Effects of a Novel High-Quality Protein Infant Formula on Energetic Efficiency and Tolerance: A Randomized Trial.

OBJECTIVES: Protein overfeeding in infants can have negative effects, such as diabetes and childhood obesity; key to reducing protein intake from formula is improving protein quality. The impact of a new infant formula [study formula (SF)] containing alpha-lactalbumin, lactoferrin, partially hydrolyzed whey, and whole milk on growth and tolerance compared to a commercial formula (CF) and a human milk reference arm was evaluated. METHODS: This randomized, double-blind trial included healthy, singleton, term infants, enrollment age ≤14 days. Primary outcome was mean daily weight gain. Secondary outcomes were anthropometrics, formula intake, serum amino acids, adverse events, gastrointestinal characteristics, and general disposition. RESULTS: Non-inferiority was demonstrated. There were no differences between the formula groups for z scores over time. Formula intake [-0.33 oz/kg/day, 95% confidence interval (CI): -0.66 to -0.01, P = 0.05] and mean protein intake (-0.13 g/kg/day, 95% CI: -0.26 to 0.00, P = 0.05) were lower in the SF infants, with higher serum essential amino acid concentrations (including tryptophan) compared to the CF infants. Energetic efficiency was 14.0% (95% CI: 8.3%, 19.7%), 13.0% (95% CI: 6.0%, 20.0%), and 18.1% (95% CI: 9.4%, 26.8%) higher for weight, length, and head circumference, respectively, in SF infants compared to the CF infants. SF infants had significantly fewer spit-ups and softer stool consistency than CF infants. CONCLUSIONS: The SF resulted in improved parent-reported gastrointestinal tolerance and more efficient growth with less daily formula and protein intake supporting that this novel formula may potentially reduce the metabolic burden of protein overfeeding associated with infant formula.

The influence of exercise during pregnancy on racial/ethnic health disparities and birth outcomes.

BACKGROUND: Non-Hispanic black (NHB) pregnant women disproportionately experience adverse birth outcomes compared to Non-Hispanic white (NHW) pregnant women. The positive effects of prenatal exercise on maternal and neonatal health may mitigate these disparities. This study evaluated the influence of prenatal exercise on racial/ethnic disparities in gestational age (GA), birthweight (BW), and risks of preterm birth (PTB), cesarean section (CS), and low-birthweight (LBW) neonates. METHODS: This study performed a secondary data analysis using data from a 24-week, two-arm exercise intervention trial (ENHANCED by Mom). Women with singleton pregnancies (< 16 weeks), aged 18-40 years, BMI between 18.5-34.99 kg/m2, and no preexisting health conditions were eligible. The aerobic exercisers (EX) participated in 150 min of moderate-intensity weekly exercise while non-exercising controls (CON) attended low-intensity stretching/breathing sessions. Data on GA, PTB (< 37 weeks), BW, LBW (< 2.5 kg), and delivery mode were collected. Poisson, median and linear regressions were performed. RESULTS: Participants with complete data (n = 125) were eligible for analyses (EX: n = 58, CON: n = 67). NHB pregnant women delivered lighter neonates (ß = - 0.43 kg, 95% CI: - 0.68, - 0.18, p = 0.001). After adjusting for prenatal exercise, racial/ethnic disparities in BW were reduced (ß = - 0.39 kg, 95% CI: - 0.65, - 0.13, p = 0.004). Prenatal exercise reduced borderline significant racial/ethnic disparities in PTB (p = 0.053) and GA (p = 0.07) with no effects found for CS and LBW. CONCLUSIONS: The findings of this study demonstrate that prenatal exercise may attenuate the racial/ethnic disparities observed in neonatal BW, and possibly GA and PTB. Larger, diverse samples and inclusion of maternal biomarkers (e.g., cytokines) are encouraged to further evaluate these relationships.

Predicting Infection in Very Preterm Infants: A Study Protocol.

BACKGROUND: Neonatal sepsis causes morbidity and mortality in preterm infants. Clinicians need a predictive tool for the onset of neonatal infection to expedite treatment and prevent morbidity. Abnormal thermal gradients, a central-peripheral temperature difference (CPtd) of >2°C or <0°C, and elevated heart rate characteristic (HRC) scores are associated with infection. OBJECTIVE: This article presents the protocol for the Predictive Analysis Using Temperature and Heart Rate Study. METHODS: This observational trial will enroll 440 very preterm infants to measure abdominal temperature and foot temperature every minute and HRC scores hourly for 28 days to compare infection data. Time with abnormal thermal gradients (Model 1) and elevated HRC scores (Model 2) will be compared to the onset of infections. For data analysis, CPtd (abdominal temperature - foot temperature) will be investigated as two derived variables, high CPtd (number/percentage of minutes with CPtd of >2°C) and low CPtd (number/percentage of minutes with CPtd of <0°C). In the infant-level model, the outcome yi will be an indicator of whether the infant was diagnosed with an infection in the first 28 days of life, and the high CPtd and low CPtd variables will be the average over the entire observation period, logit(yi) = ß0 + xiß1 + ziγ. For the day-level model, the outcome yit will be an indicator of whether the ith infant was diagnosed with an infection on the tth day from t = 4 through t = 28 or the day that infection is diagnosed (25 possible repeated measures), logit(yit) = ß0 + xitß1 + zitγ. It will be determined whether a model with only high CPtd or only low CPtd is superior in predicting infection. Also, the correlation of abnormal HRC scores with high CPtd and low CPtd values will be assessed. DISCUSSION: Study results will inform the design of an interventional study using temperatures and/or heart rate as a predictive tool to alert clinicians of cardiac and autonomic instability present with infection.

Examining Use of Dual Point Temperature Display in Servo-Control With Early Preterm Infants.

BACKGROUND: Previously, we recorded periods of time with foot higher than abdominal temperatures in association with infection in preterm infants. Monitoring dual temperatures may be an important tool to assess infant instability. Currently, incubators cannot measure and display dual temperatures in servo-control mode. PURPOSE: To examine the usability of GE Healthcare's Giraffe OmniBed with research software to measure, display, and record dual temperatures, and their differences while in servo-control. In addition, nurses' perceptions of the use and display of dual temperatures and differences were evaluated. METHODS: A multiple-case, mixed-methods design. Abdominal and foot temperatures were measured, displayed, and stored for 28 days for 14 preterm infants. Nurses were surveyed for satisfaction and preferences with the dual temperature display. Nurses noted abnormal temperature differences and infant condition in bedside journals. RESULTS: Study infants were 26 to 31 weeks of gestational age and 670 to 1410 g. Abdominal, foot, and the abdominal-foot temperature difference was measured, recorded, and downloaded successfully in all infants over all days. Nurses liked using dual temperature display with the abdominal-foot temperature difference. Surveys indicated preferences for larger displays and alarms for abnormal values. Thermal instability, stimulation, and thermistor detachment were associated with abnormal thermal gradients. Two exemplar cases are presented. IMPLICATIONS FOR PRACTICE: Monitoring dual temperatures adds information to the clinical assessment. IMPLICATIONS FOR RESEARCH: Studies are needed to examine relationships between abnormal thermal gradients and infections, infant stability, and nursing care along with the underlying physiologic mechanisms. Studies are needed for wireless dual temperature monitoring.

Screening for Opioid and Stimulant Exposure In Utero Through Targeted and Untargeted Metabolomics Analysis of Umbilical Cords.

BACKGROUND: Neonatal abstinence syndrome is an array of signs and symptoms experienced by a newborn due to abrupt discontinuation of intrauterine exposure to certain drugs, primarily opioids. In the United States, the incidence of neonatal abstinence syndrome has tripled over the past decade. The current standard of care for drug testing includes the analysis of infant urine and meconium. Sample collection is associated with several limitations, including diaper media interferences, limited sample amount, sample heterogeneity, and the need for professional staff for collection. Umbilical cord tissue has emerged as a convenient sample matrix for testing owing to its universal availability. The purpose of this study was to examine umbilical cords using an untargeted metabolomics approach to determine the detected drugs and validate an analytical method to confirm and quantify the identified drugs. METHODS: A metabolomics analysis was performed with 21 umbilical cords to screen for drugs and drug metabolites by liquid chromatography-mass spectrometry. Drugs were identified using the National Institute of Standards and Technology database, and an analytical method was developed and validated using secondary liquid chromatography-mass spectrometry instrument for positive confirmation and quantitative analysis. RESULTS: Twenty-one random umbilical cords from women were tested: 4 were positive for cocaine and the primary and secondary metabolites; one was positive for methadone, the primary metabolite; 3 were positive for cotinine, the metabolite of nicotine; and 5 were positive for acetyl norfentanyl. CONCLUSIONS: Our research is a prospective method development study using untargeted and targeted approaches to characterize steady-state drug metabolite levels in the umbilical cord matrix at the time of delivery. By characterizing drug type and concentration, this methodology can be used to develop a reliable complementary testing method for meconium toxicology screens.

Influence of Prenatal Aerobic Exercise on Fetal Morphometry.

OBJECTIVE: The purpose of this study was to determine the effects of supervised prenatal aerobic exercise on fetal morphometrics at 36 weeks of gestation. METHODS: This study used data from a, 24-week, two-arm randomized controlled trial: aerobic exercise (EX) and stretching/breathing comparison group (CON). Singleton pregnancies (< 16 weeks pregnant) and women aged 18 to 40 years, BMI between 18.5 and 34.99 kg/m2, and no preexisting chronic health conditions were eligible. The EX group participated in 150 min of moderate-intensity weekly exercise while CON group participated in low-intensity stretching/breathing. Fetal morphometric outcomes included estimated fetal weight (EFW), ponderal index (PI), abdominal circumference (AC), anterior abdominal wall thickness (AAWT), fat mass, percent body fat, fat-free mass, assessed at 36 weeks gestation. Partial spearman rank correlations were performed, adjusting for 3rd trimester weight gain. RESULTS: Of the 128 pregnant women randomized, 83 (EX [n = 46] and CON [n = 37]) were eligible for analyses. Intention-to-treat analysis showed no differences in EFW (rhos = - 0.13; p = 0.28), PI (rhos = 0.03; p = 0.81), AC (rhos = - 0.22; p = 0.09), AAWT (rhos = - 0.11; p = 0.40), fat mass (rhos = - 0.16; p = 0.23), percent body fat (rhos = - 0.10; p = 0.43), and fat-free mass (rhos = - 0.22; p = 0.08), after adjusting for 3rd trimester weight gain. Similar results were observed in the per protocol analyses. CONCLUSIONS: For Practice Moderate-intensity aerobic exercise during pregnancy was not associated with select fetal morphometrics at 36 weeks gestation. Potential differences in offspring morphometrics may only appear in the postnatal period, as previously documented. Further research into offspring tissue composition after birth is encouraged, specifically studies investigating differences in cellular signaling pathways related to adipose and skeletal muscle tissue development.

Influence of aerobic exercise on maternal lipid levels and offspring morphometrics.

BACKGROUND: Maternal BMI, lipid levels (cholesterol, triglyceride, LDL, HDL), and exercise amount are interrelated and each influence offspring body size. This study proposed to determine the influence of exercise on maternal lipid levels and infant body size. METHODS: We had 36 participants complete these measures. Participants in the aerobic exercise intervention (n = 14) completed three 50-min sessions weekly from 16 weeks gestation to delivery and were compared with a non-exercise control group (n = 22). Maternal lipid profiles were assessed at 16 and at 36 weeks gestation. Fetal body size was measured at 36 weeks gestational age using ultrasound assessment. Neonatal body size measures were acquired from birth records. Statistical analysis included two-sample t-tests, correlations, and regression models. RESULTS: Participants were similar in age, pre-pregnancy BMI, gravida, parity, education, and gestational weight gain (GWG). There were no differences in gestational age, Apgar scores at 1 and 5 min for infants of exercisers relative to controls. Exercisers had higher pre-training triglycerides (p = 0.004) and pregnancy change in triglycerides (p = 0.049) compared to controls. Head circumference was significantly larger in exercise exposed infants relative to infants of controls. Pregnancy METs had a positive relationship with birth length (r = .445, p = .006) and birth weight (r = .391, p = .02). GWG had a moderate, positive relationship with fetal abdominal circumference (r = .570, p = .004). Regression analysis indicated 5 predictors explained 61.7% of the variance in birth weight (Adj.R2 = 0.469, F(5,13) = 5,13, p = 0.02); it was found that pregnancy METs (ß = .724, p = .007), 36 week cholesterol (ß = 1.066, p = .02), and 36 week LDL (ß = -1.267, p = .006) significantly predict birth weight. Regression analysis indicated 4 predictors explained 43.8% of the variance in birth length (Adj.R2 = 0.306, F(4,17) = 3.32, p = 0.04); it was found that pregnancy METs (ß = .530, p = .03), and 36 week LDL (ß = -.891, p = .049) significantly predict birth length. CONCLUSION: The primary association and predictors of infant body size was related to pregnancy exercise and late pregnancy cholesterol and LDL levels. Considering these relationships, it is essential that women maintain aerobic exercise during pregnancy, but should also be cognizant of lipid levels during their pregnancy. Therefore intervention during pregnancy focused on infant body size should involve exercise and and quality nutritional intake foods during pregnancy.

Antihypertensive drug exposure in premature infants from 1997 to 2013.

BACKGROUND: Systemic hypertension is increasingly recognised in premature infants. There is limited evidence regarding treatment, and most published treatment recommendations are based solely on expert opinions. METHODS: We identified all infants born ⩽32 weeks of gestation and ⩽1500 g birth weight discharged from one of 348 neonatal ICUs managed by the Pediatrix Medical Group between 1997 and 2013. We defined antihypertensive drugs as vasodilators, angiotensin-converting enzyme inhibitors, ß receptor blockers, calcium channel blockers, and central α2 receptor agonists. We compared characteristics between infants who were treated with at least one antihypertensive drug during their initial hospitalisation and infants who were not prescribed antihypertensive drugs using Wilcoxon's ranked sum test or Pearson's χ2-test. RESULTS: We identified 2504/119,360 (2.1%) infants who required at least one antihypertensive drug. The median postnatal age of first exposure was 48 days (25th, 75th percentile 15, 86), and the median length of therapy was 6 days (1, 16). Hydralazine was the most commonly prescribed antihypertensive with 1280/2504 (51.1%) treated infants exposed to the drug. More than two antihypertensive drugs were administered in 582/2504 (23.2%) infants, and 199/2097 (9.5%) of the treated infants were discharged home on antihypertensive therapy. Infants who received antihypertensive drugs were of lower gestational age (p<0.001) and birth weight (p<0.001) compared with infants not prescribed antihypertensive drugs. CONCLUSIONS: Our study is the largest to describe current antihypertensive drug exposure in a cohort of exclusively premature infants born ⩽32 weeks of gestation. We found wide variations in practice for treating hypertension in premature infants.

Onabotulinum toxin a for the treatment of headache in service members with a history of mild traumatic brain injury: a cohort study.

OBJECTIVE: Post-traumatic headache (PTH) of the migraine type is a common complication of mild traumatic brain injury (including blast injuries) in active duty service members. Persistent and near-daily headache occur. Usual preventive medications may have unacceptable side effects. Anecdotal reports suggest that onabotulinum toxin A (OBA) might be an effective treatment in these patients. METHODS: This study is a real-time retrospective consecutive case series of all patients treated with OBA at the Concussion Care Clinic of Womack Army Medical Center, Ft. Bragg, NC, between August 2008 and August 2012. Clinical treatment and pharmacy records were corroborated with the electronic medical records in the Armed Forces Health Longitudinal Technology Application to determine demographics, current headache and treatment characteristics, and clinical and occupational outcomes. RESULTS: Sixty-four subjects (63 male) with mean age of 31.3 + 7.5 (range 20-59) years were evaluated and treated. Blast injuries were most common (n = 36; 56.3%) and 7 patients (11%) reported a prior history of headache. Most patients (36; 56.3%) described more than 1 headache type and 48 (75%) patients had continuous pain. The most prevalent treating diagnosis was mixed continuous headache with migraine features on more than 15 days per month (n = 26; 40.6%). The mean time from injury to the first injections was 10.8 + 21.9 (1-96) months. Forty (62.5%) patients received the Food and Drug Administration-approved chronic migraine injection protocol. Forty-one (64%) patients reported being better. Two patients discontinued for side effects. Twenty-seven (41%) remained on active duty. CONCLUSIONS: We demonstrate that active duty military patients with headaches related to concussions may benefit from treatment with OBA. Further studies are indicated.

Intimate partner violence increases adverse outcomes at birth and in early infancy.

OBJECTIVE: To determine the effect of intimate partner violence (IPV) on birth outcomes and infant hospitalization. STUDY DESIGN: Hospitalization records for the first 4 months of life for infants born in the Military Health System in 2006-2007 were linked to Family Advocacy Program-substantiated cases of IPV among military parents. Adverse outcomes were identified using International Classification of Diseases, Ninth Revision codes. Logistic regression modeling calculated the OR of children exposed to IPV experiencing adverse outcomes. RESULTS: A total of 204,546 infants were born during the study period. Among these, 173,026 infants (85%) were linked to active duty military parents. 31,603 infants (18%) experienced adverse outcomes, and 3059 infants (1.8%) were born into families with IPV. The infants exposed to IPV had a 31% increased odds of experiencing adverse outcomes compared with infants without known IPV exposure. IPV exposure increased the odds of the following outcomes: prematurity (OR, 1.45; 95% CI, 1.29-1.62), low birth weight (OR, 1.57; 95% CI, 1.25-1.97), respiratory problems (OR, 1.17; 95% CI, 1.04-1.32), neonatal hospitalization (OR, 1.39; 95% CI, 1.20-1.61), and postneonatal hospitalization (OR, 1.52; 95% CI, 1.29-1.81). After controlling for prematurity and demographic variables, IPV exposure was associated with low birth weight (OR, 1.52; 95% CI, 1.16-1.99), neonatal hospitalization (OR, 1.24; 95% CI, 1.02-1.49), and postneonatal hospitalization (OR, 1.27; 95% CI, 1.03-1.56). CONCLUSION: Infants exposed to IPV are more likely to experience adverse birth outcomes and infant hospitalization. Routinely addressing IPV during prenatal and early pediatric visits may potentially prevent these adverse outcomes.

Trends in caffeine use and association between clinical outcomes and timing of therapy in very low birth weight infants.

OBJECTIVE: To examine the effect of early initiation of caffeine therapy on neonatal outcomes and characterize the use of caffeine therapy in very low birth weight (VLBW) infants. STUDY DESIGN: We analyzed a cohort of 62 056 VLBW infants discharged between 1997 and 2010 who received caffeine therapy. We compared outcomes in infants receiving early caffeine therapy (initial dose before 3 days of life) and those receiving late caffeine therapy (initial dose at or after 3 days of life) through propensity scoring using baseline and early clinical variables. The primary outcome was the association between the timing of caffeine initiation and the incidence of bronchopulmonary dysplasia (BPD) or death. RESULTS: We propensity score-matched 29 070 VLBW infants at a 1:1. Of infants receiving early caffeine therapy, 3681 (27.6%) died or developed BPD, compared with 4591 infants (34.0%) receiving late caffeine therapy (OR, 0.74; 99% CI, 0.69-0.80). Infants receiving early caffeine had a lower incidence of BPD (23.1% vs 30.7%; OR, 0.68; 95% CI, 0.63-0.73) and a higher incidence of death (4.5% vs 3.7%; OR, 1.23; 95% CI, 1.05-1.43). Infants receiving early caffeine therapy had less treatment of patent ductus arteriosus (OR, 0.60; 95% CI, 0.55-0.65) and a shorter duration of mechanical ventilation (mean difference, 6 days; P < .001). CONCLUSION: Early caffeine initiation is associated with a decreased incidence of BPD. Randomized trials are needed to determine the efficacy and safety of early caffeine prophylaxis in VLBW infants.

Practice changes and infant health risks during the 2022 infant formula shortage: Results of a US healthcare provider survey.

BACKGROUND: In February 2022, an infant formula recall and closing of a major manufacturing center exacerbated a nationwide shortage initiated by COVID-19-related supply chain disruptions. The effects were far-reaching, impacting families and healthcare providers across the US. METHODS: A 19-item web survey was developed to better understand how the infant formula shortage impacted healthcare provider practices, resources needed and those already used, and patient health, including malnutrition. Subjective data on providers' experience were also collected. RESULTS: Two hundred forty-one providers responded, primarily registered dietitians (94%) practicing in inpatient/academic hospitals in urban and metropolitan areas. Practice adjustments included increases in patient education (100%), communication with pharmacies/durable medical equipment companies (65%), and visit durations (28%). Feeding adjustments by caregivers included new infant formula (99%), toddler (55%) or homemade (23%) formula, cow's milk (46%) or milk alternatives (32%), formula dilution (41%), and early food introduction (14%). Providers indicated an increase in malnutrition (33%), related diagnoses (including failure to thrive [31%] and deceleration in z score [27%]), and associated symptoms. Of the providers who reported malnutrition and related diagnoses, 93% also reported caregiver feeding practices that are generally not recommended. CONCLUSION: Providers made practice adjustments to mitigate the consequences associated with formula unavailability and misuse yet saw an increase in malnutrition and related diagnoses or symptoms. Subjectively, providers reported frustration that greater workloads did not result in improved outcomes, contributing to burnout. These data underscore the essentiality of supporting healthcare providers as they guide families in safe infant feeding practices.

Exercise FITT-V during pregnancy: Association with birth outcomes.

BACKGROUND: Prenatal exercise improves birth outcomes, but research into exercise dose-response effects is limited. METHODS: This study is a retrospective, secondary analysis of pooled data from three blinded, prospective, randomized controlled trials. Prenatal exercise frequency, intensity, type, time, and volume (FITT-V) were assessed in supervised sessions throughout pregnancy. Gestational age (GA), neonatal resting heart rate (rHR), morphometrics (body circumferences, weight-to-length and ponderal index) Apgar and reflex scores, and placental measures were obtained at birth. Stepwise regressions and Pearson correlations determined associations between FITT-V and birth outcomes. RESULTS: Prenatal exercise frequency reduces ponderal index (R2 = 0.15, F = 2.76, p = .05) and increased total number of reflexes present at birth (R2 = 0.24, F = 7.89, p < .001), while exercise intensity was related to greater gestational age and birth length (R2 = 0.08, F = 3.14; R2 = 0.12, F = 3.86, respectively; both p = .04); exercise weekly volume was associated with shorter hospital stay (R2 = 0.24, F = 4.73, p = .01). Furthermore, exercise type was associated with placenta size (R2 = 0.47, F = 3.51, p = .01). CONCLUSIONS: Prenatal exercise is positively related to birth and placental outcomes in a dose-dependent manner.

Exercise during pregnancy Dose: Influence on preterm birth outcomes.

BACKGROUND: Preterm delivery typically increases health risk for neonates and is associated with longer infant hospital stay and financial burden. Prenatal exercise dose (frequency, intensity, type, time, volume) have been shown to influence birth outcomes. Increased prenatal exercise dose could therefore provide a critical reduction in health risk and financial burden in preterm neonates. OBJECTIVE: It was our aim to explore the effects of prenatal exercise dose from a supervised exercise intervention in pregnant women on the occurrence of preterm (<37 weeks gestation) births, and the impact on health outcomes in preterm neonates. STUDY DESIGN: This study is a retrospective, secondary analysis of pooled data from three blinded, prospective, randomized controlled trials. Prenatal exercise dose were assessed in supervised aerobic, resistance, and combination sessions throughout pregnancy. In addition to gestational age, birth weight, resting heart rate, neonatal morphometrics (body circumferences, ponderal index), and health status (Apgar-1 and -5) metrics were obtained for 21 women at birth. One-way analysis of variance tests were used to assess the differences between dose grouped as tertiles, while Pearson correlations determined the association between dose and birth outcomes. RESULTS: Women exercised for an average of 19.6 wks (range: 6 - 21 wks) during pregnancy. Exercise during pregnancy tended to result in later preterm deliveries (p = 0.08). Greater prenatal exercise volume and duration were associated with reduced infant hospital stay post-delivery (p = 0.02). Weekly exercise volume was associated with increased Apgar scores (p = 0.01). CONCLUSION: Increased prenatal exercise volume and duration is associated with improved birth outcomes in preterm neonates.

Anorectal atresia and variants at predicted regulatory sites in candidate genes.

Anorectal atresia is a serious birth defect of largely unknown etiology but candidate genes have been identified in animal studies and human syndromes. Because alterations in the activity of these genes might lead to anorectal atresia, we selected 71 common variants predicted to be in transcription factor binding sites, CpG windows, splice sites, and miRNA target sites of 25 candidate genes, and tested for their association with anorectal atresia. The study population comprised 150 anorectal atresia cases and 623 control infants without major malformations. Variants predicted to affect transcription factor binding, splicing, and DNA methylation in WNT3A, PCSK5, TCF4, MKKS, GLI2, HOXD12, and BMP4 were associated with anorectal atresia based on a nominal P value < 0.05. The GLI2 and BMP4 variants are reported to be moderately associated with gene expression changes (Spearman's rank correlation coefficients between -0.260 and 0.226). We did not find evidence for interaction between maternal pre-pregnancy obesity and variants in MKKS, a gene previously associated with obesity, on the risk of anorectal atresia. Our results for MKKS support previously suggested associations with anorectal malformations. Our findings suggest that more research is needed to determine whether altered GLI2 and BMP4 expression is important in anorectal atresia in humans.

Influence of Supervised Maternal Aerobic Exercise during Pregnancy on 1-Month-Old Neonatal Cardiac Function and Outflow: A Pilot Study.

PURPOSE: The objective of this study is to assess the effects of supervised, recommended levels of prenatal aerobic exercise on 1-month-old infant cardiac function. METHODS: Eligible pregnant women were randomly assigned to either an aerobic exercise group that participated in 150 min of supervised, moderate-intensity (40% to 59% V̇O 2peak , 12 to 14 on Borg rating of perceived exertion) aerobic exercise per week for 24 wk or more or a nonexercising group that consisted of 150 min·wk -1 of relaxation techniques. One-month-old infant echocardiogram was performed to assess infant cardiac function , including heart rate (HR), left-ventricular stroke volume, cardiac output, cardiac index, ejection fraction, fractional shortening, and velocity time integral at the aortic valve. Pearson correlation analyses and linear regression models were performed. RESULTS: Prenatal aerobic exercise was negatively correlated with infant resting HR ( r = -0.311, P = 0.02). Similarly, when controlling for infant sex and activity state, exercise level/volume ( ß = -0.316; 95% CI, -0.029 to -0.002; P = 0.02) predicted resting infant HR ( R2 = 0.18, P = 0.02). In infants of overweight/obese women, infants of aerobic exercisers had increased fractional shortening ( P = 0.03). In addition, infant ventricular ejection fraction was correlated with maternal exercise attendance ( r = 0.418, P = 0.03) as well as a trend for exercise level ( r = 0.351, P = 0.08). Similarly, the only significant regression model for infants of overweight/obese women controls infant activity state ( ß = -0.444; 95% CI, -0.05 to -0.01; P = 0.006) and maternal exercise level ( ß = 0.492; 95% CI, 5.46-28.74; P = 0.01) predicting infant resting HR ( F = 5.79, R2 = 0.40, P = 0.003). CONCLUSIONS: The findings of this study demonstrate that women participating in exercise in the second and third trimesters of their pregnancy may have infants with increased cardiac function at 1 month of age. Importantly, the cardiac function effects were further augmented for infants born to overweight/obese women.

Hirschsprung's disease and variants in genes that regulate enteric neural crest cell proliferation, migration and differentiation.

Hirschsprung's disease (HSCR) results from failed colonization of the embryonic gut by enteric neural crest cells (ENCCs); colonization requires RET proto-oncogene (RET) signaling. We sequenced RET to identify coding and splice-site variants in a population-based case group and we tested for associations between HSCR and common variants in RET and candidate genes (ASCL1, homeobox B5 (HOXB5), L1 cell adhesion molecule (L1CAM), paired-like homeobox 2b (PHOX2B), PROK1 and PROKR1) chosen because they are involved in ENCC proliferation, migration and differentiation in animal models. We conducted a nested case-control study of 304 HSCR cases and 1215 controls. Among 38 (12.5%) cases with 34 RET coding and splice-site variants, 18 variants were previously unreported. We confirmed associations with common variants in HOXB5 and PHOX2B but the associations with variants in ASCL1, L1CAM and PROK1 were not significant after multiple comparisons adjustment. RET variants were strongly associated with HSCR (P-values between 10(-3) and 10(-31)) but this differed by race/ethnicity: associations were absent in African-Americans. Our population-based study not only identified novel RET variants in HSCR cases, it showed that common RET variants may not contribute to HSCR in all race/ethnic groups. The findings for HOXB5 and PHOX2B provide supportive evidence that genes regulating ENCC proliferation, migration and differentiation could be risk factors for HSCR.

Evaluation of genes involved in limb development, angiogenesis, and coagulation as risk factors for congenital limb deficiencies.

We conducted a population-based case-control study of single nucleotide polymorphisms (SNPs) in selected genes to find common variants that play a role in the etiology of limb deficiencies (LDs). Included in the study were 389 infants with LDs of unknown cause and 980 unaffected controls selected from all births in New York State (NYS) for the years 1998-2005. We used cases identified from the NYS Department of Health (DOH) Congenital Malformations Registry. Genotypes were obtained for 132 SNPs in genes involved in limb development (SHH, WNT7A, FGF4, FGF8, FGF10, TBX3, TBX5, SALL4, GREM1, GDF5, CTNNB1, EN1, CYP26A1, CYP26B1), angiogenesis (VEGFA, HIF1A, NOS3), and coagulation (F2, F5, MTHFR). Genotype call rates were >97% and SNPs were tested for departure from Hardy-Weinberg expectations by race/ethnic subgroups. For each SNP, odds ratios (OR)s and confidence intervals (CI)s were estimated and corrected for multiple comparisons for all LDs combined and for LD subtypes. Among non-Hispanic white infants, associations between FGF10 SNPs rs10805683 and rs13170645 and all LDs combined were statistically significant following correction for multiple testing (OR = 1.99; 95% CI = 1.43-2.77; uncorrected P = 0.000043 for rs10805683 heterozygous genotype, and OR = 2.37; 95% CI = 1.48-3.78; uncorrected P = 0.00032 for rs13170645 homozygous minor genotype). We also observed suggestive evidence for associations with SNPs in other genes including CYP26B1 and WNT7A. Animal studies have shown that FGF10 induces formation of the apical ectodermal ridge and is necessary for limb development. Our data suggest that common variants in FGF10 increase the risk for a wide range of non-syndromic limb deficiencies.

A prospective cohort study of the prevalence of growth, facial, and central nervous system abnormalities in children with heavy prenatal alcohol exposure.

BACKGROUND: Most children who are exposed to large quantities of alcohol in utero do not develop fetal alcohol syndrome (FAS). Population-based prospective data on the risk of developing components of fetal alcohol spectrum disorders (FASD), however, are limited. METHODS: This was a prospective cohort study of 9,628 women screened during their first prenatal appointment in Chile, which identified 101 who consumed at least 4 drinks/d (exposed) matched with 101 women with no reported alcohol consumption during pregnancy (unexposed). Detailed alcohol consumption data were collected during the pregnancy. Children were evaluated up to 8.5 years of age by clinicians masked to exposure status. RESULTS: One or more functional central nervous system abnormalities were present in 44.0% (22/50) of the exposed children compared to 13.6% (6/44) of the unexposed (p = 0.002). Growth restriction was present in 27.2% (25/92) of the exposed and 12.5% (12/96) of the unexposed (p = 0.02). Abnormal facial features were present in 17.3% (14/81) of the exposed children compared to 1.1% (1/89) of the unexposed children (p = 0.0002) by direct examination. Of the 59 exposed children with data available to detect at least 1 abnormality, 12 (20.3%) had no abnormalities. Binge drinking from conception to recognition of pregnancy (OR = 1.48 per day, 95% CI: 1.15 to 1.91, p = 0.002) and after recognition of pregnancy (OR= 1.41 per day, 95% CI: 1.01 to 1.95, p = 0.04) and total number of drinks consumed per week from conception to recognition of pregnancy (OR = 1.02 per drink, 95% CI: 1.01 to 1.04, p = 0.0009) were significantly associated with abnormal child outcome. CONCLUSIONS: After exposure to heavy alcohol consumption during pregnancy, 80% of children had 1 or more abnormalities associated with alcohol exposure. Patterns of alcohol use that posed the greatest risk of adverse outcomes were binge drinking and high total weekly intake. Functional neurologic impairment occurred most frequently and may be the only sign to alert physicians to prenatal alcohol exposure.