Thalidomide leads to mandible hypoplasia through inhibiting angiogenesis and secondary hemorrhage in the fetal craniofacial region in rabbits.

The effect of thalidomide on mandibular development is unclear. In this study, thalidomide was delivered to pregnant rabbits from the 8th to 14th day of gestation. Then, embryos were harvested for examination on the 16th day (GD16), 20th day (GD20) and 24th day (GD24) of gestation. The results showed obvious hemorrhage and hematoma on one side of the craniofacial region in 50 % of the thalidomide-treated embryos and obvious hemorrhage and hematoma on both sides of the craniofacial region in 50 % of the thalidomide-treated embryos at GD16. Histological examination showed soft tissues and mandible defects on the affected side of the maxillofacial region. The expression of Vegf-α, Ki67 and Sox9 on the affected side was significantly down-regulated in comparison to their expression on the unaffected side at GD20. There was also an obvious defect in the affected mandible, and the density of the skull and mandible was decreased compared to the unaffected side or the control group at GD24. These findings demonstrated that thalidomide may lead to hemorrhage and hematoma in the craniofacial region by inhibiting angiogenesis, resulting in the abnormal development of cranial neural crest cells that are involved in the normal development of the mandible in rabbits.

Bilateral oblique facial clefts and extremity anomaly in an infant after intrauterine efavirenz exposure and review of its teratogenic risk.

OBJECTIVE: Congenital anomalies may be caused by genetic or environmental factors or a combination of both. Oblique facial clefts are very rare congenital deformities. The occurrence of facial clefts and an extremity anomaly suggests a common underlying cause. Lateral oro-ocular clefts do not occur along normal developmental planes and may be part of the amnion disruption complex sequence. Our objective was to report a case of this very event, which also followed an unusual intrauterine exposure and review the literature on the teratogenic risk of efavirenz. STUDY DESIGN: We report a case of amniotic rupture sequence after fetal HIV and antiretroviral exposure. RESULT: Teratogenic exposure has been rarely reported and never after antiretroviral exposure. CONCLUSION: By reporting and registering more cases, we will be able to better assess the risks such medications pose to the developing fetus. The publication of a single case report has the potential to contribute to our knowledge of the significance of prenatal exposure to antiretrovirals and other medications for common HIV-associated disorders. It also generates a hypothesis that can be tested with further clinical data, animal models and epidemiologic studies.

Síndrome de Moebius: ¿misoprostol como teratógeno? / Möbius syndrome: misoprostol as a teratogenic?

El síndrome de Moebius (SM) es una alteración congénita poco frecuente, caracterizada por la parálisis del nervio facial y del motor ocular externo, asociada a otras malformaciones craneofaciales y musculoesqueléticas. Su etiología no está clara, aunque en su aparición se asocian algunos agentes teratógenos, como el misoprostol. El mecanismo etiopatogénico se explicaría por la disrupción vascular secundaria al efecto vasoconstrictor del fármaco, en el territorio troncoencefálico. A continuación se describe el caso de un recién nacido afectado de SM, cuya madre usó misoprostol con fines abortivos durante el primer trimestre de la gestación. En los últimos años se ha documentado un número cada vez mayor de casos de SM asociados a esta práctica (AU)

The Möbius syndrome (Moebius syndrome) is an infrequent congenital disorder characterized by facial and abducens nerve palsy as well as the external ocular motor palsy. It is associated with other craniofacial and orthopedic anomalies. Its etiology is still unclear, although in its appearance teratogenics agents such as misoprostol have been related. Misoprostol’s etiopathogenic mechanism would be explained due to a secondary vascular disruption due to the vasoconstrictor effect of the medication, in the level of the area of the brain stem. Here we report a newborn with the Möbius syndrome whose mother had used misoprostol as an abortive during the first trimester of pregnancy. There has been a large number of Möbius syndrome associated with the use of misoprostol due to abortion attempt during the last years (AU)

Unilateral radius aplasia due to lamotrigine and oxcarbazepine use in pregnancy.

Lamotrigine (LTG) has been used in epilepsia patients for treatment of partial seizures. It can cross the placenta and there are limited data about its use in pregnancy and foetal adverse effects. Extremity and cardiac malformations, dysmorphic facial appearance, coanal atresia and upper respiratory and gastrointestinal anomalies have been reported because of LTG use in pregnancy. Oxcarbazepine (OXC) is one of the new antiepileptic agents. Although the drug and its metabolites can easily pass from placenta to the foetus, available data suggest that it can be safely used during pregnancy because no teratogenicity has been reported. One infant with atrial septal defect and patent ductus arteriosus due to use of LTG and OXC in pregnancy has been reported in literature. Here, we report a female infant with micrognatia, low-set ears, facial dysmorphism and unilateral radius aplasia born to a mother who used LTG 100 mg/day and OXC 1200 mg/day during pregnancy for seizures. To our knowledge, this is the first major anomaly case associated with the combined use of these drugs. This case can provide useful data about the teratogenicity of LTG and OXC combination therapy.

High-dose retinoic acid modulates rat calvarial osteoblast biology.

Retinoic acid has been shown to adversely affect craniofacial development. Cleft palate and craniosynostosis are two examples of craniofacial defects associated with prenatal exposure to this agent. Although the effects of retinoic acid on cephalic neural crest-derived tissues have previously been studied, the specific effects of retinoic acid on the cellular biology of osteoblasts remain unclear. The purpose of this study was to analyze in detail the effects of pharmacologic doses of retinoic acid on the differentiation and proliferation of osteoblasts derived from an intramembranous source. Primary rat calvarial osteoblasts were established in culture and treated with 1 or 10 microM all-trans-retinoic acid. Retinoic acid treatment markedly increased expression of osteopontin up to 48 h after stimulation. Consistent with this early stage of differentiation, both mRNA and protein analysis of FGF receptor isoforms demonstrated a switch in predominance from fibroblast growth factor receptor 2 (fgfr2) to fgfr1. Analysis of PCNA protein confirmed inhibition of proliferation by retinoic acid. To determine whether these alterations in osteoblast biology would lead to increased differentiation, we examined short term [alkaline phosphatase (AP) activity] and long term (von Kossa staining) surrogates of bone formation in vitro. These assays confirmed that retinoic acid increased osteogenesis, with a 4-fold increase in bone nodule formation in cells treated with 10 microM retinoic acid after 28 days. Overall, our results demonstrated that pharmacologic doses of all-trans-retinoic acid decreased osteoblast proliferation and increased differentiation, suggesting that retinoic acid may effect craniofacial development by pathologically enhancing osteogenesis.