Bias analyses to investigate the impact of differential participation: Application to a birth defects case-control study.

BACKGROUND: Certain associations observed in the National Birth Defects Prevention Study (NBDPS) contrasted with other research or were from areas with mixed findings, including no decrease in odds of spina bifida with periconceptional folic acid supplementation, moderately increased cleft palate odds with ondansetron use and reduced hypospadias odds with maternal smoking. OBJECTIVES: To investigate the plausibility and extent of differential participation to produce effect estimates observed in NBDPS. METHODS: We searched the literature for factors related to these exposures and participation and conducted deterministic quantitative bias analyses. We estimated case-control participation and expected exposure prevalence based on internal and external reports, respectively. For the folic acid-spina bifida and ondansetron-cleft palate analyses, we hypothesized the true odds ratio (OR) based on prior studies and quantified the degree of exposure over- (or under-) representation to produce the crude OR (cOR) in NBDPS. For the smoking-hypospadias analysis, we estimated the extent of selection bias needed to nullify the association as well as the maximum potential harmful OR. RESULTS: Under our assumptions (participation, exposure prevalence, true OR), there was overrepresentation of folic acid use and underrepresentation of ondansetron use and smoking among participants. Folic acid-exposed spina bifida cases would need to have been ≥1.2× more likely to participate than exposed controls to yield the observed null cOR. Ondansetron-exposed cleft palate cases would need to have been 1.6× more likely to participate than exposed controls if the true OR is null. Smoking-exposed hypospadias cases would need to have been ≥1.2 times less likely to participate than exposed controls for the association to falsely appear protective (upper bound of selection bias adjusted smoking-hypospadias OR = 2.02). CONCLUSIONS: Differential participation could partly explain certain associations observed in NBDPS, but questions remain about why. Potential impacts of other systematic errors (e.g. exposure misclassification) could be informed by additional research.

Gestational thyroid hormone concentrations and risk of attention-deficit hyperactivity disorder in the Norwegian Mother, Father and Child Cohort Study.

BACKGROUND: Maternal thyroid function plays an important role in foetal brain development; however, little consensus exists regarding the relationship between normal variability in thyroid hormones and common neurodevelopmental disorders, such as attention-deficit hyperactivity disorder (ADHD). OBJECTIVE: We sought to examine the association between mid-pregnancy maternal thyroid function and risk of clinically diagnosed ADHD in offspring. METHODS: We conducted a nested case-control study in the Norwegian Mother, Father and Child Cohort Study. Among children born 2003 or later, we randomly sampled singleton ADHD cases obtained through linkage with the Norwegian Patient Registry (n = 298) and 554 controls. Concentrations of maternal triiodothyronine (T3), thyroxine (T4), T3-Uptake, thyroid-stimulating hormone (TSH) and thyroid peroxidase antibody (TPO-Ab) were measured in maternal plasma, collected at approximately 17 weeks' gestation. Indices of free T4 (FT4i) and free T3 (FT3i) were calculated. We used multivariable adjusted logistic regression to calculate odds ratios and accounted for missing covariate data using multiple imputation. We used restricted cubic splines to assess non-linear trends and provide flexible representations. We examined effect measure modification by dietary iodine and selenium intake. In sensitivity analyses, we excluded women with clinically significant thyroid disorders (n = 73). RESULTS: High maternal T3 was associated with increased risk of ADHD (5th vs 1st quintile odds ratio  2.27, 95% confidence interval 1.21, 4.26). For FT4i, both the lowest and highest quintiles were associated with an approximate 1.6-fold increase in risk of ADHD, with similar trends found for T4. The FT4i association was modified by dietary iodine intake such that the highest risk strata were confined to the low intake group. CONCLUSIONS: Both high and low concentrations of maternal thyroid hormones, although within population reference ranges, increase the risk of ADHD in offspring. Increased susceptibility may be found among women with low dietary intake of iodine and selenium.

Potential of using visual imagery to revolutionise measurement of emotional health.

Appropriate measurement of emotional health by all those working with children and young people is an increasing focus for professional practice. Most of the tools used for assessment or self-assessment of emotional health were designed in the mid-20th century using language and technology derived from pen and paper written texts. However, are they fit for purpose in an age of pervasive computing with increasingly rich audiovisual media devices being in the hands of young people? This thought piece explores how the increased use of visual imagery, especially forms that can be viewed or created on digital devices, might provide a way forward for more effective measuring of emotional health, including smiley faces, other emojis and other potential forms of visual imagery. The authors bring together perspectives from healthcare, counselling, youth advocacy, academic research, primary care and school-based mental health support to explore these issues.

Maternal dietary patterns are associated with risk of neural tube and congenital heart defects.

Studying empirically derived dietary patterns is useful in understanding dietary practice. We classified women by their dietary patterns using latent class analysis of 66 foods and studied the association of these patterns with neural tube defects (NTDs) and congenital heart defects (CHDs) in the U.S. National Birth Defects Prevention Study (1997-2005). Logistic regression models used data from 1,047 with an NTD, 6,641 with a CHD, and 6,123 controls that were adjusted for maternal characteristics and tested the effect modification of multivitamin supplement use. Four latent dietary patterns were identified: prudent, Western, low-calorie Western, and Mexican. Among participants who did not use supplements, those in the Mexican, Western, and low-calorie Western classes were significantly more likely (odds ratios of 1.6, 1.5, and 1.4, respectively) to have offspring born with NTDs than were those in the prudent class after adjustment of for dietary folic acid intake. In contrast, among supplement users, there was no difference in the incidence of NTDs between classes. Associations between dietary class and CHD subgroups were not modified by supplement use except for tetralogy of Fallot; among supplement users, those in the Western class were twice as likely (95% confidence interval: 1.4, 2.8) as the prudent class to have offspring with tetralogy of Fallot. Women who adhered to a Western diet were 1.2 (95% confidence interval: 1.03, 1.35) times more likely to have an infant with septal heart defect than were women who adhered to a prudent diet. A prudent dietary pattern, even with folate fortification, may decrease the risk of NTDs and some heart defects.

Breastfeeding and long-chain polyunsaturated fatty acid intake in the first 4 post-natal months and infant cognitive development: an observational study.

The aim of this study was to examine infant feeding and the long-chain polyunsaturated fatty acid (LCPUFA) concentration of breast milk and formulas in relation to infant development. The prospective Pregnancy, Infection and Nutrition Study (n=358) collected data on breastfeeding, breast milk samples and the formulas fed through 4months post-partum. At 12months of age, infants' development was assessed (Mullen Scales of Early Learning). Linear regression was used to examine development in relation to breastfeeding, breast milk docosahexaenoic acid (DHA) and arachidonic acid (AA) concentration, and DHA and AA concentration from the combination of breast milk and formula. The median breast milk DHA concentration was 0.20% of total fatty acids [interquartile range (IQR)=0.14, 0.34]; median AA concentration was 0.52% (IQR=0.44, 0.63). Upon adjustment for preterm birth, sex, smoking, race and ethnicity and education, breastfeeding exclusivity was unrelated to development. Among infants exclusively breastfed, breast milk LCPUFA concentration was not associated with development (Mullen composite, DHA: adjusted ß=-1.3, 95% confidence interval: -10.3, 7.7). Variables combining DHA and AA concentrations from breast milk and formula, weighted by their contribution to diet, were unassociated with development. We found no evidence of enhanced infant development related to the LCPUFA content of breast milk or formula consumed during the first four post-natal months.

The effect of fetal heart rate on the peak systolic velocity of the fetal middle cerebral artery.

OBJECTIVE: To estimate the effect of an increase in the basal heart rate of the fetus on the middle cerebral artery peak systolic velocity (MCA-PSV). METHODS: This was a prospective longitudinal cohort. Patients between 14 and 36 weeks of gestation were enrolled (N=66). Ultrasound examinations were performed monthly. MCA-PSV measurements were assessed at 0-degree angle of insonation at basal fetal heart rate and after application of vibroacoustic stimulation. RESULTS: A total of 514 MCA-PSV measurements were obtained in 66 fetuses. No difference in fetal heart rate before and after vibroacoustic stimulation was noted before 27 weeks of gestation. A significant increase in fetal heart rate after vibroacoustic stimulation was detected from a mean+/-standard deviation gestational age of 27.1+/-1.3 weeks onward. A significant decrease in the MCA-PSV was noted between before vibroacoustic stimulation and after vibroacoustic stimulation measurements for examinations 3,4, and 5 (P<.001 for all). CONCLUSION: Acceleration of the fetal heart rate in the third trimester is associated with a decrease in the middle cerebral artery peak systolic velocity. Assessment of the MCA-PSV for the detection of fetal anemia, particularly in the third trimester, should be undertaken during a period of baseline fetal heart rate to avoid the potential of a false-negative result. LEVEL OF EVIDENCE: II.

Self-reported vitamin supplementation in early pregnancy and risk of miscarriage.

Miscarriage is a common and poorly understood adverse pregnancy outcome. In this study, the authors sought to evaluate the relation between self-reported use of prenatal vitamins in early pregnancy and the risk of miscarriage. Between 2000 and 2008, 4,752 US women were prospectively enrolled in Right From the Start. Information about vitamin use was obtained from a first-trimester interview. Discrete-time hazard models were used, candidate confounders were assessed, and the following variables were included in the model: study site, maternal age, gravidity, marital status, education, race/ethnicity, smoking, and use of progesterone in early pregnancy. Approximately 95% of participants reported use of vitamins during early pregnancy. A total of 524 women had a miscarriage. In the final adjusted model, any use of vitamins during pregnancy was associated with decreased odds of miscarriage (odds ratio = 0.43, 95% confidence interval: 0.30, 0.60) in comparison with no exposure. These results should be viewed in the context of a potentially preventive biologic mechanism mitigated by possible confounding by healthy behaviors and practices that are also associated with vitamin supplement use during pregnancy.

Caffeine and miscarriage risk.

BACKGROUND: Coffee and caffeine have been inconsistently found to be associated with increased risk of clinical miscarriage-a potentially important association given the high prevalence of exposure. METHODS: Women were recruited before or early in pregnancy and interviewed regarding sources of caffeine, including assessment of changes over the perinatal period. We identified 2407 clinically-recognized pregnancies resulting in 258 pregnancy losses. We examined the relationship of coffee and caffeine intake with clinically-recognized pregnancy loss prior to 20 weeks' completed gestation, using a discrete-time continuation ratio logistic survival model. RESULTS: Coffee and caffeine consumption at all 3 time points were unrelated to total miscarriage risk and the risk of loss after the interview. Reported exposure at the time of the interview was associated with increased risk among those with losses before the interview. CONCLUSIONS: There is little indication of possible harmful effects of caffeine on miscarriage risk within the range of coffee and caffeine consumption reported, with a suggested reporting bias among women with losses before the interview. The results may reflect exposure misclassification and unmeasured heterogeneity of pregnancy losses.

Maternal food insecurity is associated with increased risk of certain birth defects.

Food insecurity represents a lack of access to enough food to meet basic needs. We hypothesized that food insecurity may increase birth defect risks, because it is an indicator of increased stress or compromised nutrition, which are both implicated in birth defect etiologies. This study used population-based case-control data. Included in the analysis were 1,189 case mothers and 695 control mothers who were interviewed by telephone. We calculated a food insecurity score as the number of affirmative responses to 5 questions from a shortened instrument designed to measure food insecurity. OR for the food insecurity score specified as a linear term indicated that a higher score was associated with increased risk of cleft palate, d-transposition of the great arteries, tetralogy of Fallot, spina bifida, and anencephaly, but not with cleft lip with or without cleft palate, after adjustment for maternal race-ethnicity, education, BMI, intake of folic acid-containing supplements, dietary intake of folate and energy, neighborhood crime, and stressful life events. In addition, several models suggested effect modification by certain factors. For example, for anencephaly, among women with the worst score for neighborhood crime (i.e. 6), the OR associated with a 1-unit change in the food insecurity score was 1.57 (95% CI 1.06, 2.33), whereas among women with a low crime score (i.e. 2), the corresponding OR was 1.16 (95% CI 0.96, 1.38). This study suggests that increased risks of certain birth defects may be included among the negative consequences of food insecurity.

Second trimester folate status and preterm birth.

OBJECTIVE: The purpose of this study was to show that maternal folate status during pregnancy may be related to preterm birth. STUDY DESIGN: Women were recruited at 24 to 29 weeks' gestation from 1995 to 2000 into the Pregnancy, Infection, and Nutrition Study. Those who completed an interview and a food frequency questionnaire, or provided a blood sample for radioassay of serum (n = 2026) and red blood cell (n = 1034) folate were included. RESULTS: Mean daily dietary folate intake was 463 microg (SD +/- 248). Intake