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Context: Lower neurocognitive development scores at age 2 yr have been reported in association with euthyroid hypothyroxinemia during early pregnancy. Objective: The objective of this study was to further explore this association with euthyroid hypothyroxinemia during early pregnancy. Design: This was an observational, nested case-control study. Setting: The study was conducted at physician offices and prenatal clinics throughout Maine. Study Subjects: Between May 2004 and March 2006, TSH was measured in 5734 women in conjunction with second-trimester Down syndrome screening. After completion of pregnancy, free T4 was measured in stored second-trimester sera from euthyroid women (TSH 0.1–3.5 mIU/ml; n = 5560). Women with free T4 at the third centile or less (n = 99) were matched with women whose free T4 was at the 10th to the 90th centile (n = 99). Interventions: There were no interventions. Main Outcome Measure: Bayley Scales of Infant Development (BSID III) were administered to the 198 offspring at age 2 yr. Scores for cognitive, language, and motor development were compared between matched pairs of offspring from the two groups before and after correcting for relevant variables. Results: Unadjusted BSID-III scores (cognitive, language, and motor) were lower by about 3% at age 2 yr among offspring of 98 hypothyroxinemic women (cases), reaching borderline significance for cognitive and motor scores. After adjustment for gestational age, the child's age at testing, maternal weight, and education, all differences diminished and became nonsignificant. Scores less than 85 were more frequent among case children but did not reach statistical significance (P = 0.14). Conclusions: Isolated hypothyroxinemia during the second trimester is not associated with significantly lower BSID-III scores at age 2 yr, compared with scores for offspring of matched euthyroxinemic women.

Objective: To further explore first and second trimester reference ranges for thyroid stimulating hormone (TSH) and examine within-person variability of TSH and thyroid peroxidase (TPO) antibody. Setting: Women coming for routine prenatal care in early pregnancy agreed to participate in a trial of integrated serum screening for Down's syndrome. Two serum samples were obtained from each woman, one each in the first and second trimesters. These samples were also available for TSH and TPO measurements in the present study. Methods: TSH and TPO antibody measurements were performed in 1126 women with ultrasound-dated pregnancies who provided serum samples in both trimesters. TSH reference ranges were established for the entire cohort and for the antibody-negative subgroup. Within-person variability of TSH measurements between trimesters was examined. Results: Median TSH values are lower in the first trimester than in the second (1.00 versus 1.29 mIU/l), but 98th centile values are higher (5.20 versus 4.18 mIU/l). High correlation exists between individual women's first and second trimester TSH measurements (r=0.75, r2=0.56, p2=0.94). Conclusion: Proper interpretation of TSH measurements during pregnancy requires that laboratories establish and monitor appropriate reference ranges. TSH levels show high within-person consistency between trimesters.

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.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.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).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.

Objective Cell-free DNA is a marker of cellular apoptosis and necrosis. We wished to determine if maternal smoking affects maternal and fetal serum cell-free DNA levels. Methods Case–control sets of stored second-trimester serum-screening samples from 27 smoking and 90 nonsmoking pregnant women were developed. Smoking status was confirmed by measuring serum cotinine levels. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and DYS1 levels were determined using real-time polymerase chain reaction (PCR) to measure total and fetal cell-free DNA, respectively. At delivery, medical records were reviewed to confirm gender and determine other factors that could affect DNA values. Results Smoking was associated with significantly elevated GAPDH levels compared with nonsmokers (median: 97 662 genome equivalents (GE)/mL vs 38 217 GE/mL; p = 0.018). DYS1 levels were not statistically significantly elevated in smokers (p = 0.29). Other factors that affected DYS1 levels included maternal age in nonsmokers only (r2 = 0.30, p = 0.013) and maternal Synthroid use (p = 0.0045) Conclusion Pregnant smokers have threefold higher levels of total cell-free DNA compared with pregnant nonsmokers. Maternal age and Synthroid exposure may also affect circulating cell-free fetal DNA levels. Copyright © 2008 John Wiley & Sons, Ltd.

We collected information about household smoking habits from 518 mothers when they made their first well child visit with a 6 to 8-week old infant. A urine sample was also collected from the infant, the cotinine concentration measured, and the measurement correlated with data provided by the mother. Eight percent of the infant urine cotinine values fell at or above 10 micrograms/L in the 305 households where no smoking was reported. Corresponding rates were 44 percent in the 96 households where a member other than the mother smoked, 91 percent in the 43 households where only the mother smoked, and 96 percent in the 74 households where both the mother and another household member smoked. In households where the mother smoked, infant urine cotinine levels were lower in the summer, and higher when the infant was breast-fed. A screening question about family smoking habits in conjunction with well child care could effectively define a group of infants exposed to environmental tobacco smoke and thus be at greater risk for respiratory diseases.

Objectives Integrated serum screening for Down syndrome is potentially more effective than current second-trimester screening. We report results of an intervention trial of integrated serum screening that involved 229 primary prenatal care practitioners throughout Maine. Methods Women provided a first-trimester serum (for PAPP-A) followed by a second-trimester serum (for AFP, uE3, hCG, and DIA). These five marker measurements were used to calculate a Down syndrome risk in the second trimester. Screen-positive women (risk ≥ 1:100) were managed according to standard practice. Results During 24 months' enrollment, 11 159 women provided a first-trimester sample (61% of women receiving screening services). Nine thousand seven hundred twenty-three women also provided a second-trimester sample; 8773 women satisfied gestational age criteria for testing in both trimesters. Integrated serum screening detected 14 of 16 Down syndrome cases (87%) and 79% after adjustment for trimester-of-ascertainment bias. The initial false-positive rate was 3.2% and was 2.7% when restricted to ultrasound-dated pregnancies. Performance was better than any combination of second-trimester markers. Implementation challenges included initial samples being collected too early and sample matching. Conclusions Integrated serum screening for Down syndrome was successfully implemented in primary care settings; screening performance was consistent with predictions. It provides an accessible and acceptable alternative to screening protocols that require nuchal translucency measurements. Copyright © 2005 John Wiley & Sons, Ltd.

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.

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.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.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.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.

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.

To examine the relationship between elevated antiphospholipid antibody levels in the maternal circulation and late fetal death, we carried out a case-control study in which levels of anticardiolipin and antiphosphatidylserine antibodies were measured in banked second-trimester sera from 309 pregnancies ending in fetal death and from 618 viable control pregnancies. The sera were obtained from a population base of approximately 22,000 pregnancies enrolled for maternal alpha-fetoprotein screening between 15 and 20 weeks' gestation. The anticardiolipin immunoglobulin G level was markedly elevated (15.6 SD) in one serum sample associated with a fetal death. Otherwise, the anticardiolipin and antiphosphatidylserine measurements were similar in the two populations. Several other factors known to be associated with fetal death were also examined, and these all demonstrated the expected relationship. Antiphospholipid antibody measurements obtained at 15 weeks' gestation or later in the general pregnancy population are not helpful in identifying pregnancies at risk for fetal death.

URATO, JULIETTE MADAN, ROBERT QUINN, ANDREA PULKKINEN, SABRINA D. CRAIGO, Tufts University New England Medical Center, Boston, Massachusetts, Foundation for Blood Research, Scarborough, Maine OBJECTIVE: It is well-established that maternal smoking during pregnancy is associated with several pregnancy complications, including preterm birth. Yet, while many women smoke during pregnancy, it is not known which of these will deliver prematurely. Inhibin A levels are known to be elevated in pregnant smokers compared with nonsmokers. Our objective was to determine if Inhibin A levels in pregnant smokers are associated with preterm delivery. STUDY DESIGN: A retrospective cohort study was performed. 7,795 pregnant smokers were identified in a database of 39,421 pregnant women who participated in a statewide serum screening program from 1999 to 2005. Pregnancy outcomes were obtained from the Maine birth records database that was cross-referenced to the serum screening database. Relative risks and 95% confidence intervals for preterm birth were estimated based on Inhibin A level. RESULTS: In the cohort of 7,795 smokers, there were 726 births 37 weeks (9.31%), 201 births 34 weeks (2.58%), and 76 births 30 weeks (0.97%). For pregnant smokers an elevated Inhibin A level was associated with preterm birth (see Table.) An Inhibin A level 2.0 MOM was found in 195 of the 726 pregnant smokers with a preterm birth 37 weeks (26.9%), 64 of the 201 34 weeks (31.8%), and 25 of the 76 30 weeks (32.9%). CONCLUSION: Pregnant smokers with an Inhibin A level 2.0 MOM are at increased risk of preterm birth. Those pregnant smokers with INH A levels 2.5 are at particularly high risk. A significant proportion of the smokers who will deliver prematurely will have an Inhibin A level 2.0 MOM.

Pregnancy-specific /3 1-glycoprotein (SP1) is produced by the placenta and released into the maternal circulation in steadily increasing amounts, with peak concentrations occurring at the thirty-eighth gestational week. Low SP1 levels have been found in association with intrauterine growth disorders in the third trimester, but this association has been less clear in the second trimester.1 Second-trimester SP, observations have been sparse. We carried out the present study to evaluate further whether a relationship might exist between second-trimester SP1 levels and birth weight and to compare SP1 with a-fetoprotein (AFP), the association of which with birth weight is already well defined. We selected 84 frozen, banked second-trimester serum specimens associated with viable singleton infants s2,500 gm. We then selected an equal number of similarly stored serum samples associated with infants ~3,500 gm, matched for maternal weight and gestational age. Fetal sex distributions were the same in both groups. The population from which samples were obtained was white. SP1 and AFP measurements were performed on these samples by means of radioimmunoassays developed in our laboratory. Median SP1 and AFP values are presented for lowbirth weight and normal-birth weight groups in Table l. While significant differences exist between the groups for both proteins measured, AFP is the more striking of the two. The two graphs in Fig. I contain