Thalidomide and neurotrophism.

BACKGROUND: Following the thalidomide disaster (1958-62), Henkel and Willert analysed the pattern of dysmelia in the long bones (J Bone Joint Surg Br. 51:399-414, 1969) and the extremities, Willert and Henkel (Z Orthop Ihre Grenzgeb. 107:663-75, 1970). Willert's material from deformed extremities is re-examined here asking "How does thalidomide reduce the skeleton?" MATERIALS AND METHODS: We reviewed the original data collection of Willert and Henkel (Z Orthop Ihre Grenzgeb. 107:663-75, 1970), comprising musculoskeletal histology slides from 30 children affected by thalidomide with radiographs of hands (19 cases) and feet (4 cases). RESULTS: All original observations by Willert and Henkel (Z Orthop Ihre Grenzgeb. 107:663-75, 1970), were verified. Radial rays of the hand disappeared early, but the foot was spared until late. Radiology confirms that bone reduction in the hand (aplasia or hypoplasia in the thumb and index finger) coincides with sensory segmental nerve C6. In the foot, reduction of the toes is rare, but mesenchymal excess (polydactyly) occurs in the hallux (L5 sclerotome), usually associated with absent tibia (L4 sclerotome). Histology confirms skeletal mesenchymal components to be unremarkable, contrasting with grossly abnormal bony architecture, a striking discordance between microscopic and macroscopic findings. No necrosis or vascular pathology was seen. CONCLUSION: The basic lesion was an abnormal quantity rather than quality of mesenchyme. Cell populations result from cellular proliferation, controlled in early limb bud formation by neurotrophism. Thalidomide is a known sensory neurotoxin in adults. In the embryo, sensorineural injury alters neurotrophism, causing increased or diminished cell proliferation in undifferentiated mesenchyme. Differentiation into normal cartilage occurs later, but within an altered mesenchymal mass. Reduction or excess deformity results, with normal histology, a significant finding. The primary pathological condition is not in the skeleton, but in the nerves.

Antenatal Diagnosis of Fetal Retinoid Syndrome at 20 Weeks of Gestation: A Case Report.

INTRODUCTION: Isotretinoin, a synthetic derivative of vitamin A, is one of the most potent human teratogens, and is mainly utilized for the treatment of severe recalcitrant nodular acne. Retinoic acid embryopathy is well defined in the literature. CASE REPORT: The mother was referred for a fetal posterior fossa abnormality, first detected at 20 weeks of gestation. The mother used isotretinoin until 18 weeks gestation. Ultrasound examination revealed hypertelorism, cerebellar hypoplasia, vermian agenesis, truncus arteriosus, anotia, thymic aplasia, corpus callosum hypoplasia. An intrauterine diagnosis of fetal retinoid syndrome was confirmed by fetopsy after termination of pregnancy. CONCLUSION: The typical findings of fetal retinoid syndrome can be visualized with ultrasound in early second trimester.

The effects of microduplication 1q21.1 and in-utero isotretinoin exposure.

The impact of in-utero isotretinoin exposure has been widely reported, with many affected pregnancies failing to reach term.1 2 Due to the low numbers of in-utero isotretinoin exposed pregnancies, the interactions between this drug and rare genetic defects such as microduplication 1q21.1 are unclear, particularly how they might manifest phenotypically. We present this case of in-utero isotretinoin exposure occurring in a child with microduplication 1q21.1. The child was born with congenital abnormalities which did not fit into a single syndrome. Regrettably in-utero exposure to isotretinoin continues to occur. We hope this case will trigger further discussion on the dangers of dispensing Isotretinoin without ensuring stringent pregnancy testing and its potential interaction with genetic abnormalities, in particular with microduplication 1q21.1.

Complex Anatomic Abnormalities of the Lower Leg Muscles and Tendons Associated With Phocomelia: A Case Report.

Musculoskeletal anatomy is widely known to have components that stray from the norm in the form of variant muscle and tendon presence, absence, origin, insertion, and bifurcation. Although these variant muscles and tendons might be deemed incidental and insignificant findings by most, they can be important contributors to pathologic physiology or, more importantly, an option for effective treatment. In the present case report, we describe a patient with phocomelia and Müllerian abnormalities secondary to in utero thalidomide exposure. The patient had experienced recurrent bilateral foot pain accompanied by numbness, stiffness, swelling, and longstanding pes planus. These symptoms persisted despite conservative treatment with orthotics, steroids, and nonsteroidal anti-inflammatory drugs. Radiographic imaging showed dysmorphic and degenerative changes of the ankle and foot joints. Further investigation with magnetic resonance imaging revealed complex anatomic abnormalities, including the absence of the posterior tibialis and peroneus brevis, lateralization of the peroneus longus, and the presence of a variant anterior compartment muscle. The variant structure was likely a previously described anterior compartment variant, anterior fibulocalcaneus, and might have been a source of the recurrent pain. Also, the absence of the posterior tibialis might have caused the pes planus in the present patient, considering that posterior tibialis tendon dysfunction is the most common cause of acquired pes planus. Although thalidomide infrequently affects the lower extremities, its effects on growth and development were likely the cause of this rare array of anatomic abnormalities and resulting ankle and foot pathologic features.

Prenatal sonographic diagnosis of fetal valproate syndrome: a case report.

BACKGROUND: Prenatal exposure of mother to valproate (VPA) causes teratogenic effects in the fetus, namely fetal valproate syndrome (FVS). We report a case of fetal valproate syndrome rarely diagnosed by prenatal sonographic examination. CASE PRESENTATION: Our patient was a female infant who was born to a 27-year-old nulliparous Japanese woman with epilepsy. The mother was diagnosed with infantile epilepsy at 1 year of age and had been using three antiepileptic drugs, including valproate, but preconceptional counseling was not performed. At 25 weeks of gestation, contracture of the fetal right wrist joint suggestive of a radial ray defect was observed by transabdominal ultrasonography. The fetus demonstrated growth retardation starting from 32 weeks of gestation. In addition, saddle nose as a facial anomaly was detected by three-dimensional ultrasound at 37 weeks of gestation. Accordingly, we suspected that the fetus had fetal valproate syndrome. At 39 weeks of gestation, the mother delivered an infant weighing 2056 g. The neonate had characteristic features of fetal valproate syndrome, such as facial configuration, slight muscular hypotonia of the whole body, breathing problems, right-hand articular contracture accompanied by radial ray defect, and cardiovascular malformation. CONCLUSIONS: When obstetricians manage epileptic pregnant women without enough preconceptional counseling or adjustment for antiepileptic drugs, careful sonographic observation of the fetus is mandatory.

Sex-Specific Alterations of White Matter Developmental Trajectories in Infants With Prenatal Exposure to Methamphetamine and Tobacco.

IMPORTANCE: Methamphetamine is a common illicit drug used worldwide. Methamphetamine and/or tobacco use by pregnant women remains prevalent. However, little is known about the effect of comorbid methamphetamine and tobacco use on human fetal brain development. OBJECTIVE: To investigate whether microstructural brain abnormalities reported in children with prenatal methamphetamine and/or tobacco exposure are present at birth before childhood environmental influences. DESIGN, SETTING, AND PARTICIPANTS: A prospective, longitudinal study was conducted between September 17, 2008, and February 28, 2015, at an ambulatory academic medical center. A total of 752 infant-mother dyads were screened and 139 of 195 qualified neonates were evaluated (36 methamphetamine/tobacco exposed, 32 tobacco exposed, and 71 unexposed controls). They were recruited consecutively from the community. EXPOSURES: Prenatal methamphetamine and/or tobacco exposure. MAIN OUTCOMES AND MEASURES: Quantitative neurologic examination and diffusion tensor imaging performed 1 to 3 times through age 4 months; diffusivities and fractional anisotropy (FA) assessed in 7 white matter tracts and 4 subcortical brain regions using an automated atlas-based method. RESULTS: Of the 139 infants evaluated, 72 were female (51.8%); the mean (SE) postmenstrual age at baseline was 41.5 (0.27) weeks. Methamphetamine/tobacco-exposed infants showed delayed developmental trajectories on active muscle tone (group × age, P < .001) and total neurologic scores (group × age, P = .01) that normalized by ages 3 to 4 months. Only methamphetamine/tobacco-exposed boys had lower FA (group × age, P = .02) and higher diffusivities in superior (SCR) and posterior corona radiatae (PCR) (group × age × sex, P = .002; group × age × sex, P = .01) at baseline that normalized by age 3 months. Only methamphetamine/tobacco- and tobacco-exposed girls showed persistently lower FA in anterior corona radiata (ACR) (group, P = .04; group × age × sex, P = .01). Tobacco-exposed infants showed persistently lower axial diffusion in the thalamus and internal capsule across groups (P = .02). CONCLUSIONS AND RELEVANCE: Prenatal methamphetamine/tobacco exposure may lead to delays in motor development, with less coherent fibers and less myelination in SCR and PCR only in male infants, but these abnormalities may normalize by ages 3 to 4 months after cessation of stimulant exposure. In contrast, persistently less coherent ACR fibers were observed in methamphetamine/tobacco- and tobacco-exposed girls, possibly from increased dendritic branching or spine density due to epigenetic influences. Persistently lower diffusivity in the thalamus and internal capsule of all tobacco-exposed infants suggests aberrant axonal development. Collectively, prenatal methamphetamine and/or tobacco exposure may lead to delayed motor development and white matter maturation in sex- and regional-specific manners.

Micro-CT imaging: Developing criteria for examining fetal skeletons in regulatory developmental toxicology studies - A workshop report.

During the past two decades the use and refinements of imaging modalities have markedly increased making it possible to image embryos and fetuses used in pivotal nonclinical studies submitted to regulatory agencies. Implementing these technologies into the Good Laboratory Practice environment requires rigorous testing, validation, and documentation to ensure the reproducibility of data. A workshop on current practices and regulatory requirements was held with the goal of defining minimal criteria for the proper implementation of these technologies and subsequent submission to regulatory agencies. Micro-computed tomography (micro-CT) is especially well suited for high-throughput evaluations, and is gaining popularity to evaluate fetal skeletons to assess the potential developmental toxicity of test agents. This workshop was convened to help scientists in the developmental toxicology field understand and apply micro-CT technology to nonclinical toxicology studies and facilitate the regulatory acceptance of imaging data. Presentations and workshop discussions covered: (1) principles of micro-CT fetal imaging; (2) concordance of findings with conventional skeletal evaluations; and (3) regulatory requirements for validating the system. Establishing these requirements for micro-CT examination can provide a path forward for laboratories considering implementing this technology and provide regulatory agencies with a basis to consider the acceptability of data generated via this technology.

Human fetal malformations associated with the use of an angiotensin II receptor antagonist: case report.

INTRODUCTION: The potential risks related to drug exposure during pregnancy represent a vast chapter in modern obstetrics and data regarding the safety of antihypertensive drugs during pregnancy are relatively scarce. CASE REPORT: A 37-year-old patient discovered her fifth pregnancy at our hospital after 26 weeks and 4 days of gestation. She reported a history of hypertension and was currently being treated with Losartan. Hospitalization was recommended for the patient and further evaluation of fetal vitality was performed. On the fourth day an ultrasound was performed, resulting in a severe oligohydramnios, fetal centralization and abnormal ductus venosus. After 36 hours, the newborn died. Pathologic evaluation: At autopsy, the skullcap had large fontanels and deficient ossification. The kidneys were slightly enlarged. A microscopic examination detected underdevelopment of the tubules and the presence of some dilated lumens. Immunohistochemical detection of epithelial membrane antigen was positive. Immunoreactivity of CD 15 was also assayed to characterize the proximal tubules, and lumen collapse was observed in some regions. DISCUSSION: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor antagonists (ARAs) are among the most widely prescribed drugs for hypertension. They are often used by hypertensive women who are considering become pregnant. While their fetal toxicity in the second or third trimesters has been documented, their teratogenic effect during the first trimester has only recently been demonstrated. CONCLUSION: Constant awareness by physicians and patients should be encouraged, particularly in regard to the prescription of antihypertensive drugs in women of childbearing age who are or intend to become pregnant.

[Report of the French Comité national technique de l'échographie de dépistage prénatal (CNTEDP)--Recommendations for second line prenatal ultrasound]. / Rapport du Comité national technique de l'échographie de dépistage prénatal (CNTEDP): recommandations pour l'échographie de diagnostic.

OBJECTIVES: The committee has among its functions, to promote a quality assurance policy for obstetrics and foetal ultrasound scans by participating in the development of an information strategy for the professionals and the public on the interest and limits of these techniques, and in the development of rules for good practice. Thus, the committee produced in 2005 a good practice's recommendations report concerning the screening ultrasound scans. It pursued its work with a similar report concerning this time the "diagnostic" prenatal ultrasound or second line prenatal ultrasound. The present report has set its objective to define as precisely as possible the content of a "diagnostic" ultrasound scan and what should be expected from it. MATERIALS AND METHODS: A group of experts from the committee members has functioned as a task team that met on a regular basis. First, in the context of a professional consensus and a review of the literature, it determined the clinical goals in regard to the indication of the "diagnostic" ultrasound scan. After discussing different formats of the scan test procedure, some intuitive hypotheses on the content of the test were developed. Each criteria was validated by the group of experts with a statistics' definition and a diagnosis' capacity. The hypotheses were finally validated or discarded after confrontation with the data of the literature. Finally, the content of the report was discussed during the plenary sessions of the CNTEDP, the National Committee on the Technical aspect for PreNatal Ultrasound Screening. All the items validated in format document have been the subject of a consensus with a right to veto. The preliminary report was reviewed by a group of six readers not members of the CNTEPD. RESULTS: The "diagnostic" ultrasound scan test is organized in two parts: one common part made of the content of the screening test, to which is added the study of the anatomic structures and taking some additional pictures. The sonologist must then do a specific scan study for the organ suspected or diagnosed with an anomaly. Subsequently, a series of ten format documents per anomaly is proposed to guide the examiner (i.e., abdomen, chest, heart, genitourinary, cerebrospinal, skeletal and limbs, IUGR, polyhydramnios, infection, twin pregnancy). These documents suggest a check-list of items to study during the scan, specific pictures to take, and, give some comments on the management plan. DISCUSSION AND CONCLUSION: The CPDPN, the Multidisciplinary Committee for PreNatal Diagnosis, since it was established in 1994, has contributed to structure most of the activity of the prenatal diagnosis, but did not answer the question of the quality of the second line prenatal ultrasound. Screening ultrasound, and focused ultrasound scan are not "levels" in the scan procedure, but different and supplementary studies contributing to the quality of the mother and her foetus follow-up. This report of the CNTEDP, in defining the content of this scan test, clarifies the objectives of the diagnostic test compared to the screening test, and subsequently gives the public a better understanding of what is expected or due in regard to our prenatal screening strategy. A reliable second level scan, affordable and consistent, is a label of good quality for our prenatal strategy. The recommendations of the committee should be understood in a large perspective of quality assurance, that includes an initial and a continuous medical education, a quality control system for the echograph, and a procedure to inform the public.

Maternal use of cyclobenzaprine (Flexeril) may induce ductal closure and persistent pulmonary hypertension in neonates.

A full-term male infant presented shortly after birth with respiratory distress. An echocardiogram done within the first hour of life showed an elevated pulmonary artery pressure, an associated right ventricular hypertrophy without a patent ductus arteriosus. The patient was treated for persistent pulmonary hypertension with favorable response. Maternal history was unremarkable except for chronic low back pain treated with cyclobenzaprine (Flexeril®). A proposed mechanism for cyclobenzaprine includes inhibition of norepinephrine and serotonin reuptake, factors known to inhibit prostaglandin and nitric oxide. These two factors are the leading causes of in-utero ductal closure. This report is the first to indicate that cyclobenzaprine use during late pregnancy should be considered a potential cause of early ductal closure.

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.

Abortion failure after illegal use of misoprostol--a case report.

OBJECTIVE: To report on a unique medical situation after self-obtained use of misoprostol in a country where abortion is illegal. CASE: A 29-year-old woman was seen at 12 weeks' gestation with a history of use of 10,800 microg of misoprostol orally and vaginally over the preceding six weeks. She had experienced mild-to-moderate pelvic pain but no vaginal bleeding. Because the pregnancy was intrauterine and viable, surgical termination could not be carried out. The risks of fetal congenital anomalies due to in utero exposure to misoprostol were discussed with the patient. A detailed ultrasonography at 16 weeks' gestation revealed no anomaly. Vaginal delivery at 38 weeks' gestation resulted in the birth of a baby without discernible congenital anomalies. CONCLUSIONS: In countries where abortion is illegal, women should be informed about the risks associated with unsupervised self-induced abortion with misoprostol.

Birth defects following exposure to efavirenz-based antiretroviral therapy during pregnancy: a study at a regional South African hospital.

OBJECTIVES: To determine the prevalence and type of birth defects among infants following exposure to efavirenz-based antiretroviral therapy (EFV-based ART) during pregnancy. METHODS: A Pregnancy Registry was established to enable prospective follow-up of women taking EFV-based ART. In women who conceived on EFV-based ART, EFV was switched with another drug if they presented during the first trimester but was continued if they presented at or after 14 weeks' gestation. Pregnant women needing lifelong ART were commenced on EFV-based ART from 14 weeks' gestation onwards. Infants were followed up for 6 weeks after birth. RESULTS: Between January 2006 and December 2008, 623 ART-naive pregnant women initiated EFV-based ART in the second/third trimester and 195 women conceived on EFV-based ART. Birth defects were observed in 16 of 623 live births [2.6%; 95% confidence interval (CI) 1.5-4.2] and in six of 184 live births (3.3%; 95% CI 1.2-7.0) from women exposed to EFV in the second/third trimester and first trimester, respectively. The prevalence of birth defects was not significantly different between the first and second/third trimester EFV exposure (prevalence ratio 1.27; 95% CI 0.50-3.20; P = 0.301). CONCLUSION: No significant increase in the prevalence of birth defects following exposure to EFV-based ART in the first trimester was observed in this cohort. However, the limited number of first trimester EFV-exposed infants precludes definitive conclusions on the teratogenicity or safety of EFV.

History, heresy and radiology in scientific discovery.

Nowadays, most drugs reach the market after research has established their pharmacology, safety and efficacy. That was not always the case 50 years ago. Thalidomide was used before its target cell or mode of action were known. Commencing with the thalidomide catastrophe--an epidemic of gross birth defects (1958-1962)--thalidomide's origins are revisited to show how this drug came to be made and sold in the 1950s. Thalidomide intersected with Australian radiology in the 1970s. The site and mode of action of the drug was deduced from X-rays of thalidomide-induced bone defects, which have classical radiological signs of sensory neuropathic osteoarthropathy. The longitudinal reduction deformities follow the distribution of segmental sensory innervation of the limb skeleton, indicating neural crest as the target organ. Injury to one level of neural crest halts normal neurotrophism and deletes the dependent segment--a previously unrecognised embryonic mechanism that explains most non-genetic birth defects. The final common pathway is neural crest injury and failure of normal neurotrophism to result in longitudinal reduction deformities, for example, phocomelia.

Persistent fifth aortic arch in a patient with a history of intrauterine thalidomide exposure.

Persistence of the fifth aortic arch is a very rare congenital anomaly often associated with various other congenital cardiac and aortic abnormalities. It is important to be aware of this anomaly and not confuse it with other aortic pathology.

Congenital diaphragmatic hernia and microtia in a newborn with mycophenolate mofetil (MMF) exposure: phenocopy for Fryns syndrome or broad spectrum of teratogenic effects?

A newborn female infant born to a woman on immunosuppressive medications including mycophenolate mofetil (MMF) for a renal graft secondary to lupus nephritis presented with congenital diaphragmatic hernia (CDH) and additional findings of microtia, esophageal atresia with tracheoesophageal fistula, cleft palate, congenital heart defect, digital anomalies, and dysmorphic facial features. Pulmonary hypoplasia resulted in death at day 2 of life. She was presumed to have Fryns syndrome based on diagnostic criteria established for this recessive disorder with prominent features including CDH, facial anomalies, and nail hypoplasia. In retrospect, this infant's findings are more likely the result of teratogenic exposure to MMF, as more recent data have emerged linking aural atresia, digital anomalies, and dysmorphic features to this drug. To date, this is the only human report of CDH in an infant with prenatal exposure to MMF, although the manufacturer's package insert alludes to animal studies with a broad spectrum of malformations, including CDH. Thus, a teratogenic exposure can mimic a known Mendelian genetic syndrome, and caution is urged in presuming a genetic etiology for infants with potential teratogenic exposure to relatively new drugs with limited published animal data.

Can prenatal ultrasound detect the effects of in-utero alcohol exposure? A pilot study.

OBJECTIVES: The aim of this pilot study was to explore possible ultrasound parameters for the early detection of alcohol-mediated fetal somatic and central nervous system (CNS) maldevelopment. Maternal alcohol ingestion during pregnancy may lead to fetal alcohol spectrum disorders (FASD), which encompass a broad range of structural abnormalities including growth impairment, specific craniofacial features and CNS abnormalities. Early detection of fetuses at risk of FASD would support earlier interventions. METHODS: We performed a longitudinal prospective pilot study from 2004 to 2006 at two sites in Ukraine. A sample of pregnant women who reported consuming moderate-to-heavy amounts of alcohol participated in a comprehensive maternal interview, and received ultrasound evaluation of fetal growth and specific fetal brain measurements during the second and third trimesters. These measurements were compared with those collected from a group of pregnant women who consumed little-to-no alcohol during pregnancy, and who were recruited and followed in the same manner. RESULTS: From 6745 screened women, 84 moderate-to-heavy alcohol users and 82 comparison women were identified and ultrasound examinations performed. After controlling for maternal smoking, alcohol-exposed fetuses had shorter mean femur length, caval-calvarial distance and frontothalamic measurements in the second trimester (P < 0.05), and alcohol-exposed fetuses also had shorter frontothalamic distance measurements in the third trimester relative to comparison fetuses (P < 0.05). In addition, after controlling for maternal smoking, both mean orbital diameter and biparietal diameter measurements were significantly smaller on average in the alcohol-exposed group in the third trimester relative to comparison fetuses (P < 0.05). CONCLUSIONS: Significant differences in selected somatic and brain measurements were noted between alcohol-exposed and comparison fetuses, suggesting these markers may be further explored for clinical utility in prenatal identification of affected children. Further study correlating these findings with alcohol-related physical features of the newborn and subsequent comparisons of neuro-developmental outcomes will help define potential uses of prenatal ultrasound for intervention and prevention of FASD.