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Prenatal smoking and drinking are associated with sudden infant death syndrome and neurodevelopmental disorders. Infants with these outcomes also have altered autonomic nervous system (ANS) regulation. We examined the effects of prenatal smoking and drinking on newborn ANS function.Pregnant women were enrolled in Northern Plains, USA (NP) and Cape Town (CT), South Africa. Daily drinking and weekly smoking data were collected prenatally. Physiological measures were obtained during sleep 12-96 h post-delivery.In all, 2913 infants from NP and 4072 from CT were included. In active sleep, newborns of mothers who smoked throughout pregnancy, compared to non-smokers, had higher breathing rates (2.2 breaths/min; 95% CI: 0.95, 3.49). Quit-early smoking was associated with reductions in beat-to-beat heart rate variability (HRV) in active (-0.08 s) and quiet sleep (-0.11 s) in CT. In girls, moderate-high continuous smoking was associated with increased systolic (3.0 mmHg, CI: 0.70, 5.24) and diastolic blood pressure (2.9 mmHg, CI: 0.72, 5.02). In quiet sleep, low-continuous drinking was associated with slower heart rate (-4.5 beat/min). In boys, low-continuous drinking was associated with a reduced ratio of low-to-high frequency HRV (-0.11, CI: -0.21, -0.02).These findings highlight potential ANS pathways through which prenatal drinking and smoking may contribute to neurodevelopment outcomes.In this prospective cohort study of 6985 mother-infant dyads prenatal drinking and smoking were associated with multiple ANS parameters. Smoking was associated with increased neonatal breathing rates among all infants, and heart rate variability (HRV) and blood pressure (BP) among girls. Drinking was associated with reductions in HR and BP among all newborns, and reductions in the ratio of low to-high frequency HRV among boys. These findings suggest that prenatal smoking and drinking alter newborn ANS which may presage future neurodevelopmental disorders.

This study is the first to examine spectrum-wide (1 to 250 Hz) differences in electroencephalogram (EEG) power between eyes open (EO) and eyes closed (EC) resting state conditions in 486 children. The results extend the findings of previous studies by characterizing EEG power differences from 30 to 250 Hz between EO and EC across childhood. Developmental changes in EEG power showed spatial and frequency band differences as a function of age and EO/EC condition. A 64-electrode system was used to record EEG at 4, 5, 7, 9, and 11 years of age. Specific findings were: (1) the alpha peak shifts from 8 Hz at 4 years to 9 Hz at 11 years, (2) EC results in increased EEG power (compared to EO) at lower frequencies but decreased EEG power at higher frequencies for all ages, (3) the EEG power difference between EO and EC changes from positive to negative within a narrow frequency band which shifts toward higher frequencies with age, from 9 to 12 Hz at 4 years to 32 Hz at 11 years, (4) at all ages EC is characterized by an increase in lower frequency EEG power most prominently over posterior regions, (5) at all ages, during EC, decreases in EEG power above 30 Hz are mostly over anterior regions of the scalp. This report demonstrates that the simple challenge of opening and closing the eyes offers the potential to provide quantitative biomarkers of phenotypic variation in brain maturation by employing a brief, minimally invasive protocol throughout childhood.

Laura A Conrad,1 Natalie Buchinsky,2 Luis M Acosta,2 J David Nugent,3 Khalil W Savary,4 Rachel L Miller,5 Nurdant Emanet,6 Julie Herbstman,2 Beatrice Beebe,6 Michael M Myers,3 William P Fifer,3 Matthew S Perzanowski2 1Division of Respiratory and Sleep Medicine, Albert Einstein College of Medicine, New York, NY, USA; 2Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA; 3Division of Developmental Neuroscience, Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA; 4Department of Pediatrics, Rutgers University, Newark, NJ, USA; 5Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 6Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USACorrespondence: Matthew S PerzanowskiDepartment of Environmental Health Sciences, Mailman School of Public Health, Columbia University, 722 West 168th St, 11th Floor, New York, NY, 10032, USATel +1 212-305-3465Fax +1 212-305-4012Email mp2217@cumc.columbia.eduIntroduction: Previously, we found that reported infant rhinorrhea and watery eyes without a cold (RWWC) predicted school age exercise-induced wheeze, emergency department visits, and hospitalizations. These findings were independent of allergic sensitization, and we theorized that increased parasympathetic tone underlay the association. We also reported that increased heart-rate variability (HRV) in infants predicted wheeze in 2– 3 year-olds. In a convenience sample of children participating in a birth cohort study, we tested the hypothesis that infants with RWWC would have elevated HRV, indicating increased parasympathetic tone.Methods: RWWC symptoms since birth were queried for 3-month-old children. At 4-months, HRV was assessed (root mean square of successive differences [RMSSD]) during a standardized infant–mother still-face paradigm, which included 2 minutes of mother/child play immediately followed by 2 minutes of the mother maintaining a still-face.Results: Among participants (n=38), RWWC was common for girls (32%) and boys (21%). The children with the greatest decrease in RMSSD between play and still-face challenge (lowest tertile) had a higher prevalence of RWWC as compared with children in the higher tertiles (50% vs 16%, P=0.045). In a logistic regression model controlling for sex, age and time between HRV and RWWC assessment, children with greater decrease in HRV between play and still-face (lowest tertile) had greater odds of having RWWC (odds ratio=6.0, P=0.029).Conclusion: In this relatively small study, we demonstrated greater decreases in HRV in response to a stressor among children with reported RWWC, suggesting that these children might have increased parasympathetic tone and/or overall greater vagal reactivity.Keywords: watery eyes, still-face challenge, rhinitis, exercise-induced asthma, autonomic nervous system, heart rate variability

Prenatal alcohol exposure (PAE) has been linked to poor pregnancy outcomes, yet there is no recognized standard for PAE assessment, and the specific effects of quantity, frequency, and timing remain largely unknown. The Safe Passage Study was designed to investigate the role of PAE in a continuum of poor peri- and postnatal outcomes. The objective of this manuscript is to describe the rationale for, and feasibility of, modifications to the traditional Timeline Followback (TLFB) for collecting PAE information in a large cohort of pregnant women. Participants from the Northern Plains region (in the United States) and Cape Town, South Africa, were followed prospectively using a modified 30-day TLFB interview, administered up to five times, to obtain detailed PAE information. Required modifications for our population included capturing information regarding sharing, type/brand, container size, and duration, in order to accurately record the amount of alcohol consumed. PAE status was defined for 99.9% of the 11,892 enrolled pregnancies at least once during pregnancy and for 92% across all trimesters. Of 53,823 drinks reported, 98% had all items necessary for standard drink computation. Sharing was reported for 74% of drinks in Cape Town, South Africa and for 10% in the Northern Plains. Compared to referent values from the traditional TLFB, 74% and 67% of drinks had different alcohol-by-volume and container size, respectively. Furthermore, a statistically significant difference was found between the number of containers reported and the number of standard drinks computed, using information from the modified TLFB. This is the first study of this size to wholly encompass all of these changes into a single measure in order to more accurately calculate daily consumption and assess patterns over time. The methods used to collect PAE information and create alcohol exposure measures likely increased the accuracy of standard drinks reported and could be generalized to other populations.

Precise identification of drinking and smoking patterns during pregnancy is crucial to better understand the risk to the fetus. The purpose of this manuscript is to describe the methodological approach used to define prenatal drinking and smoking trajectories from a large prospective pregnancy cohort, and to describe maternal characteristics associated with different exposure patterns. In the Safe Passage Study, detailed information regarding quantity, frequency, and timing of exposure was self-reported up to four times during pregnancy and at 1 month post-delivery. Exposure trajectories were developed using data from 11,692 pregnancies (9,912 women) where pregnancy outcome was known. Women were from three diverse populations: white (23%) and American Indian (17%) in the Northern Plains, US, and mixed ancestry (59%) in South Africa (other/not specified [1%]). Group-based trajectory modeling was used to identify 5 unique drinking trajectories (1 none/minimal, 2 quitting groups, 2 continuous groups) and 7 smoking trajectories (1 none/minimal, 2 quitting groups, 4 continuous groups). Women with pregnancies assigned to the low- or high-continuous drinking groups were less likely to have completed high school and were more likely to have enrolled in the study in the third trimester, be of mixed ancestry, or be depressed than those assigned to the none/minimal or quit-drinking groups. Results were similar when comparing continuous smokers to none/minimal and quit-smoking groups. Further, women classified as high- or low-continuous drinkers were more likely to smoke at moderate-, high-, and very high-continuous levels, as compared to women classified as non-drinkers and quitters. This is the first study of this size to utilize group-based trajectory modeling to identify unique prenatal drinking and smoking trajectories. These trajectories will be used in future analyses to determine which specific exposure patterns subsequently manifest as poor peri- and postnatal outcomes.

Characterization of patterns of alcohol consumption during pregnancy encompasses multiple factors such as magnitude, frequency, and timing of exposure throughout gestation. Traditional statistical models are limited in dealing with multivariate and diverse patterns of exposure as in the context of this analysis. We propose a finite mixture model-based approach to derive clusters of alcohol exposure of participants in the Safe Passage Study (PASS). Daily alcohol consumption data for 11,083 pregnant women have been clustered in 10 different exposed groups. The resulting cluster analysis was able to characterize alcohol consumption in a comprehensive framework capable of taking into account both quantity and timing of exposure as well as the occurrence of binge drinking.

Importance Research to date has not determined a safe level of alcohol or tobacco use during pregnancy. Electroencephalography (EEG) is a noninvasive measure of cortical function that has previously been used to examine effects of in utero exposures and associations with neurodevelopment. Objective To examine the association of prenatal exposure to alcohol (PAE) and tobacco smoking (PTE) with brain activity in newborns. Design, Setting, and Participants This prospective cohort study enrolled mother-newborn dyads from December 2011 through August 2015, with data analyzed from June 2018 through June 2019. Pregnant women were recruited from clinical sites in Cape Town, South Africa, and the Northern Plains region of the US. Participants were a subset of newborns enrolled in the Safe Passage Study. Exclusions included birth at less than 37 or more than 41 weeks’ gestation, multiple birth, or maternal use of psychiatric medication during pregnancy. Exposures PAE and PTE groups were determined by cluster analysis. Main Outcomes and Measures Analyses of covariance were run on EEG spectral power at 12 scalp locations across the frequency spectrum from 1 to 45 Hz in 3-Hz bins by sleep state. Results The final sample consisted of 1739 newborns (median [interquartile range] gestational age at birth, 39.29 [1.57] weeks; 886 [50.9%] were female; median [interquartile range] newborn age at assessment, 48.53 [44.96] hours). Newborns whose mothers were in the low continuous (95% CI, −0.379 to −0.031;P Conclusions and Relevance These findings suggest that even low levels of PAE or PTE are associated with changes in offspring brain development.

Exposure to antenatal stressors affects autonomic regulation in fetuses. Whether the presence of congenital heart disease (CHD) alters the developmental trajectory of autonomic regulation is not known.This prospective observational cohort study aimed to further characterize autonomic regulation in fetuses with CHD; specifically hypoplastic left heart syndrome (HLHS), transposition of the great arteries (TGA), and tetralogy of Fallot (TOF).From 11/2010 to 11/2012, 92 fetuses were enrolled: 41 controls and 51 with CHD consisting of 19 with HLHS, 12 with TGA, and 20 with TOF. Maternal abdominal fetal electrocardiogram (ECG) recordings were obtained at 3 gestational ages: 19-27 weeks (F1), 28-33 weeks (F2), and 34-38 weeks (F3).Fetal ECG was analyzed for mean heart rate along with 3 measures of autonomic variability of the fetal heart rate: interquartile range, standard deviation, and root mean square of the standard deviation of the heart rate (RMSSD), a measure of parasympathetic activity.During F1 and F2 periods, HLHS fetuses demonstrated significantly lower mean HR than controls (p0.05). Heart rate variability at F3, as measured by standard deviation, interquartile range, and RMSSD was lower in HLHS than controls (p0.05). Other CHD subgroups showed a similar, though non-significant trend towards lower variability.Autonomic regulation in CHD fetuses differs from controls, with HLHS fetuses most markedly affected.

Gonadotropin-releasing hormone (GnRH) neurons migrate from the vomeronasal organ (VNO) in the nasal compartment to the basal forebrain in mice, beginning on embryonic day 11 (E11). These neurons use vomeronasal axons as guides to migrate through the nasal mesenchyme. Most GnRH neurons then migrate along the caudal branch of the vomeronasal nerve to reach the hypothalamus. We show here that stromal cell-derived factor-1 [SDF-1, also known as chemokine C-X-C motif ligand 12 (CXCL12)] is expressed in the embryonic nasal mesenchyme from as early as E10 in an increasing rostral to caudal gradient that is most intense at the border of the nasal mesenchyme and the telencephalon. Chemokine C-X-C motif receptor 4 (CXCR4), the receptor for SDF-1, is expressed by neurons in the olfactory epithelium and VNO. Cells derived from these sensory epithelia, including migrating GnRH neurons and ensheathing glial precursors of the migrating mass (MM), also express CXCR4, suggesting that they may use SDF-1 as a chemokine. In support of this, most GnRH neurons of CXCR4(−/−) mice fail to exit the VNO at E13, and comparatively few GnRH neurons reach the forebrain. There is also a significant decrease in the total number of GnRH neurons in CXCR4(−/−) mice and an increase in cell death within the VNO relative to controls. The MM is smaller in CXCR4(−/−) mice, suggesting that some MM cells also require SDF-1/CXCR4 function for migration and survival.