Validation of Claims-Based Algorithm for Lyme Disease, Massachusetts, USA.

Compared with notifiable disease surveillance, claims-based algorithms estimate higher Lyme disease incidence, but their accuracy is unknown. We applied a previously developed Lyme disease algorithm (diagnosis code plus antimicrobial drug prescription dispensing within 30 days) to an administrative claims database in Massachusetts, USA, to identify a Lyme disease cohort during July 2000-June 2019. Clinicians reviewed and adjudicated medical charts from a cohort subset by using national surveillance case definitions. We calculated positive predictive values (PPVs). We identified 12,229 Lyme disease episodes in the claims database and reviewed and adjudicated 128 medical charts. The algorithm's PPV for confirmed, probable, or suspected cases was 93.8% (95% CI 88.1%-97.3%); the PPV was 66.4% (95% CI 57.5%-74.5%) for confirmed and probable cases only. In a high incidence setting, a claims-based algorithm identified cases with a high PPV, suggesting it can be used to assess Lyme disease burden and supplement traditional surveillance data.

Positive Childhood Experiences and Chronic Pain Among Children and Adolescents in the United States.

Positive childhood experiences (PCEs) are associated with better mental and physical health outcomes and moderate the negative effects of adverse childhood experiences (ACEs). However, knowledge of the associations between PCEs and childhood chronic pain is limited. We conducted a cross-sectional analysis of 2019 to 2020 National Survey of Children's Health (NSCH) to evaluate associations between PCEs and childhood chronic pain. Parents of 47,514 children ages 6 to 17 years old reported on their child's exposure to 7 PCEs and 9 ACEs. Associations between PCEs and chronic pain were evaluated using weighted, multivariate logistic regression analyses adjusted for sociodemographic factors. We found that PCEs had dose-dependent associations with pediatric chronic pain; children exposed to higher numbers of PCEs (5-7 PCEs) had the lowest reported rate of chronic pain (7.1%), while children exposed to 2 or fewer PCEs had the highest rate of chronic pain (14.7%). The adjusted analysis confirmed that children experiencing 5 to 7 PCEs had significantly lower odds of chronic pain relative to children experiencing 0 to 2 PCEs (adjusted odds ratio (aOR): .47, 95% confidence interval (CI): .39-.61, P < .0001). PCEs moderated associations between ACEs and chronic pain: among children reporting 2 or more ACEs, those reporting 5 to 7 PCEs were significantly less likely to report chronic pain as compared to children only reporting 0 to 2 PCEs (aOR: .64, 95%CI: .45-.89, P = .009). In conclusion, children with greater PCEs exposure had lower prevalence rates of chronic pain. Furthermore, PCEs was associated with reduced prevalence of chronic pain among children exposed to ACEs. PERSPECTIVE: This article estimates associations between survey-measured PCEs and pediatric chronic pain among children in the United States. Promoting PCEs could improve pediatric pain outcomes.

Combination of Fundal Height and Ultrasound to Predict Small for Gestational Age at Birth.

OBJECTIVE: The objective of the study was to determine whether adding longitudinal measures of fundal height (FH) to the standard cross-sectional FH to trigger third trimester ultrasound estimated fetal weight (EFW) would improve small for gestational age (SGA) prediction. STUDY DESIGN: We developed a longitudinal FH calculator in a secondary analysis of a prospective cohort study of 1,939 nonobese pregnant women who underwent serial FH evaluations at 12 U.S. clinical sites. We evaluated cross-sectional FH measurement ≤ -3 cm at visit 3 (mean: 32.0 ± 1.6 weeks) versus the addition of longitudinal FH up to and including visit 3 to trigger an ultrasound to diagnose SGA defined as birth weight <10th percentile. If the FH cut points were not met, the SGA screen was classified as negative. If FH cut points were met and EFW was <10th percentile, the SGA screen was considered positive. If EFW was ≥10th percentile, the SGA screen was also considered negative. Sensitivity, specificity, and positive predictive value (PPV) and negative predictive value (NPV) were computed. RESULTS: In a comparison of methods, 5.8% of women were classified as at risk of SGA by both cross-sectional and longitudinal classification methods; cross-sectional FH identified an additional 4.0%, and longitudinal fundal height identified a separate, additional 4.5%.Using cross-sectional FH as an ultrasound trigger, EFW had a PPV and NPV for SGA of 69 and 92%, respectively. After adding longitudinal FH, PPV increased to 74%, whereas NPV of 92% remained unchanged; however, the number of women who underwent triggered EFW decreased from 9.7 to 5.7%. CONCLUSION: An innovative approach for calculating longitudinal FH to the standard cross-sectional FH improved identification of SGA birth weight, while simultaneously reducing the number of triggered ultrasounds. As an essentially free-of-charge screening test, our novel method has potential to decrease costs as well as perinatal morbidity and mortality (through better prediction of SGA). KEY POINTS: · We have developed an innovative calculator for fundal height trajectory.. · Longitudinal fundal height improves detection of SGA.. · As a low cost screening test, the fundal height calculator may decrease costs and morbidity through better prediction of SGA..

Travelers' preferences for tick-borne encephalitis vaccination.

BACKGROUND: This study aimed to quantify preferences and risk tolerance for a tick-borne encephalitis (TBE) vaccination. RESEARCH DESIGN AND METHODS: A stated-preference survey instrument was administered to international travelers living in the United States to elicit preferences for a no-cost TBE vaccine when planning an international trip, conditional upon four different qualitative levels of endemic TBE risk. RESULTS: The likelihood of choosing the vaccine increased with a destination's level of endemic risk. Most respondents (94%) would choose to receive the vaccine at the highest risk level presented in the survey (i.e. when multiple TBE cases among humans are reported year after year); 6% of the sample would choose not to receive the vaccine at any risk level. Respondents who engage in outdoor activities were twice as likely as the average respondent to choose vaccination rather than opting out of vaccination, and were one-third more likely than the average respondent to choose to receive the vaccine at the lowest risk level. CONCLUSIONS: Respondents were highly interested in a TBE vaccine, assuming no cost, and most were willing to be vaccinated at all qualitative TBE risk levels. Respondents who participated in outdoor activities were more likely than the average respondent to choose the vaccine.

Maternal Socioeconomic Factors and Racial/Ethnic Differences in Neonatal Anthropometry.

Disparities in birthweight by maternal race/ethnicity are commonly observed. It is unclear to what extent these disparities are correlates of individual socioeconomic factors. In a prospective cohort of 1645 low-risk singleton pregnancies included in the NICHD Fetal Growth Study (2009-2013), neonatal anthropometry was measured by trained personnel using a standard protocol. Socioeconomic characteristics included employment status, marital status, health insurance, annual income, and education. Separate adjusted generalized linear models were fit to both test the effect of race/ethnicity and the interaction of race/ethnicity and socioeconomic characteristics on neonatal anthropometry. Mean infant birthweight, length, head circumference, and abdominal circumference all differed by race/ethnicity (p < 0.001). We observed no statistically significant interactions between race/ethnicity and full-time employment/student status, marital status, insurance, or education in association with birthweight, neonatal exam weight, length, or head or abdominal circumference at examination. The interaction between income and race/ethnicity was significant only for abdominal circumference (p = 0.027), with no other significant interactions for other growth parameters, suggesting that racial/ethnic differences in neonatal anthropometry did not vary by individual socioeconomic factors in low-risk women. Our results do not preclude structural factors, such as lifetime exposure to poverty, as an explanation for racial/ethnic disparities.

Maternal Serum Lipid Trajectories and Association with Pregnancy Loss and Length of Gestation.

OBJECTIVE: We characterized lipid trajectories and investigated lipids and rate of pregnancy lipid change with the risk of pregnancy loss or preterm delivery <37 weeks. STUDY DESIGN: In a secondary analysis of 337 women with one to two prior losses assigned to placebo in a randomized controlled trial at four centers (2007-2012), cholesterol, low- and high-density lipoprotein cholesterol (HDL-C), and triglycerides were measured up to 6 months prepregnancy (time 0) and pregnancy up to 7 visits. Trajectories were created using linear mixed models. Multivariable logistic regression with adjustment for maternal characteristics and cholesterol was performed. RESULTS: Lipids decreased from prepregnancy to 4 to 5 weeks, followed by an increase, and were biphasic or triphasic depending on the lipid component. Between 4 and 8 weeks, for every 1-unit increase in HDL-C, there was a 22% decreased odds of loss <14 weeks (odds ratio: 0.78; 95% confidence interval: 0.60, 0.99) and 24% decreased odds of loss or preterm delivery 14 to <37 weeks (odds ratio: 0.76; 95% confidence interval: 0.60, 0.96). CONCLUSION: There were no associations with other lipid components or other time points. An impaired rise of HDL-C early in pregnancy may signal maladaptation to pregnancy that is associated with pregnancy loss or preterm delivery.

Fetal growth patterns in pregnancy-associated hypertensive disorders: NICHD Fetal Growth Studies.

BACKGROUND: Fetal growth patterns in pregnancy-associated hypertensive disorders is poorly understood because prospective longitudinal data are lacking. OBJECTIVE: The objective of the study was to compare longitudinal fetal growth trajectories between normotensive women and those with pregnancy-associated hypertensive disorders. STUDY DESIGN: This is a study based on data from a prospective longitudinal cohort study of fetal growth performed at 12 US sites (2009-2013). Project gestational age was confirmed by ultrasound between 8 weeks 0 days and 13 weels 6 days, and up to 6 ultrasounds were performed across gestation. Hypertensive disorders were diagnosed based on 2002 American College of Obstetricians and Gynecologists guidelines and grouped hierarchically as severe preeclampsia (including eclampsia or HELLP [hemolysis, elevated liver enzymes, and low platelet count] syndrome), mild preeclampsia, severe gestational hypertension, mild gestational hypertension, or unspecified hypertension. Women without any hypertensive disorder constituted the normotensive group. Growth curves for estimated fetal weight and individual biometric parameters including biparietal diameter, head circumference, abdominal circumference, and femur and humerus length were calculated for each group using linear mixed models with cubic splines. Global and weekly pairwise comparisons were performed between women with a hypertensive disorder compared with normotensive women to analyze differences while adjusting for confounding variables. Delivery gestational age and birthweights were compared among groups. RESULTS: Of 2462 women analyzed, 2296 (93.3%) were normotensive, 63 (2.6%) had mild gestational hypertension, 54 (2.2%) mild preeclampsia, 32 (1.3%) severe preeclampsia, and 17 (0.7%) unspecified hypertension. Compared with normotensive women, those with severe preeclampsia had estimated fetal weights that were reduced between 22 and 38 weeks (all weekly pairwise values of P < .008). Women with severe preeclampsia compared with those without hypertension also had significantly smaller fetal abdominal circumference between 23-31 and 33-37 weeks' gestation (weekly pairwise values of P < .04). Scattered weekly growth differences were noted on other biometric parameters between these 2 groups. The consistent differences in estimated fetal weight and abdominal circumference were not observed between women with other hypertensive disorders and those who were normotensive. Women with severe preeclampsia delivered significantly earlier (mean gestational age 35.9 ± 3.2 weeks) than the other groups (global P < .0001). Birthweights in the severe preeclampsia group were also significantly lower (mean -949.5 g [95% confidence interval, -1117.7 to -781.2 g]; P < .0001) than in the normotensive group. CONCLUSION: Among women with pregnancy-associated hypertensive disorders, only those destined to develop severe preeclampsia demonstrated a significant and consistent difference in fetal growth (ie, smaller estimated fetal weight and abdominal circumference) when compared with normotensive women.

Longitudinal changes in maternal anthropometry in relation to neonatal anthropometry.

OBJECTIVE: To characterize the association of longitudinal changes in maternal anthropometric measures with neonatal anthropometry and to assess to what extent late-gestational changes in maternal anthropometry are associated with neonatal body composition. DESIGN: In a prospective cohort of pregnant women, maternal anthropometry was measured at six study visits across pregnancy and after birth, neonates were measured and fat and lean mass calculated. We estimated maternal anthropometric trajectories and separately assessed rate of change in the second (15-28 weeks) and third trimester (28-39 weeks) in relation to neonatal anthropometry. We investigated the extent to which tertiles of third-trimester maternal anthropometry change were associated with neonatal outcomes. SETTING: Women were recruited from twelve US sites (2009-2013).ParticipantsNon-obese women with singleton pregnancies (n 2334). RESULTS: A higher rate of increase in gestational weight gain was associated with larger-birth-weight infants with greater lean and fat mass. In contrast, higher rates of increase in maternal anthropometry measures were not associated with infant birth weight but were associated with decreased neonatal lean mass. In the third trimester, women in the tertile of lowest change in triceps skinfold (-0·57 to -0·06 mm per week) had neonates with 35·8 g more lean mass than neonates of mothers in the middle tertile of rate of change (-0·05 to 0·06 mm per week). CONCLUSIONS: The rate of change in third-trimester maternal anthropometry measures may be related to neonatal lean and fat mass yet have a negligible impact on infant birth weight, indicating that neonatal anthropometry may provide additional information over birth weight alone.

Cost-Effectiveness of the Pneumococcal Conjugate Vaccine (10- or 13-Valent) Versus No Vaccination for a National Immunization Program in Tunisia or Algeria.

INTRODUCTION: To evaluate the expected impact of the Algeria national immunization program (NIP) and potential impact for a Tunisia NIP, this study assessed the public health and economic value of vaccination, through a cost-effectiveness analysis, for a PCV13 or PCV10 NIP, compared with no vaccination. METHODS: A decision-analytic model was programmed in Microsoft Excel™ and adapted to evaluate the clinical and economic outcomes of PCV vaccination. Assuming a steady state, the model estimated invasive pneumococcal disease (IPD; bacteremia and meningitis), all-cause pneumonia (inpatient and outpatient), and all-cause otitis media cases as well as the associated costs from a payer perspective. The base case scenario assumed direct effects for both PCVs and indirect effects (against IPD) for PCV13 only. RESULTS: In Algeria, compared with no vaccination program, PCV13 would save 2177 lives and avoid nearly 349,000 cases of IPD, pneumonia, and AOM at a highly cost-effective value of $308 per QALY. In Tunisia, PCV13 would save 308 lives and avoid 1305 cases of IPD, 4833 cases of pneumonia, and 54,957 cases of AOM at a highly cost-effective value of $848 per QALY. PCV10 prevented 1224 deaths and 270,483 cases of disease in Algeria and prevented 172 deaths and 56,610 cases in Tunisia. PCV10 was cost-effective in both Algeria at $731/QALY and in Tunisia at $1366/QALY. CONCLUSION: The ongoing NIP in Algeria is projected to reduce the impact and economic toll of pneumococcal disease in Algeria. If an NIP were also introduced in Tunisia, a commensurate impact would be expected. PCV NIPs are highly cost-effective, highly impactful public health interventions. FUNDING: Pfizer.

Fetal Growth Patterns in Pregnancies With First-Trimester Bleeding.

OBJECTIVE: To assess the relationship between first-trimester vaginal bleeding and fetal growth patterns. METHODS: We conducted a secondary analysis of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Singletons, a prospective cohort study of low-risk, nonobese women with healthy lifestyles. Duration of bleeding was self-reported at enrollment (10 0/7 to 13 6/7 weeks of gestation) and categorized as 0, 1, or more than 1 day. Longitudinal measures of fetal biometrics were obtained in up to six study visits, and estimated fetal weight was computed. Growth trajectories were created for biometrics and estimated fetal weight. When global tests among groups was significant (P<.05), week-specific global and pairwise differences were tested. Birth weight and risk of a small-for-gestational-age (SGA) neonate were secondary outcomes. All analyses were adjusted for maternal age, weight, height, parity, and racial-ethnic group and neonatal sex in a sensitivity analysis. RESULTS: In 2,307 eligible women, 410 (17.8%) reported first-trimester bleeding, of whom 176 bled for 1 day and 234 bled for more than 1 day. Women with more than 1 day of bleeding demonstrated decreased fetal abdominal circumference from 34 to 39 weeks of gestation compared with women without bleeding. For women with more than 1 day of bleeding, compared with women without bleeding, estimated fetal weight was 68-107 g smaller from 35 to 39 weeks of gestation. Mean birth weight at term was 88 g smaller, confirming differences in calculated fetal weight, and SGA neonates were delivered to 148 (8.5%), 9 (5.7%), and 33 (15.7%) women in the no bleeding, 1 day, and more than 1 day of bleeding groups, respectively. CONCLUSION: More than 1 day of first-trimester vaginal bleeding was associated with smaller estimated fetal weight late in pregnancy driven by smaller abdominal circumference. The magnitude of decrease in birth weight was small, albeit comparable with observed decreases associated with maternal smoking. It remains unknown whether early pregnancy bleeding is associated with short-term or long-term morbidity and whether additional intervention would be of benefit. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00912132.

Combined Influence of Gestational Weight Gain and Estimated Fetal Weight on Risk Assessment for Small- or Large-for-Gestational-Age Birth Weight: A Prospective Cohort Study.

OBJECTIVES: To evaluate the frequency with which gestational weight gain and estimated fetal weight do not track across gestation and to assess the risk of small-for-gestational-age (SGA) and large-for-gestational-age (LGA) birth weight as a function of tracking. METHODS: This study included a pregnancy cohort (2009-2013) of 2438 women from 4 racial/ethnic groups in the United States. We calculated race- and trimester-specific gestational weight gain and estimated fetal weight z scores. The prevalence of how often gestational weight gain and estimated fetal weight did not or did directly track was examined by grouping z scores into measure-specific categories (<-1 SD, -1 to + 1 SD, and >1 SD) and then examining 2-measure combinations. Trimester-specific relative risks for SGA and LGA births were estimated with a gestational weight gain and estimated fetal weight z score interaction. We estimated coefficients for selected gestational weight gain and estimated fetal weight values (-1 SD, 0 SD, and +1 SD) compared with the referent of 0 SD for both measures. Small and large for gestational age were calculated as birth weight below the 10th and at or above the 90th percentiles, respectively. RESULTS: Gestational weight gain and estimated fetal weight were within 1 SD 55.5%, 51.5%, and 48.2% of the time in the first, second, and third trimesters, respectively. There was no significant interaction between gestational weight gain and estimated fetal weight on the risk of SGA in the first and second trimesters (interaction term P = .48; P = .79). In the third trimester, there was a significant interaction (P = .002), resulting in a 71% (95% confidence interval, 1.45-2.02) increased risk of SGA when estimated fetal weight was low and gestational weight gain was high. These relationships were similar for the risk of LGA. CONCLUSIONS: Deviations in either measure, even in the presence of average gestational weight gain or estimated fetal weight, still suggest an increased risk of SGA and LGA.

Patterns of gestational weight gain and birthweight outcomes in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Singletons: a prospective study.

BACKGROUND: Inadequate or excessive total gestational weight gain is associated with increased risks of small- and large-for-gestational-age births, respectively, but evidence is sparse regarding overall and trimester-specific patterns of gestational weight gain in relation to these risks. Characterizing the interrelationship between patterns of gestational weight gain across trimesters can reveal whether the trajectory of gestational weight gain in the first trimester sets the path for gestational weight gain in subsequent trimesters, thereby serving as an early marker for at-risk pregnancies. OBJECTIVE: We sought to describe overall trajectories of gestational weight gain across gestation and assess the risk of adverse birthweight outcomes associated with the overall trajectory and whether the timing of gestational weight gain (first vs second/third trimester) is differentially associated with adverse outcomes. STUDY DESIGN: We conducted a secondary analysis of a prospective cohort of 2802 singleton pregnancies from 12 US prenatal centers (2009 through 2013). Small and large for gestational age were calculated using sex-specific birthweight references <5th, <10th, or ≥90th percentiles, respectively. At each of the research visits, women's weight was measured following a standardized anthropometric protocol. Maternal weight at antenatal clinical visits was also abstracted from the prenatal records. Semiparametric, group-based, latent class, trajectory models estimated overall gestational weight gain and separate first- and second-/third-trimester trajectories to assess tracking. Robust Poisson regression was used to estimate the relative risk of small- and large-for-gestational-age outcomes by the probability of trajectory membership. We tested whether relationships were modified by prepregnancy body mass index. RESULTS: There were 2779 women with a mean of 15 (SD 5) weights measured across gestation. Four distinct gestational weight gain trajectories were identified based on the lowest Bayesian information criterion value, classifying 10.0%, 41.8%, 39.2%, and 9.0% of the population from lowest to highest weight gain trajectories, with an inflection at 14 weeks. The average rate in each trajectory group from lowest to highest for 0-<14 weeks was -0.20, 0.04, 0.21, and 0.52 kg/wk and for 14-39 weeks was 0.29, 0.48, 0.63, and 0.79 kg/wk, respectively; the second lowest gaining trajectory resembled the Institute of Medicine recommendations and was designated as the reference with the other trajectories classified as low, moderate-high, or high. Accuracy of assignment was assessed and found to be high (median posterior probability 0.99, interquartile range 0.99-1.00). Compared with the referent trajectory, a low overall trajectory, but not other trajectories, was associated with a 1.55-fold (95% confidence interval, 1.06-2.25) and 1.58-fold (95% confidence interval, 0.88-2.82) increased risk of small-for-gestational-age <10th and <5th, respectively, while a moderate-high and high trajectory were associated with a 1.78-fold (95% confidence interval, 1.31-2.41) and 2.45-fold (95% confidence interval, 1.66-3.61) increased risk of large for gestational age, respectively. In a separate analysis investigating whether early (<14 weeks) gestational weight gain tracked with later (≥14 weeks) gestational weight gain, only 49% (n = 127) of women in the low first-trimester trajectory group continued as low in the second/third trimester, and had a 1.59-fold increased risk of small for gestational age; for the other 51% (n = 129) of women without a subsequently low second-/third-trimester gestational weight gain trajectory, there was no increased risk of small for gestational age (relative risk, 0.75; 95% confidence interval, 0.47-1.38). Prepregnancy body mass index did not modify the association between gestational weight gain trajectory and small for gestational age (P = 0.52) or large for gestational age (P = .69). CONCLUSION: Our findings are reassuring for women who experience weight loss or excessive weight gain in the first trimester; however, the risk of small or large for gestational age is significantly increased if women gain weight below or above the reference trajectory in the second/third trimester.

Maternal stress and neonatal anthropometry: the NICHD Fetal Growth Studies.

BACKGROUND: The effect of maternal mood disorders on neonatal measurements is not well-defined. The Fetal Growth Studies-Singletons provide a unique opportunity to evaluate the relationship between perceived maternal stress and neonatal growth measurements. OBJECTIVE: The purpose of this study was to determine whether perceived maternal stress during pregnancy is associated with anthropometric measurements in the neonate. STUDY DESIGN: This analysis was based on a prospective, multicenter longitudinal study of fetal growth. Women 18-40 years old with a body mass index of 19.0-29.9 kg/m2 were screened at 8+0 to 13+6 weeks gestation for low-risk status associated with optimal fetal growth (eg, healthy, nonsmoking) and underwent serial sonographic examination at 6 study visits throughout gestation. At each study visit, women completed the Cohen's Perceived Stress Survey, which could have a score that ranges from 0-40. We used a latent class trajectory model to identify distinct groupings (ie, classes) of the Perceived Stress Survey trajectories over pregnancy. Trend analysis was used to determine whether neonatal measurements including birthweight, length, head circumference, and abdominal circumference differed by Perceived Stress Survey class and whether this relationship was modified by maternal race/ethnicity, after adjustment for gestational age at delivery, maternal height, age, and parity. RESULTS: Of the 2334 women enrolled in the study, 1948 women had complete neonatal anthropometry and were included in the analysis. Latent class analysis identified 3 Perceived Stress Survey trajectory classes, with mean Perceived Stress Survey scores of 2.82 (low), 7.95 (medium), and 14.80 (high). Neonatal anthropometric measures of birthweight, length, head circumference and abdominal circumference were similar (P=.78, =.10, =.18, and =.40 respectively), regardless of the participants' Perceived Stress Survey class. There was no effect modification by maternal race/ethnicity. CONCLUSION: Neonatal measurements did not differ by levels of perceived stress among low-risk pregnant women.

Preconception maternal lipoprotein levels in relation to fecundability.

STUDY QUESTION: Are maternal preconception lipid levels associated with fecundability? SUMMARY ANSWER: Fecundability was reduced for all abnormal female lipid levels including total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and total triglyceride levels. WHAT IS KNOWN ALREADY: Subfecundity affects 7-15% of the population and lipid disorders are hypothesized to play a role since cholesterol acts as a substrate for the synthesis of steroid hormones. Evidence illustrating this relationship at the mechanistic level is mounting but few studies in humans have explored the role of preconception lipids in fecundity. STUDY DESIGN, SIZE, DURATION: A secondary analysis of the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial (2007-2011), a block-randomized, double-blind, placebo-controlled trial. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 1228 women, with 1-2 prior pregnancy losses and without a diagnosis of infertility, attempting pregnancy for up to six menstrual cycles were recruited from clinical sites in Utah, New York, PA and Colorado. Time to pregnancy was the number of menstrual cycles to pregnancy as determined by positive hCG test or ultrasound. Individual preconception lipoproteins were measured at baseline, prior to treatment randomization and dichotomized based on clinically accepted cut-points as total cholesterol ≥200 mg/dl, LDL-C ≥130 mg/dl, HDL-C <50 mg/dl and triglycerides ≥150 mg/dl. MAIN RESULTS AND THE ROLE OF CHANCE: There were 148 (12.3%) women with elevated total cholesterol, 94 (7.9%) with elevated LDL-C, 280 (23.2%) with elevated triglycerides and 606 (50.7%) with low HDL-C. The fecundability odds ratio (FOR) was reduced for all abnormal lipids before and after confounder adjustment, indicating reduced fecundability. Total cholesterol ≥200 mg/dl was associated with 24% (FOR: 0.76, 95% CI: 0.59, 0.97) and 29% (FOR: 0.71, 95% CI: 0.55, 0.93) reduced fecundability for hCG-detected and ultrasound-confirmed pregnancy, respectively, compared with total cholesterol <200 mg/dl. There was a 19-36% decrease in the probability of conception per cycle for women with abnormal lipoprotein levels, though additional adjustment for central adiposity and BMI attenuated observed associations. LIMITATIONS, REASONS FOR CAUTION: Although the FOR is a measure of couple fecundability, we had only measures of female lipid levels and can therefore not confirm the findings from a previous study indicating the independent role of male lipids in fecundity. The attenuated estimates and decreased precision after adjustment for central adiposity and obesity indicate the complexity of potential causal lipid pathways, suggesting other factors related to obesity besides dyslipidemia likely contribute to reduced fecundability. WIDER IMPLICATIONS OF THE FINDINGS: Our results are consistent with one other study relating preconception lipid concentrations to fecundity and expand these findings by adding critically important information about individual lipoproteins. As lipid levels are modifiable they may offer an inexpensive target to improve female fecundability. STUDY FUNDING AND COMPETING INTEREST(S): This study was funded by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The authors have declared that no conflicts of interest exist. TRIAL REGISTRATION NUMBER: #NCT00467363.

Low Gestational Weight Gain and Risk of Adverse Perinatal Outcomes in Obese and Severely Obese Women.

BACKGROUND: Our objective was to estimate associations between gestational weight gain z scores and preterm birth, neonatal intensive care unit admission, large- and small-for-gestational age birth, and cesarean delivery among grades 1, 2, and 3 obese women. METHODS: We included singleton infants born in Pennsylvania (2003-2011) to grade 1 (body mass index 30-34.9 kg/m, n = 148,335), grade 2 (35-39.9 kg/m, n = 72,032), or grade 3 (≥40 kg/m, n = 47,494) obese mothers. Total pregnancy weight gain (kg) was converted to gestational age-standardized z scores. Multivariable Poisson regression models stratified by obesity grade were used to estimate associations between z scores and outcomes. A probabilistic bias analysis, informed by an internal validation study, evaluated the impact of body mass index and weight gain misclassification. RESULTS: Risks of adverse outcomes did not substantially vary within the range of z scores equivalent to 40-week weight gains of -4.3 to 9 kg for grade 1 obese, -8.2 to 5.6 kg for grade 2 obese, and -12 to -2.3 kg for grade 3 obese women. As gestational weight gain increased beyond these z score ranges, there were slight declines in risk of small-for-gestational age birth but rapid rises in cesarean delivery and large-for-gestational age birth. Risks of preterm birth and neonatal intensive care unit admission were weakly associated with weight gain. The bias analysis supported the validity of the conventional analysis. CONCLUSIONS: Gestational weight gain below national recommendations for obese mothers (5-9 kg) may not be adversely associated with fetal growth, gestational age at delivery, or mode of delivery.

Child academic achievement in association with pre-pregnancy obesity and gestational weight gain.

BACKGROUND: Recent data suggest that children of mothers who are obese before pregnancy, or who gain too much weight during pregnancy, may be at an increased risk of cognitive impairments. METHODS: Mother-infant dyads enrolled in a birth cohort study in Pittsburgh, Pennsylvania (1983-1986), were followed from early pregnancy to 14 years postpartum (n=574). Math, reading and spelling achievements were assessed at ages 6 and 10 years using the Wide Range Achievement Test-Revised, and at age 14 years using the Wechsler Individual Achievement Test Screener. Self-reported total GWG was converted to gestational age-standardised z-scores. Generalised estimating equations were used to estimate the effects of GWG and pre-pregnancy body mass index (BMI) on academic achievement at 6, 10 and 14 years, while adjusting for maternal race, child sex, parity, employment, family income, maternal intelligence, maternal depression, pre-pregnancy BMI (in GWG models only) and the home environment. RESULTS: The mean (SD) BMI was 23.4 (5.7) kg/m(2) and the mean (SD) GWG reported at delivery was 14.4 (5.9) kg. There was a significant non-linear association between pre-pregnancy BMI and an offspring's academic achievement. At 6, 10 and 14 years, an offspring's academic scores were inversely associated with pre-pregnancy BMI beyond 22 kg/m(2). High GWG (>1 SD) was associated with approximately 4-point lower reading (adjusted ß (adjß) -3.75, 95% CI -7.1 to -0.4) and spelling scores (adjß -3.90, 95% CI -7.8 to -0.2), compared with GWG -1 to +1 SD. CONCLUSIONS: Future studies in larger and socioeconomically diverse populations are needed to confirm maternal weight and weight gain as causal determinants of a child's academic skills, and whether this effect persists into adulthood.

Maternal Obesity and Excessive Gestational Weight Gain Are Associated with Components of Child Cognition.

BACKGROUND: Maternal overweight and obesity affect two-thirds of women of childbearing age and may increase the risk of impaired child cognition. OBJECTIVE: Our objective was to test the hypothesis that high/low gestational weight gain (GWG) and high/low prepregnancy BMI were associated with offspring intelligence quotient (IQ) and executive function at age 10. METHODS: Mother-infant dyads (n = 763) enrolled in a birth cohort study were followed from early pregnancy to 10 y postpartum. IQ was assessed by trained examiners with the use of the Stanford Binet Intelligence Scale-4th edition. Executive function was assessed by the number of perseverative errors on the Wisconsin Card Sorting Test and time to complete Part B on the Trail Making Test. Self-reported total GWG was converted to gestational-age-standardized GWG z score. Multivariable linear regression and negative binomial regression were used to estimate independent and joint effects of GWG and BMI on outcomes while adjusting for covariates. RESULTS: At enrollment, the majority of women in the Maternal Health Practices and Child Development cohort were unmarried and unemployed, and more than one-half reported their race as black. The mean ± SD GWG z score was -0.5 ± 1.8, and 27% of women had a pregravid BMI ≥ 25. The median (IQR) number of perseverative errors was 23 (17, 29), the mean ± SD time on Part B was 103 ± 42.6 s, and 44% of children had a low average IQ (≤ 89). Maternal obesity was associated with 3.2 lower IQ points (95% CI: -5.6, -0.8) and a slower time to complete the executive function scale Part B (adjusted ß: 12.7 s; 95% CI: 2.8, 23 s) compared with offspring of normal-weight mothers. Offspring of mothers whose GWG was >+1 SD, compared with -1 to +1 SD, performed 15 s slower on the executive function task (95% CI: 1.8, 28 s). There was no association between GWG z score and offspring composite IQ score (adjusted ß: -0.32; 95% CI: -0.72, 0.10). Prepregnancy BMI did not modify these associations. CONCLUSIONS: Although GWG may be important for executive function, maternal BMI has a stronger relation than GWG to both offspring intelligence and executive function. Our findings contribute to evidence linking maternal obesity to long-term child outcomes.

Maternal prepregnancy obesity and cause-specific stillbirth.

BACKGROUND: In high-income countries, maternal obesity is one of the most important modifiable causes of stillbirth, yet the pathways underpinning this association remain unclear. OBJECTIVE: We estimated the association between maternal prepregnancy body mass index (BMI) and the risk of stillbirth defined by pathophysiologic contributors or causes. DESIGN: Using a case-cohort design, we randomly sampled 1829 singleton deliveries from a cohort of 68,437 eligible deliveries at Magee-Womens Hospital in Pittsburgh, Pennsylvania (2003-2010), and augmented it with all remaining cases of stillbirth for a total of 658 cases. Stillbirths were classified based on probable cause(s) of death (maternal medical conditions, obstetric complications, fetal abnormalities, placental diseases, and infection). A panel of clinical experts reviewed medical records, placental tissue slides and pathology reports, and fetal postmortem reports of all stillbirths. Causes of fetal death were assigned by using the Stillbirth Collaborative Research Network Initial Causes of Fetal Death protocol from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Proportional hazards models were used to estimate the BMI-stillbirth association after adjustment for confounders. RESULTS: The rate of stillbirth among lean, overweight, obese, and severely obese women was 7.7, 10.6, 13.9, and 17.3 per 1000 live-born and stillborn infants, respectively. Adjusted stillbirth HRs (95% CIs) were 1.4 (1.1, 1.8) for overweight, 1.8 (1.3, 2.4) for obese, and 2.0 (1.5, 2.8) for severely obese women, respectively, compared with lean women; associations strengthened when limited to antepartum stillbirths. Obesity and severe obesity were associated with stillbirth resulting from placental diseases, hypertension, fetal anomalies, and umbilical cord abnormalities. BMI was not related to stillbirth caused by placental abruption, obstetric conditions, or infection. CONCLUSIONS: Multiple mechanisms appear to link obesity to stillbirth. Interventions to reduce stillbirth among obese mothers should consider targeting stillbirth due to hypertension and placental diseases-the most common causes of fetal death in this at-risk group.

Comparison of gestational weight gain z-scores and traditional weight gain measures in relation to perinatal outcomes.

BACKGROUND: Conventional measures of gestational weight gain (GWG) are correlated with pregnancy duration, and may induce bias to studies of GWG and perinatal outcomes. A maternal weight-gain-for-gestational-age z-score chart is a new tool that allows total GWG to be classified as a standardised z-score that is independent of gestational duration. Our objective was to compare associations with perinatal outcomes when GWG was assessed using gestational age-standardised z-scores and conventional GWG measures. METHODS: We studied normal-weight (n=522 120) and overweight (n=237 923) women who delivered liveborn, singleton infants in Pennsylvania, 2003-11. GWG was expressed using gestational age-standardised z-scores and three traditional measures: total GWG (kg), rate of GWG (kg per week of gestation), and the GWG adequacy ratio (observed GWG/GWG recommended by the Institute of Medicine). Log-binomial regression models were used to assess associations between GWG and preterm birth, and small- and large-for-gestational-age births, while adjusting for race/ethnicity, education, smoking, and other confounders. RESULTS: The association between GWG z-score and preterm birth was approximately U-shaped. The risk of preterm birth associated with weight gain <10th percentile of each measure was substantially overestimated when GWG was classified using total kilogram and was moderately overestimated using rate of GWG or GWG adequacy ratio. All GWG measures had similar associations with small- or large-for-gestational-age birth. CONCLUSIONS: Our findings suggest that studies of gestational age-dependent outcomes misspecify associations if total GWG, rate of GWG, or GWG adequacy ratio are used. The potential for gestational age-related bias can be eliminated by using z-score charts to classify total GWG.