Robert G. Best

DECLINE IN PREVALENCE OF NEURAL TUBE DEFECTS IN A HIGH-RISK REGION OF THE UNITED STATES

Objectives. To conduct surveillance for neural tube defects (NTDs) in a high-risk region of the United States and to prevent occurrence and recurrence of NTDs through the periconceptional use of folic acid supplements. Design. Active and passive methods were used for surveillance of NTD-affected pregnancies and births during a 6-year period (October 1992–September 1998). Individual genetic counseling was used to prevent NTD recurrences and a public awareness campaign was used to reduce NTD occurrences. Setting. State of South Carolina. Patients. All cases of spina bifida, anencephaly, and encephalocele identified among 278 122 live births and fetal deaths to South Carolina residents during 1992–1998 were included. Main Outcome Measure. Changes in occurrence and recurrence rates during a 6-year period. Results. Over the 6 years of surveillance, the prevalence rates for NTDs decreased from 1.89 to .95 cases per 1000 live births and fetal deaths. The prevalence decrease is explained primarily by a decrease in cases of spina bifida. Isolated NTDs accounted for 297/360 (82%) NTDs and 63/360 (18%) had at least 1 other structural anomaly. Females predominated among isolated NTDs but the sex distribution was equal among NTD cases with other anomalies. Prevalence rates for whites (1.48 cases per 1000 live births and fetal deaths) were higher than rates for blacks (.87 cases per 1000 live births and fetal deaths). There were no NTD recurrences in 113 subsequent pregnancies to mothers of infants with isolated NTDs who took periconceptional folic acid. The rate of periconceptional folic acid use among women of childbearing years increased from 8% to 35% during the 6-year project period. Conclusion. The prevalence of NTDs in a high-risk region has declined coincident with the increased periconceptional use of folic acid supplements among women of childbearing age.neural tube defects, high-risk region, birth defects, folic acid, spina bifida, anencephaly, encephalocele.

Noninvasive prenatal screening for fetal aneuploidy, 2016 update: a position statement of the American College of Medical Genetics and Genomics.

Disclaimer: This statement is designed primarily as an educational resource for clinicians to help them provide quality medical services. Adherence to this statement is completely voluntary and does not necessarily assure a successful medical outcome. This statement should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed toward obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this statement. Clinicians also are advised to take notice of the date this statement was adopted and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.Noninvasive prenatal screening using cell-free DNA (NIPS) has been rapidly integrated into prenatal care since the initial American College of Medical Genetics and Genomics (ACMG) statement in 2013. New evidence strongly suggests that NIPS can replace conventional screening for Patau, Edwards, and Down syndromes across the maternal age spectrum, for a continuum of gestational age beginning at 9–10 weeks, and for patients who are not significantly obese. This statement sets forth a new framework for NIPS that is supported by information from validation and clinical utility studies. Pretest counseling for NIPS remains crucial; however, it needs to go beyond discussions of Patau, Edwards, and Down syndromes. The use of NIPS to include sex chromosome aneuploidy screening and screening for selected copy-number variants (CNVs) is becoming commonplace because there are no other screening options to identify these conditions. Providers should have a more thorough understanding of patient preferences and be able to educate about the current drawbacks of NIPS across the prenatal screening spectrum. Laboratories are encouraged to meet the needs of providers and their patients by delivering meaningful screening reports and to engage in education. With health-care-provider guidance, the patient should be able to make an educated decision about the current use of NIPS and the ramifications of a positive, negative, or no-call result.Genet Med 18 10, 1056–1065.

Numerical chromosome abnormalities in spermatozoa of fertile and infertile men detected by fluorescence in situ hybridization

Fluorescence in situ hybridization (FISH) with single-color chromosome-specific probes was used to study the rates of disomy for chromosome 1, 16, X, and Y in sperm of fertile and infertile subjects. Diploidy rates were studied using a two-color cocktail of probes for chromosomes 17 and 18 in the same sperm samples. Two-color methodology was not available at the outset of the study. A total of 450,580 spermatozoa were studied from 21 subjects (9 fertile, 12 infertile). Significant differences were observed in the disomy rates between chromosomes with the highest frequency observed for chromosome 16 (0.17%) and the lowest for the Y chromosome (0.10%). No differences were observed between fertile and infertile subjects for either diploidy or disomy. Total disomy rates for chromosomes 1, 16, X and Y ranged from 0.34% to 0.84% among infertile subjects, and 0.32% to 0.61% among fertile subjects. Our data suggest that generalized aneuploidy in sperm is not a major contributor to unexplained infertility.

Ethical issues in genetic counseling: A comparison of M.S. counselor and medical geneticist perspectives

New technologies available in the field of medical genetics have increased the importance of responsible ethical decision-making among genetic counselors. A 1985 national survey of M.D. and Ph.D. genetic counselors assessed ethical attitudes using case scenarios designed to simulate dilemmas faced in genetic counseling (Wertz and Fletcher, 1988b). The current study focuses on attitudes of M.S. genetic counselors using similar scenarios, allowing for effective comparisons. M.S. counselors were more willing than M.D. and Ph.D. counselors to maintain patient confidentiality when screening for Huntingtons Disease and occupational diseases, and a greater number would agree to counsel patients pursuing prenatal testing for sex selection. A majority of M.S. counselors would disclose an XY karyotype to a phenotypically female patient. M.S. counselors reasoned that respect for patient autonomy and patient confidentiality justified their decisions in many cases. The importance of these principles is discussed and questioned.

Efficacy of progesterone vaginal suppositories in alleviation of nervous symptoms in patients with premenstrual syndrome

PurposeTo further investigate the efficacy of progesterone in the treatment of the symptoms of premenstrual syndrome (PMS).Materials and MethodsFrom an initial cohort of 25 subjects diagnosed with moderate to severe PMS, 17 reproductive age females completed the 7-month, doubleblind, placebo controlled trial using 200-mg vaginal progestone suppositories. Multiple modalities for evaluating symptoms were employed, including the Spielberger self-evaluation rating, the Beck depression inventory, and the Hamilton anxiety scale. In addition, each subject was interviewed by a psychiatrist on a monthly basis; ovulation was determined monthly using a basal body temperature chart; serum hormonal assays included beta endorphin, progesterone, follicle stimulating hormone, luteinizing hormone, estradiol, and prolactin.ResultsHormonal assays confirmed no differences between treatment and control groups. Overall scores on all test vehicles were likewise not significantly different between the two groups; however, in the subcategory of nervous symptoms, a significant improvement was found in symptoms relating to tension, mood swings, irritability, anxiety and lack of control.ConclusionsMetabolites of progesterone (pregnanolone and allopregnanolone) may play a physiologic role as anxiolytic agents, perhaps modifying mood and anxiety; the current study confirms the utility of twice daily, 200-mg progesterone vaginal suppositories, in the alleviation of some PMS symptoms relating to anxiety and irritability. Further evaluation may be warranted to ascertain which patients in the known heterogeneous PMS population may be most likely to benefit from such treatment.

Genetics of Hypertension: What Is Next?

Hypertension or an elevated blood pressure continues to be a major risk factor for cardiovascular disease. Despite intensive public education including lifestyle modification programs and the availability of safe and effective pharmacologic agents to treat hypertension, the treatment and control of hypertension is suboptimal. Over the past several decades, there have been tremendous advances in the use of genetics to prevent, detect, and treat human disease states. Despite these advances and an intensive effort, the application of genetics to the broad population with hypertension has not met expectations. This review will address our present understanding and use of genetics in hypertension and areas where genetics may impact significantly our approach and clinical treatment of hypertension in the future.

Spontaneous ovarian tumors in twelve baboons: a review of ovarian neoplasms in non‐human primates

Abstract: Twelve spontaneous ovarian tumors were found in the Southwest Foundation for Biomedical Research baboon colony. These included four granulosa cell tumors, three teratomas, two endometrioid carcinomas, one seromucinous cystadenofibroma, a cystic papillary adenocarcinoma, and an ovarian carcinoma. Age was a pre‐disposing factor. With one exception, the tumors of surface epithelial‐ and sex cord‐stromal origin occurred in baboons over 17 years of age. The exceptional animal was 7 years of age when a malignant granulosa cell tumor with Sertoli cell differentiation was identified. The two endometrioid tumors, which were found in 17‐ and 30‐year‐old animals, were both associated with endometriosis. In contrast, the teratomas, which are tumors of germ cell origin, were found in younger animals, i.e. 17 years of age or younger. One case of an ovarian carcinoma with metastases was observed in a 6‐month‐old infant. Cases of spontaneous ovarian tumors from the literature are reviewed.

Maternal serum placental alkaline phosphatase level and risk for preterm delivery

OBJECTIVE The purpose of this study was to determine whether elevated midtrimester serum placental alkaline phosphatase levels are predictive of preterm delivery. STUDY DESIGN By use of banked serum specimens from a sample of women who had received maternal serum alpha-fetoprotein screening, placental alkaline phosphatase values for multiples of the median were obtained from 270 mothers who had experienced a preterm delivery and from 1598 mothers of term, appropriate-for-gestational-age infants. Specimens were analyzed for placental alkaline phosphatase by means of a monoclonal antibody enzyme-linked immunosorbent assay. Logistic regression was used to determine whether placental alkaline phosphatase was associated with preterm birth, while potential confounders were controlled for. RESULTS Women with placental alkaline phosphatase levels > or = 2.0 multiples of the median were significantly more likely to be delivered of a preterm infant in the current pregnancy compared with women with levels < 2.0 multiples of the median (odds ratio 2.9, 95% confidence interval 2.1 to 3.9). The likelihood of preterm birth increased significantly with higher multiples of the median (p < 0.001). CONCLUSION Women with elevated placental alkaline phosphatase levels are at increased risk for preterm delivery. Additional studies are needed to evaluate the clinical utility of placental alkaline phosphatase testing as a means of identifying mothers at risk for preterm birth.

Maternal obesity, folate intake, and neural tube defects in offspring

BACKGROUND We investigated the association between maternal obesity (body mass index [BMI] ≥ 30) and the risk of a neural tube defect affected pregnancy (NTD). We also studied relationships between perinatal folate intake from food and the NTD risk by maternal BMI. METHODS Data came from a state-wide case-control study conducted between 1992 and 1997 in South Carolina including 179 women with NTD-affected pregnancies and 288 women without NTD-affected births. A majority of case mothers (77%) and controls (86%) were interviewed within 6 months after delivery or pregnancy termination. Logistic regression models were used to examine the association between maternal obesity and the NTD risk after adjusting for maternal race, age, education, smoking, alcohol/drug use, chronic conditions, and multivitamin use within six periconceptional months. Stratified analysis by maternal BMI (≥25 vs. <25) was conducted for the association between food folate and the NTD risk. RESULTS After adjustment for confounders, obese women (BMI ≥ 30) had twice higher odds of having an NTD-affected pregnancy (odds ratios [OR] = 2.06, 95% confidence interval [CI] = 1.12, 3.81) than normal weight women (BMI: 18.0-24.9). Compared to the lowest quartile of average daily folate intake from food, the upper three quartiles had lower odds of NTDs in offspring. The NTD-protective association was stronger in overweight/obese women (BMI ≥ 25) than in normal/underweight women (BMI < 25). CONCLUSIONS These results support previous studies suggesting maternal obesity as a risk factor for NTDs. Higher intakes of dietary folate were associated with decreased NTD risk that was stronger in overweight and obese women.

Long Term Maintenance of Neural Tube Defects Prevention in a High Prevalence State

OBJECTIVE To assess the efficacy of folic acid (FA) supplementation and fortification in preventing neural tube defects (NTDs) in a high prevalence region of the United States. STUDY DESIGN Active and passive surveillance methods were used to identify all fetuses/infants affected with an NTD in South Carolina. Prevalence rates were compared with FA intake to determine the effects of increased intake on NTD occurrence and recurrence. RESULTS From 1992 to 2009, 916 NTD cases occurred in South Carolina, with isolated defects comprising 79% of cases. The NTD rate decreased 58% during this period. There was one NTD-affected pregnancy in 418 subsequent pregnancies (0.2%) in mothers with earlier NTD-affected pregnancies who consumed periconceptional FA supplements, and there were 4 NTDs in 66 pregnancies (6.1%) in which the mother did not take FA supplements. FA supplementation increased from 8% to 35% from 1992 to 2007, and knowledge of the protective benefits of FA increased from 8% to 65% in women of childbearing age. CONCLUSIONS Increased periconceptional intake of FA appeared to reduce NTDs in a high-prevalence region. The rate of spina bifida and anencephaly in South Carolina is now essentially the same (0.69 cases per 1000 live births and fetal deaths) as the 1998 to 2005 US rate (0.69).