Isotretinoin is an active substance used in the treatment of acne. It is a retinoid, meaning a derivative of vitamin A. It is generally reserved for the treatment of severe acne that is resistant to antibiotics combined with topical treatments [1]. Since a series of 21 malformations published by Lammer et al., the teratogenic risk associated with isotretinoin has been well established [2]. Administered during the periconceptional period, isotretinoin can cause severe birth defects. The malformations observed in cases of exposure to retinoic acid include, among others, abnormalities of the ear, central nervous system, thymus, and heart. Additionally, miscarriages have been reported. In the absence of structural organ abnormalities, 30–60% of neurodevelopmental disorders have been reported [3]. Isotretinoin appears to have a tropism for neural crest cells, leading to abnormalities of central nervous system, heart, and thymus [2].

Thus, effective contraception in women of childbearing age has been recommended when initiating isotretinoin. Since then, only rare sporadic cases have been reported.

All previously described malformations have been reported postnatally. In this article, we describe prenatal ultrasound images of isotretinoin embryofetopathy, with a particular form of cardiac involvement. The fetus presented with severe malformations of the central nervous system and a particular form of conotruncal heart disease that has not yet been described.

This study took place in a tertiary maternity unit of Dalal Jamm Hospital, in Dakar, Senegal in 2023.

The patient was a 29-year-old primigravida. She presented in our tertiary unit for morphological ultrasound at 22 weeks. She had no surgical history. She was being treated for acne in the dermatology department with Roaccutane (isotretinoin) at 20 mg daily. She was taking contraception based on estrogen-progestin pills. Amenorrhea occurred after she delayed taking her pills for eight days. There was no consanguinity in the couple or history of genetic abnormalities.

The patient was referred at 22 weeks of gestation for special morphological ultrasound due to first-trimester retinoid exposure.

Clinical examination was normal, with blood pressure at 115/70 mmHg, and the uterine height measured 21 cm.

Ultrasound revealed a eutrophic fetus with an estimated fetal weight in the 48th percentile. At the cephalic pole, we observed a complete agenesis of the cerebellar vermis (Figure 1) without other associated brain abnormalities. The ear pavilion was anteverted, detached, and bulging (Figure 2).

In the thorax, there was a situs solitus with normal cardiac orientation. Morphological assessment of the heart revealed an overriding aorta with a ventricular septal defect (VSD) and dilated right ventricle (Figure 3) and moderate pulmonary trunk dilation (Figure 4). Thymus aplasia was also observed. Other organs appeared normal.

Thus, the anomalies observed were consistent with those described in retinoid fetopathies:

• Morphological ear abnormalities;

• Complete agenesis of the median vermis; and

• A conotruncal heart defect characterized by pulmonary valve agenesis.

Termination of pregnancy was not proposed as, according to local law, it is prohibited in cases of fetal abnormalities. Regular follow-up was conducted. At 36 weeks of gestation, the patient delivered spontaneously at a level II healthcare facility. The parents opted out of further medical care. The mother informed our team of the death of newborn on day 7.

The teratogenic effects of retinoic acid are well documented [1],[4]. The risk of embryofetopathy ranges from approximately 14–35% [4],[5] following isotretinoin exposure during the first trimester, with daily doses between 0.5 and 1.5 mg/kg [2],[5]. Studies suggest also spontaneous abortion in approximately 7% of exposures [1],[6]. The largest series was published in 1985, involving 154 women exposed to isotretinoin and 21 malformed children described postnatally [2]. So, it is well known that isotretinoin exposure during pregnancy induces birth defect, spontaneous abortion, or neurodevelopmental delay [2],[7],[8]. Despite all reported cases, a substantial proportion of pregnant women are exposed to isotretinoin. Autret-Leca et al. reported, between 2003 and 2006, 147 cases of isotretinoin exposure during the teratogenic risk period [9]. Teratogenic period risk is defined as one month before conception and during pregnancy [9]. Prevention is recommended, including pregnancy testing before prescription and effective contraceptive method for women of childbearing age. As our case has highlighted, the cases currently reported are rather due to non-compliance with contraceptive recommendations or forgetfulness [9].

Case reports have documented the postnatal spectrum of isotretinoin-related malformations. Malformations of the central nervous system, cephalic pole, and heart defect have been reported. Table 1 summarizes the types of malformations by affected organ and their prevalence (Table 1) [1],[2],[4],[5].

Posterior fossa cava malformations are most commons central nervous system abnormalities in isotretinoin fetopathy. Cerebellar vermis agenesia or hypoplasia and cerebellar hypoplasia are reported in 41.7% of isotretinoin fetopathy [1],[2],[4],[5]. In the present case a cerebellar vermis agenesia was noted. Moreover, hydrocephalus is reported in 37.5% cases.

Anotia or microtia are characteristics of isotretinoin fetopathy. These anomalies are described in 70.8% of cases. Also, stenosis of the external auditory canal is described in more than half of the cases (54.8%) [1],[2],[4],[5]. We described another form of anomaly of the ear pavilion, a normal size but abnormal shaped of ears.

This allows us to conclude that ear anomalies can take different forms in isotretinoin fetopathy. It is therefore necessary to look for exposure when ear abnormalities are detected on antenatal ultrasound.

In more than half of the cases described (58.4%), conotruncal heart defect or transposition of the great vessels was noted. Conotruncal heart disease included tetralogy of Fallot, double outlet right ventricle, ventricular septal defect, truncus arteriosus, aortic arch interrupted, and open septum pulmonary atresia [1],[2],[4],[5].

Furthermore, we describe a previously unreported form of conotruncal heart defect related to isotretinoin exposure: pulmonary valve agenesis. This is the only conotruncal heart defect not yet described in isotretinoin fetopathy.

Therefore, in any case of conotruncal heart defect associated with craniofacial and brain anomalies, isotretinoin exposure during the first trimester or pre-conception months should be considered.

Intake of 13-cis-RA (isotretinoin or Accutane) during pregnancy leads to teratogenic effects. The threshold dose that causes teratogenicity is unknown. But it is well recognized that abnormal migration of cranial-neural crest cells or a defect in early axial patterning cause many defects [10].

Therefore, effective contraception must be prescribed taking into account the risk of forgetting pills.

This article is the first to describe the prenatal ultrasound findings of isotretinoin fetopathy. It also reports new variants of previously described abnormalities, particularly involving the ears and heart. The association of a conotruncal heart defect with craniofacial and brain anomalies should prompt investigation of isotretinoin exposure during the periconceptional period.

Contraceptive measures should be rigorously monitored, with effective communication regarding the risks of severe embryofetopathy.