Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects.

We examined the relation of multivitamin intake in general, and folic acid in particular, to the risk of neural tube defects in a cohort of 23,491 women undergoing maternal serum alpha-fetoprotein screening or amniocentesis around 16 weeks of gestation. Complete questionnaires and subsequent pregnancy outcome information was obtained in 22,776 pregnancies, 49 of which ended in a neural tube defect. The prevalence of neural tube defect was 3.5 per 1000 among women who never used multivitamins before or after conception or who used multivitamins before conception only. The prevalence of neural tube defects for women who used folic acid-containing multivitamins during the first 6 weeks of pregnancy was substantially lower--0.9 per 1000 (prevalence ratio, 0.27; 95% confidence interval, 0.12 to 0.59 compared with never users). For women who used multivitamins without folic acid during the first 6 weeks of pregnancy and women who used multivitamins containing folic acid beginning after 7 or more weeks of pregnancy, the prevalences were similar to that of the nonusers and the prevalence ratios were close to 1.0.

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

In a prospective study of maternal serum alpha-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 alpha-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 alpha-fetoprotein value was associated with chromosomal defects (relative risk = 11.6) for fetal death (relative risk = 3.3). Either high or low maternal serum alpha-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 alpha-fetoprotein screening provides an important adjunctive tool for the identification of high-risk pregnancy and adverse neonatal outcome.

Kinetics and clinical effects of flurazepam in young and elderly noninsomniacs.

Twenty-six healthy subjects from 19 to 85 yr old took single 15-mg doses of flurazepam (FLZ). Concentrations of desalkylfurazepam (DAFLZ), its principal metabolite, were measured by gas-liquid chromatography in multiple samples drawn 7 or more days after the dose. For the first 6 to 8 hr after drug, several additional FLZ metabolites appeared in plasma, but only DAFLZ was detected from 12 hr onward. Its elimination half-life (t1/2) (range, 37 to 289 hr) was longer in elderly than in young men (mean 74 and 160 hr, p less than 0.05), but t1/2 in young and elderly women was much the same (90 and 120 hr, P = NS). Eighteen of the 26 subjects then received FLZ, 15 mg, nightly for 15 consecutive nights. Blood samples were drawn during FLZ dosage and in the withdrawal period, and morning self-ratings of mood and sleep patterns were obtained using visual analogue scales. DAFLZ cumulation was extensive, with a mean cumulation ratio of 7.5. Mean steady-state plasma levels of DAFLZ were higher in elderly than in young men (81 and 53 ng/ml, P less than 0.05), but values were essentially the same in elderly and young women (85 and 86 ng/ml). Single-dose t1/2 correlated with washout t1/2 after termination of FLZ treatment (r = 0.87, P less than 0.01). Clinical self-ratings indicated increases over time in perception of morning sedation; changes slowly reverted to baseline in the week after dosage. Sleep patterns also improved on FLZ (shortened latency, longer duration, "deeper" sleep). After termination of treatment, sleep parameters returned to baseline with a suggestion of "overshoot" sleep disturbance at days 5 and 7 after drug. There was no evidence of increased sensitivity to FLZ in the elderly. Subjects did not perceive any impairment of intellectual function or motor performance, and no other adverse reactions were reported.

A data validation program nucleus.

A data validation program designed for flexibility and user-modification is presented. It is assumed that the data to be validated consist of packets; i.e., groups of records with a common value in a record-linking field. Acceptance or rejection of data is on a packet basis. Individual field validation is specified by user-supplied tables. Multiple field checking and field interaction checking on both an intra-record and an inter-record basis may be specified by user-supplied subprograms. The program is written in PL/I using structured programming techniques. Further modifications such as record size and key positions are possible at pre-processor time.

Single- and multiple-dose kinetics of oral lorazepam in humans: the predictability of accumulation.

Six healthy volunteers participated in single- and multiple-dose pharmacokinetic studies of oral lorazepam. Following single 4-mg oral doses, peak plasma lorazepam concentrations ranging from 40 to 70 ng/ml were reached within 3 hr of the dose. Values of absorption half-life averaged 25 min (range 10.3-42.7 min), and elimination half-life (t1/2 beta) averaged 14.2 hr (range 8.4-23.9 hr). During 15 consecutive days of 3 mg per day administered in divided doses, accumulation to the steady-state condition was complete within several days of the initiation of therapy. Values of accumulation half-life (mean 21.1 hr) were slightly longer than t1/2beta, and the two were not well correlated. Observed accumulation ratios (mean 1.88) were very close to those predicted from the single-dose study (mean 1.77), but the correlation between the two (r = 0.51) was not significant in the small sample size. "Washout" half-life values (mean 14.9 hr) were highly correlated with t1/2beta (r = 0.92). Clearance of a single intravenous dose of antipyrine determined prior to the multiple-dose lorazepam study (mean 0.86 ml/min/kg) was essentially identical to that determined after the study (mean 0.87 ml/ min/kg). Overall, the rate and extent of lorazepam accumulation during multiple dosage were reasonably well predicted by the single-dose kinetic study. However, accurate prediction for any specific individual was not always achieved. Stimulation or inhibition by lorazepam of its own clearance probably does not explain imprecise prediction, since single-dose t1/2beta and washout half-life values were essentially identical. Furthermore, chronic lorazepam exposure has no apparent effect on hepatic hydroxylation capacity as measured by clearance of exogenously administered antipyrine.

Clinical pharmacokinetics of lorazepam. II. Intramuscular injection.

A single dose of 4 mg of lorazepam was injected into the deltoid muscles of six healthy male volunteers. Multiple venous blood samples were drawn during 48 hr after the dose and all urine was collected for 24 hr after the dose. Concentrations of lorazepam and its major metabolite, lorazepam glucuronide, were determined by electron-capture gas-liquid chromatography. Lorazepam was rapidly absorbed from the injection site, reaching peak concentrations within 3 hr. Mean pharmacokinetic pamrameters for unchanged lorazepam were: apparent absorption half-life: 21.2 min; elimination half-life: 13.6 hr; volume of distribution: 0.9 L/kg; total clearance: 58.2 ml/min. Lorazepam glucuronide rapidly appeared in plasma, reached peak concentrations within 12 hr of the dose, then was eliminated approximately in parallel with the parent drug. Within 24 hr a mean of 47.6% of the dose was recovered in the urine as lorazepam glucuronide and less than 0.5% was recovered as unchanged lorazepam.