ABSTRACT Environmental causes of birth defects have increasingly been recognized since the mid-20th century. The teratogenic effects of maternal infections such as rubella and therapeutic drugs such as thalidomide were first reported by alert clinicians. Among clinicians and researchers who have contributed significantly to our knowledge of these environmental causes, Norman Gregg was a Sydney ophthalmologist whose seminal study in 1941 identified maternal rubella as a cause of birth defects. The teratogenic effects of thalidomide were first noted in 1961 by William McBride, a Sydney obstetrician, and independently confirmed by Widukind Lenz, a German pediatrician. Marsh Edwards, an Australian veterinary scientist, showed experimentally that maternal hyperthermia caused birth defects in various animal species. While it is likely that alert individual clinicians or researchers will continue to signal the first clues about new environmental causes of birth defects, especially therapeutic drugs, it is now usually teams of laboratory researchers and epidemiologists who are more likely to provide definitive evidence of these new teratogens.
ABSTRACT Even though from preclinical testing to drug risk labeling, the situation with drugs in pregnancy has improved substantially since the thalidomide scandal, there is still an increasing need to provide healthcare professionals and patients with updated individualized risk information for clinical decision making. For the majority of drugs, clinical experience is still insufficient with respect to their safety in pregnancy. There is often uncertainty in how to interpret the available scientific data. Based on 20 years of experience with Teratology Information Services (TIS) cooperating in the European Network of Teratology Information Services (ENTIS) methods of risk interpretation, follow-up of exposed pregnancies through the consultation process and their evaluation is discussed. Vitamin K antagonists, isotretinoin and angiotensin (AT) II-receptor-antagonists are presented as examples of misinterpretation of drug risks and subjects of research based on observational clinical data recorded in TIS. As many TIS are poorly funded, advocacy is necessary by establishing contacts with decision makers in health politics and administration, informing them of the high return in terms of health outcomes and cost savings provided by TIS as reference institutions in clinical teratology.
ABSTRACT In this review, our work on CHARGE syndrome will be used to exemplify the role of rare cases in birth defects research. The analysis of 29 cases with mutations of CHD7, the causative gene for CHARGE syndrome, clarified the relative importance of the cardinal features, including facial nerve palsy and facial asymmetry. Concurrently, in situ hybridization using chick embryos studies were performed to delineate the expression pattern of Chd7. The Chd7-positive regions in the chick embryos and the anatomical defects commonly seen in patients with CHARGE syndrome were well correlated: expression in the optic placode corresponded with defects such as coloboma, neural tube with mental retardation, and otic placode with ear abnormalities. The correlation between expression in the branchial arches and nasal placode with the clinical symptoms of CHARGE syndrome, however, became apparent when we encountered two unique CHARGE syndrome patients: one with a DiGeorge syndrome phenotype and the other with a Kallman syndrome phenotype. A unifying hypothesis that could explain both the DiGeorge syndrome phenotype and the Kallman syndrome phenotype in patients with CHARGE syndrome may be that the mutation in CHD7 is likely to exert its effect in the common branch of the two pathways of neural crest cells. As exemplified in CHARGE syndrome research, rare cases play a critical role in deciphering the mechanisms of human development. Close collaboration among animal researchers, epidemiologists and clinicians hopefully will enhance and maximize the scientific value of rare cases.
ABSTRACT Most known human teratogens are associated with a unique or characteristic pattern of major and minor malformations and this pattern helps to establish the causal link between the teratogenic exposure and the outcome. Although traditional case-control and cohort study designs can help identify potential teratogens, there is an important role for small cohort studies that include a dysmorphological examination of exposed and unexposed infants for minor structural defects. In combination with other study design approaches, the small cohort study with a specialized physical examination fulfills a necessary function in screening for new potential teratogens and can help to better delineate the spectrum and magnitude of risk for known teratogens.
Abstract Embryonic stem (ES) cells or induced pluripotent stem (iPS) cells are expected as a surrogate cell source for regenerative medicine. Many researchers have reported the differentiation method of insulin-expressing pancreatic β cells from ES or iPS cells. However, the detailed molecular mechanisms underlying the differentiation of ES or iPS cells into pancreatic lineages are still unclear. We have established a feeder cell-based differentiation system into pancreatic progenitor cells, and revealed the signaling pathways that are involved in the differentiation of ES cells into mesendoderm, endoderm and pancreatic progenitor cells. Recently, we demonstrated that the extracellular environment, particularly the laminin-integrin signaling and heparan sulfate proteoglycan, is important for the regionalization of definitive endoderm cells into pancreatic lineages. These results provide new insights for the differentiation mechanism of pancreatic cell lineages.
ABSTRACT Peptic ulcer disease (PUD) is a common disease which can also occur in pregnant women. However, the possible association of PUD and related drug treatments in pregnant women with the risk of structural birth defects (i.e. congenital abnormalities [CA]) in their offspring has not been estimated in controlled population-based epidemiological studies. Thus, the prevalence of PUD in pregnant women who later delivered babies (cases) with different CA and in pregnant women who delivered newborns without CA (controls) was compared in the Hungarian Case-Control Surveillance of Congenital Abnormalities. Controls were matched to cases. Of 22 843 cases with congenital abnormalities, 182 (0.80%) had mothers with reported/recorded PUD, while of 38 151 controls, 261 (0.68%) were born to mothers with reported/recorded PUD. However, PUD(?) based on maternal information and/or unspecified diagnostic criteria, and PUD(!) based on endoscopic diagnosis showed different variables of mothers and newborn infants. Thus, finally, 20 case mothers and 58 control mothers with PUD(!) and related drugs were evaluated in detail. There was no higher risk for total CA group in the offspring of mothers with PUD during pregnancy (adjusted OR with 95% CI: 0.6, 0.3-0.9). Specific CA groups in cases were also assessed versus controls, but specified CA had no higher risk in the offspring of pregnant women with PUD and related drug treatments. In conclusion, a higher rate of CA was not found in the offspring of mothers with PUD.
ABSTRACT The objective of the present study was to check the efficacy of progress in the medical care of epileptic pregnant women on the basis of the reduction of different congenital abnormalities (CAs) in their offspring. First, the prevalence of medically recorded epilepsy was compared in 95 pregnant women who later had offspring with different CAs (case group) and 90 pregnant women who later delivered newborn infants without CA (control group) and matched to cases in the Hungarian Case-Control Surveillance System of Congenital Abnormalities, 1980–1996. Second, the rate of different CAs was compared in the offspring of epileptic pregnant women between 1980 and 1989 and 1990–1996. Cleft lip with or without cleft palate, cleft palate, cardiovascular CAs, oesophageal atresia/stenosis, hypospadias and multiple CAs showed a higher risk in the offspring of pregnant women with epilepsy treated with different antiepileptic drugs, explained mainly by polytherapy. There was no higher risk for total CAs after monotherapy. There was no significantly lower rate of total CAs in the offspring of epileptic pregnant women during the second period of the study. The efficacy of special medical care of epileptic pregnant women was not shown on the basis of decrease in the rate of CAs in the offspring of epileptic pregnant women.
ABSTRACT Perlman syndrome is a rare syndrome characterized by polyhydramnios, fetal overgrowth, facial dysmorphism, visceromegaly, nephroblastomatosis and predisposition to Wilms tumor. Here we report on a newborn with a prenatal history of polyhydramnios who presented with nephromegaly, hypotonia, macrosomia, facial dysmorphism, cholestasis and characteristic ultrasonographic and computed tomographic appearances of renal abnormalities that are observed with Perlman syndrome. Perlman syndrome is a rare entity with a high neonatal mortality rate. This is the first case in which cholestasis has been observed. Close follow-up should be carried out for early detection of Wilms tumor.