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Biomedical subjects

G J Knight

Publications and source records attributed to G J Knight.

At least 37 records · Page 2Linked to original sources
PubMed1995

Elevated midtrimester serum methylmalonic acid levels as a risk factor for neural tube defects.

The role of folic acid in the primary prevention of neural tube defects (NTDs) is well established. However, questions related to the protective mechanism remain unanswered. To help answer these questions, we designed a case-control study to assess the role of folate- and cobalamin-related metabolites in the pathogenesis of NTDs. Concentrations of folate, cobalamin, and 14 other related metabolites were measured by gas chromatography/mass spectrometry in midtrimester serum specimens from 32 women with an NTD-affected pregnancy and from 132 control women, and in serum specimens from 46 nonpregnant women who had a history of NTD-affected pregnancy and from 43 nonpregnant control women. Log-transformed means of metabolites were compared between case and control women for both the midtrimester and nonpregnant groups. In the pregnant group, serum methylmalonic acid (MMA) concentrations were higher among case women than among control women (130 vs 105 nM). There was a strong dose-response relationship between midtrimester serum MMA level and the risk for an NTD-affected pregnancy, with the relative risk increasing 13-fold for women with MMA levels > 90th percentile. In the nonpregnant group, there was no difference in serum MMA levels between case and control women (140 vs 140 nM). Thus, the serum MMA levels of women in the midtrimester of pregnancies unaffected by NTDs were significantly lower than the levels of nonpregnant women, whereas the levels of women whose pregnancies were affected by NTDs were similar to those of nonpregnant women. The finding of elevated MMA serum concentrations among women in the midtrimester of NTD-affected pregnancies suggests that cobalamin may be involved in the etiology of NTDs. The possible role of cobalamin in relation to the protective effect of folic acid needs further evaluation.

Adult↗
PubMed1995

Effect of parity on human chorionic gonadotrophin levels and Down's syndrome screening.

OBJECTIVE: To investigate further the association between parity and human chorionic gonadotrophin (hCG) levels during the second trimester and determine whether prenatal screening for Down's syndrome might be made more efficient by adjusting for this variable. METHODS: Measurements of hCG were analysed in relation to parity from a cohort of 16,675 singleton pregnancies with viable outcomes, and from 108 singleton pregnancies affected by Down's syndrome. Cigarette smoking during pregnancy and maternal age were also analysed in relation to hCG levels. RESULTS: For both unaffected pregnancies and pregnancies with Down's syndrome the median hCG levels were 7% lower in parous than in nulliparous women. A dose-response relation was also documented for the unaffected pregnancies. When para 0, para 1, and para 2 women were studied separately, hCG levels rose steadily as age advanced. Adjusting hCG levels for parity led to a 0.1% reduction in variance of the distribution of hCG measurements in unaffected pregnancies and to a negligible increase in Down's syndrome screening efficiency. CONCLUSION: The effect of parity is not sufficiently great to warrant routine adjustment of hCG levels as part of prenatal screening for Down's syndrome.

Adult↗
PubMed1994

Reducing the need for amniocentesis in women 35 years of age or older with serum markers for screening.

BACKGROUND: As maternal age advances, the risk of fetal Down's syndrome increases. Pregnant women 35 years of age or older are routinely offered amniocentesis because of this risk. Recently, maternal serum markers have been reported to be useful in screening for Down's syndrome, primarily in younger women. We therefore investigated whether offering amniocentesis only to selected women 35 years of age or older who were identified by screening measurements in serum might prove a useful alternative to the current practice. METHODS: We studied 5385 women with singleton pregnancies who were 35 years of age or older and were undergoing routine amniocentesis. Along with information about the pregnancy, we obtained a serum sample for measurement of alpha-fetoprotein, unconjugated estriol, and human chorionic gonadotropin. Individual estimates of the risk of Down's syndrome in the fetus were calculated for each pregnancy before the karyotype was known. RESULTS: If amniocentesis had been reserved for the women calculated to have a risk greater than 1 in 200 of having a fetus with Down's syndrome, 48 of the 54 cases of Down's syndrome (89 percent) would have been identified, 25 percent of the unaffected pregnancies would also have been identified as being at high risk for Down's syndrome (false positives). Seven of 15 fetuses (47 percent) with other trisomies, 11 of 25 (44 percent) with sex aneuploidy, and 1 of 9 (11 percent) with miscellaneous chromosomal abnormalities would also have been detected. In practice, such screening would have made 75 percent of the amniocentesis unnecessary, along with a proportion of the amniocentesis-associated fetal losses. If the cutoff for the risk of Down's syndrome were set higher than 1 in 200, both the rate of detection and the false positive rate would be lower. Conversely, these rates would be higher if the cutoff were set lower. CONCLUSIONS: Prenatal screening of serum to generate individual estimates of the risk of Down's syndrome in the fetus can provide a basis for decision making in the cases of women 35 years of age or older, as it does in younger pregnant women, and is an alternative to current testing practices.

Adult↗
PubMed1994

Human chorionic gonadotropin and unconjugated oestriol measurements in insulin-dependent diabetic pregnant women being screened for fetal Down syndrome.

This prospective study investigates the relationship between insulin-dependent diabetes and maternal serum levels of alpha-fetoprotein (AFP), unconjugated oestriol (uE3), and human chorionic gonadotropin (hCG). It also examines the potential impact on screening for Down syndrome. The population-based cohort included 20,321 pregnant women in Maine who underwent routine serum screening for Down syndrome in the second trimester. The cohort included 52 women with insulin-dependent diabetes. Maternal serum AFP levels are now routinely adjusted for insulin-dependent diabetes. These adjustments, therefore, were made routinely in the diabetic women, but no equivalent adjustments were made for uE3 and hCG values. The initial false-positive rate (using all three markers) among the women with diabetes was not significantly different from that in the non-diabetic population (7.7 and 5.4 per cent, respectively). Prior to adjustment for insulin-dependent diabetes, the median AFP level in the 52 women was 0.73 multiples of the median (MOM); the median levels of uE3 and hCG were 0.93 and 0.98 MOM, respectively. When the uE3 and hCG levels were adjusted, the initial false-positive rate was unchanged. Median serum levels of uE3 were significantly higher in the 33 women whose onset of diabetes was prior to 19 years of age (0.99 MOM) than in the 19 women whose onset of diabetes was at age 19 or older (0.84 MOM). This is the first population-based study to investigate the relationship between diabetes and serum levels of AFP, uE3, and hCG, and confirms earlier observations from a case-control study that found only slightly lower uE3 and hCG levels.

Adult↗
PubMed1994

Second-trimester diurnal variation of maternal serum alpha-fetoprotein, human chorionic gonadotropin, and unconjugated oestriol: is it present and does it affect the prediction of a patient's risk for fetal Down syndrome?

Both a cross-sectional and a longitudinal study were performed to investigate whether or not the collection time should be taken into consideration when generating a patient's risk for fetal Down syndrome with multiple marker screening. Diurnal variations of third-trimester alpha-fetoprotein (AFP) levels and first-trimester human chorionic gonadotropin (hCG) levels have been previously reported. In addition, large episodic fluctuations of conjugated and unconjugated oestriol (uE3) as well as a diurnal variation have also been reported in the third trimester. If the levels of these analytes routinely fluctuate during the day, they could affect a patient's risk calculation for fetal Down syndrome. The longitudinal study evaluated ten non-diabetic women who underwent sequential sampling for AFP, hCG, and uE3. The cross-sectional study evaluated 1953 patients for these three markers whose time of sampling was recorded between 8.00 a.m. and 5.59 p.m. Using either study design, no significant effect was seen in the median MOM levels of the screening analytes as a function of the time of day.

Biomarkers↗
PubMed1994

Second-trimester maternal serum alpha-fetoprotein, unconjugated estriol, and hCG levels in pregnancies with ventral wall defects.

OBJECTIVE: To determine if second-trimester maternal serum concentrations of unconjugated estriol (E3) and hCG are altered in pregnancies associated with fetal gastroschisis or omphalocele. METHODS: Concentrations of alpha-fetoprotein (AFP), unconjugated E3, and hCG were measured in a case-control study involving 23 cases of gastroschisis, 17 cases of omphalocele, and 200 matched unaffected pregnancies. RESULTS: As reported previously, median AFP levels were significantly higher in pregnancies with gastroschisis and omphalocele compared to unaffected pregnancies (9.42 and 4.18 multiples of the unaffected population median [MoM], respectively). The median hCG values were not significantly different for the two defects (1.10 and 1.13 MoM, respectively). Six of the cases of omphalocele were associated with other anomalies, but exclusion of these cases from the analysis did not alter the conclusions. CONCLUSIONS: Unconjugated E3 and hCG measurements are not useful in screening for, or distinguishing between, open ventral wall defects. Alpha-fetoprotein measurements alone will detect nearly all cases of gastroschisis and most cases of omphalocele.

Abdominal Muscles↗
PubMed1994

Replacing creatinine measurements with specific gravity values to adjust urine cotinine concentrations.

Creatinine and specific gravity (relative density) measurements both allow differences in urine concentration to be taken into account in determining urine cotinine concentrations. In this study we demonstrate that the variance of urine cotinine measurements is reduced comparably when either creatinine or specific gravity measurements are used for correction. This reduction in variability improves the correlation between urine cotinine measurements and clinical endpoints. In this study, the clinical endpoints were pulmonary function in a population of nonsmoking children with asthma, 42% of whom were reported to have been exposed to environmental tobacco smoke. When corrected by either creatinine measurements or specific gravity values, the urine cotinine measurements performed as well or better than reported exposure (and comparably with each other) in assessments of lung function. A dose-response relationship was also more consistently apparent. Specific gravity values can be used reliably in place of creatinine values to adjust urine cotinine measurements for both research and clinical purposes.

Asthma↗
PubMed1993

Association between exposure to environmental tobacco smoke and exacerbations of asthma in children.

BACKGROUND: Exposure to environmental tobacco smoke, as reported by parents, has been linked to diminished pulmonary function and more frequent exacerbations of asthma in children with the disease. Further insight into this association might be gained by using urine cotinine levels to measure actual exposure. METHODS: We measured urine cotinine levels in 199 children with asthma; 145 also underwent pulmonary-function studies. A parent answered questions about each child's exposure to environmental tobacco smoke. Acute exacerbations of asthma during the preceding year were documented through blinded review of medical records. Possible confounding factors were accounted for by the use of multivariate analysis and by comparisons of serum theophylline levels in exposed and unexposed children. RESULTS: The median urine cotinine levels were 5.6 ng per milliliter in the 116 children reported not to have been exposed to tobacco smoke, 13.1 ng per milliliter in the 53 children exposed to cigarette smoking by the mother or other persons, and 55.8 ng per milliliter in the 30 children exposed to cigarette smoking by the mother and other persons. Acute exacerbations of asthma increased with exposure, whether such exposure was reported by a parent or identified on the basis of the cotinine level; the relative risks for the highest as compared with the lowest exposure category were 1.8 (95 percent confidence interval, 1.4 to 2.2) for reported exposure and 1.7 (95 percent confidence interval, 1.4 to 2.1) for exposure indicated by cotinine levels. The forced expiratory volume in one second (FEV1), the forced expiratory flow between 25 and 75 percent of vital capacity, and the ratio of FEV1 to forced vital capacity also decreased with increases in both measures of exposure. CONCLUSIONS: Measurement of urine cotinine levels provides further evidence of an association between exposure to environmental tobacco smoke and pulmonary morbidity in children with asthma. These data emphasize the need for systematic, persistent efforts to stop the exposure of children with asthma to environmental tobacco smoke.

Adolescent↗
PubMed1993

Maternal serum screening for fetal Down syndrome in the United States: a 1992 survey.

OBJECTIVE: Our purpose was to determine the status of screening for fetal Down syndrome in the United States in 1992. STUDY DESIGN: Information was sought from laboratories participating in two proficiency testing programs. RESULTS: The 301 responding laboratories (98%) annually provided services to 2,113,000 pregnant women. Of these laboratories, 242 provided Down syndrome screening (1,924,000 pregnant women); 55% used alpha-fetoprotein levels alone, 30% used alpha-fetoprotein, unconjugated estriol, and human chorionic gonadotropin combined, and 14% used alpha-fetoprotein and human chorionic gonadotropin combined. All laboratories used clinically validated analytes. Nearly all screened at appropriate gestational ages, used a validated algorithm, and used risk as the screening variable. However, many laboratories, especially smaller ones, were unable to monitor their performances adequately. CONCLUSION: Since 1988 maternal serum screening for Down syndrome has approximately doubled, and other analyte measurements have been added in nearly one fourth of the screened pregnancies. Most laboratories appear to be performing adequately, although there is room for improvement.

Chorionic Gonadotropin↗
PubMed1993

Simultaneous fetal and maternal cotinine levels in pregnant women smokers.

OBJECTIVE: Our purpose was to determine the simultaneous concentrations of serum cotinine in both fetal and maternal blood. STUDY DESIGN: Serum cotinine levels were measured in 11 maternal-fetal pairs at percutaneous umbilical blood sampling. Statistical analysis was performed by means of a one-group t test to determine whether the ratio of fetal-to-maternal cotinine was significantly different from 1. RESULTS: Fetal cotinine levels ranged from 75% to 110% of maternal values (mean ratio 0.90, 95% confidence interval 0.83 to 0.97). Fetal levels were significantly lower than maternal concentrations (p = 0.02). CONCLUSIONS: Cotinine, a metabolite of nicotine used to quantify exposure to tobacco smoke, readily gains access to the fetal circulation. Fetal cotinine concentrations in pregnant women smokers are, on average, 90% of maternal values throughout gestation.

Cotinine↗
PubMed1993

Cigarette smoking and levels of maternal serum alpha-fetoprotein, unconjugated estriol, and hCG: impact on Down syndrome screening.

OBJECTIVE: To investigate the association between maternal cigarette smoking and serum levels of alpha-fetoprotein (AFP), unconjugated estriol (uE3), and hCG and to determine whether it is appropriate to take smoking status into account when screening for fetal Down syndrome. METHODS: Smoking information was obtained from 23,668 pregnant women at the time of routine screening for fetal Down syndrome. Serum levels of AFP, uE3, and hCG were stratified by smoking status and compared. Individual risks for fetal Down syndrome were analyzed both before and after adjusting the hCG levels for the effect of smoking. The prevalence of Down syndrome in the study population was calculated for both smokers and non-smokers. RESULTS: The average AFP, uE3, and hCG levels in women who smoked cigarettes were 3% greater (95% confidence interval [CI] 2-4%), 3% less (95% CI 2-4%), and 23% less (95% CI 22-24%), respectively, compared with levels in non-smokers. At comparable maternal ages, women who smoked cigarettes were identified as being at high risk for fetal Down syndrome 40% less often than non-smokers (4.0 versus 7.1% at a risk level of 1:250). Adjusting hCG levels for smoking status reduced the overall false-positive rate from 6.4 to 6.1% (using a term risk cutoff level of 1:250). The predicted effect on detection was small (a 0.7% increase). The prevalence of Down syndrome was lower among smokers, but the difference was not statistically significant (odds ratio 0.51, 95% CI 0.15-1.5). CONCLUSIONS: Adjusting the serum markers used for Down syndrome screening for the effect of maternal smoking has a small effect on overall screening performance. Given the uncertainty over whether there is a lower birth prevalence among women who smoke cigarettes, such adjustment is not currently justified.

Adult↗
PubMed1992

Prenatal screening for Down's syndrome with use of maternal serum markers.

BACKGROUND: Approximately 35 percent of all cases of Down's syndrome in fetuses can be detected by measuring maternal serum alpha-fetoprotein during the second trimester in the general population of pregnant women. Recent case-control studies indicate that this detection rate could be approximately doubled by measuring serum levels of unconjugated estriol and chorionic gonadotropin, which are abnormally low and abnormally high, respectively, in women carrying fetuses affected by Down's syndrome. METHODS: We prospectively screened 25,207 women and adolescents in the second trimester of pregnancy and assigned each a risk of fetal Down's syndrome with an algorithm that took into account measurements of all three serum markers in combination with maternal age. On this basis, 1661 subjects (6.6 percent) were initially assigned a second-trimester risk of fetal Down's syndrome of at least 1 in 190, and 962 (3.8 percent) were offered amniocentesis for chromosomal analysis after verification of gestational age. Gestational age was determined on the basis of the first day of the last menstrual period or, when available, by ultrasonography. RESULTS: Among the 760 women and adolescents who chose amniocentesis, 20 cases of fetal Down's syndrome were detected, along with 7 other chromosomal disorders. There was 1 additional case of fetal Down's syndrome among the 202 women who chose not to have amniocentesis. The rate of detection of Down's syndrome was thus 58 percent (21 of 36 expected cases), and the frequency of identifying a fetus with Down's syndrome in women undergoing amniocentesis was 1 per 38 amniocenteses (95 percent confidence interval, 1 in 25 to 1 in 62). CONCLUSIONS: Measuring serum alpha-fetoprotein, chorionic gonadotropin, and estriol is more effective in screening for fetal Down's syndrome than measuring maternal serum alpha-fetoprotein alone. Such an expanded protocol can readily be incorporated into existing prenatal screening programs.

Adolescent↗