, with regard to pregnancy outcomes and malformations, our study was merely descriptive, so causal conclusions cannot be drawn. Estimating causal effects would have required a different design including the consideration of relevant confounders, as well as a larger sample of exposed children. The latter might be achieved by a consortium of large databases. We strongly advise against simplified calculations in which the proportion of live births with malformations in our study is compared to the corresponding proportion reported for all live births in Germany in order to estimate risks. Such a comparison could be very misleading for various reasons (e.g., due to differences in age and thus presumably also in the prevalence of comorbidities, different proportions with induced abortions and thus missing malformation status). Fifth, as in most databases used to investigate drug utilization and safety during pregnancy, pregnancy outcomes clearly classified as “miscarriages” are underrepresented in our database, i.e., the frequency of this outcome was underestimated in our study. To address this limitation, we also searched for incomplete pregnancies with no outcome recorded. It seems plausible that these were miscarriages not requiring medical treatment or induced abortions without medical indication, i.e., not reimbursed by health insurances. Although not perfect as it still remained unclear whether it was a miscarriage or induced abortion, we think this approach was valuable to capture the number of exposed pregnancies more completely. Sixth, to assess the presence of malformations in children exposed during pregnancy, we conducted an in-depth patient profile review based on all diagnoses and procedure codes available in GePaRD but did not have additional clinical data.

A main strength of our study is the large claims database that has been shown to be representative of persons with statutory health insurance in Germany in terms of drug dispensations [32]. The available data allowed us to assess trends in isotretinoin dispensations over a 15-year period. Due to the use of claims data, our analyses were not affected by recall or non-responder bias. Furthermore, the sophisticated methods developed for GePaRD (i) to identify pregnancy outcomes [17], which were further optimized to capture incomplete pregnancies; (ii) to link mothers’ and babies’ data [19]; and (iii) to estimate the beginning of pregnancy—predominantly based on the estimated date of delivery—which is expected to minimize misclassification of gestational age [18], are strengths of our study. We also consider it a strength of our study that we conducted sensitivity analyses to systematically assess whether pregnancies may have started during the recommended one-month washout period after treatment cessation.

The prevalence of isotretinoin use among girls and women of childbearing age increased in Germany between 2004 and 2019, and there were a considerable number of pregnancies likely exposed to isotretinoin in a critical period. This highlights the importance of monitoring compliance with the existing risk minimization measures for isotretinoin in Germany.

Supporting information

S1 Checklist. STROBE Statement—checklist of items that should be included in reports of observational studies.

(DOCX)

Click here for additional data file.^{(19.1KB, docx)}

S1 Table. Number of girls and women aged 13–49 years with at least 1 dispensation of isotretinoin between 2004 and 2019 in GePaRD by age group and year of prescription.

(DOCX)

Click here for additional data file.^{(27.9KB, docx)}

S2 Table. Prescriptions of Isotretinoin dispensed to girls and women aged 13–49 years between 2004 and 2019 in GePaRD: Distribution of the specialty of the prescribing physician.

(DOCX)

Click here for additional data file.^{(23.6KB, docx)}

S3 Table. Number of pregnancies exposed to isotretinoin between 2004 and 2019 in GePaRD by age group and year of beginning of pregnancy.

(DOCX)

Click here for additional data file.^{(29.2KB, docx)}

Acknowledgments

The authors would like to thank Marieke Niemeyer and Philipp Alexander Volkmar for statistical programming of analysis datasets and double-independent programming of results as well as all statutory health insurance providers which provided data for this study, namely AOK Bremen/Bremerhaven, DAK-Gesundheit, Die Techniker Krankenkasse (TK), and hkk Krankenkasse.

Abbreviations

ATC: Anatomical Therapeutic Chemical
CI: confidence interval
DDD: defined daily dose
FAERS: FDA Adverse Event Reporting System
GePaRD: German Pharmacoepidemiological Research Database
IQR: interquartile range

Data Availability

As we are not the owners of the data we are not legally entitled to grant access to the data of the German Pharmacoepidemiological Research Database. In accordance with German data protection regulations, access to the data is granted only to employees of the Leibniz Institute for Prevention Research and Epidemiology – BIPS on the premises of the institute and in the context of approved research projects. Third parties may only access the data in cooperation with the Leibniz Institute for Prevention Research and Epidemiology – BIPS and after signing an agreement for guest researchers. Please contact gepard@leibniz-bips.de for help with this process.

Funding Statement

The study was partly funded by the German Federal Institute for Drugs and Medical Devices, Bonn (BfArM, V-18281/ 68605 / 2019-2020) (https://www.bfarm.de). The study proposal was submitted by UH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References

1.Nast A, Dréno B, Bettoli V, Bukvic Mokos Z, Degitz K, Dressler C, et al. European evidence-based (S3) guideline for the treatment of acne–update 2016 –short version. J Eur Acad Dermatol Venereol. 2016;30(8):1261–8. doi: 10.1111/jdv.13776 [DOI] [PubMed] [Google Scholar]
2.Layton A. The use of isotretinoin in acne. Dermatoendocrinol. 2009;1(3):162–9. Epub 2010/05/04. doi: 10.4161/derm.1.3.9364 ; PubMed Central PMCID: PMC2835909. [DOI] [PMC free article] [PubMed] [Google Scholar]
3.Marson JW, Baldwin HE. Isotretinoin update. Dermatol Rev. 2021;2(6):331–42. doi: 10.1002/der2.100 [DOI] [Google Scholar]
4.Dai WS, LaBraico JM, Stern RS. Epidemiology of isotretinoin exposure during pregnancy. J Am Acad Dermatol. 1992;26(4):599–606. Epub 1992/04/01. doi: 10.1016/0190-9622(92)70088-w . [DOI] [PubMed] [Google Scholar]
5.EMA. Updated measures for pregnancy prevention during retinoid use 2018. [cited 2023 Nov 14]. Available from: https://www.ema.europa.eu/en/documents/referral/retinoid-article-31-referral-updated-measures-pregnancy-prevention-during-retinoid-use_en.pdf. [Google Scholar]
6.Bérard A, Azoulay L, Koren G, Blais L, Perreault S, Oraichi D. Isotretinoin, pregnancies, abortions and birth defects: a population-based perspective. Br J Clin Pharmacol. 2007;63(2):196–205. Epub 2007/01/12. doi: 10.1111/j.1365-2125.2006.02837.x ; PubMed Central PMCID: PMC1859978. [DOI] [PMC free article] [PubMed] [Google Scholar]
7.Henry D, Dormuth C, Winquist B, Carney G, Bugden S, Teare G, et al. Occurrence of pregnancy and pregnancy outcomes during isotretinoin therapy. CMAJ. 2016;188(10):723–30. Epub 2016/04/27. doi: 10.1503/cmaj.151243 ; PubMed Central PMCID: PMC4938682. [DOI] [PMC free article] [PubMed] [Google Scholar]
8.MacDonald SC, Cohen JM, Panchaud A, McElrath TF, Huybrechts KF, Hernández-Díaz S. Identifying pregnancies in insurance claims data: Methods and application to retinoid teratogenic surveillance. Pharmacoepidemiol Drug Saf. 2019;28(9):1211–21. Epub 2019/07/23. doi: 10.1002/pds.4794 ; PubMed Central PMCID: PMC6830505. [DOI] [PMC free article] [PubMed] [Google Scholar]
9.Rouzès A, Jonville-Béra AP. Exposure to isotretinoin during pregnancy in France: 25 years of follow-up. Therapie. 2014;69(1):53–63. Epub 2014/04/05. doi: 10.2515/therapie/2014008 . [DOI] [PubMed] [Google Scholar]
10.Tkachenko E, Singer S, Sharma P, Barbieri J, Mostaghimi A. US Food and Drug Administration reports of pregnancy and pregnancy-related adverse events associated with isotretinoin. JAMA Dermatol. 2019;155(10):1175–9. doi: 10.1001/jamadermatol.2019.1388 [DOI] [PMC free article] [PubMed] [Google Scholar]
11.Zomerdijk IM, Ruiter R, Houweling LMA, Herings RMC, Sturkenboom MCJM, Straus SMJM, et al. Isotretinoin exposure during pregnancy: a population-based study in The Netherlands. BMJ Open. 2014;4(11):e005602–e. doi: 10.1136/bmjopen-2014-005602 . [DOI] [PMC free article] [PubMed] [Google Scholar]
12.Leibniz Institute for Prevention Research and Epidemiology – BIPS. The German Pharmacoepidemiological Research Database (GePaRD). 2022 [cited 2023 Nov 14]. Available from: https://www.bips-institut.de/en/research/research-infrastructures/gepard.html.
13.Haug U, Schink T. German Pharmacoepidemiological Research Database (GePaRD). In: Sturkenboom M, Schink T, editors. Databases for Pharmacoepidemiological Research: Springer; 2020. p. 119–24. [Google Scholar]
14.Bundesministerium für Gesundheit. Das deutsche Gesundheitssystem. 2020. [cited 2023 Nov 14]. Available from: https://www.bundesgesundheitsministerium.de/fileadmin/Dateien/5_Publikationen/Gesundheit/Broschueren/200629_BMG_Das_deutsche_Gesundheitssystem_DE.pdf. [Google Scholar]
15.Statista GmbH. PKV, BMG. Anzahl der Mitglieder und Versicherten der gesetzlichen und privaten Krankenversicherung in den Jahren 2016 bis 2022 (in Millionen). 2022 [cited 2023 Nov 14]. Available from: https://de.statista.com/statistik/daten/studie/155823/umfrage/gkv-pkv-mitglieder-und-versichertenzahl-im-vergleich/. [Google Scholar]
16.Mikolajczyk RT, Kraut AA, Garbe E. Evaluation of pregnancy outcome records in the German Pharmacoepidemiological Research Database (GePaRD). Pharmacoepidemiol Drug Saf. 2013;22(8):873–80. Epub 2013/06/05. doi: 10.1002/pds.3467 . [DOI] [PubMed] [Google Scholar]
17.Wentzell N, Schink T, Haug U, Ulrich S, Niemeyer M, Mikolajczyk R. Optimizing an algorithm for the identification and classification of pregnancy outcomes in German claims data. Pharmacoepidemiol Drug Saf. 2018;27(9):1005–10. Epub 2018/07/20. doi: 10.1002/pds.4588 . [DOI] [PubMed] [Google Scholar]
18.Schink T, Wentzell N, Dathe K, Onken M, Haug U. Estimating the beginning of pregnancy in German claims data: Development of an algorithm with a focus on the expected delivery date. Front Public Health. 2020;8:350. Epub 2020/09/10. doi: 10.3389/fpubh.2020.00350 ; PubMed Central PMCID: PMC7434962. [DOI] [PMC free article] [PubMed] [Google Scholar]
19.Garbe E, Suling M, Kloss S, Lindemann C, Schmid U. Linkage of mother-baby pairs in the German Pharmacoepidemiological Research Database. Pharmacoepidemiol Drug Saf. 2011;20(3):258–64. Epub 2011/02/26. doi: 10.1002/pds.2038 . [DOI] [PubMed] [Google Scholar]
20.Federal institute for drugs and medical devices (BfArM). Gebrauchsinformation Isotretinoin 2010. [cited 2023 Nov 14]. Available from: https://www.bfarm.de/SharedDocs/Downloads/DE/Arzneimittel/Pharmakovigilanz/Risikoinformationen/RI_rhb/2010/isotretinoin_gi.pdf;jsessionid=82B953280A3A52A8CF7EA909EB8DD0E3.intranet661?__blob=publicationFile. [Google Scholar]
21.EUROCAT. EUROCAT guide 1.4 and reference documents. 2018 [cited 2023 Nov 14]. Available from: https://eu-rd-platform.jrc.ec.europa.eu/sites/default/files/Full_Guide_1_4_version_28_DEC2018.pdf.
22.Kassenärztliche Bundesvereinigung. Richtlinie der Kassenärztlichen Vereinigung nach §75 Absatz 7 SGB V zur Vergabe der Arzt-, Betriebsstätten-, sowie der Praxisnetznummern. 2021 [cited 2023 Nov 14]. Available from: https://www.kbv.de/media/sp/Arztnummern_Richtlinie.pdf.
23.Platzbecker K, Wentzell N, Kollhorst B, Haug U. Fingolimod, teriflunomide and cladribine for the treatment of multiple sclerosis in women of childbearing age: description of drug utilization and exposed pregnancies in Germany. Mult Scler Relat Disord. 2022;67:104184. doi: 10.1016/j.msard.2022.104184 [DOI] [PubMed] [Google Scholar]
24.Fricke U. Dermatika und Wundbehandlungsmittel. In: Schwabe U, Paffrath D, editors. Arzneimittelverordnungs-Report 2005. Heidelberg: Springer Berlin; 2005. p. 579. [Google Scholar]
25.Günter J, Fricke U. Dermatika In: Schwabe U, Ludwig WD, editors. Arzneimittelverordnungs-Report 2020. Heidelberg: Springer Berlin; 2020. p. 507. [Google Scholar]
26.Habeshian KA, Cohen BA. Current issues in the treatment of acne vulgaris. Pediatrics. 2020;145(Suppl 2):S225–s30. Epub 2020/05/03. doi: 10.1542/peds.2019-2056L . [DOI] [PubMed] [Google Scholar]
27.Bundesministerium für Gesundheit. DART 2020. Abschlussbericht. 2022 [cited 2023 Nov 14]. Available from: https://www.bundesgesundheitsministerium.de/fileadmin/Dateien/3_Downloads/D/DART_2020/BMG_DART_2020_Abschlussbericht_bf.pdf. [Google Scholar]
28.Gollnick HPM, Buer J, Beissert S, Sunderkätter C. Verantwortlicher Umgang mit Antibiotika: Notwendigkeit der Antibiotikareduktion in der Aknetherapie. J German Society Dermatology. 2016;14(12):1319–27. doi: 10.1111/ddg.13048 [DOI] [PubMed] [Google Scholar]
29.Crijns I, Straus S, Luteijn M, Gispen-de Wied C, Raine J, de Jong-van den Berg L. Implementation of the harmonized EU isotretinoin Pregnancy Prevention Programme: a questionnaire survey among European regulatory agencies. Drug Saf. 2012;35(1):27–32. Epub 2011/11/05. doi: 10.2165/11595570-000000000-00000 . [DOI] [PubMed] [Google Scholar]
30.Schaefer C, Meister R, Weber-Schoendorfer C. Isotretinoin exposure and pregnancy outcome: an observational study of the Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy. Arch Gynecol Obstet. 2009;281(2):221. doi: 10.1007/s00404-009-1112-2 [DOI] [PubMed] [Google Scholar]
31.Haug U. Verordnung von teratogenen Arzneimitteln bei Frauen im gebärfähigen Alter in Deutschland. Bulletin zur Arzneimittelsicherheit. 2020;(4):4–9. [Google Scholar]
32.Fassmer A, Schink T, editors. Repräsentativität von ambulanten Arzneiverordnungen in der German Pharmacoepidemiological Research Database (GePaRD). 9 Jahrestagung der Deutschen Gesellschaft für Epidemiologie (DGEpi); 2014; Ulm, Germany.

PLoS Med. doi: 10.1371/journal.pmed.1004339.r001

Decision Letter 0

Philippa C Dodd

7 Oct 2022

Dear Dr Reinold,

Thank you for submitting your manuscript entitled "Use of isotretinoin among girls and women of childbearing age and occurrence of isotretinoin-exposed pregnancies in Germany" for consideration by PLOS Medicine.

Your manuscript has now been evaluated by the PLOS Medicine editorial staff as well as by an academic editor with relevant expertise and I am writing to let you know that we would like to send your submission out for external peer review.

However, before we can send your manuscript to reviewers, we need you to complete your submission by providing the metadata that is required for full assessment. To this end, please login to Editorial Manager where you will find the paper in the 'Submissions Needing Revisions' folder on your homepage. Please click 'Revise Submission' from the Action Links and complete all additional questions in the submission questionnaire.

Please re-submit your manuscript within two working days, i.e. by Oct 11 2022 11:59PM.

Once your full submission is complete, your paper will undergo a series of checks in preparation for peer review. Once your manuscript has passed all checks it will be sent out for review.

Feel free to email us at plosmedicine@plos.org if you have any queries relating to your submission.

Kind regards,

Philippa Dodd, MBBS MRCP PhD

Senior Editor

PLOS Medicine

PLoS Med. doi: 10.1371/journal.pmed.1004339.r002

Decision Letter 1

Philippa C Dodd

24 Aug 2023

Dear Dr. Reinold,

Thank you very much for submitting your manuscript "Use of isotretinoin among girls and women of childbearing age and occurrence of isotretinoin-exposed pregnancies in Germany" (PMEDICINE-D-22-03260R1) for consideration at PLOS Medicine.

Your paper was evaluated by a senior editor and discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.

In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.

In addition, we request that you upload any figures associated with your paper as individual TIF or EPS files with 300dpi resolution at resubmission; please read our figure guidelines for more information on our requirements: http://journals.plos.org/plosmedicine/s/figures. While revising your submission, please upload your figure files to the PACE digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at PLOSMedicine@plos.org.

We expect to receive your revised manuscript by Sep 14 2023 11:59PM. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

We ask every co-author listed on the manuscript to fill in a contributing author statement, making sure to declare all competing interests. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. If new competing interests are declared later in the revision process, this may also hold up the submission. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT. You can see our competing interests policy here: http://journals.plos.org/plosmedicine/s/competing-interests.

Please use the following link to submit the revised manuscript:

https://www.editorialmanager.com/pmedicine/

Your article can be found in the "Submissions Needing Revision" folder.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

We look forward to receiving your revised manuscript.

Sincerely,

Philippa Dodd, MBBS MRCP PhD

PLOS Medicine

plosmedicine.org

-----------------------------------------------------------

Requests from the editors:

COMMENTS FROM THE ACADEMIC EDITOR

My main concern with this is the lack of detail on the identification of "relevant" congenital anomalies. This is unclear and the data presented are insufficient.

Standard, rigorous, definitions of major congenital anomalies reportable to Eurocat should be used. Further details of who, and how, assessments were made, along with ICD10 coding of the anomaly and further treatments.

Figure 2 only shows the base case. Of the anomalies presented Congenital cystic liver disease is hereditary (so not influenced by exposure); Pyloric stenosis and hip dysplasia would not usually be reportable to EUORCAT (minor); and the nature and relevance of the inner ear, eye(other) and cardiac (other) anomalies are unclear. Further information about the coded diagnoses and why these have been considered "relevant" is necessary.

There is not presentation at all of the 30% of congenital anomalies referenced in the sensitivity analysis.

These figures need to be carefully described and accurately presented - I would prefer with appropriate confidence intervals around them, so as to show the imprecision of estimates given the small numbers.

As the authors point out - unintentional pregnancy while taking retinoids is a problem. Careful and accurate information about biologically plausible abnormalities should be provided, so as women can make appropriate decisions about pregnancy continuation.

At the moment the presentation feels sensationalistic- "up to 30% abnormal babies" could become a take home message, and it is not backed up by data, nor qualified with the appropriate caveats or limitations of the study. There is a risk that women could be encouraged to terminate pregnancies on the basis of this publication, assuming the risk to be much higher than it actually is. I would therefore propose major revision.

COMMENTS FROM THE EDITORS

GENERAL

Please respond to all editor and reviewer comments detailed below in full.

Please ensure that the study is reported according to the STROBE guideline, and include the completed STROBE checklist as Supporting Information. Please add the following statement, or similar, to the Methods: "This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (S1 Checklist)."

The STROBE guideline can be found here: http://www.equator-network.org/reporting-guidelines/strobe/

When completing the checklist, please use section and paragraph numbers, rather than page or line numbers as these often change in the event of publication.

*** When reporting and discussing your results you consistently refer to percentages as opposed to whole numbers which can be un-/mis-informative. Throughout all sub-sections of the manuscript please clearly detail numerators and denominators to provide complete information to the reader ***

TITLE

Please revise your title according to PLOS Medicine's style. Your title must be nondeclarative and not a question. It should begin with main concept if possible. "Effect of" should be used only if causality can be inferred, i.e., for an RCT. Please place the study design ("A randomized controlled trial," "A retrospective study," "A modelling study," etc.) in the subtitle (ie, after a colon).

DATA AVAILABILITY STATEMENT

Thank you for your clear statement. Please define the abbreviation ‘BIPS’. Please include contact information for data requests (web or email address). Note that a study author cannot be the contact person for the data.

ABSTRACT

Please structure your abstract using the PLOS Medicine headings (Background, Methods and Findings, Conclusions).

Please combine the Methods and Findings sections into one section, “Methods and findings”.

Abstract Methods and Findings:

Please ensure that all numbers presented in the abstract are present and identical to numbers presented in the main manuscript text.

Please include the study design (i.e., observational cohort study), number of participants, length of follow up, and main outcome measures.

Please quantify the main results with 95% CIs and p values. When reporting p values, please report as p<0.001 and where higher the exact p values as p=0.002, for example. If not, to help facilitate transparent data reporting, please clearly describe the reason(s) why not.

Please include any important dependent variables that are adjusted for in the analyses.

Please include numerators and denominators used to derive percentages.

Please include a summary of adverse events assessed in the study.

In the last sentence of the Abstract Methods and Findings section, please describe the main limitation(s) of the study's methodology.

Abstract Conclusions:

Please address the study implications without overreaching what can be concluded from the data; the phrase "In this study, we observed ..." may be useful.

Please interpret the study based on the results presented in the abstract, emphasizing what is new without overstating your conclusions.

Please avoid vague statements such as "these results have major implications for policy/clinical care". Mention only specific implications substantiated by the results.

Please avoid assertions of primacy ("We report for the first time....")

AUTHOR SUMMARY

At this stage, we ask that you include a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The authors summary should consist of 2-3 succinct bullet points under each of the following headings:

• Why Was This Study Done? Authors should reflect on what was known about the topic before the research was published and why the research was needed.

• What Did the Researchers Do and Find? Authors should briefly describe the study design that was used and the study’s major findings. Do include the headline numbers from the study, such as the sample size and key findings.

• What Do These Findings Mean? Authors should reflect on the new knowledge generated by the research and the implications for practice, research, policy, or public health. Authors should also consider how the interpretation of the study’s findings may be affected by the study limitations. In the final bullet point of ‘What Do These Findings Mean?’, please describe the main limitations of the study in non-technical language.

The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract. Please see our author guidelines for more information: https://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summary

INTRODUCTION

Line 23 – please replace ‘Background’ with ‘Introduction’

Line 24 – not sure that ‘application’ is the best word to use here. Perhaps instead, ‘Systemic (oral) treatment using the vitamin A derivative…is indicated in moderate to severe acne…’

Line 30 – please remove the word ‘also’

Line 49 – the use of the term ‘occurrence’ lacks nuance. Do you mean incidence or prevalence, perhaps?

Please indicate whether your study is novel and how you determined that.

If there has been a systematic review of the evidence related to your study (or you have conducted one), please refer to and reference that review and indicate whether it supports the need for your study.

METHODS and RESULTS

Did your study have a prospective protocol or analysis plan? Please state this (either way) early in the Methods section.

a) If a prospective analysis plan (from your funding proposal, IRB or other ethics committee submission, study protocol, or other planning document written before analyzing the data) was used in designing the study, please include the relevant prospectively written document with your revised manuscript as a Supporting Information file to be published alongside your study, and cite it in the Methods section. A legend for this file should be included at the end of your manuscript.

b) If no such document exists, please make sure that the Methods section transparently describes when analyses were planned, and when/why any data-driven changes to analyses took place.

c) In either case, changes in the analysis-- including those made in response to peer review comments-- should be identified as such in the Methods section of the paper, with rationale.

For all observational studies, in the manuscript text we ask that you please indicate:

(1) the specific hypotheses you intended to test,

(2) the analytical methods by which you planned to test them,

(3) the analyses you actually performed and,

(4) when reported analyses differ from those that were planned, transparent explanations for differences that affect the reliability of the study's results. If a reported analysis was performed based on an interesting but unanticipated pattern in the data, please be clear that the analysis was data-driven.

It may be worth briefly elaborating on the healthcare set-up in Germany for those unfamiliar. Is everyone insured? How well does the database capture individuals?

Lines 72, 73 and 143 – please replace ‘prevalence [of use]’ with ‘prevalent [use of isotretinoin]’ (this is an incorrect use of a noun versus adjective).

Line 145 onwards – please include numerators and denominators used to derive percentages.

Please define the length of follow up (eg, in mean, SD, and range).

Line 148 – you use the term ‘rates’ apparently interchangeably with prevalence. Please amend. Please ensure attention to detail when describing your measured outcomes using the same term throughout for consistency and clarity.

Please provide the actual numbers of events for the outcomes, not just summary statistics or ORs.

Please present numerators and denominators used to derive percentages.

Please quantify results with 95% CIs and p values. When reporting p values please report as p<0.001 and where higher, the exact p value as p=0.002, for example.

When a p value is given please also report the statistical test used to determine it. If not reporting p values for the purpose of transparent data reporting please clearly state the reason(s) why not.

Please indicate whether analyses are adjusted or unadjusted and where relevant the factors that are adjusted for. Where adjusted analyses are reported, to help facilitate transparent data reporting, please also report unadjusted analyses for comparison.

TABLES

Please provide a table showing the baseline characteristics of the study population, suggest including this as table 1 and incorporating information presented in the current table 1 into it.

Please ensure that each table is affiliated to an appropriate caption which clearly describes its content without the need to refer to the text.

Please clearly indicate whether your analyses are adjusted and if so for which factors.

Where adjusted analyses are presented please also present unadjusted analyses for comparison.

FIGURES

Please ensure that each figure is affiliated to an appropriate caption which clearly describes its content without the need to refer to the text.

Please consider using a color palate suitable to those with color blindness in order to make your figures more accessible.

DISCUSSION

Please present and organize the Discussion as follows: a short, clear summary of the article's findings; what the study adds to existing research and where and why the results may differ from previous research; strengths and limitations of the study; implications and next steps for research, clinical practice, and/or public policy; one-paragraph conclusion. We think that the main structural elements are there but additional detail could be helpful in some places – the strengths and limitations, for example.

Line 322 – please remove the funding statement and include only in the submission form – it will be compiled as metadata in the event of publication.

Line 327 – please remove the ethics statement and include only in the methods section of the your manuscript.

Line 336 – please remove the conflict of interest statement and include only in the submission form it will be compiled as metadata in the event of publication.

Line 350 – please remove the data availability statement and include only in the manuscript submission form it will be compiled as metadata in the event of publication.

REFERENCES

For in-text reference callouts citations should be placed in square brackets as follows, ‘…[1,3,6]’. Please note the absence of spaces between different citations.

In the bibliography please ensure that up to but no more then 6 author names are listed followed by et al.

Please ensure all web references include an accessed date.

Please see our website for other reference guidelines https://journals.plos.org/plosmedicine/s/submission-guidelines#loc-references

SUPPORTING INFORMATION

Please ensure to cite your Supporting Information as outlined here: https://journals.plos.org/plosmedicine/s/supporting-information

As above, please include the STROBE checklist and a copy of a relevant protocol and/or statistical analysis plan as available.

Table S1 – what do the percentages show here? Suggest placing total numbers at the top of the table for clarity. The final column could then read ‘Total study population’.

Fig S2 – is it necessary that these data be presented in both a table and a figure? It stands to reason that prescribing would be primarily by dermatologists and GPs which is what the data show. There’s nothing surprising about this, unless we missed something. Notably, I actually prefer the figure.

Comments from the reviewers:

Reviewer #1: Alex McConnachie, Statistical Review

The paper by Reinold and colleagues reports on the use of isotretinoin among women of childbearing age between 2004 and 2019 in Germany using a database covering 20% of the national population, linked to data on pregnancy and child outcomes. This review considers the statistical aspects of the paper.

On the one hand, there is not much to review. The authors present the data quite clearly, but do not use any statistical tests to analyse the data. This is fine; sometimes there is no need for statistical modelling to make the point.

However, reading the paper, I felt that there was a gap, in that the incidence of congenital malformations following isotretinoin-exposed pregnancies is reported only for the base case. Table 2 reports pregnancy outcomes for the base case plus a number of alternative scenarios as sensitivity analyses. This table could easily include a row showing the overall number and percentage of live births leading to congenital malformations. Currently, only the data for the base case is presented, in the text and in Figure 2. Adding the overall numbers for the sensitivity analyses would be useful, I think. One would hope that there are fewer malformations amongst those pregnancies less likely to be exposed to the drug. It may, however, require considerable effort to obtain this information.

My main concern with the paper, and possibly beyond my remit, is in Figure 2. This reports very low numbers of individuals. In my experience, working with unconsented data for research purposes, it is usual for reports involving small numbers of individuals to be suppressed, to prevent identification of individuals. It could be that the child with multiple malformations is unique in Germany over this time period. Someone who knows about this particular case could identify them in this paper. Is this individual woman aware that they were exposed to isotretinoin during their pregnancy? Would they find it acceptable that other people could work this out by reading the paper?

I do not know what the journal policy is on the publication of information about small numbers of individuals with rare conditions, without the consent of the patients involved, but I feel this needs to be considered.

Reviewer #2: The authors have presented a clear and well written study about the increasing use of isotretinoin in Germany and occurrence of isotretinoin exposed pregnancies. I think it is an important contribution to the literature and highlights the importance of continuing to monitor the adherence to pregnancy prevention programs.

My main concern is how the number of exposed days was estimated. The problem with DDDs is that it is the average dose for the main indication which may not correspond to a real dose that any individual uses. For example, in Norway today, 30 tablet packages are sold with 20 mg, to be taken once or twice daily. This means that the 30 mg dose is likely not representative of any patient's real daily dose. Would it make more sense to assume 30 days-supply from the prescription date for the main analysis or as a sensitivity analysis?

Background, lines 46-47: Rather than "late treatment cessation before pregnancy," it would make more sense to phrase as: "…the extent to which conceptions occurring shortly after discontinuation of treatment contributes to the number of exposed pregnancies." It was not immediately clear what you meant.

A similar sentence was written in the discussion, lines 215-216: "…It seems that isotretinoin is stopped too shortly before pregnancy." Again, this works the other way. Pregnancies occur to shortly after stopping treatment. This is a violation of the pregnancy prevention program and should be avoided.

Very few pregnancies included were clearly classified as spontaneous abortions. I think this could be described as a limitation because it is unclear whether the observations of "No pregnancy outcome was recorded" are spontaneous or induced. For this reason, in the discussion, line 212: "About 45%" could be changed to "at least" 45% since there were 20.7% where the outcome was not recorded and these are assumed to be abortions.

Methods, lines 110-111: You may wish to describe the qualifications or background of those carrying out the code profile review.

Figure S2 is not mentioned in the results section. Please add this (likely to be re-numbered S1).

Error in Table 2: % of pregnancies with "No pregnancy outcome was recorded" - for sensitivity analysis A) this should say 23.0%

Reviewer #3: In this study, the authors described the isotretinoin use in women of childbearing age in Germany, the occurrence of isotretinoin-exposed pregnancies, and malformations among children exposed in utero. I have a couple of comments for the authors to consider:

1. For the definition of exposure, why the first eight weeks of pregnancy was used, instead of other number of weeks? If two prescriptions overlap, do you add up their DDD?

2. Based on the Methods section, I am not entirely sure how the authors required health insurance coverage of the patients and the follow-up of the patients in the study. It would be great if the authors could clarify this.

3. Based on Table 2, it seems the % of pregnancy outcomes varied substantially based on different definitions of exposure. I think this is one of the major limitations of the study. I strongly recommend the authors to expand the discussion on this in Limitations and how it impacts the interpretation of the study results.

4. Given the small sample size, I would be careful about using the relative measures describing the changes over the years. For example, 63% increase of isotretinoin use was described while the absolute change was only 0.7 per 1000 patients from 2004 to 2019. Same for the number of isotretinoin exposed pregnancies. I suggest the authors tone down the conclusions based on relative measures and focus more on the absolute measure.

Any attachments provided with reviews can be seen via the following link:

[LINK]

PLoS Med. doi: 10.1371/journal.pmed.1004339.r003

Decision Letter 2

Philippa C Dodd

7 Dec 2023

Dear Dr. Haug,

Thank you very much for re-submitting your manuscript "Use of isotretinoin among girls and women of childbearing age and occurrence of isotretinoin-exposed pregnancies in Germany: A descriptive study" (PMEDICINE-D-22-03260R2) for review by PLOS Medicine.

I have discussed the paper with my colleagues and the academic editor and it was also seen again by 2 reviewers. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

We expect to receive your revised manuscript within 1 week. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript.

Please note, when your manuscript is accepted, an uncorrected proof of your manuscript will be published online ahead of the final version, unless you've already opted out via the online submission form. If, for any reason, you do not want an earlier version of your manuscript published online or are unsure if you have already indicated as such, please let the journal staff know immediately at plosmedicine@plos.org.

If you have any questions in the meantime, please contact me or the journal staff on plosmedicine@plos.org.

We look forward to receiving the revised manuscript by Dec 14 2023 11:59PM.

Best wishes,

Pippa

Philippa Dodd, MBBS MRCP PhD

PLOS Medicine

plosmedicine.org

pdodd@plos.org

------------------------------------------------------------

COMMENTS FROM THE ACADEMIC EDITOR

The authors have done a good job of addressing comments and I am happy. One small additional from me - would the authors consider using preferred terminology of miscarriage rather than the term "spontaneous abortion".

COMMENTS FROM THE EDITORS

GENERAL

Thank you for your detailed and considered responses to previous editor and reviewer comments. Please see below for further comments which we require that you address prior to publication.

We agree with Academic Editor (above) that revising your use of terminology would be preferable. Please amend throughout all subsections of the manuscript and supporting files.

TITLE

Please revise the title replacing ‘descriptive’ with ‘population-based’.

ABSTRACT

Line 10 – ‘prescription’ might be preferable to ‘supply’ for explicit clarity.

Line 15/16 – please clearly define the numerical values contained within brackets (confidence intervals). Please use commas instead of hyphens to separate upper and lower bounds as the latter can be confused with reporting of negative values. We accept your response regarding inclusion of p values.

AUTHOR SUMMARY

Line 43 – suggest ‘…period, it is possible that additional pregnancies could have also been exposed when the pregnancy was conceived before the end of the washout period.’ Or similar.

Line 47 – suggest ‘were’ instead of ‘was’.

Line 54 – suggest ‘…dose of isotretinoin’.

METHODS and RESULTS

As above please amend statistical reporting to separate upper and lower CI bounds with commas as opposed to hyphens. Please check and amend throughout all sub-sections of the manuscript and supporting files.

Line 234 – please replace ‘N’ with ‘n’ for consistency.

FIGURES

Figure 1 – please define GePaRD in the caption. Please indicate in the caption that the shaded areas represent 95% confidence intervals (not just on the axis).

DISCUSSION

We appreciate your inclusion of sub-headings to direct the reader to the different parts o your study question. We generally prefer to format the discussion as continuous prose and suggest that actually sub-headings are not necessary. If you disagree, then a compromise could be leaving in those at lines 297 and 320 and removing the rest.

Line 285 – suggest stating ‘20% of the population’ as per elsewhere in the manuscript.

Line 286 – ‘increased by 63%’ is correct in proportional terms but somewhat overinflates the magnitude of the issue when considering the data that follows. Please revise so as not to overstate findings.

Line 289 – please quantify the number of users that you derive this percentage from.

Line 291 – suggest ‘…most critical for fetal development.’ instead perhaps.

Line 294 – is this 45% of 178? It might be helpful to simply state the number here as opposed to the percentage considering the discussion of outcomes also from your sensitivity analyses which could confuse matters.

Line 421 – please remove the funding statement from the end of the manuscript and include only in the manuscript submission form when you re-submit the masncuript. It will be compiled as metadata at the time of publication.

We appreciate, as you say that the study was not designed to assess level of risk, but you do quote numbers of congenital abnormalities. As such we think it would be helpful to report the expected risk of congenital abnormalities and atrial septal defects, in the German population, at least in the discussion (and perhaps also in the abstract).

REFERENCES

Line 444 – ref #5 please remove the word ‘date’ and just detail the actual date. Please check and amend elsewhere as necessary (I note also refs 12 and 15 but this is not exhaustive).

SUPPORTING INFORMATION

In the published article, supporting information files are accessed only through a hyperlink attached to the captions. For this reason, you must list captions at the end of your manuscript file. You may include a caption within the supporting information file itself, as long as that caption is also provided in the manuscript file. Do not submit a separate caption file.

Throughout, please define GePaRD

S1 checklist – thank you for including the checklist as required. Please change column header ‘Page No’ to ‘Section & Paragraph’ or similar. Please also revise to indicate that your statements (funding, for example) can be found in the submission form as metadata.

STATEMENTS FOR SUBMISSION

As detailed above please ensure all are removed from the main manuscript and included only in the manuscript submission form when you re-submit the manuscript.

SOCIAL MEDIA

To help us extend the reach of your research, please detail any X (formerly Twitter) handles you wish to be included when we tweet this paper (including your own, your coauthors’, your institution, funder, or lab) in the manuscript submission form when you re-submit the manuscript.

COMMENTS FROM THE REVIEWERS

Reviewer #1: Alex McConnachie, Statistical Review

I thank the authors for their consideration of my original points. I am very glad that they went to the extra effort to obtain the outcomes for children classified as exposed in the sensitivity analyses - I think this makes the data more complete. I am also satisfied with the additional confirmation that it is ethically acceptable to publish these data in such detail.

I have no further comments.

Reviewer #2: Thank you for the clear response. You have addressed all of my comments. Two minor things: for consistency, I recommend to add "at least" before "45% of exposed pregnancies ended in an induced abortion" in the abstract. In the revision on page 18, line 333 there is a typo: :"to" should be "too"

Any attachments provided with reviews can be seen via the following link:

[LINK]

PLoS Med. doi: 10.1371/journal.pmed.1004339.r004

Decision Letter 3

Philippa C Dodd

21 Dec 2023

Dear Dr Haug,

On behalf of my colleagues and the Academic Editor, Dr Sarah Stock, I am pleased to inform you that we have agreed to publish your manuscript "Use of isotretinoin among girls and women of childbearing age and occurrence of isotretinoin-exposed pregnancies in Germany: A population-based study" (PMEDICINE-D-22-03260R3) in PLOS Medicine.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. Please be aware that it may take several days for you to receive this email; during this time no action is required by you. Once you have received these formatting requests, please note that your manuscript will not be scheduled for publication until you have made the required changes.

In the meantime, please log into Editorial Manager at http://www.editorialmanager.com/pmedicine/, click the "Update My Information" link at the top of the page, and update your user information to ensure an efficient production process.

PRESS

We frequently collaborate with press offices. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximise its impact. If the press office is planning to promote your findings, we would be grateful if they could coordinate with medicinepress@plos.org. If you have not yet opted out of the early version process, we ask that you notify us immediately of any press plans so that we may do so on your behalf.

We also ask that you take this opportunity to read our Embargo Policy regarding the discussion, promotion and media coverage of work that is yet to be published by PLOS. As your manuscript is not yet published, it is bound by the conditions of our Embargo Policy. Please be aware that this policy is in place both to ensure that any press coverage of your article is fully substantiated and to provide a direct link between such coverage and the published work. For full details of our Embargo Policy, please visit http://www.plos.org/about/media-inquiries/embargo-policy/.

Thank you again for submitting to PLOS Medicine, it has been a pleasure handling your manuscript. We look forward to publishing your paper.

Best wishes,

Pippa

Philippa Dodd, MBBS MRCP PhD

PLOS Medicine

pdodd@plos.org

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Checklist. STROBE Statement—checklist of items that should be included in reports of observational studies.

(DOCX)

Click here for additional data file.^{(19.1KB, docx)}

S1 Table. Number of girls and women aged 13–49 years with at least 1 dispensation of isotretinoin between 2004 and 2019 in GePaRD by age group and year of prescription.

(DOCX)

Click here for additional data file.^{(27.9KB, docx)}

S2 Table. Prescriptions of Isotretinoin dispensed to girls and women aged 13–49 years between 2004 and 2019 in GePaRD: Distribution of the specialty of the prescribing physician.

(DOCX)

Click here for additional data file.^{(23.6KB, docx)}

S3 Table. Number of pregnancies exposed to isotretinoin between 2004 and 2019 in GePaRD by age group and year of beginning of pregnancy.

(DOCX)

Click here for additional data file.^{(29.2KB, docx)}

Data Availability Statement

[pmed.1004339.ref001] 1.Nast A, Dréno B, Bettoli V, Bukvic Mokos Z, Degitz K, Dressler C, et al. European evidence-based (S3) guideline for the treatment of acne–update 2016 –short version. J Eur Acad Dermatol Venereol. 2016;30(8):1261–8. doi: 10.1111/jdv.13776 [DOI] [PubMed] [Google Scholar]

[pmed.1004339.ref002] 2.Layton A. The use of isotretinoin in acne. Dermatoendocrinol. 2009;1(3):162–9. Epub 2010/05/04. doi: 10.4161/derm.1.3.9364 ; PubMed Central PMCID: PMC2835909. [DOI] [PMC free article] [PubMed] [Google Scholar]

[pmed.1004339.ref003] 3.Marson JW, Baldwin HE. Isotretinoin update. Dermatol Rev. 2021;2(6):331–42. doi: 10.1002/der2.100 [DOI] [Google Scholar]

[pmed.1004339.ref004] 4.Dai WS, LaBraico JM, Stern RS. Epidemiology of isotretinoin exposure during pregnancy. J Am Acad Dermatol. 1992;26(4):599–606. Epub 1992/04/01. doi: 10.1016/0190-9622(92)70088-w . [DOI] [PubMed] [Google Scholar]

[pmed.1004339.ref005] 5.EMA. Updated measures for pregnancy prevention during retinoid use 2018. [cited 2023 Nov 14]. Available from: https://www.ema.europa.eu/en/documents/referral/retinoid-article-31-referral-updated-measures-pregnancy-prevention-during-retinoid-use_en.pdf. [Google Scholar]

[pmed.1004339.ref006] 6.Bérard A, Azoulay L, Koren G, Blais L, Perreault S, Oraichi D. Isotretinoin, pregnancies, abortions and birth defects: a population-based perspective. Br J Clin Pharmacol. 2007;63(2):196–205. Epub 2007/01/12. doi: 10.1111/j.1365-2125.2006.02837.x ; PubMed Central PMCID: PMC1859978. [DOI] [PMC free article] [PubMed] [Google Scholar]

[pmed.1004339.ref007] 7.Henry D, Dormuth C, Winquist B, Carney G, Bugden S, Teare G, et al. Occurrence of pregnancy and pregnancy outcomes during isotretinoin therapy. CMAJ. 2016;188(10):723–30. Epub 2016/04/27. doi: 10.1503/cmaj.151243 ; PubMed Central PMCID: PMC4938682. [DOI] [PMC free article] [PubMed] [Google Scholar]

[pmed.1004339.ref008] 8.MacDonald SC, Cohen JM, Panchaud A, McElrath TF, Huybrechts KF, Hernández-Díaz S. Identifying pregnancies in insurance claims data: Methods and application to retinoid teratogenic surveillance. Pharmacoepidemiol Drug Saf. 2019;28(9):1211–21. Epub 2019/07/23. doi: 10.1002/pds.4794 ; PubMed Central PMCID: PMC6830505. [DOI] [PMC free article] [PubMed] [Google Scholar]

[pmed.1004339.ref009] 9.Rouzès A, Jonville-Béra AP. Exposure to isotretinoin during pregnancy in France: 25 years of follow-up. Therapie. 2014;69(1):53–63. Epub 2014/04/05. doi: 10.2515/therapie/2014008 . [DOI] [PubMed] [Google Scholar]

[pmed.1004339.ref010] 10.Tkachenko E, Singer S, Sharma P, Barbieri J, Mostaghimi A. US Food and Drug Administration reports of pregnancy and pregnancy-related adverse events associated with isotretinoin. JAMA Dermatol. 2019;155(10):1175–9. doi: 10.1001/jamadermatol.2019.1388 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pmed.1004339.ref011] 11.Zomerdijk IM, Ruiter R, Houweling LMA, Herings RMC, Sturkenboom MCJM, Straus SMJM, et al. Isotretinoin exposure during pregnancy: a population-based study in The Netherlands. BMJ Open. 2014;4(11):e005602–e. doi: 10.1136/bmjopen-2014-005602 . [DOI] [PMC free article] [PubMed] [Google Scholar]

[pmed.1004339.ref012] 12.Leibniz Institute for Prevention Research and Epidemiology – BIPS. The German Pharmacoepidemiological Research Database (GePaRD). 2022 [cited 2023 Nov 14]. Available from: https://www.bips-institut.de/en/research/research-infrastructures/gepard.html.

[pmed.1004339.ref013] 13.Haug U, Schink T. German Pharmacoepidemiological Research Database (GePaRD). In: Sturkenboom M, Schink T, editors. Databases for Pharmacoepidemiological Research: Springer; 2020. p. 119–24. [Google Scholar]

[pmed.1004339.ref014] 14.Bundesministerium für Gesundheit. Das deutsche Gesundheitssystem. 2020. [cited 2023 Nov 14]. Available from: https://www.bundesgesundheitsministerium.de/fileadmin/Dateien/5_Publikationen/Gesundheit/Broschueren/200629_BMG_Das_deutsche_Gesundheitssystem_DE.pdf. [Google Scholar]

[pmed.1004339.ref015] 15.Statista GmbH. PKV, BMG. Anzahl der Mitglieder und Versicherten der gesetzlichen und privaten Krankenversicherung in den Jahren 2016 bis 2022 (in Millionen). 2022 [cited 2023 Nov 14]. Available from: https://de.statista.com/statistik/daten/studie/155823/umfrage/gkv-pkv-mitglieder-und-versichertenzahl-im-vergleich/. [Google Scholar]

[pmed.1004339.ref016] 16.Mikolajczyk RT, Kraut AA, Garbe E. Evaluation of pregnancy outcome records in the German Pharmacoepidemiological Research Database (GePaRD). Pharmacoepidemiol Drug Saf. 2013;22(8):873–80. Epub 2013/06/05. doi: 10.1002/pds.3467 . [DOI] [PubMed] [Google Scholar]

[pmed.1004339.ref017] 17.Wentzell N, Schink T, Haug U, Ulrich S, Niemeyer M, Mikolajczyk R. Optimizing an algorithm for the identification and classification of pregnancy outcomes in German claims data. Pharmacoepidemiol Drug Saf. 2018;27(9):1005–10. Epub 2018/07/20. doi: 10.1002/pds.4588 . [DOI] [PubMed] [Google Scholar]

[pmed.1004339.ref018] 18.Schink T, Wentzell N, Dathe K, Onken M, Haug U. Estimating the beginning of pregnancy in German claims data: Development of an algorithm with a focus on the expected delivery date. Front Public Health. 2020;8:350. Epub 2020/09/10. doi: 10.3389/fpubh.2020.00350 ; PubMed Central PMCID: PMC7434962. [DOI] [PMC free article] [PubMed] [Google Scholar]

[pmed.1004339.ref019] 19.Garbe E, Suling M, Kloss S, Lindemann C, Schmid U. Linkage of mother-baby pairs in the German Pharmacoepidemiological Research Database. Pharmacoepidemiol Drug Saf. 2011;20(3):258–64. Epub 2011/02/26. doi: 10.1002/pds.2038 . [DOI] [PubMed] [Google Scholar]

[pmed.1004339.ref020] 20.Federal institute for drugs and medical devices (BfArM). Gebrauchsinformation Isotretinoin 2010. [cited 2023 Nov 14]. Available from: https://www.bfarm.de/SharedDocs/Downloads/DE/Arzneimittel/Pharmakovigilanz/Risikoinformationen/RI_rhb/2010/isotretinoin_gi.pdf;jsessionid=82B953280A3A52A8CF7EA909EB8DD0E3.intranet661?__blob=publicationFile. [Google Scholar]

[pmed.1004339.ref021] 21.EUROCAT. EUROCAT guide 1.4 and reference documents. 2018 [cited 2023 Nov 14]. Available from: https://eu-rd-platform.jrc.ec.europa.eu/sites/default/files/Full_Guide_1_4_version_28_DEC2018.pdf.

[pmed.1004339.ref022] 22.Kassenärztliche Bundesvereinigung. Richtlinie der Kassenärztlichen Vereinigung nach §75 Absatz 7 SGB V zur Vergabe der Arzt-, Betriebsstätten-, sowie der Praxisnetznummern. 2021 [cited 2023 Nov 14]. Available from: https://www.kbv.de/media/sp/Arztnummern_Richtlinie.pdf.

[pmed.1004339.ref023] 23.Platzbecker K, Wentzell N, Kollhorst B, Haug U. Fingolimod, teriflunomide and cladribine for the treatment of multiple sclerosis in women of childbearing age: description of drug utilization and exposed pregnancies in Germany. Mult Scler Relat Disord. 2022;67:104184. doi: 10.1016/j.msard.2022.104184 [DOI] [PubMed] [Google Scholar]

[pmed.1004339.ref024] 24.Fricke U. Dermatika und Wundbehandlungsmittel. In: Schwabe U, Paffrath D, editors. Arzneimittelverordnungs-Report 2005. Heidelberg: Springer Berlin; 2005. p. 579. [Google Scholar]

[pmed.1004339.ref025] 25.Günter J, Fricke U. Dermatika In: Schwabe U, Ludwig WD, editors. Arzneimittelverordnungs-Report 2020. Heidelberg: Springer Berlin; 2020. p. 507. [Google Scholar]

[pmed.1004339.ref026] 26.Habeshian KA, Cohen BA. Current issues in the treatment of acne vulgaris. Pediatrics. 2020;145(Suppl 2):S225–s30. Epub 2020/05/03. doi: 10.1542/peds.2019-2056L . [DOI] [PubMed] [Google Scholar]

[pmed.1004339.ref027] 27.Bundesministerium für Gesundheit. DART 2020. Abschlussbericht. 2022 [cited 2023 Nov 14]. Available from: https://www.bundesgesundheitsministerium.de/fileadmin/Dateien/3_Downloads/D/DART_2020/BMG_DART_2020_Abschlussbericht_bf.pdf. [Google Scholar]

[pmed.1004339.ref028] 28.Gollnick HPM, Buer J, Beissert S, Sunderkätter C. Verantwortlicher Umgang mit Antibiotika: Notwendigkeit der Antibiotikareduktion in der Aknetherapie. J German Society Dermatology. 2016;14(12):1319–27. doi: 10.1111/ddg.13048 [DOI] [PubMed] [Google Scholar]

[pmed.1004339.ref029] 29.Crijns I, Straus S, Luteijn M, Gispen-de Wied C, Raine J, de Jong-van den Berg L. Implementation of the harmonized EU isotretinoin Pregnancy Prevention Programme: a questionnaire survey among European regulatory agencies. Drug Saf. 2012;35(1):27–32. Epub 2011/11/05. doi: 10.2165/11595570-000000000-00000 . [DOI] [PubMed] [Google Scholar]

[pmed.1004339.ref030] 30.Schaefer C, Meister R, Weber-Schoendorfer C. Isotretinoin exposure and pregnancy outcome: an observational study of the Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy. Arch Gynecol Obstet. 2009;281(2):221. doi: 10.1007/s00404-009-1112-2 [DOI] [PubMed] [Google Scholar]

[pmed.1004339.ref031] 31.Haug U. Verordnung von teratogenen Arzneimitteln bei Frauen im gebärfähigen Alter in Deutschland. Bulletin zur Arzneimittelsicherheit. 2020;(4):4–9. [Google Scholar]

[pmed.1004339.ref032] 32.Fassmer A, Schink T, editors. Repräsentativität von ambulanten Arzneiverordnungen in der German Pharmacoepidemiological Research Database (GePaRD). 9 Jahrestagung der Deutschen Gesellschaft für Epidemiologie (DGEpi); 2014; Ulm, Germany.

PERMALINK

Use of isotretinoin among girls and women of childbearing age and occurrence of isotretinoin-exposed pregnancies in Germany: A population-based study

Jonas Reinold

Bianca Kollhorst

Nadine Wentzell

Katharina Platzbecker

Ulrike Haug

Roles

Abstract

Background

Methods and findings

Conclusions

Author summary

Why was this study done?

What did the researchers do and find?

What do these findings mean?

Introduction

Methods

Data source

Study design and study population

Prevalent use of isotretinoin among girls and women of childbearing age

Identification of exposed pregnancies

Exploration of potential malformations among exposed children

Data analysis

Ethics and approvals

Results

Prevalence of isotretinoin use among girls and women of childbearing age

Fig 1. Age-specific and age-standardized prevalence with 95% CIs (shaded area) of isotretinoin use per 1,000 girls and women aged 13–49 years between 2004 and 2019 in the GePaRD.

Exposed pregnancies

Characterization of exposed children

Table 2. Malformations observed in live-born children exposed to isotretinoin during pregnancy in GePaRD between 2004 and 2019.

Discussion

Supporting information

Acknowledgments

Abbreviations

Data Availability

Funding Statement

References

Decision Letter 0

Philippa C Dodd

Roles

Decision Letter 1

Philippa C Dodd

Roles

Decision Letter 2

Philippa C Dodd

Roles

Decision Letter 3

Philippa C Dodd

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases