Association of common maternal infections with birth outcomes: a multinational cohort study.

PURPOSE: It is unclear whether common maternal infections during pregnancy are risk factors for adverse birth outcomes. We assessed the association between self-reported infections during pregnancy with preterm birth and small-for-gestational-age (SGA) in an international cohort consortium. METHODS: Data on 120,507 pregnant women were obtained from six population-based birth cohorts in Australia, Denmark, Israel, Norway, the UK and the USA. Self-reported common infections during pregnancy included influenza-like illness, common cold, any respiratory tract infection, vaginal thrush, vaginal infections, cystitis, urinary tract infection, and the symptoms fever and diarrhoea. Birth outcomes included preterm birth, low birth weight and SGA. Associations between maternal infections and birth outcomes were first assessed using Poisson regression in each cohort and then pooled using random-effect meta-analysis. Risk ratios (RR) and 95% confidence intervals (CI) were calculated, adjusted for potential confounders. RESULTS: Vaginal infections (pooled RR, 1.10; 95% CI, 1.02-1.20) and urinary tract infections (pooled RR, 1.17; 95% CI, 1.09-1.26) during pregnancy were associated with higher risk of preterm birth. Similar associations with low birth weight were also observed for these two infections. Fever during pregnancy was associated with higher risk of SGA (pooled RR, 1.07; 95% CI, 1.02-1.12). No other significant associations were observed between maternal infections/symptoms and birth outcomes. CONCLUSION: Vaginal infections and urinary infections during pregnancy were associated with a small increased risk of preterm birth and low birth weight, whereas fever was associated with SGA. These findings require confirmation in future studies with laboratory-confirmed infection diagnosis.

Estimating the effect of diuretics and inhaled corticosteroids for evolving bronchopulmonary dysplasia in preterm infants.

BACKGROUND: Off-label treatment of extremely preterm infants with diuretics and inhaled corticosteroids (ICS) for evolving bronchopulmonary dysplasia (BPD) is common. Their effectiveness in reducing mortality or BPD severity, and optimal treatment timing, are unclear. OBJECTIVES: To determine whether diuretic treatment or ICS administration for infants with early evolving (between 10-27 days postnatal) and progressively evolving (28th-day-36th-week postnatal) BPD are independently associated with reduced mortality and moderate or severe BPD at 36-weeks postmenstrual age (PMA). METHODS: We examined neonates born before 28 weeks' gestation and admitted to neonatal intensive care units on postnatal Day 0 between 2006 and 2016 using data collected during routine care recorded within the Paediatric Health Information System (PHIS). An early evolving BPD cohort consisted of infants treated with oxygen, positive pressure or mechanical ventilation at 10 days postnatal. The progressively evolving BPD cohort consisted of infants treated with these modalities at 28 days. In new users, we evaluated the effect of diuretic and ICS treatment on mortality or BPD severity at 36 weeks PMA, adjusting for time-dependent confounding by respiratory status using marginal structural models. RESULTS: Early evolving BPD was present in 10,135 patients; progressively evolving BPD in 11,728. New diuretic exposure during early evolving BPD (adjusted risk ratio [aRR] 0.77, 95% confidence interval [CI] 0.65, 0.93) was associated with decreased mortality or moderate/severe BPD risk. New diuretics (aRR 0.86, 95% CI 0.75, 0.99) during progressively evolving BPD between 28-days-36-weeks PMA were less strongly associated with mortality or moderate/severe BPD reduction. There was no strong association for ICS in patients with early evolving (aRR: 1.40; 95% CI: 0.79, 2.51) or progressively evolving BPD (aRR 1.16, 95% CI 0.95, 1.49). CONCLUSION: Diuretics, but not ICS, for evolving BPD were associated with mortality and BPD risk reduction.

Associations between maternal exposure to surgery or pregnancy exposure to fluorinated anesthetics and children's cognitive development and educational outcomes.

A transgenerational, epigenetic effect of anesthesia, particularly fluorinated agents, has been examined in rat models, but translation to humans is unclear. This study examined associations of maternal lifetime exposure to anesthesia and pregnancy exposure to fluorinated anesthetics with child cognitive and educational outcomes. Women in the US Collaborative Perinatal Project (1959-1963) reported lifetime history of surgeries, and the obstetric record captured pregnancy exposure to anesthetics. Children were followed to age 7 for global cognitive ability and educational outcomes (n=47,977). Logistic and linear regressions were adjusted for maternal and child birth years, race and ethnicity, smoking, education, parity, study site. Many outcomes were not associated with exposure to maternal surgery that occurred at various life stages. However, maternal surgery in early childhood was associated both with being in a special school or not in school (adj OR=1.42; 95% CI 1.02, 1.98) and with slightly better cognitive ability across childhood (e.g., WISC IQ (adj ß=0.59; CI 0.13, 1.04) (especially among boys)). Maternal surgery in puberty was associated with slightly lower IQ (adj ß = -0.42; CI -0.79, -0.05) and poorer spelling at age 7. Children's prenatal exposure to fluorinated anesthetics was associated with slightly better spelling ability (adj ß = 1.20; CI 0.02, 2.38) but lower performance IQ at age 7 (only among boys, adj ß = -1.97; CI -3.88, -0.06). This study shows inconsistent evidence of effects of maternal exposure to surgery or prenatal exposure to fluorinated agents on child developmental and educational outcomes Residual confounding by indication and socioeconomic status may explain observed associations.

Association between Prenatal Marijuana and Tobacco Smoke Exposures and Small for Gestational Age at Birth.

OBJECTIVE: The aim of this study was to determine the association of prenatal marijuana exposure with and without tobacco smoke exposure and small for gestational age (SGA) at birth. STUDY DESIGN: We conducted a secondary analysis of the prospective Lifestyle and Early Achievement in Families (LEAF) cohort enrolled from 2010 to 2015. We included singleton nonanomalous liveborn pregnancies. We assessed marijuana use inclusive of any pregnancy urine specimen with a Δ9-THC-COOH concentration of more than 15 ng/mL by mass spectrometry, self-report on questionnaire, and/or electronic health record; and self-reported maternal tobacco use. Because of the high co-frequency of marijuana with tobacco exposure in pregnancy and the known association between tobacco and fetal growth restriction, we modeled the exposure as: both marijuana and tobacco (hereafter "co-use"), only marijuana, only tobacco, and neither (reference). Incidence of SGA in each group was compared with the neither group. The primary outcome was SGA less than 10th percentile, and secondarily less than 5th percentile, using parity-specific definitions per 2017 US natality reference data. RESULTS: Among 325 assessed mothers, 46% had neither exposure, 11% had only prenatal marijuana exposure, 20% only tobacco exposure, and 23% co-use exposure. A third (33%) of infants were SGA less than 10th percentile and 20% SGA less than 5th percentile. Marijuana exposure only was associated with an increased risk of SGA less than 10th percentile (43 vs. 26%; adjusted relative risk [aRR]: 1.66; 95% confidence interval [CI]: 1.02-2.69), and SGA less than5th percentile (30 vs. 13%; aRR: 2.26; 95% CI: 1.15-4.47). Tobacco was not associated with SGA less than 10th percentile, but was with SGA less than 5th percentile (26 vs. 13%; aRR: 2.01; 95% CI: 1.13, 3.56). Co-use was not associated with increased SGA risk in multivariate analysis, but was in sensitivity analysis when tobacco use was defined using a cotinine assay rather than self-report (SGA <10th percentile, aRR: 1.97; 95% CI: 1.24-3.15) and (SGA <5th percentile, aRR: 2.03; 95% CI: 1.09-3.78). CONCLUSION: Prenatal marijuana exposure in addition to tobacco may increase the risk of SGA. Given the rising prevalence of marijuana use in pregnancy, further research is warranted to understand how in utero marijuana exposure may impact fetal growth and birth weight with and without tobacco exposure. KEY POINTS: · Marijuana and tobacco are commonly used together in pregnancy.. · Prenatal marijuana and tobacco exposure may increase the risk of a small for gestational age infant.. · Further research is warranted to understand how in utero marijuana exposure impacts fetal growth..

Risk Perceptions about Cannabis Use and Receipt of Health-Related Information during Pregnancy.

PURPOSE: To understand risk perception about cannabis use during pregnancy. DESIGN: Mixed -Methods. Setting: Focus groups. Participants: Mothers. METHOD: Focus groups were conducted to learn about person's experiences with pregnancy, health-related behaviors, perception of risky behaviors (cannabis use), and receipt of health-related information during pregnancy. Participants completed the Electronic Health Literacy Scale, the Single Item Literacy Screener, and questions about whether topics were discussed during their prenatal care. Data were coded and analyzed iteratively for emerging themes. Descriptive statistics were used to characterize the sample. RESULTS: Twenty-one persons (mean age = 34.4, 57% African American, 38% White, 5% Multi-racial) participated in 4 focus groups. One-third of the participants used cannabis; 24% used alcohol; and 48% used tobacco during pregnancy. Participant's perceptions and use of cannabis during pregnancy were shaped by relief from pregnancy-related symptoms, recommendations from health care providers that cannabis is safe, anecdotal stories from friends and family, fear associated with prescription medications, and preference for "natural" remedies. The context of distrust of providers permeated these themes. The sample displayed poor e-health literacy compared to other adult samples. CONCLUSION: Inter-related factors that influence cannabis use among persons who are pregnant should be considered when establishing trust between patients and providers, creating messages for patients about cannabis use during pregnancy, and when implementing interventions to improve provider-patient communication about health risk behaviors.

Early childhood growth trajectories in a Medicaid population.

BACKGROUND: Evidence on the role of early growth trajectories and later obesity risk is primarily based on privately insured or universally insured samples. OBJECTIVES: We aimed to characterize and determine factors associated with early growth trajectories and estimate associations with overweight/obesity risk in a Medicaid-insured and uninsured cohort. METHODS: Infants seen at a large pediatric academic centre in 2010-2016 were included. Weight and length/height measurements were converted to age and sex-specific BMI z-scores (BMIz) based on the World Health Organization (WHO) Growth Standards. Group-based trajectories were modelled using BMIz created groups. Logistic and log-binomial regression models estimated associations between membership in trajectories and maternal/child factors and overweight or obesity at 36, 48, and 60 months, separately. Analyses were performed between 2019 and 2021. RESULTS: The best-fitting model identified five BMIz trajectories among 30 189 children and 310 113 clinical encounters; two trajectories showed rapid rise in BMIz. Lower maternal education, pre-pregnancy maternal overweight/obese status, and maternal smoking were positively associated with both rapid-rising BMIz trajectories. Children in either of the two rapid-rising trajectories were 3.00 (95% CI: 2.85, 3.25), 2.97 (95% CI: 2.77, 3.18) and 2.76 (95% CI: 2.53, 3.01) times more likely to have overweight or obesity at 36, 48, and 60 months, respectively compared to children in the stable trajectory groups. CONCLUSIONS: Among Medicaid insured and uninsured children, several maternal and child characteristics were associated with early rapid-rise in BMIz. Clinical monitoring of early rapidly rising BMI may be important to address modifiable risk factors for obesity in families from low-income households.

Common maternal infections during pregnancy and childhood leukaemia in the offspring: findings from six international birth cohorts.

BACKGROUND: Previous epidemiological studies have found positive associations between maternal infections and childhood leukaemia; however, evidence from prospective cohort studies is scarce. We aimed to examine the associations using large-scale prospective data. METHODS: Data were pooled from six population-based birth cohorts in Australia, Denmark, Israel, Norway, the UK and the USA (recruitment 1950s-2000s). Primary outcomes were any childhood leukaemia and acute lymphoblastic leukaemia (ALL); secondary outcomes were acute myeloid leukaemia (AML) and any childhood cancer. Exposures included maternal self-reported infections [influenza-like illness, common cold, any respiratory tract infection, vaginal thrush, vaginal infections and urinary tract infection (including cystitis)] and infection-associated symptoms (fever and diarrhoea) during pregnancy. Covariate-adjusted hazard ratio (HR) and 95% confidence interval (CI) were estimated using multilevel Cox models. RESULTS: Among 312 879 children with a median follow-up of 13.6 years, 167 leukaemias, including 129 ALL and 33 AML, were identified. Maternal urinary tract infection was associated with increased risk of any leukaemia [HR (95% CI) 1.68 (1.10-2.58)] and subtypes ALL [1.49 (0.87-2.56)] and AML [2.70 ([0.93-7.86)], but not with any cancer [1.13 (0.85-1.51)]. Respiratory tract infection was associated with increased risk of any leukaemia [1.57 (1.06-2.34)], ALL [1.43 (0.94-2.19)], AML [2.37 (1.10-5.12)] and any cancer [1.33 (1.09-1.63)]; influenza-like illness showed a similar pattern but with less precise estimates. There was no evidence of a link between other infections and any outcomes. CONCLUSIONS: Urinary tract and respiratory tract infections during pregnancy may be associated with childhood leukaemia, but the absolute risk is small given the rarity of the outcome.

Gestational Weight Gain and Adverse Maternal and Neonatal Outcomes for Pregnancies Complicated by Pregestational and Gestational Diabetes.

OBJECTIVE: This study aimed to investigate the association between excess and less than recommended gestational weight gain (GWG) and adverse maternal and neonatal outcomes in women with pregestational and gestational diabetes. STUDY DESIGN: We conducted a secondary analysis of the National Institute of Child Health and Human Development (NICHD) Consortium on Safe Labor (CSL) study. We included deliveries >23 weeks of nonanomalous singletons with either pregestational or gestational diabetes. The exposure was GWG greater than or less than compared with the U.S. Institute of Medicine recommendations for total pregnancy weight gain per prepregnancy body mass index. Consistent with the 2020 Delphi outcome for diabetes in pregnancy, maternal outcomes included cesarean delivery and preeclampsia and neonatal outcomes included small for gestational age (SGA), large for gestational age (LGA), macrosomia >4,000 g, preterm birth <37 weeks, stillbirth, and neonatal death. We modeled both absolute GWG and GWG z-scores, standardized for gestational duration. Multivariable logistic regression with generalized estimating equations was used, adjusting for age, race/ethnicity, parity, prior cesarean delivery, chronic hypertension, tobacco use, U.S. region, and delivery year. RESULTS: Of 8,322 deliveries (n = 8,087 women) complicated by pregestational or gestational diabetes, 47% were in excess, 27% were within, and 26% were less than GWG recommendations. Deliveries with excess absolute GWG were at higher adjusted odds of cesarean delivery, preeclampsia, LGA, and macrosomia, compared with those within recommendations. Similar results were observed when using standardized GWG z-scores, in addition to higher likelihood of preterm birth and neonatal death. Less than recommended GWG was associated with a lower likelihood of these adverse outcomes but higher SGA. Additionally, less GWG by z-score was associated with a lower likelihood of stillbirth. CONCLUSION: Excess GWG increases the risk of adverse maternal and neonatal outcomes for women with pregestational and gestational diabetes. Less GWG than recommended may decrease this risk. KEY POINTS: · Understanding the impact of GWG modeled using both absolute and standardized measures is needed.. · Among pregnant women with diabetes, excess GWG was common and increased the risk of adverse outcomes and less than recommended GWG may decrease the risk of adverse outcomes, including stillbirth.. · Current recommendations may require revision for women with diabetes in pregnancy..

Marijuana use and sleep quality during pregnancy.

OBJECTIVE: Marijuana use among pregnant women is on the rise in part due to the perception that marijuana may improve problems related to pregnancy such as poor sleep. This study's objective was to examine associations between marijuana use and sleep quality among a sample of women during pregnancy. MATERIAL AND METHODS: The sample included women seeking prenatal care at The Ohio State University Wexner Medical Center (2010-2015). Intake assessments included medical, demographic, and socioeconomic domains, as well as the Pittsburgh Sleep Quality Index. Marijuana use during pregnancy was determined using urine screens, chart abstraction, and self-report. Women completed standardized questionnaires regarding sleep quality, depressive symptoms, anxiety, stress, and discrimination at enrollment and each subsequent trimester. A linear mixed-effect model was used to assess the relationship between sleep variables and marijuana use adjusted for maternal race, education, household income, age, marital status, depressive symptoms, anxiety, stress, discrimination, and use of tobacco and other substances during pregnancy. Women completed the sleep quality assessments for a total of 294 pregnancies, which comprise the study population. RESULTS: Among the study sample (n = 294), 93 women used marijuana and 201 women did not use marijuana during their pregnancies. Women who used marijuana (n = 93) were more likely to identify as African-American (73% vs 58%; p = .01), report government health insurance (98% vs 89%; p = .001), use tobacco during pregnancy (66% vs 33%; p < .001), report less household income (70% vs 43% < 10,000 annual household income; p < .001), and be unmarried (69% vs 49%; p < .001) compared to women who did not. Mean sleep quality was similar among women who did (µ = 7.6; SD = 4.0) and did not use marijuana during pregnancy (µ = 7.7; SD = 4.0), and both groups had a mean score worse than the conventional cutoff for poor sleep quality (>5). In fact, both groups reported worse sleep than is typically observed among cohorts reporting poor sleep, which have ranged from 5.3 to 6.3. CONCLUSIONS: Current findings did not suggest differences in sleep quality between women who used and did not use marijuana during pregnancy. Findings are contrary to the perception that marijuana use alleviates sleep-related problems during pregnancy. Given well-documented adverse outcomes associated with prenatal marijuana exposure for children and the increase in women using marijuana during pregnancy, providers should be prepared to discuss possible harms associated with marijuana use during pregnancy as well as provide psychoeducational information and service referrals to those interested. Future studies could improve upon this design by assessing objective measures of sleep, such as actigraphy, as well as marijuana use repeatedly throughout pregnancy, which may be a more optimal strategy for illuminating potential relationships between marijuana use and sleep during pregnancy.

Prophylactic Indomethacin in extremely preterm infants: association with death or BPD and observed early serum creatinine levels.

OBJECTIVES: To identify the relationship between prophylactic indomethacin (PI) administration and (1) mortality and bronchopulmonary dysplasia (BPD) at 36-week postmenstrual age (PMA) (primary outcome), and (2) to evaluate for PI-associated acute kidney injury. STUDY DESIGN: Retrospective cohort investigation of 22-28 weeks gestation infants (N = 1167) who were admitted to Nationwide Children's Hospital on postnatal days 0-1 between May 2009 and September 2017 and survived ≥24-h postnatal. The associations of PI treatment with mortality or BPD, and other secondary outcomes, were evaluated via multivariable robust-error-variance Poisson regression. RESULTS: The adjusted risks of death or BPD (1.02, 95% CI: 0.83, 1.25), BPD (0.97, 95% CI: 0.77, 1.21), and death 1.33 (95% CI: 0.84, 2.10) by 36-week PMA were unchanged following PI treatment after multivariable adjustment. No changes in mean creatinine levels were detected in exposed versus unexposed infants to suggest PI-induced AKI. CONCLUSION: Prophylactic indomethacin treatment was unrelated to mortality or BPD outcomes.

Perinatal photoperiod and childhood cancer: pooled results from 182,856 individuals in the international childhood cancer cohort consortium (I4C).

Experimental evidence suggests that perinatal light imprinting of circadian clocks and systems may affect downstream physiology and cancer risk in later life. For humans, the predominant circadian stimulus is the daily light-dark cycle. Herein, we explore associations between perinatal photoperiod characteristics (photoperiod: duration of daylight as determined by time-of-year and location) and childhood cancer risk. We use pooled data on 182,856 mothers and babies from prospective birth cohorts in six countries (Australia, Denmark, Israel, Norway, UK, USA) within the International Childhood Cancer Cohort Consortium (I4C). Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). In line with predicted differential dose-responses, restricted cubic splines indicate a potential non-linear, non-monotonic relationship between perinatal mean daily photoperiod (0-24 h) and childhood cancer risk. In a restricted analysis of 154,121 individuals who experienced third trimester photoperiods exclusively within the 8-16-h range, the relative risk of developing childhood cancer decreased by 9% with every hour increase in third trimester mean daily photoperiod [HR: 0.91 (95%CIs: 0.84-0.99)]. In conclusion, in this first study of perinatal photoperiod and childhood cancer, we detected an inverse ["protective"] linear association between third trimester mean daily photoperiod and childhood cancer risk in the 8-16-h set of the total study population. Limited statistical power impeded the investigation of risks with individuals exposed to more extreme photoperiods. Future studies are needed to confirm differential photoperiod-associated risks and further investigations into the hypothesized circadian imprinting mechanism are warranted.

Antecedents of Objectively Diagnosed Diffuse White Matter Abnormality in Very Preterm Infants.

BACKGROUND: Diffuse white matter abnormality (diffuse excessive high signal intensity) is the most common finding on structural brain magnetic resonance imaging (MRI) at term-equivalent age in very preterm infants. Yet, there remains a large gap in our understanding of the etiology of diffuse white matter abnormality. Our objective was to evaluate perinatal and neonatal inflammation-associated antecedents of diffuse white matter abnormality on MRI. METHODS: We prospectively enrolled 110 very preterm infants born at ≤31 weeks gestational age and collected data on multiple perinatal/neonatal exposures, especially inflammation initiating-illnesses. We performed structural MRI at term-equivalent age and quantified the volume of diffuse white matter abnormality objectively. Multivariable regression was used to identify clinical antecedents of diffuse white matter abnormality. RESULTS: The mean (S.D.) birth gestational age of the final study sample of 98 very preterm infants was 28.3 (2.5) weeks. Multiple inflammation initiating-illnesses were associated with diffuse white matter abnormality in univariate analyses. In multivariable linear regression analyses controlling for gestational age, severe retinopathy of prematurity (P < 0.001) and bronchopulmonary dysplasia (P = 0.006) were independent risk factors, whereas maternal treatment with 17-hydroxyprogesterone (P < 0.001) was protective of later development of objectively quantified diffuse white matter abnormality. CONCLUSIONS: We identified several perinatal and neonatal antecedent clinical factors associated with diffuse white matter abnormality. Although we found some support for inflammation as a common underlying mechanism, larger studies are needed to validate inflammation as a potential common pathway to the development of diffuse white matter abnormality in very preterm infants.

Dual-specificity phosphatase (DUSP) genetic variants predict pulmonary hypertension in patients with bronchopulmonary dysplasia.

BACKGROUND: Pulmonary hypertension (PH) in patients with bronchopulmonary dysplasia (BPD) results from vasoconstriction and/or vascular remodeling, which can be regulated by mitogen-activated protein kinases (MAPKs). MAPKs are deactivated by dual-specificity phosphatases (DUSPs). We hypothesized that single-nucleotide polymorphisms (SNPs) in DUSP genes could be used to predict PH in BPD. METHODS: Preterm infants diagnosed with BPD (n = 188) were studied. PH was defined by echocardiographic criteria. Genomic DNA isolated from patient blood samples was analyzed for 31 SNPs in DUSP genes. Clinical characteristics and minor allele frequencies were compared between BPD-PH (cases) and BPD-without PH (control) groups. Biomarker models to predict PH in BPD using clinical and SNP data were tested by calculations of area under the ROC curve. RESULTS: In our BPD cohort, 32% (n = 61) had PH. Of the DUSP SNPs evaluated, DUSP1 SNP rs322351 was less common, and DUSP5 SNPs rs1042606 and rs3793892 were more common in cases than in controls. The best fit biomarker model combines clinical and DUSP genetic data with an area under the ROC curve of 0.76. CONCLUSION: We identified three DUSP SNPs as potential BPD-PH biomarkers. Combining clinical and DUSP genetic data yields the most robust predictor for PH in BPD.

The association between birth order and childhood leukemia may be modified by paternal age and birth weight. Pooled results from the International Childhood Cancer Cohort Consortium (I4C).

The "delayed infection hypothesis" states that a paucity of infections in early childhood may lead to higher risks of childhood leukemia (CL), especially acute lymphoblastic leukemia (ALL). Using prospectively collected data from six population-based birth cohorts we studied the association between birth order (a proxy for pathogen exposure) and CL. We explored whether other birth or parental characteristics modify this association. With 2.2 × 106 person-years of follow-up, 185 CL and 136 ALL cases were ascertained. In Cox proportional hazards models, increasing birth order (continuous) was inversely associated with CL and ALL; hazard ratios (HR) = 0.88, 95% confidence interval (CI): (0.77-0.99) and 0.85: (0.73-0.99), respectively. Being later-born was associated with similarly reduced hazards of CL and ALL compared to being first-born; HRs = 0.78: 95% CI: 0.58-1.05 and 0.73: 0.52-1.03, respectively. Successive birth orders were associated with decreased CL and ALL risks (P for trend 0.047 and 0.055, respectively). Multivariable adjustment somewhat attenuated the associations. We found statistically significant and borderline interactions between birth weight (p = 0.024) and paternal age (p = 0.067), respectively, in associations between being later-born and CL, with the lowest risk observed for children born at <3 kg with fathers aged 35+ (HR = 0.18, 95% CI: 0.06-0.50). Our study strengthens the theory that increasing birth order confers protection against CL and ALL risks, but suggests that this association may be modified among subsets of children with different characteristics, notably advanced paternal age and lower birth weight. It is unclear whether these findings can be explained solely by infectious exposures.

The impact of female fetal sex on preeclampsia and the maternal immune milieu.

OBJECTIVE: Small studies suggest that fetal sex alters maternal inflammation. We examined the association between fetal sex, preeclampsia and circulating maternal immune markers. METHODS: This was a secondary data analysis within a nested case-control study of 216 preeclamptic women and 432 randomly selected normotensive controls from the Collaborative Perinatal Project. All women had singleton, primiparous pregnancies without chronic health conditions. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for associations between female fetal sex and preeclampsia. Outcomes included preeclampsia, preterm preeclampsia (<37 and <34 weeks), and normotensive preterm birth <37 weeks. Associations between female fetal sex and immune markers [interleukin (IL)-6, IL4, IL5, IL12, IL10, IL8, IL1-beta, interferon (IFN)-gamma, tumor necrosis factor (TNF)-beta, and transforming growth factor-beta] were examined using a statistical method developed for large proportions of censored biomarker data. Models were adjusted for maternal age, race, body mass index, and smoking. RESULTS: Women with early preterm preeclampsia (<34 weeks) had higher odds of having a female fetus (ORadj. 3.2, 95% CI 1.1-9.6) and women with normotensive preterm birth had lower odds (ORadj. 0.5, 95% CI 0.3-0.9). Female fetal sex was associated with lower first trimester pro-inflammatory IFNγ and IL-12 but higher second trimester pro-inflammatory IL1ß and TNFß, anti-inflammatory IL4r, and regulatory cytokines IL5 and IL10. Female fetal sex was associated with higher postpartum IL10 in preeclamptic women only. CONCLUSIONS: We identified sexual dimorphism in maternal inflammation. Longitudinal studies are needed to determine if fetal sex impacts the maternal immune milieu across pregnancy.

Preterm Birth and Gestational Length in Four Race-Nativity Groups, Including Somali Americans.

OBJECTIVE: To compare preterm birth rates and gestational length in four race-nativity groups including Somali Americans. METHODS: Using a retrospective cohort study design of Ohio birth certificates, we analyzed all singleton births between 2000 and 2015 from four groups of women categorized as U.S.-born, non-Hispanic white (USBW), U.S.-born, non-Hispanic black (USBB), African-born black (ABB, primarily of West African birth country), and Somalia-born (SB). An algorithm trained on maternal names was used to confirm Somali ethnicity. Gestational length was analyzed as completed weeks or aggregated by clinically relevant periods. Risk of spontaneous and health care provider-initiated preterm birth was calculated in a competing risk model. RESULTS: Births to women in the designated groups accounted for 1,960,693 births (USBW n=1,638,219; USBB n=303,028; ABB n=10,966, and SB n=8,480). Women in the SB group had a lower preterm birth rate (5.9%) compared with women in the USBB (13.0%), ABB (8.4%), and USBW (7.9%) groups (P<.001). Women in the SB group had a higher frequency of postterm pregnancy (5.8% vs less than 1%, P<.001 for all groups). The lower rate of preterm birth in the SB group was unrelated to differences in parity or smoking or whether preterm birth was spontaneous or health care provider-initiated. The lower rate of preterm birth and tendency for prolonged gestation was attenuated in ethnic Somali women born outside Somalia. CONCLUSION: We report a positive disparity in preterm birth and a tendency for prolonged gestation for ethnic Somali women in Ohio. Etiologic studies in multiethnic cohorts aimed to uncover the sociobiological determinants of gestational length may lead to practical approaches to reduce prematurity in the general population.

Research standardization tools: pregnancy measures in the PhenX Toolkit.

Only through concerted and well-executed research endeavors can we gain the requisite knowledge to advance pregnancy care and have a positive impact on maternal and newborn health. Yet the heterogeneity inherent in individual studies limits our ability to compare and synthesize study results, thus impeding the capacity to draw meaningful conclusions that can be trusted to inform clinical care. The PhenX Toolkit (http://www.phenxtoolkit.org), supported since 2007 by the National Institutes of Health, is a web-based catalog of standardized protocols for measuring phenotypes and exposures relevant for clinical research. In 2016, a working group of pregnancy experts recommended 15 measures for the PhenX Toolkit that are highly relevant to pregnancy research. The working group followed the established PhenX consensus process to recommend protocols that are broadly validated, well established, nonproprietary, and have a relatively low burden for investigators and participants. The working group considered input from the pregnancy experts and the broader research community and included measures addressing the mode of conception, gestational age, fetal growth assessment, prenatal care, the mode of delivery, gestational diabetes, behavioral and mental health, and environmental exposure biomarkers. These pregnancy measures complement the existing measures for other established domains in the PhenX Toolkit, including reproductive health, anthropometrics, demographic characteristics, and alcohol, tobacco, and other substances. The preceding domains influence a woman's health during pregnancy. For each measure, the PhenX Toolkit includes data dictionaries and data collection worksheets that facilitate incorporation of the protocol into new or existing studies. The measures within the pregnancy domain offer a valuable resource to investigators and clinicians and are well poised to facilitate collaborative pregnancy research with the goal to improve patient care. To achieve this aim, investigators whose work includes the perinatal population are encouraged to utilize the PhenX Toolkit in the design and implementation of their studies, thus potentially reducing heterogeneity in data measures across studies. Such an effort will enhance the overall impact of individual studies, increasing the ability to draw more meaningful conclusions that can then be translated into clinical practice.

Comparative Effectiveness of Nonsteroidal Anti-inflammatory Drug Treatment vs No Treatment for Patent Ductus Arteriosus in Preterm Infants.

Importance: Patent ductus arteriosus (PDA) is associated with increased mortality and worsened respiratory outcomes, including bronchopulmonary dysplasia (BPD), in preterm infants. Nonsteroidal anti-inflammatory drugs (NSAIDs) are efficacious in closing PDA, but the effectiveness of NSAID-mediated PDA closure in improving mortality and preventing BPD is unclear. Objective: To determine the effectiveness of NSAID treatment for PDA in reducing mortality and moderate/severe BPD at 36 weeks postmenstrual age. Design, Setting, and Participants: This cohort study included 12 018 infants born at 28 gestational weeks or younger discharged between January 2006 and December 2013 from neonatal intensive care units in 25 US children's hospitals included in the Pediatric Health Information System. We performed an instrumental variable analysis that incorporated clinician preference-based, institutional variation in NSAID treatment frequency to determine the effect of NSAID treatment for PDA on mortality and BPD. Exposures: Proportion of NSAID-treated infants born at each infant's institution within ±6 months of that infant's birth. Main Outcomes and Measures: The primary composite outcome was death, moderate, or severe BPD at 36 weeks postmenstrual age. Results: Of the 6370 male and 5648 female infants in this study, 4995 (42%) were white, 3176 (26%) were African American, 1823 (15%) were Hispanic, and 1555 (13%) were other races/ethnicities. The proportion of NSAID-treated infants at each infant's hospital within ±6 months of that infant's birth was associated with NSAID treatment and not associated with gestation, race/ethnicity, or sex. An infant's chances of receiving NSAID treatment increased by 0.84% (95% CI, 0.8-0.9; P < .001) for every 1% increase in the annual NSAID treatment percentage at a given hospital. An instrumental variable analysis demonstrated no association between NSAID treatment and the odds of mortality or BPD (odds ratio, 0.94; 95% CI, 0.70-1.25; P = .69), mortality (odds ratio, 0.73; 95% CI, 0.43-1.13; P = .18), or BPD (odds ratio, 1.01; 95% CI, 0.73-1.45; P = .94) in survivors. Conclusions and Relevance: When we incorporated clinician preference-based practice variation as an instrument to minimize the effect of unmeasured confounding, we detected no changes in the odds of mortality or moderate/severe BPD among similar preterm infants born at 28 weeks or younger following NSAID treatment for PDA initiated 2 to 28 days postnatally. Our findings agree with available randomized clinical trial evidence and support a conservative approach to PDA management.

First and second trimester immune biomarkers in preeclamptic and normotensive women.

INTRODUCTION: Circulating immune markers may be associated with preeclampsia but further investigations in early pregnancy and among preeclampsia subtypes are warranted. We examined immune markers in 208 preeclamptic women and 411 normotensive controls. METHODS: Our study was nested within the Collaborative Perinatal Project. A total of 242 women had first trimester serum samples and 392 had second trimester serum samples. Preeclampsia was defined as hypertension >20weeks of gestation with proteinuria or pulmonary edema, oliguria, or convulsions. Preterm preeclampsia was defined as preeclampsia with delivery less than 37weeks of gestation. Associations between immune markers RANTES, interleukin (IL)-6, IL4, IL5, IL12, IL10, IL8, IL1-beta, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha and beta, transforming growth factor (TGF)-beta and preeclampsia were explored using a modified version of cox regression developed to address data with non-detectable levels. Models were adjusted for body mass index, gestational age of blood sampling, fetal sex, smoking, socioeconomic status and maternal age. RESULTS: In first trimester samples, IL-12 was associated with preeclampsia (p=0.0255). IFN-gamma (p=0.0063), IL1-beta (p=0.0006), IL5 (p=0.0422) and TNFr (p=0.0460) were associated with preterm preeclampsia only. In second trimester samples, IL1-beta was associated with preeclampsia (p=0.0180) and term preeclampsia (p=0.0454). After correction for multiple comparisons, only IL1-beta remained associated with preterm preeclampsia in the first trimester (p=0.0288). DISCUSSION: Elevated first trimester IL1-beta appears to be associated with preterm preeclampsia. However, few associations were observed in the second trimester. Systemic immune markers alone may not be useful for preeclampsia prediction.