Department of Medical Genetics, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul, Turkey.
Department of Medical Genetics, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul, Turkey.
Eur J Obstet Gynecol Reprod Biol. 2023 Dec;291:148-155. doi: 10.1016/j.ejogrb.2023.10.024. Epub 2023 Oct 18.
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.
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.
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.
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.
致畸剂是所有已知先天性畸形原因的 5%。根据 2006 年之前进行的研究，异维 A 酸（一种维 A 酸衍生药物）在妊娠期间暴露时，导致先天性畸形的比例为 21-52%。然而，后来的研究中先天性畸形的比例要低得多。本研究的目的是调查怀孕期间、怀孕前和未接触任何致畸剂的对照组中异维 A 酸暴露导致先天性畸形的发生率。
在这项队列研究中，我们将 2009 年至 2020 年间我院收治的孕妇分为两组：怀孕期间和怀孕前异维 A 酸暴露（n=77）和怀孕前异维 A 酸暴露（n=75）。我们通过简单随机抽样法从非致畸剂暴露的孕妇中选择对照组。产科医生通过超声（USG）（头臀径用于孕早期；双顶径和股骨长用于孕中期）计算所有妊娠的年龄。分娩后，儿科遗传专家检查所有婴儿。对表现出复杂表型的婴儿进行全外显子组测序（WES）。
在怀孕期间和怀孕前、怀孕前异维 A 酸暴露和对照组中，活产（分别为 64.3%、88%、93.3%）、先天性畸形（分别为 28.6%、6.1%、1.4%）、流产（分别为 13%、2.7%、4%）、终止妊娠（分别为 32.5%、9.3%、2.7%）和早产（11.9%、16.7%、2.9%）（分别为 p<0.001、p<0.001、p=0.014、p<0.001）存在统计学差异。我们在五名患者中发现了新的表型特征。
我们的研究表明，研究设计、长期随访、致畸咨询以及对具有新表型特征的复杂表型实施先进的分子分析，有助于了解异维 A 酸暴露与先天性畸形之间的关系。在评估先天性畸形时，我们发现怀孕期间和怀孕前异维 A 酸暴露与对照组之间存在统计学显著差异，但怀孕前异维 A 酸暴露与对照组之间未发现统计学显著差异。该研究的另一个发现是，WES 可能是评估异维 A 酸暴露婴儿复杂表型的有效方法；然而，还需要进一步研究。
