Aubrey Milunsky

Teratogenicity of High Vitamin A Intake

Background Studies in animals indicate that natural forms of vitamin A are teratogenic. Synthetic retinoids chemically similar to vitamin A cause birth defects in humans; as in animals, the defects appear to affect tissues derived from the cranial neural crest. Methods Between October 1984 and June 1987, we identified 22,748 pregnant women when they underwent screening either by measurement of maternal serum alpha-fetoprotein or by amniocentesis. Nurse interviewers obtained information on the womens diet, medications, and illnesses during the first trimester of pregnancy, as well as information on their family and medical history and exposure to environmental agents. We obtained information on the outcomes of pregnancy from the obstetricians who delivered the babies or from the women themselves. Of the 22,748 women, 339 had babies with birth defects; 121 of these babies had defects occurring in sites that originated in the cranial neural crest. Results For defects associated with cranial-neural-crest tis...

Methotrexate-induced congenital malformations.

The case of an infant born after the unsuccessful abortifacient use of methotrexate is reported. The resulting multiple congenital anomalies included absence of the frontal bone, synostosis of the lambdoid and coronal sutures, multiple anomalous ribs, unusual facies, and absence of digits on the left foot with only one digit on the right foot. Mental and motor development was normal, but growth was markedly retarded. The clinical data are compared with 7 other reported cases. The high incidence of cranial anomalies is noted.

A prospective study of the risk of congenital defects associated with maternal obesity and diabetes mellitus

This study was designed to evaluate the effects of maternal obesity and diabetes mellitus on the risk of nonchromosomal congenital defects. We used data from 22,951 pregnant women enrolled in a prospective cohort study of early prenatal exposures and pregnancy outcome. The relative risks [prevalence ratios (PRs)] of major nonchromosomal congenital defects associated with obesity and diabetes, alone or in combination, were calculated using multiple logistic regression analysis. In this study, in the absence of diabetes, obese women (body mass index ≥28) had no higher risk, overall, of having an offspring with a major defect [PR = 0.95; 95% confidence interval (CI) = 0.62–1.5[. Their offspring, however, did have a higher prevalence of certain types of defects, including orofacial clefts; club foot; cardiac septal defects; and, to a lesser extent, hydrocephaly and abdominal wall defects. Women with pre-existing or gestational diabetes who were not obese also had no excess risk overall of having offspring affected by a major defect (PR = 0.98; 95% CI = 0.43–2.2), although they did have a higher prevalence of musculoskeletal defects. The pregnancies of women who were both obese and diabetic were 3.1 times as likely (95% CI = 1.2–7.6) to result in an offspring with a defect than were those of nonobese, nondiabetic women, which suggests that obesity and diabetes mellitus may act synergistically in the pathogenesis of congenital anomalies. The defects were largely craniofacial or musculoskeletal.

Genetic disorders and the fetus

This 6th Edition maintains its pre-eminence as the major repository of facts about prenatal diagnosis. It provides a critical analysis and synthesis of established and new knowledge based on the long experience of authorities in their respective fields. A broad international perspective is presented through authoritative contributions from authors in 11 countries. Its an essential resource for all engaged in prenatal genetic diagnosis, especially obstetricians, maternal-fetal medicine specialists, medical geneticists, genetic counsellors, and pediatricians, but also many other specialties.

Predictive values, relative risks, and overall benefits of high and low maternal serum α-fetoprotein screening in singleton pregnancies: New epidemiologic data

Abstract In a prospective study of maternal serum α-fetoprotein screening for both high and low values, we assessed the overall predictive value, sensitivity, specificity and relative risks for congenital defects and complications of pregnancy. Among 13,486 women with singleton pregnancies interviewed at the time of screening (15 to 20 weeks of gestation), 3.9% had high and 3.4% had low values. A high maternal serum α-fetoprotein value was associated with the following adverse outcomes: neural tube defects (relative risk = 224), other major congenital defects (relative risk = 4.7), fetal deaths (relative risk = 8.1), neonatal death (relative risk = 4.7), low birth weight (relative risk = 4.0), newborn complications (relative risk = 3.6), oligohydramnios (relative risk = 3.4), abruptio placentae (relative risk = 3.0) and preeclamptic toxemia (relative risk = 2.3). A low maternal serum α-fetoprotein value was associated with chromosomal defects (relative risk = 11.6) for fetal death (relative risk = 3.3). Either high or low maternal serum a-fetoprotein values were associated with 34.2% of all major congenital defects, 19.1% of all stillbirths and fetal-neonatal deaths, 11.0% of major pregnancy complications, and 15.9% of serious newborn complications. Maternal serum α-fetoprotein screening provides an important adjunctive tool for the identification of high-risk pregnancy and adverse neonatal outcome.

Ataxia, Dementia, and Hypogonadotropism Caused by Disordered Ubiquitination

BACKGROUND The combination of ataxia and hypogonadism was first described more than a century ago, but its genetic basis has remained elusive. METHODS We performed whole-exome sequencing in a patient with ataxia and hypogonadotropic hypogonadism, followed by targeted sequencing of candidate genes in similarly affected patients. Neurologic and reproductive endocrine phenotypes were characterized in detail. The effects of sequence variants and the presence of an epistatic interaction were tested in a zebrafish model. RESULTS Digenic homozygous mutations in RNF216 and OTUD4, which encode a ubiquitin E3 ligase and a deubiquitinase, respectively, were found in three affected siblings in a consanguineous family. Additional screening identified compound heterozygous truncating mutations in RNF216 in an unrelated patient and single heterozygous deleterious mutations in four other patients. Knockdown of rnf216 or otud4 in zebrafish embryos induced defects in the eye, optic tectum, and cerebellum; combinatorial suppression of both genes exacerbated these phenotypes, which were rescued by nonmutant, but not mutant, human RNF216 or OTUD4 messenger RNA. All patients had progressive ataxia and dementia. Neuronal loss was observed in cerebellar pathways and the hippocampus; surviving hippocampal neurons contained ubiquitin-immunoreactive intranuclear inclusions. Defects were detected at the hypothalamic and pituitary levels of the reproductive endocrine axis. CONCLUSIONS The syndrome of hypogonadotropic hypogonadism, ataxia, and dementia can be caused by inactivating mutations in RNF216 or by the combination of mutations in RNF216 and OTUD4. These findings link disordered ubiquitination to neurodegeneration and reproductive dysfunction and highlight the power of whole-exome sequencing in combination with functional studies to unveil genetic interactions that cause disease. (Funded by the National Institutes of Health and others.).

Prenatal diagnosis of neural tube defects: VIII. The importance of serum alpha-fetoprotein screening in diabetic pregnant women☆

Maternal serum alpha-fetoprotein (AFP) screening of routine pregnancy is a valuable tool for the prenatal detection of neural tube defects (NTDs). Against our background experience with greater than 24,000 screened pregnancies, we have studied 411 pregnant insulin-dependent diabetic women. More than a tenfold increase (19.5/1,000) in the frequency of NTDs was observed in the offspring of these diabetic patients (p less than 0.000001). Serum AFP values were lower in diabetic than in nondiabetic women. Our data indicate that the normal standard of care for diabetic pregnancy should include serum AFP screening.

High concentration of hexacosanoate in cultured skin fibroblast lipids from adrenoleukodystrophy patients.

Abstract Cultured skin fibroblasts from nine patients with the clinical diagnosis of adrenoleukodystrophy (ALD) and 16 control individuals were studied for fatty acid compositions. Total lipids from 7 of the 9 ALD samples showed a high content of hexacosanoic acid (26:0) and a higher ratio of 26:0 to 22:0 acids (0.78–0.92) than the controls (0.03 to 0.09). The samples obtained from two patients with atypical marifestations had a ratio similar to control values. A similar abnormality was demonstrated in the sphingomyelin fatty acids. Diagnosis of ALD and study of its disease mechanism may thus be feasible in skin fibroblast cultures.

Prenatal diagnosis of neural tube defects

Abstract Total cholinesterase activity in amniotic fluid obtained from 150 fetuses was measured. Elevated values were found in 94% of samples from fetuses known to have neural tube defects (spina bifida, anencephaly) when compared to nonbloody samples from normal fetuses. Contamination of amniotic fluid with blood was observed to elevate total cholinesterase activity in some, but not all, such specimens. Total cholinesterase activity did not vary gestational age between 15 two 24 weeks. These data were compared to our large alpha-fetoprotein (AFP) assay experience used for the prenatal detection of neural tube defects. We concluded that the assay of total cholinesterase activity in amniotic fluid could be useful adjunct to the AFP assay, especially in those samples contaminated with blood.

Folate Intake and the Risk of Neural Tube Defects: An Estimation of Dose-Response

Background. Studies have shown that folic acid supplementation in early pregnancy markedly reduces the risk of neural tube defects (NTDs). Investigation of the relation between relative dose of supplemental folic acid or total folate intake and NTD risk is limited. Methods. We used data from 23,228 women, predominantly from the northeastern United States, enrolled between October 1984 and June 1987 in a prospective study of early prenatal exposures and pregnancy outcomes. Diet and vitamin intake data were gathered in the early second trimester. NTDs were ascertained through prenatal testing and by report of the delivering physician. Data analyses included multiple logistic regression and restricted spline regression modeling. Results. For each additional 500 dietary folate equivalents consumed per day, the prevalence of NTDs decreased by 0.78 cases (95% confidence interval [CI] = 0.47–1.09) per 1,000 pregnancies. Compared with women having the lowest total folate intakes (0–149 folate equivalents per day), the prevalence of NTDs declined by 34%, 30%, 56% and 77% among the offspring of those women consuming 150–399, 400–799, 800–1199 and ≥ 1200 folate equivalents per day, respectively (P-value for linear trend = 0.016). Conclusions. Our results suggest that NTD risk declines markedly with modest increases of total folate in early pregnancy. Total folate dose, rather than supplemental folate alone, should be considered in formulating public health guidelines for NTD prevention.