George J. Knight

Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child.

BACKGROUND When thyroid deficiency occurs simultaneously in a pregnant woman and her fetus, the childs neuropsychological development is adversely affected. Whether developmental problems occur when only the mother has hypothyroidism during pregnancy is not known. METHODS In 1996 and 1997, we measured thyrotropin in stored serum samples collected from 25,216 pregnant women between January 1987 and March 1990. We then located 47 women with serum thyrotropin concentrations at or above the 99.7th percentile of the values for all the pregnant women, 15 women with values between the 98th and 99.6th percentiles, inclusive, in combination with low thyroxine levels, and 124 matched women with normal values. Their seven-to-nine-year-old children, none of whom had hypothyroidism as newborns, underwent 15 tests relating to intelligence, attention, language, reading ability, school performance, and visual-motor performance. RESULTS The children of the 62 women with high serum thyrotropin concentrations performed slightly less well on all 15 tests. Their full-scale IQ scores on the Wechsler Intelligence Scale for Children, third edition, averaged 4 points lower than those of the children of the 124 matched control women (P= 0.06); 15 percent had scores of 85 or less, as compared with 5 percent of the matched control children. Of the 62 women with thyroid deficiency, 48 were not treated for the condition during the pregnancy under study. The full-scale IQ scores of their children averaged 7 points lower than those of the 124 matched control children (P=0.005); 19 percent had scores of 85 or less. Eleven years after the pregnancy under study, 64 percent of the untreated women and 4 percent of the matched control women had confirmed hypothyroidism. CONCLUSIONS Undiagnosed hypothyroidism in pregnant women may adversely affect their fetuses; therefore, screening for thyroid deficiency during pregnancy may be warranted.

Maternal serum screening for Down's syndrome in early pregnancy.

The possibility of improving the effectiveness of antenatal screening for Downs syndrome by measuring human chorionic gonadotrophin concentrations in maternal serum during the second trimester to select women for diagnostic amniocentesis was examined. The median maternal serum human chorionic gonadotrophin concentration in 77 pregnancies associated with Downs syndrome was twice the median concentration in 385 unaffected pregnancies matched for maternal age, gestational age, and duration of storage of the serum sample. Measuring human chorionic gonadotrophin in maternal serum was an effective screening test, giving a lower false positive rate (3%) at a 30% detection rate than that for maternal age (5%) and the two existing serum screening tests, unconjugated oestriol (7%) and alpha fetoprotein (11%). The most effective screening results were obtained with all four variables combined; at the same 30% detection rate the false positive rate declined to 0.5%. The new screening method would detect over 60% of affected pregnancies, more than double that achievable with the same amniocentesis rate in existing programmes (5%), and could reduce the number of children born with Downs syndrome in the United Kingdom from about 900 a year to about 350 a year.

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 childs 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.

Prenatal Screening for Down's Syndrome with Use of Maternal Serum Markers

Abstract Background. Approximately 35 percent of all cases of Downs 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 Downs syndrome. Methods. We prospectively screened 25,207 women and adolescents in the second trimester of pregnancy and assigned each a risk of fetal Downs 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 Downs syndrome of at least 1 in 190, and 962 (3.8 percent) were offered amniocentesis for chromosomal analysis after verification of gestationa...

Screening of Maternal Serum for Fetal Down's Syndrome in the First Trimester

BACKGROUND Screening of maternal serum to identify fetuses with Downs syndrome is now routinely offered during the second trimester of pregnancy. Prenatal screening by means of serum assays or ultrasonographic measurements, either alone or in combination, may also be possible in the first trimester. METHODS We measured serum alpha-fetoprotein, unconjugated estriol, human chorionic gonadotropin (hCG), the free beta subunit of hCG, and pregnancy-associated protein A in 4412 women (82 percent of whom were 35 years of age or older) who came to 16 prenatal diagnostic centers for chorionic-villus sampling or early amniocentesis at 9 to 15 weeks of gestation. Ultrasound measurements of fetal nuchal translucency were also reported. Fetal chromosomal analysis was performed in all pregnancies. Altogether, there were 61 fetuses with Downs syndrome. RESULTS A total of 48 pregnancies affected by Downs syndrome and 3169 unaffected pregnancies were identified before 14 weeks of gestation; the rates of detection of Downs syndrome for the five serum markers were as follows: 17 percent for alpha-fetoprotein, 4 percent for unconjugated estriol, 29 percent for hCG, 25 percent for the free beta subunit of hCG, and 42 percent for pregnancy-associated protein A, at false positive rates of 5 percent. The results of the measurements of serum hCG and its free beta subunit were highly correlated. When used in combination with the serum concentration of pregnancy-associated protein A and maternal age, the detection rate was 63 percent for hCG (95 percent confidence interval, 47 to 76 percent) and 60 percent for its free beta subunit (95 percent confidence interval, 45 to 74 percent). Measurements of nuchal translucency varied considerably between centers and could not be reliably incorporated into our calculations. CONCLUSIONS Screening for Downs syndrome in the first trimester is feasible, with use of measurements of pregnancy-associated protein A and either hCG or its free beta subunit in maternal serum.

Cigarette consumption and serum cotinine in relation to birthweight.

The concentration of serum cotinine (the major metabolite of nicotine) was measured in sera from 4211 women at between 15 and 21 weeks gestation to determine whether a serum cotinine level was a better predictor of low birthweight than the self‐reported number of cigarettes smoked per day. Both cotinine levels and smoking history were significantly associated with reduced birthweight, but cotinine correlated significantly better. Smokers of ≤25 cigarettes per day, representing the 2·7% of women with the greatest cigarette consumption, had infants 289 g lighter than the 68% of women who were non‐smokers. Women with serum cotinine levels in the top 2·7% (≤284 ng/ml) had infants 441 g lighter than the 68% of women with the lowest cotinine levels (≤24 ng/ml). Our results strengthen the evidence linking smoking with low birthweight and also demonstrate that cotinine can be satisfactorily used to assess and monitor cigarette smoking in pregnancy.

REFINEMENTS IN MANAGING MATERNAL WEIGHT ADJUSTMENT FOR INTERPRETING PRENATAL SCREENING RESULTS

This study examines the relationship between maternal weight and serum levels of alpha‐fetoprotein, unconjugated oestriol, and human chorionic gonadotropin in a population of 47 585 women being provided with prenatal screening for Downs syndrome and open neural tube defects. The study population contains sufficient numbers of women at the extremes of weight to allow the determination that a reciprocal‐linear equation more accurately describes the weight relationship for two of the three analytes than the currently used log‐linear equations. The reciprocal‐linear equations, while more appropriate, provide only a minimal advantage over the log‐linear equations. A more important finding is that published weight equations may not be optimal for some screening programmes, due to differences in the mean weight of the populations being tested. Screening programmes are encouraged to calculate their own weight correction formulae, based on data from their own population, and to monitor the mean maternal weight to detect when modifications in the weight correction formulae might be indicated.

MULTIPLE MARKER SCREENING FOR DOWN SYNDROME IN TWIN PREGNANCIES

This study documents the screening performance, in practice, of a published protocol for interpreting second‐trimester Down syndrome risk in twin pregnancies, using maternal serum biochemical markers. Within a cohort of 35 150 pregnancies, 410 twin pregnancies were identified. The rate of twinning was positively associated with maternal age. Of the 274 twin pregnancies known prior to screening, 15 (5·5 per cent) were classified as being screen‐positive for Down syndrome. When maternal age and dating method were taken into account, the screen‐positive rates in twin and singleton pregnancies did not differ significantly. Nine of the 14 screen‐positive women with viable twin pregnancies chose amniocentesis [64 per cent, 95 per cent confidence interval (CI) 35–87]. No cases of Down syndrome were identified. Based on modelling, an estimated 73 per cent of monozygotic twin pregnancies and 43 per cent of dizygotic twin pregnancies with Down syndrome would be identified at a 5 per cent false‐positive rate. The overall detection rate would be about 53 per cent. When laboratories offer multiple marker screening to women with twin pregnancies, the false‐positive rate ought to be similar to that found in singleton pregnancies; the detection rate is, however, likely to be lower for dizygotic twins.

Maternal Serum Screening for Down Syndrome in Early Pregnancy

The possibility of improving the effectiveness of antenatal screening for Downs syndrome by measuring human chorionic gonadotrophin concentrations in maternal serum during the second trimester to select women for diagnostic amniocentesis was examined. The median maternal serum human chorionic gonadotrophin concentration in 77 pregnancies associated with Downs syndrome was twice the median concentration in 385 unaffected pregnancies matched for maternal age, gestational age, and duration of storage of the serum sample. Measuring human chorionic gonadotrophin in maternal serum was an effective screening test, giving a lower false positive rate (3%) at a 30% detection rate than that for maternal age (5%) and the two existing serum screening tests, unconjugated oestriol (7%) and alpha fetoprotein (11%). The most effective screening results were obtained with all four variables combined; at the same 30% detection rate the false positive rate declined to 0.5%. The new screening method would detect over 60% of affected pregnancies, more than double that achievable with the same amniocentesis rate in existing programmes (5%), and could reduce the number of children born with Downs syndrome in the United Kingdom from about 900 a year to about 350 a year.

Second-trimester serum cotinine levels in nonsmokers in relation to birth weight

In this study the relationship between birth weight and passive exposure to tobacco smoke is assessed for the first time by serum cotinine measurements. Among 1231 nonsmoking white women whose blood was sampled during the second trimester of pregnancy, 31.4% had serum cotinine levels between 1.0 and 9.9 ng/ml and were therefore considered to be passively exposed to tobacco smoke. The crude mean birth weight of infants of the women passively exposed to smoke was 107 gm lower than that of infants of unexposed women, and that difference remained after the application of a multivariate analysis that included the major known birth weight-associated covariates. These findings are consistent with a causal relationship between passive exposure to tobacco smoke and birth weight and suggest that the dose-response relationship may not be linear.