A new perspective on isotretinoin in pregnancy: Pregnancy outcomes, evaluation of complex phenotypes, and importance of teratological counselling

Objectives Teratogens are responsible for 5% of all known causes of congenital anomalies. Isotretinoin, a retinoic acid–derived agent, leads to congenital anomalies in 21-52% of cases when exposure occurs during pregnancy according to studies conducted before 2006. However, rates of congenital anomalies were much lower in later studies. The purpose of this study was to investigate the rates of congenital anomalies in isotretinoin exposure during pregnancy, isotretinoin exposure before pregnancy, and a control group unexposed to any teratogenic agents. Study Design In this cohort study, we divided pregnant women admitted to our center between 2009 and 2020 into two groups: isotretinoin exposure before and during the pregnancy (n=77) and isotretinoin exposure before the pregnancy (n=75). We selected the control group from among the non-teratogen exposed pregnant women with a simple random sampling method. Obstetricians calculated the ages of all pregnancies via ultrasound (USG) (crown-rump diameter for the first trimester; biparietal diameter and femur length for the second trimester). After birth, a pediatric genetics specialist examined all babies. Whole-exome sequencing (WES) was conducted on the babies who displayed complex phenotypes. Results Among the isotretinoin exposure before and during the pregnancy, isotretinoin exposure before the pregnancy, and the control groups, there were statistically significant differences in live births (respectively, 64.3%, 88%, 93.3%), congenital anomalies (respectively, 28.6%, 6.1%, 1.4%), miscarriages (respectively, 13%, 2.7%, 4%), terminations (respectively, 32.5%, 9.3%, 2.7%), and premature births (11.9%, 16.7%, 2.9%) (respectively, p<0.001, p<0.001, p=0.014, p<0.001). We detected novel phenotypical features in five patients. Conclusions Our study demonstrated that study design, long-term follow-up, teratological counseling, and implementation of advanced molecular analysis in complex phenotypes with novel phenotypical features are beneficial for understanding the association of congenital anomalies with isotretinoin exposure. While evaluating congenital anomalies, we detected statistically significant differences between isotretinoin exposure before and during the pregnancy vs control, but we did not detect any statistically significant differences between isotretinoin exposure before the pregnancy and controls. Another finding of the study is that WES might be an efficient way to evaluate complex phenotypes in isotretinoin-exposed babies; however, further research is required.