Abstract
Background
Oral retinoids are used to treat various dermatological conditions, and their use is increasing in women of childbearing age. However, there is limited knowledge on the incidence of adverse outcomes after retinoid exposure during pregnancy. We aimed to evaluate the risk of adverse outcomes associated with oral retinoid exposure during pregnancy.
Methods
We conducted a retrospective cohort study using the NHIS mother-child linked healthcare database in South Korea. We included all women who gave live birth from April 1, 2009 to December 31, 2020 and their children. The exposure was defined as having ≥ 1 prescription of isotretinoin, alitretinoin, and acitretin from one month before pregnancy to the delivery. The outcomes of interest were adverse child outcomes including major congenital malformations, low birth weight, and neurodevelopmental disorders (autism spectrum disorder and intellectual disorder), and adverse pregnancy outcomes including gestational diabetes mellitus, preeclampsia, and postpartum hemorrhage. Propensity score-based matching weights were used to control for various potential confounders. For congenital malformation, low birth weight, and adverse pregnancy outcomes, we calculated relative risk (RR) with 95% confidence interval (CI) using a generalized linear model and for neurodevelopmental disorders, we estimated hazard ratio (HR) with 95% CI using the Cox proportional hazard model.
Results
Of 3,894,184 pregnancies, we identified 720 pregnancies (0.02%) as the oral retinoid-exposed group. The incidence of major congenital malformation was 400.6 per 10,000 births for oral retinoid-exposed group and 357.9 per 10,000 births for unexposed group and the weighted RR was 1.10 (95% CI, 0.65–1.85) in oral retinoid-exposed group compared with unexposed group. The neurodevelopmental disorder showed a potential increased risk, with the weighted HR of 1.63 (95% CI, 0.60–4.41) for autism spectrum disorder and 1.71 (95% CI, 0.60–4.93) for the intellectual disorder, although it did not reach statistical significance. For low birth weight and adverse pregnancy outcomes, no association was observed with oral retinoid exposure during pregnancy.
Conclusion
This study found no significantly increased risk of congenital malformations, autism spectrum disorders, and intellectual disability associated with oral retinoid exposure during pregnancy; however, given the limitations such as including only the live births and increased point estimate, potential risk cannot be fully excluded.
Keywords: Retinoids, Pregnancy, Adverse Child Outcomes, Adverse Pregnancy Outcomes
Graphical Abstract
INTRODUCTION
Oral retinoids, which include isotretinoin, alitretinoin, and acitretin, are highly effective agents to treat various skin diseases, including acne, eczema, and psoriasis, that are chronic or do not respond to conventional treatment.1,2 Among women of childbearing age, the usage of oral retinoids has increased with the latest study reporting a level of prevalence increase from −0.016 to 0.43 per 1,000 women in European countries between 2010 and 2020.3,4 However, retinoids are known as potential teratogens, as their ability to regulate cell growth and apoptosis may result in malformations of the craniofacial, cardiovascular, thymic, and central nervous systems.5,6 As a result, many countries including South Korea and United States have implemented a contraceptive program to prevent pregnancy among oral retinoid users.7,8,9,10,11
The teratogenic effects of oral retinoids were initially established through animal studies.12,13 Subsequently, several observational studies were conducted to assess the risk of congenital malformation in humans; however, many of these studies were either small14,15,16,17,18,19 or outdated.5,20 Moreover, a meta-analysis that included 380 retinoid-exposed pregnancies revealed varying prevalence of congenital malformations, with studies conducted before 2006 reporting rates of 20–30%, whereas studies conducted after 2006 showed rates of 4–15%.21 It may not be surprising that majority of the studies have been conducted before the implementation of risk management program (RMP) that were leaded to restriction in prescription duration in many countries. However, considering that nearly half of all pregnancies are unintended, it is necessary to update our understanding on the risk of adverse outcomes associated with prenatal retinoid exposure based on nationwide real-world data that include the period after the RMP.22 In real-world practice, a substantial proportion of pregnant women exposed to retinoids undergo an elective abortion,15,23,24 and those who continue their pregnancies would remain concerned about the potential risk of retinoids.
Therefore, we conducted a nationwide cohort study to estimate the incidence and risk of adverse outcomes associated with oral retinoid exposure during pregnancy and also identify patterns of oral retinoid exposure. In this study, we not only analyzed the risk of congenital malformations but also examined the risk of neurodevelopmental disorders, low birth weight and adverse pregnancy outcomes which have not been evaluated.
METHODS
Study design and data sources
A retrospective population-based cohort study was conducted using the National Health Insurance Service-National Health Insurance Database (NHIS-NHID) of South Korea, from 2008 to 2021. NHIS provides mandatory public health insurance to all residents in South Korea and individuals can maintain this coverage until emigration or death. Thus, the NHIS-NHID encompasses the entire population in South Korea.25 This database includes comprehensive information on sociodemographic characteristics of individual patients and procedures, diagnosis, prescription records from all levels of care (e.g., inpatient, outpatient, and emergency department visits), and health examination records. We specifically used the mother-offspring cohort provided by the NHIS, which is established on the basis of a distinctive health insurance identification number shared among family members. This NHIS mother-offspring cohort has been widely used in previous perinatal pharmacoepidemiologic studies.26,27,28
Study population and exposure
We identified all women who gave live birth from 1 April 2009 to 31 December 2020. Exposure of interest was oral retinoids, which include alitretinoin, isotretinoin, and acitretin. The exposure window was defined as the one month before pregnancy until the day before the delivery date, considering the half-life of retinoids.29 In analyzing the risk of gestational diabetes mellitus (GDM) and preeclampsia, we defined the exposure window as early pregnancy (until 139 days after the start of pregnancy) as these outcomes start to occur from the 20th week of gestation. We considered the women as retionid-exposed if the women had overlapping prescription records during the exposure window and as retinoid unexposed if the women did not have overlapping prescription records during the exposure window. The start of pregnancy was estimated using a previously validated algorithm in administrative database based on the delivery date and preterm birth diagnosis.30 For the analysis of congenital malformations, we additionally defined the exposure window as 1 month before pregnancy to the end of the first trimester, the period known as organogenesis.
Adverse child and pregnancy outcomes
The adverse child outcomes of interest included major congenital malformation, low birth weight, and neurodevelopmental disorders. Major congenital malformations were defined as having at least two diagnosis codes on separate days or one diagnosis code with death within one year of birth. Major congenital malformations were categorized into 12 groups based on the EUROCAT classification.31 Neurodevelopmental disorders included autism spectrum disorder and intellectual disorder defined as the presence of two or more diagnosis codes on separate days, with identification after the minimum age criterion.32
The adverse pregnancy outcomes of interest included GDM, preeclampsia, and postpartum hemorrhage. All outcomes were identified based on ICD-10 codes in our database; the detailed code lists and assessment period for each outcomes are described in Supplementary Table 1.
Maternal characteristics
We defined several potential confounders or proxies of confounders which include sociodemographic characteristics (maternal age, residence, socioeconomic status), obstetric characteristics (nulliparity, multifetal gestation, mode of delivery), indications of oral retinoids (acne, Dermatitis/eczema, psoriasis), comorbidities, co-medications, and measures of healthcare utilization. We also assessed maternal smoking and obesity status using the health examination records (Supplementary Table 1).
Statistical analysis
The baseline characteristics of the oral retinoid-exposed and unexposed group were described using mean and standard deviation (SD) for continuous variables, or frequency and percentage for categorical variables. Standardized mean difference (SMD) was used to indicate the difference between the two groups, with an SMD value below 0.1 indicating the absence of a significant difference.
In this study, we used matching weights to adjust for potential confounders.33,34 By using matching weights, we were able to include all the individuals in our analyses which maximizes the utilization of available data. Propensity scores were estimated by multivariable logistic regression including all the pre-defined potential confounders listed in the maternal baseline characteristics section except smoking and obesity status owing to the high proportion of missing value. For analyses of congenital malformation, low birth weight, and adverse pregnancy outcomes, we calculated the incidence per 10,000 births or pregnancies and estimated crude and weighted relative risk (RR) with 95% confidence intervals (CIs) based on the generalized linear model. For analyses of neurodevelopmental disorders, we computed the incidence rate per 10,000 person-years and estimated the crude and weighted hazard ratio (HR) with 95% CIs using a Cox proportional hazard model. We also aimed to evaluate the incidence and risk of outcomes by individual ingredients; however, due to the limited number of pregnancies exposed to alitretinoin (n = 24) and acitretin (n = 53), we were only able to analyze the isotretinoin. All data analyses were performed using SAS Enterprise Guide, version 7.1 (SAS Institute Inc., Cary, NC, USA).
As a sensitivity analysis, we redefined the exposure window as the start of pregnancy to the delivery date instead of 1 month before pregnancy to the day before the delivery date. We also redefined the exposure based on the prescription date, in contrast to the main analysis, where exposure was defined by overlapping prescription records during the exposure window.
Patterns of retinoid exposure in pregnant women
In this study, we also aimed to describe the patterns of retinoid exposure among pregnant women. We examined the number of pregnancies with retinoid exposure from one year before pregnancy to one year after delivery. This analysis was performed in two-week intervals, and we assessed the pattern of exposure to oral retinoids and the individual retinoids (alitretinoin, isotretinoin, and acitretin), respectively. We also analyzed annual trends in the prevalence of oral retinoid exposure per 10,000 pregnancies from 2009 to 2020. These trends were evaluated by pre-pregnancy period (from one month before pregnancy until until the day before the start of pregnancy) and 1st, 2nd, and 3rd trimester. Additionally, we analyzed the prevalence on a quarterly basis between 2018 and 2020, considering the time of RMP implementation in South Korea, which was June 2019.
Ethics statement
The study protocol was reviewed and approved by the Institutional Review Board of Sungkyunkwan University (No. 2023-07-031). Informed consent was not required as this study was conducted using deidentified claims data.
RESULTS
Between April 2009 and December 2020, we identified 3,894,184 pregnancies that resulted in live births. Of these, 720 (0.02%) pregnancies were identified as oral retinoid-exposed group. Overall, oral retinoid prescriptions continuously decreased during the year preceding the start of pregnancy (Fig. 1). This trend continued throughout the pregnancy, with the most significant decrease observed in the first two months of pregnancy, from 248 pregnancies to 64 pregnancies. The oral retinoid prescriptions gradually increased after the delivery date; however, after a year of birth, the number of exposed did not fully return to the level of the year prior to pregnancy. This pattern was consistent within isotretinoin, while the number of pregnancies exposed to alitretinoin and acitretin after delivery was higher than that before pregnancy.
Fig. 1. Patterns of (A) oral retinoid usage, (B) isotretinoin usage, (C) alitretinoin usage, and (D) acitretin usage in the pregnant women.
The prevalence of pregnancies exposed to retinoids ranged from 1.42 per 10,000 pregnancies in 2020 to 2.13 per 10,000 pregnancies in 2011 (Fig. 2, Supplementary Table 2). Majority of the exposures to retinoids during pregnancy occurred within the first trimester. When examining the prevalence between 2018 and 2020 in a quarterly basis, there was a slight decrease in the prevalence of oral retinoid exposure after the implementation of risk management plan in June 2019 (Supplementary Fig. 1).
Fig. 2. Annual trends in the prevalence of oral retinoid exposure among pregnant women.
aTotal period is from one month before pregnancy to the day before the delivery date.
bPre-pregnancy period is defined as one month before pregnancy to the day before the pregnancy starts.
Compared to unexposed pregnancies, women exposed to oral retinoids during pregnancy tended to be younger, had a lower socioeconomic status, and had more diagnoses of dermatological disorders. They were more frequent users of medications including antibiotics and anxiolytics, and had more intense healthcare utilization. After applying matching weights, all characteristics were balanced, with a SMD of less than 0.1 (Table 1). The incidence of major congenital malformationwas 400.6 per 10,000 births for oral retinoid-exposed during pregnancy and 357.9 per 10,000 births for oral retinoid unexposed group. Compared with unexposed pregnancies, oral retinoid exposure during pregnancy was not significantly associated with overall congenital malformation, with an adjusted RR of 1.10 (95% CI, 0.65–1.85) (Table 2). When exposure window was limited to the first trimester, the incidence of major congenital malformation increased to 432.8 per 10,000 births, and the point estimate of weighted RR also slightly increased to 1.17 (95% CI, 0.68–2.00). Among the subgroups, the nervous system malformation showed a nonsignificant high risk in oral retinoid-exposed during pregnancy with weighted RR of 3.06 (0.47–20.08). For low birth weight, no significant risk was observed in oral retinoid-exposed group (weighted RR, 1.07; 95% CI, 0.66–1.74).
Table 1. Demographic and clinical characteristics of oral retinoid exposed and unexposed pregnancies.
| Characteristics | Unweighted | Weighteda | |||||
|---|---|---|---|---|---|---|---|
| Oral retinoid exposed pregnancies (n = 720) | Unexposed pregnancies (n = 3,893,464) | SMDb | Oral retinoid exposed pregnancies (n = 715) | Unexposed pregnancies (n = 730) | SMDb | ||
| Type of oral retinoids | |||||||
| Isotretinoin | 643 (89.3) | N/A | N/A | N/A | |||
| Alitretinoin | 24 (3.3) | N/A | N/A | N/A | |||
| Acitretin | 53 (7.4) | N/A | N/A | N/A | |||
| Maternal age at delivery | 29.7 ± 4.7 | 32.0 ± 4.2 | −0.50 | 30 ± 4.7 | 30 ± 0.1 | 0.00 | |
| Maternal age at delivery, yr | 0.53 | 0.07 | |||||
| < 20 | 5 (0.7) | 9,775 (0.3) | 5 (0.7) | 6 (0.8) | |||
| 20–24 | 103 (14.3) | 169,115 (4.3) | 102 (14.3) | 95 (13.0) | |||
| 25–29 | 241 (33.5) | 851,807 (21.9) | 239 (33.4) | 246 (33.8) | |||
| 30–34 | 257 (35.7) | 1,826,649 (46.9) | 256 (35.7) | 275 (37.7) | |||
| 35–39 | 98 (13.6) | 891,057 (22.9) | 97 (13.6) | 96 (13.1) | |||
| 40–44 | 16 (2.2) | 140,390 (3.6) | 16 (2.2) | 12 (1.6) | |||
| 45+ | 0 (0.0) | 4,671 (0.1) | 0 (0.0) | 0 (0.0) | |||
| Medical aid recipients | 15 (2.1) | 23,879 (0.6) | 0.13 | 15 (2.1) | 17 (2.3) | −0.01 | |
| Income level quartile | 0.27 | 0.00 | |||||
| 1st (lowest) | 180 (25.0) | 665,554 (17.1) | 178 (24.9) | 180 (24.7) | |||
| 2nd | 217 (30.1) | 976,621 (25.1) | 216 (30.2) | 220 (30.1) | |||
| 3rd | 192 (26.7) | 1,403,075 (36.0) | 190 (26.6) | 196 (26.8) | |||
| 4th (highest) | 131 (18.2) | 848,214 (21.8) | 131 (18.3) | 134 (18.4) | |||
| Region of residence | −0.05 | −0.07 | |||||
| Urban | 182 (25.3) | 1,068,854 (27.5) | 181 (25.3) | 206 (28.2) | |||
| Rural | 538 (74.7) | 2,824,610 (72.6) | 534 (74.7) | 524 (71.8) | |||
| Nulliparous | 472 (65.6) | 1,987,135 (51.0) | 0.30 | 469 (65.5) | 479 (65.7) | 0.00 | |
| Multifetal gestation | 4 (0.6) | 68,693 (1.8) | −0.11 | 4 (0.6) | 4 (0.6) | −0.01 | |
| Co-medications | |||||||
| Antibiotics | 612 (85.0) | 2,711,126 (69.6) | 0.37 | 608 (85.0) | 622 (85.2) | −0.01 | |
| Antidiabetics | 11 (1.5) | 59,365 (1.5) | 0.00 | 11 (1.5) | 11 (1.6) | 0.00 | |
| Antidepressants | 14 (1.9) | 47,678 (1.2) | 0.06 | 14 (1.9) | 14 (2.0) | 0.00 | |
| Antihypertensives | 33 (4.6) | 126,625 (3.3) | 0.07 | 33 (4.6) | 34 (4.7) | 0.00 | |
| Antihistamines | 494 (68.6) | 2,014,065 (51.7) | 0.35 | 490 (68.5) | 502 (68.8) | −0.01 | |
| Antipsychotics | 99 (13.8) | 263,136 (6.8) | 0.23 | 99 (13.8) | 102 (14.0) | −0.01 | |
| Anxiolytics | 61 (8.5) | 183,336 (4.7) | 0.15 | 61 (8.5) | 63 (8.7) | −0.01 | |
| Corticosteroids | 435 (60.4) | 1,181,597 (30.3) | 0.63 | 430 (60.2) | 446 (61.2) | −0.02 | |
| Lipid-lowering drug | 6 (0.8) | 9,805 (0.3) | 0.08 | 6 (0.8) | 7 (0.9) | −0.01 | |
| Indications | |||||||
| Acne | 513 (71.3) | 6,344 (0.2) | 2.21 | 508 (71.1) | 523 (71.6) | −0.01 | |
| Dermatitis/eczema | 388 (53.9) | 776,157 (19.9) | 0.75 | 383 (53.6) | 400 (54.8) | −0.02 | |
| Psoriasis | 62 (8.6) | 11,217 (0.3) | 0.41 | 57 (8.0) | 69 (9.5) | −0.05 | |
| Comorbidities | |||||||
| Anxiety | 11 (1.5) | 29,574 (0.8) | 0.07 | 11 (1.5) | 11 (1.5) | 0.00 | |
| Depression | 11 (1.5) | 27,814 (0.7) | 0.08 | 11 (1.5) | 11 (1.6) | 0.00 | |
| Diabetes | 22 (3.1) | 78,659 (2.0) | 0.07 | 22 (3.1) | 22 (3.1) | 0.00 | |
| Dyslipidemia | 19 (2.7) | 70,819 (1.8) | 0.06 | 19 (2.7) | 20 (2.7) | −0.01 | |
| Hypertension | 6 (0.8) | 38,553 (1.0) | −0.02 | 6 (0.8) | 6 (0.9) | 0.00 | |
| PCOS | 3 (0.4) | 35,921 (0.9) | −0.06 | 3 (0.4) | 4 (0.5) | −0.01 | |
| Psychiatric disorder | 23 (3.2) | 39,860 (1.0) | 0.15 | 23 (3.2) | 24 (3.3) | 0.00 | |
| Obesity | 0.08 | 0.05 | |||||
| Yes | 40 (5.6) | 259,184 (6.7) | 39.3 (5.5) | 33 (4.5) | |||
| No | 289 (40.1) | 1,678,371 (43.1) | 287.3 (40.2) | 303 (41.5) | |||
| Missing | 391 (54.3) | 1,955,909 (50.2) | 388.8 (54.4) | 394 (54.1) | |||
| Smoking | 0.11 | 0.07 | |||||
| Yes | 20 (2.8) | 81,712 (2.1) | 20 (2.8) | 16 (2.2) | |||
| No | 306 (42.5) | 1,850,017 (47.5) | 304 (42.4) | 318 (43.6) | |||
| Missing | 394 (54.7) | 1,961,735 (50.4) | 392 (54.8) | 395 (54.2) | |||
| Mode of delivery | 0.00 | 0.03 | |||||
| Vaginal delivery | 422 (58.6) | 2,286,158 (58.7) | 419 (58.5) | 438 (60.0) | |||
| Cesarean delivery | 298 (41.4) | 1,607,306 (41.3) | 297 (41.5) | 291 (40.0) | |||
| No. of inpatient visits | 0.1 ± 0.5 | 0.1 ± 0.3 | 0.03 | 0.1 ± 0.5 | 0.1 ± 0.0 | 0.01 | |
| No. of outpatient visits | 8.4 ± 6.9 | 5.5 ± 5.8 | 0.46 | 8.4 ± 6.9 | 8.4 ± 0.1 | −0.02 | |
| No. of emergency department visits | 0.1 ± 0.5 | 0.1 ± 0.4 | 0.11 | 0.1 ± 0.5 | 0.1 ± 0.0 | 0.00 | |
Values are presented as number (%) or mean ± standard deviation.
SMD = standardized mean difference, N/A = not applicable, PCOS = polycystic ovarian syndrome.
aObesity and smoking status were not included in the propensity score calculation.
bValue > 0.1 indicates a significant difference between exposed pregnancy and total pregnancy.
Table 2. Risk of adverse birth outcomes associated with oral retinoid exposure during pregnancy.
| Variables | Oral retinoid unexposed during pregnancya (n = 3,963,150) | Oral retinoid exposed during pregnancya (n = 724) | Relative risk (95% CI) | Oral retinoid exposed during first trimestera (n = 647) | Relative risk (95% CI) | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Events | Incidenceb | Events | Incidenceb | Crude | Weighted | Events | Incidenceb | Crude | Weighted | ||
| Overall congenital malformation | 141,849 | 357.9 | 29 | 400.6 | 1.12 (0.78–1.60) | 1.10 (0.65–1.85) | 28 | 432.8 | 1.21 (0.84–1.74) | 1.17 (0.68–2.00) | |
| Nervous system | 8,361 | 21.1 | 5 | 69.1 | 3.27 (1.37–7.84) | 3.06 (0.47–20.08) | 5 | 77.3 | 3.66 (1.53–8.77) | 3.49 (0.49–24.83) | |
| Eye | 3,323 | 8.4 | 0 | 0 | - | - | 0 | 0 | - | - | |
| Ear, face, and neck | 890 | 2.2 | 0 | 0 | - | - | 0 | 0 | - | - | |
| Heart | 83,346 | 210.3 | 14 | 193.4 | 0.92 (0.55–1.54) | 0.84 (0.41–1.69) | 14 | 216.4 | 1.03 (0.61–1.73) | 0.92 (0.45–1.87) | |
| Respiratory system | 1,429 | 3.6 | 0 | 0 | 0 | 0 | |||||
| Oral-facial cleft | 5,111 | 12.9 | 2 | 27.6 | 2.14 (0.54–8.55) | 2.73 (0.19–38.94) | 1 | 15.5 | 1.20 (0.17–8.50) | 1.54 (0.07–34.2) | |
| Gastro-intestinal system | 8,325 | 21 | 1 | 13.8 | 0.66 (0.09–4.66) | 0.95 (0.06–14.34) | 1 | 15.5 | 0.74 (0.10–5.22) | 1.04 (0.06–16.8) | |
| Abdominal wall defects | 463 | 1.2 | 0 | 0 | - | - | 0 | 0 | - | - | |
| Kidney and urinary system | 18,652 | 47.1 | 7 | 96.7 | 2.05 (0.98–4.29) | 2.27 (0.60–8.55) | 7 | 108.2 | 2.30 (1.10–4.80) | 2.59 (0.65–10.37) | |
| Genital organs | 4,801 | 12.1 | 0 | 0 | - | - | 0 | 0 | - | - | |
| Limb | 11,771 | 29.7 | 1 | 13.8 | 0.47 (0.07–3.30) | 0.52 (0.05–5.82) | 1 | 15.5 | 0.52 (0.07–3.69) | 0.58 (0.05–6.65) | |
| Others | 3,731 | 9.4 | 1 | 13.8 | 1.47 (0.21–10.40) | 2.16 (0.07–68.45) | 1 | 15.5 | 1.64 (0.23–11.64) | 2.40 (0.07–86.44) | |
| Neonatal outcome | |||||||||||
| Low birth weight | 178,113 | 449.4 | 32 | 442 | 0.98 (0.70–1.38) | 1.07 (0.66–1.74) | N/A | N/A | N/A | N/A | |
CI = confidence interval, N/A = not applicable.
aNumber of births.
bIncidence per 10,000 births.
Compared to unexposed group, the oral retinoid-exposed group had a higher incidence rate of autism spectrum disorders (20.9 vs. 9.1 per 10,000 person-years), and intellectual disabilities (18.8 vs. 6.8 per 10,000 person-years). Before applying matching weights, significantly increased risk in autism spectrum disorder (crude HR, 2.32; 95% CI, 1.25–4.31) and intellectual disability (2.76, 1.44–5.30) were observed. After applying matching weights, the HR was attenuated to 1.63 (0.60–4.41) for autism spectrum disorder and 1.71 (0.60–4.93) for intellectual disorder (Table 3).
Table 3. Risk of neurodevelopmental disorder associated with oral retinoid exposure during pregnancy.
| Neurodevelopmental disorders | Oral retinoid exposed during pregnancya (n = 723) | Oral retinoid unexposed during pregnancyb (n = 3,956,891) | Hazard ratio (95% CI) | |||||
|---|---|---|---|---|---|---|---|---|
| Person-year | Events | Incidence rateb | Person-year | Events | Incidence rateb | Crude | Weighted | |
| Autism spectrum disorder | 4,783 | 10 | 20.9 | 25,733,556 | 23,512 | 9.1 | 2.32 (1.25–4.31) | 1.63 (0.60–4.41) |
| Intellectual disability | 4,794 | 9 | 18.8 | 25,770,741 | 17,567 | 6.8 | 2.76 (1.44–5.30) | 1.71 (0.60–4.93) |
CI = confidence interval.
aNumber of births with at least one year of follow-up.
bIncidence rate per 10,000 person-years.
Regarding adverse pregnancy outcomes, oral retinoid exposure during pregnancy was not associated with the risk of GDM (weighted RR, 0.94; 0.65–1.39), preeclampsia (weighted RR, 0.54; 0.20–1.46), or postpartum hemorrhage (weighted RR, 1.03; 0.63–1.71) (Table 4).
Table 4. Risk of adverse pregnancy outcomes associated with oral retinoid exposure during pregnancy.
| Adverse pregnancy outcome | Oral retinoid exposed during pregnancya | Oral retinoid unexposed during pregnancy | Relative risk (95% CI) | |||||
|---|---|---|---|---|---|---|---|---|
| No. of pregnancies | Events | Incidenceb | No. of pregnancies | Events | Incidenceb | Crude | Weighted | |
| GDM | 675 | 47 | 696.3 | 3,963,151 | 343,648 | 867.1 | 0.75 (0.58–1.00) | 0.94 (0.65–1.39) |
| Preeclampsia | 675 | 6 | 88.9 | 3,963,151 | 38,020 | 95.9 | 0.93 (0.42–2.06) | 0.54 (0.20–1.46) |
| Postpartum hemorrhage | 720 | 30 | 416.7 | 3,893,464 | 155,304 | 398.9 | 1.04 (0.74–1.48) | 1.03 (0.63–1.71) |
CI = confidence interval, GDM = gestational diabetes mellitus.
aFor GDM and preeclampsia, the exposure window was early pregnancy (until 139 days after the start of pregnancy), and for postpartum hemorrhage the exposure window was entire pregnancy period.
bIncidence per 10,000 pregnancies.
When analyzing the risk of isotretinoin exposure during pregnancy, the results were largely consistent (Supplementary Tables 3, 4, 5). Results from various sensitivity analyses also showed generally consistent findings (Supplementary Tables 6, 7, 8, 9, 10, 11).
DISCUSSION
Using the nationwide claims database of South Korea, we examined the patterns of oral retinoid exposure in pregnant women and estimated the risk of adverse outcomes among oral retinoid-exposed pregnancies. The annual prevalence of oral retinoid exposure between 2009 and 2020 ranged from 1.42 to 2.13 per 10,000 pregnancies. Of 3,894,184 pregnancies, 720 were exposed to oral retinoids during pregnancy and we found that the risk of overall congenital malformations was nonsignificantly higher than that of the unexposed pregnancies. Similarly, elevated risks for autism spectrum disorder and intellectual disorder were observed in oral retinoid-exposed pregnancies, although the CIs were wide and intersected the null. For the adverse pregnancy outcomes including GDM, preeclampsia, and postpartum hemorrhage, we did not observe differences in risk between oral retinoid-exposed and unexposed pregnancies.
In this study, we examined the usage patterns of oral retinoids across the pregnancy and the annual prevalence of oral retinoid exposure during pregnancy. The number of pregnancies exposed to oral retinoids gradually decreased during the one year before the pregnancy starts. This may suggest that women who are planning to become pregnant are avoiding oral retinoid use. The decrease in oral retinoid use persisted until the end of the pregnancy, with the most significant reduction occurring in the first two months of pregnancy. The use of oral retinoids started to increase after delivery, with acitretin and alitretinoin being used more than before pregnancy; however, isotretinoin did not return to pre-pregnancy levels within one year after delivery. The differences in these results may be related to the indications. While psoriasis and eczema show higher or similar prevalence in women of childbearing age, the prevalence of acne is observed to decrease with age.35,36,37
Previous studies have reported varying rates of congenital malformations following retinoid exposure during pregnancy, ranging from 4% to 30%.5,17,18 Moreover, a meta-analysis found that the odds ratio of fetal malformations associated with pregnancies exposed to oral retinoids was heterogeneous between studies conducted before and after 2006, decreasing from 33.78 to 1.04.21 While this meta-analysis was only based on 3 studies, it would still be noteworthy to discuss potential explanations regarding this decreased risk. First, this may be attributed to the increased detection of congenital malformations via prenatal diagnosis.38 Given that most studies evaluating congenital malformations have been conducted based on live births, those diagnosed with malformations through prenatal diagnosis and chose to have an abortion may have affected the incidence of congenital malformations. It may also have been influenced by increased awareness of oral retinoids as teratogens through efforts such as pregnancy prevention programs in many countries, which has led oral retinoid users to use them more cautiously than in the past. Moreover, significant change in policy such as restriction of prescription duration after the implementation of RMP may had impact as well.39 Lastly, residual confounding may in part explain the discrepancy as it cannot be fully excluded in observational studies. In our study, using the large nationwide database, we were able to control for potential confounders using matching weights. The incidence of major congenital malformations in the oral retinoid-exposed group was 400.6 per 10,000 births, and in unexposed group, it was 357.9 per 10,000 births, with weighted RR (95% CI) of 1.10 (0.65–1.85). Overall, our study showed a nonsignificant increased risk of congenital malformations in oral retinoid-exposed pregnancies; however, given the limited available evidence on the safety of oral retinoids during pregnancy, additional studies are warranted to examine the incidence of congenital malformations. Specifically, studies that encompass non-live births (e.g., abortion, stillbirth) would be informative considering that most of the existing studies (including this study) only comprised pregnancies that ended in live birth.
Our study also evaluated the incidence and risk of adverse child outcomes other than congenital malformations which included low birth weight and neurodevelopmental disorders. The incidence and risk of low birth weight in oral retinoid-exposed group did not differ from the unexposed group. In contrast, we observed a potential increase in the risk of autism spectrum disorder (HR, 1.63; 95% CI, 0.60–4.41) and intellectual disability (HR, 1.71; 95% CI, 0.60–4.93), although the CIs were wide and intersected the null. Indeed, animal studies and in vitro research have demonstrated that retinoic acid is involved in the patterning and differentiation of neurons.40,41 Specifically, retinoic acid can play role in the formation of the neural plate and neural tube axis by acting as a transcription factor or contributing to the differentiation of neurons and glial cells.42 In support, case reports continue to report autism spectrum disorder and intellectual disability in children of mothers exposed to oral retinoids during pregnancy.16,43,44 Moreover, in the similar context, the nervous system malformations was shown to have higher risk in terms of point estimate (3.06), which further leaves the concern about the effect on the development of the nervous system. However, due to the rarity of these outcomes, our study lacked the statistical power to conclude the association. Thus, future studies are warranted to evaluate the neurodevelopmental risks that includes the other types of disorders (e.g., ADHD) associated with oral retinoid exposure during pregnancy based on large sample size and sufficient follow-up period. Meanwhile, this study’s result implies the need for clinicians and pregnant women to be aware of the potential long-term impact of oral retinoid exposure during pregnancy, even in the absence of congenital malformations.
Regarding the adverse pregnancy outcomes, no significant differences in the risk of GDM, preeclampsia, and postpartum hemorrhage were observed in oral retinoid-exposed pregnancies compared to unexposed pregnancies. In this study, we analyzed the risk of adverse pregnancy outcomes in terms of generating the overall safety evidence associated with oral retinoid use in pregnant women. Our results indicate that there are no significant risk in adverse pregnancy outcomes associated with oral retinoid exposure during pregnancy.
This study has several limitations. First, our study only included women who had live births. Women exposed to oral retinoids who experienced abortion or stillbirth were not included, thus we may have underestimated the incidence of congenital malformations which were led to stillbirth or termination. Second, defining the exposure based on the day’s supply of the oral retinoids overlapping the exposure window may result in misclassification as we cannot confirm the patient’s adherence. To increase the specificity in the exposure definition, we conducted a sensitivity analysis in which we defined the exposure as at least one prescription during the relevant window. The results of the sensitivity analysis were consistent with our initial findings. Third, although we defined the exposure window as one month before pregnancy to account for the pharmacokinetic characteristics of oral retinoids, there are differences in individual drug metabolism.29,45,46 Therefore, we performed a sensitivity analysis in which the exposure period was redefined from the start of pregnancy to the day before the delivery date, and our results remained largely consistent. Fourth, we were unable to perform subgroup analyses for individual oral retinoids such as alitretinoin and acitretin due to the small number of exposed pregnancies. Moreover, for rare outcomes including several subgroups of congenital malformation, the estimates were relatively imprecise with wide CIs. Lastly, as our study was based on the claims database, oral retinoid prescriptions that are not covered by the insurance were not captured.
In summary, this nationwide population-based study found a nonsignificantly increased risk of congenital malformation, autism spectrum disorder, and intellectual disorder in oral retinoid-exposed pregnancies. For low birth weight, and adverse pregnancy outcomes, we did not observe increased risk in oral retinoid-exposed pregnancies. Our study has updated the available evidence on the risk of congenital malformation associated with oral retinoids and provides initial evidence regarding neurodevelopmental disorders and other pregnancy outcomes. However, as our study only included the live births, future research that encompasses non-live births, as well as information on non-reimbursed prescribed medications would be necessary to fully understand the risk of oral retinoid exposure during pregnancy.
ACKNOWLEDGMENTS
This work was supported by the National Research Foundation of Korea grant funded by the Korea government. (No. RS-2023-00208978). The funders had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.
Footnotes
Funding: This work was supported by the National Research Foundation of Korea grant funded by the Korea government (No. RS-2023-00208978), and was partly supported by a grant (21153MFDS607) from the Ministry of Food and Drug Safety, Korea.
Disclosure: The authors declare no potential conflict of interest relevant to this study. Ju-Young Shin received grants from the Ministry of Food and Drug Safety, the Ministry of Health and Welfare, the National Research Foundation of South Korea, and pharmaceutical companies, including LG chem, UCB, and Pfizer, outside the submitted work.
- Conceptualization: You W, Choi A, Han JY, Lee JH, Shin JY.
- Data curation: You W, Choi A, Lee H.
- Formal analysis: You W, Lee H.
- Funding acquisition: Shin JY.
- Investigation: You W.
- Methodology: You W, Choi A, Han JY, Lee JH, Shin JY.
- Project administration: Shin JY.
- Supervision: Shin JY.
- Visualization: You W, Choi A.
- Writing - original draft: You W, Choi A.
- Writing - review & editing: You W, Choi A, Han JY, Lee JH, Shin JY.
SUPPLEMENTARY MATERIALS
Codes and assessment period of the exposure, outcomes, and baseline characteristics
The number and the prevalence of oral retinoid exposure before and during pregnancya
Risk of adverse birth outcomes associated with isotretinoin exposure during pregnancy
Risk of neurodevelopmental associated with isotretinoin exposure during pregnancy
Risk of adverse pregnancy outcomes associated with isotretinoin exposure during pregnancy
Risk of adverse birth outcomes associated with oral retinoid exposure during pregnancy: sensitivity analysis on redefining the exposure windowa
Risk of neurodevelopmental disorder associated with oral retinoid exposure during pregnancy: sensitivity analysis on redefining the exposure windowa
Risk of adverse pregnancy outcomes associated with oral retinoid exposure during pregnancy: sensitivity analysis on redefining the exposure windowa
Risk of adverse birth outcomes associated with oral retinoid exposure during pregnancy: sensitivity analysis on redefining the exposure based on the prescription date
Risk of neurodevelopmental disorder associated with oral retinoid exposure during pregnancy: sensitivity analysis on redefining the exposure based on the prescription date
Risk of adverse pregnancy outcomes associated with oral retinoid exposure during pregnancy: sensitivity analysis on redefining the exposure based on the prescription date
Temporal trends in the prevalence of retinoid exposure from 2017 to 2020 on a quarterly basis.
References
- 1.Futoryan T, Gilchrest BA. Retinoids and the skin. Nutr Rev. 1994;52(9):299–310. doi: 10.1111/j.1753-4887.1994.tb01461.x. [DOI] [PubMed] [Google Scholar]
- 2.Pang ML, Murase JE, Koo J. An updated review of acitretin--a systemic retinoid for the treatment of psoriasis. Expert Opin Drug Metab Toxicol. 2008;4(7):953–964. doi: 10.1517/17425255.4.7.953. [DOI] [PubMed] [Google Scholar]
- 3.Durán CE, Riera-Arnau J, Abtahi S, Pajouheshnia R, Hoxhaj V, Gamba M, et al. Impact of the 2018 revised Pregnancy Prevention Programme by the European Medicines Agency on the use of oral retinoids in females of childbearing age in Denmark, Italy, Netherlands, and Spain: an interrupted time series analysis. Front Pharmacol. 2023;14:1207976. doi: 10.3389/fphar.2023.1207976. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Reinold J, Kollhorst B, Wentzell N, Platzbecker K, Haug U. Use of isotretinoin among girls and women of childbearing age and occurrence of isotretinoin-exposed pregnancies in Germany: a population-based study. PLoS Med. 2024;21(1):e1004339. doi: 10.1371/journal.pmed.1004339. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Lammer EJ, Chen DT, Hoar RM, Agnish ND, Benke PJ, Braun JT, et al. Retinoic acid embryopathy. N Engl J Med. 1985;313(14):837–841. doi: 10.1056/NEJM198510033131401. [DOI] [PubMed] [Google Scholar]
- 6.Melnik BC. Apoptosis may explain the pharmacological mode of action and adverse effects of isotretinoin, including teratogenicity. Acta Derm Venereol. 2017;97(2):173–181. doi: 10.2340/00015555-2535. [DOI] [PubMed] [Google Scholar]
- 7.European Medicines Agency. Retinoid-containing medicinal products. [Updated 2018]. [Accessed November 7, 2023]. https://www.ema.europa.eu/en/medicines/human/referrals/retinoid-containing-medicinal-products .
- 8.iPLEDGE. Committed to pregnancy prevention. [Accessed November 7, 2023]. https://ipledgeprogram.com/#Main .
- 9.SORIATANE® (Acitretin) Capsules. [Updated 2024]. [Accessed April 25, 2024]. http://www.soriatane.com .
- 10.RetiCheck. Retinoid medication pregnancy prevention program. [Updated 2023]. [Accessed November 7, 2023]. http://reticheck.com/bbs/content.php?co_id=a01 .
- 11.Choi EJ, Han JY. Non-compliance with pregnancy prevention recommendations for isotretinoin in Korea between 2019–2020. Obstet Gynecol Sci. 2021;64(2):201–208. doi: 10.5468/ogs.20247. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Kamm JJ. Toxicology, carcinogenicity, and teratogenicity of some orally administered retinoids. J Am Acad Dermatol. 1982;6(4):652–659. doi: 10.1016/s0190-9622(82)70054-4. [DOI] [PubMed] [Google Scholar]
- 13.Kochhar DM, Penner JD, Tellone CI. Comparative teratogenic activities of two retinoids: effects on palate and limb development. Teratog Carcinog Mutagen. 1984;4(4):377–387. doi: 10.1002/tcm.1770040407. [DOI] [PubMed] [Google Scholar]
- 14.Cheetham TC, Wagner RA, Chiu G, Day JM, Yoshinaga MA, Wong L. A risk management program aimed at preventing fetal exposure to isotretinoin: retrospective cohort study. J Am Acad Dermatol. 2006;55(3):442–448. doi: 10.1016/j.jaad.2006.05.018. [DOI] [PubMed] [Google Scholar]
- 15.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. doi: 10.1111/j.1365-2125.2006.02837.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Barbero P, Lotersztein V, Bronberg R, Perez M, Alba L. Acitretin embryopathy: a case report. Birth Defects Res A Clin Mol Teratol. 2004;70(10):831–833. doi: 10.1002/bdra.20078. [DOI] [PubMed] [Google Scholar]
- 17.Zomerdijk IM, Ruiter R, Houweling LM, Herings RM, Sturkenboom MC, Straus SM, et al. Isotretinoin exposure during pregnancy: a population-based study in The Netherlands. BMJ Open. 2014;4(11):e005602. doi: 10.1136/bmjopen-2014-005602. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.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. 2010;281(2):221–227. doi: 10.1007/s00404-009-1112-2. [DOI] [PubMed] [Google Scholar]
- 19.Cha EH, Kim N, Kwak HS, Han HJ, Joo SH, Choi JS, et al. Pregnancy and neonatal outcomes after periconceptional exposure to isotretinoin in Koreans. Obstet Gynecol Sci. 2022;65(2):166–175. doi: 10.5468/ogs.21354. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Recommendations for isotretinoin use in women of childbearing potential. Teratology. 1991;44(1):1–6. doi: 10.1002/tera.1420440102. [DOI] [PubMed] [Google Scholar]
- 21.Choi EJ, Kim N, Kwak HS, Han HJ, Chun KC, Kim YA, et al. The rates of major malformations after gestational exposure to isotretinoin: a systematic review and meta-analysis. Obstet Gynecol Sci. 2021;64(4):364–373. doi: 10.5468/ogs.20373. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Han JY, Nava-Ocampo AA, Koren G. Unintended pregnancies and exposure to potential human teratogens. Birth Defects Res A Clin Mol Teratol. 2005;73(4):245–248. doi: 10.1002/bdra.20132. [DOI] [PubMed] [Google Scholar]
- 23.Yook JH, Han JY, Choi JS, Ahn HK, Lee SW, Kim MY, et al. Pregnancy outcomes and factors associated with voluntary pregnancy termination in women who had been treated for acne with isotretinoin. Clin Toxicol (Phila) 2012;50(10):896–901. doi: 10.3109/15563650.2012.739287. [DOI] [PubMed] [Google Scholar]
- 24.Mitchell AA, Van Bennekom CM, Louik C. A pregnancy-prevention program in women of childbearing age receiving isotretinoin. N Engl J Med. 1995;333(2):101–106. doi: 10.1056/NEJM199507133330206. [DOI] [PubMed] [Google Scholar]
- 25.Cheol Seong S, Kim YY, Khang YH, Heon Park J, Kang HJ, Lee H, et al. Data Resource Profile: The National Health Information Database of the National Health Insurance Service in South Korea. Int J Epidemiol. 2017;46(3):799–800. doi: 10.1093/ije/dyw253. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Choi A, Noh Y, Jeong HE, Choi EY, Man KK, Han JY, et al. Association between proton pump inhibitor use during early pregnancy and risk of congenital malformations. JAMA Netw Open. 2023;6(1):e2250366. doi: 10.1001/jamanetworkopen.2022.50366. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Choi EY, Jeong HE, Noh Y, Choi A, Yon DK, Han JY, et al. Neonatal and maternal adverse outcomes and exposure to nonsteroidal anti-inflammatory drugs during early pregnancy in South Korea: a nationwide cohort study. PLoS Med. 2023;20(2):e1004183. doi: 10.1371/journal.pmed.1004183. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Noh Y, Jeong HE, Choi A, Choi EY, Pasternak B, Nordeng H, et al. Prenatal and infant exposure to acid-suppressive medications and risk of allergic diseases in children. JAMA Pediatr. 2023;177(3):267–277. doi: 10.1001/jamapediatrics.2022.5193. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Nulman I, Berkovitch M, Klein J, Pastuszak A, Lester RS, Shear N, et al. Steady-state pharmacokinetics of isotretinoin and its 4-oxo metabolite: implications for fetal safety. J Clin Pharmacol. 1998;38(10):926–930. doi: 10.1002/j.1552-4604.1998.tb04388.x. [DOI] [PubMed] [Google Scholar]
- 30.Margulis AV, Setoguchi S, Mittleman MA, Glynn RJ, Dormuth CR, Hernández-Díaz S. Algorithms to estimate the beginning of pregnancy in administrative databases. Pharmacoepidemiol Drug Saf. 2013;22(1):16–24. doi: 10.1002/pds.3284. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.European Commission. EUROCAT: European network of population-based registries for the epidemiological surveillance of congenital anomalies. [Updated 2023]. [Accessed November 7, 2023]. https://eu-rd-platform.jrc.ec.europa.eu/eurocat/data-collection/guidelines-for-data-registration_en .
- 32.Pedersen CB, Mors O, Bertelsen A, Waltoft BL, Agerbo E, McGrath JJ, et al. A comprehensive nationwide study of the incidence rate and lifetime risk for treated mental disorders. JAMA Psychiatry. 2014;71(5):573–581. doi: 10.1001/jamapsychiatry.2014.16. [DOI] [PubMed] [Google Scholar]
- 33.Li L, Greene T. A weighting analogue to pair matching in propensity score analysis. Int J Biostat. 2013;9(2):215–234. doi: 10.1515/ijb-2012-0030. [DOI] [PubMed] [Google Scholar]
- 34.Yoshida K, Hernández-Díaz S, Solomon DH, Jackson JW, Gagne JJ, Glynn RJ, et al. Matching weights to simultaneously compare three treatment groups: comparison to three-way matching. Epidemiology. 2017;28(3):387–395. doi: 10.1097/EDE.0000000000000627. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Rönmark EP, Ekerljung L, Lötvall J, Wennergren G, Rönmark E, Torén K, et al. Eczema among adults: prevalence, risk factors and relation to airway diseases. Results from a large-scale population survey in Sweden. Br J Dermatol. 2012;166(6):1301–1308. doi: 10.1111/j.1365-2133.2012.10904.x. [DOI] [PubMed] [Google Scholar]
- 36.Fernández-Armenteros JM, Gómez-Arbonés X, Buti-Solé M, Betriu-Bars A, Sanmartin-Novell V, Ortega-Bravo M, et al. Epidemiology of psoriasis. a population-based study. Actas Dermosifiliogr (Engl Ed) 2019;110(5):385–392. doi: 10.1016/j.ad.2018.10.015. [DOI] [PubMed] [Google Scholar]
- 37.Collier CN, Harper JC, Cafardi JA, Cantrell WC, Wang W, Foster KW, et al. The prevalence of acne in adults 20 years and older. J Am Acad Dermatol. 2008;58(1):56–59. doi: 10.1016/j.jaad.2007.06.045. [DOI] [PubMed] [Google Scholar]
- 38.MacArthur C, Hansen M, Baynam G, Bower C, Kelty E. Trends in prenatal diagnosis of congenital anomalies in Western Australia between 1980 and 2020: a population-based study. Paediatr Perinat Epidemiol. 2023;37(7):596–606. doi: 10.1111/ppe.12983. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Ministry of Food and Drug Safety. Implementing a pregnancy prevention program for retinoid medications. [Updated 2019]. [Accessed May 8, 2024]. https://www.mfds.go.kr/brd/99/down.do?brd_id=ntc0021&seq=43375&data_tp=A&file_seq=2 .
- 40.Janesick A, Wu SC, Blumberg B. Retinoic acid signaling and neuronal differentiation. Cell Mol Life Sci. 2015;72(8):1559–1576. doi: 10.1007/s00018-014-1815-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Kubickova B, Martinkova S, Bohaciakova D, Nezvedova M, Liu R, Brozman O, et al. Effects of all-trans and 9-cis retinoic acid on differentiating human neural stem cells in vitro. Toxicology. 2023;487:153461. doi: 10.1016/j.tox.2023.153461. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Maden M. Retinoid signalling in the development of the central nervous system. Nat Rev Neurosci. 2002;3(11):843–853. doi: 10.1038/nrn963. [DOI] [PubMed] [Google Scholar]
- 43.Patraquim C, Silva A, Pereira Â, Gonçalves-Rocha M, Fernandes J, Pereira A. Isotretinoin embryopathy: report of one case. J Pediatr Neonatal Individ Med. 2015;5(1):e050108 [Google Scholar]
- 44.Troncoso Sch M, Rojas H C, Bravo C E. Isotretinoin embryopathy. Report of one case. Rev Med Chil. 2008;136(6):763–766. [PubMed] [Google Scholar]
- 45.Schmitt-Hoffmann AH, Roos B, Sauer J, Spickermann J, Stoeckel K, Edwards D, et al. Pharmacokinetics, efficacy and safety of alitretinoin in moderate or severe chronic hand eczema. Clin Exp Dermatol. 2011;36(Suppl 2):29–34. doi: 10.1111/j.1365-2230.2011.04035.x. [DOI] [PubMed] [Google Scholar]
- 46.Carretero G, Ribera M, Belinchón I, Carrascosa JM, Puig L, Ferrandiz C, et al. Guidelines for the use of acitretin in psoriasis. Actas Dermosifiliogr. 2013;104(7):598–616. doi: 10.1016/j.adengl.2013.01.001. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Codes and assessment period of the exposure, outcomes, and baseline characteristics
The number and the prevalence of oral retinoid exposure before and during pregnancya
Risk of adverse birth outcomes associated with isotretinoin exposure during pregnancy
Risk of neurodevelopmental associated with isotretinoin exposure during pregnancy
Risk of adverse pregnancy outcomes associated with isotretinoin exposure during pregnancy
Risk of adverse birth outcomes associated with oral retinoid exposure during pregnancy: sensitivity analysis on redefining the exposure windowa
Risk of neurodevelopmental disorder associated with oral retinoid exposure during pregnancy: sensitivity analysis on redefining the exposure windowa
Risk of adverse pregnancy outcomes associated with oral retinoid exposure during pregnancy: sensitivity analysis on redefining the exposure windowa
Risk of adverse birth outcomes associated with oral retinoid exposure during pregnancy: sensitivity analysis on redefining the exposure based on the prescription date
Risk of neurodevelopmental disorder associated with oral retinoid exposure during pregnancy: sensitivity analysis on redefining the exposure based on the prescription date
Risk of adverse pregnancy outcomes associated with oral retinoid exposure during pregnancy: sensitivity analysis on redefining the exposure based on the prescription date
Temporal trends in the prevalence of retinoid exposure from 2017 to 2020 on a quarterly basis.