Electrophysiological correlates of inhibitory control in children: Relations with prenatal maternal risk factors and child psychopathology.

Inhibitory control plays an important role in children's cognitive and socioemotional development, including their psychopathology. It has been established that contextual factors such as socioeconomic status (SES) and parents' psychopathology are associated with children's inhibitory control. However, the relations between the neural correlates of inhibitory control and contextual factors have been rarely examined in longitudinal studies. In the present study, we used both event-related potential (ERP) components and time-frequency measures of inhibitory control to evaluate the neural pathways between contextual factors, including prenatal SES and maternal psychopathology, and children's behavioral and emotional problems in a large sample of children (N = 560; 51.75% females; Mage = 7.13 years; Rangeage = 4-11 years). Results showed that theta power, which was positively predicted by prenatal SES and was negatively related to children's externalizing problems, mediated the longitudinal and negative relation between them. ERP amplitudes and latencies did not mediate the longitudinal association between prenatal risk factors (i.e., prenatal SES and maternal psychopathology) and children's internalizing and externalizing problems. Our findings increase our understanding of the neural pathways linking early risk factors to children's psychopathology.

In Utero Exposure to Alcohol and Tobacco and Electroencephalogram Power During Childhood.

Importance: Prenatal alcohol exposure (PAE) and prenatal tobacco exposure (PTE) are risk factors associated with adverse neurobehavioral and cognitive outcomes. Objective: To quantify long-term associations of PAE and PTE with brain activity in early and middle childhood via electroencephalography (EEG). Design, Setting, and Participants: This cohort study included participants enrolled in the Safe Passage Study (August 2007 to January 2015), from which a subset of 649 participants were followed up in the Environmental Influences on Child Health Outcomes Program. From September 2018 through November 2022, EEG recordings were obtained at ages 4, 5, 7, 9, or 11 years. Data were analyzed from November 2022 to November 2023. Exposures: Maternal self-reported consumptions of alcohol and tobacco during pregnancy were captured at the recruitment interview and at up to 3 visits during pregnancy (20-24, 28-32, and ≥34 weeks' gestation). Classifications of PAE (continuous drinking, quit-early drinking, and nondrinking) and PTE (continuous smoking, quit-early smoking, and nonsmoking) were previously obtained. Main Outcomes and Measures: EEG band powers (theta, alpha, beta, gamma) were extracted from the EEG recordings. Linear regression models were used to estimate the associations of PAE and PTE with EEG estimates. Results: The final sample included 649 participants (333 [51.3%] female) aged 4, 5, 7, 9, or 11 years. Children whose mothers were in the quit-early drinking cluster had increased alpha power (0.116 [95% CI, 0.023 to 0.209] µV2; P = .02) compared with individuals without PAE. The magnitude of this increase was approximately double for children exposed to continuous drinking (0.211 [95% CI, 0.005 to 0.417] µV2; P = .04). Children whose mothers were in the continuous smoking cluster had decreased beta power (-0.031 [95% CI, -0.059 to -0.003] µV2; P = .03) and gamma power (-0.020 [95% CI, -0.039 to -0.000] µV2; P = .04) compared with the nonsmoking cluster. In exploratory sex-stratified models, male participants in the quit-early PAE cluster had greater EEG power in the alpha band (0.159 [95% CI, 0.003 to 0.315] µV2; P = .04) compared with those with no PAE, and the difference was approximately double for male participants with continuous PAE (0.354 [95% CI, 0.041 to 0.667] µV2; P = .03). Male participants in the continuous PTE cluster had decreased beta (-0.048 [95% CI, -0.090 to - 0.007] µV2; P = .02) and gamma (-0.032 [95% CI, -0.061 - 0.002] µV2; P = .04) power compared with those with no PTE. Conclusions and Relevance: These findings suggest that even low levels of PAE and PTE were associated with long-term alterations of brain activity.

Neonatal rhinorrhea, heart rate variability, and childhood exercise-induced wheeze.

Background: There is increasing evidence linking infant rhinorrhea to school-age exercise-induced wheeze (EIW) via a parasympathetic nervous system pathway. The ratio of the root mean square of successive differences in heart beats (RMSSD) measured in quiet sleep versus active sleep (RMSSDQS:AS) is a novel biomarker in asthma. Objective: We tested the hypotheses that (1) neonatal rhinorrhea predicts childhood EIW independent of other neonatal respiratory symptoms, (2) neonatal RMSSDQS:AS predicts childhood EIW, and (3) RMSSDQS:AS mediates the association between neonatal rhinorrhea and childhood EIW. Methods: Participants from the Safe Passage/Environmental Influences on Child Health Outcomes (PASS/ECHO) prospective birth cohort had heart rate variability extracted from electrocardiogram traces acquired in the first month of life. Parents reported on rhinorrhea in their child at age 1 month and on EIW in their child at ages 4 to 11 years. Results: In models (N = 831) adjusted for potential confounders and covariates, including neonatal wheeze, cough and fever, neonatal rhinorrhea-predicted childhood EIW (relative risk [RR] = 2.22; P = .040), specifically, among females (RR = 3.38; P = .018) but not males (RR = 1.39; P = .61). Among participants contributing data in both active and quiet sleep (n = 231), RMSSDQS:AS predicted EIW (RR = 2.36; P = .003) and mediated the effect estimate of neonatal rhinorrhea predicting EIW among females. Half of the females with a higher RMSSDQS:AS and neonatal rhinorrhea (n = 5 of 10) developed EIW as compared with 1.8% of the other females (n = 2 of 109) (P < .001). Conclusions: Our findings support dysregulation of the parasympathetic nervous system in infancy as one of the possible underlying mechanisms for the development of EIW later in childhood among females, which could aid in the development of future interventions.

Prenatal smoking and drinking are associated with altered newborn autonomic functions.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: These findings highlight potential ANS pathways through which prenatal drinking and smoking may contribute to neurodevelopment outcomes. IMPACT: 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.

Longitudinal characterization of EEG power spectra during eyes open and eyes closed conditions in children.

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.

A Novel Method for the Extraction of Fetal ECG Signals from Wearable Devices.

The role of fetal surveillance for the prediction and timely assessment of fetal distress is widely established. Fetal ECG (fECG) monitoring via wearable devices is a feasible solution for performing continuous monitoring of fetal wellbeing and it has seen a net increase in popularity in recent years. In this paper, we propose a novel adaptation of the Smart AdaptiVe Ecg Recognition (SAVER) algorithm for the detection of fECG in long-duration recordings acquired in clinical as well as unconventional settings. The methodology was trained and tested on 50 recordings of duration 1 hour ( 59.33 ±5.54 min) obtained using the Monica AN24 fetal monitor. We validated the performance against the automatic extraction performed by the Monica DK software. Our results show superior reliability of the proposed methodology in extracting fECG and associated estimates of fetal heart rate (fHR). Clinical relevance- The proposed methodology provides an efficient and reliable approach for the extraction of fECG signals acquired via wearable technologies, enabling continuous monitoring of fECG in and outside clinical settings.

Facilitating early parent-infant emotional connection improves cortical networks in preterm infants.

Exposure to environmental adversities during early brain development, such as preterm birth, can affect early brain organization. Here, we studied whether development of cortical activity networks in preterm infants may be improved by a multimodal environmental enrichment via bedside facilitation of mother-infant emotional connection. We examined functional cortico-cortical connectivity at term age using high-density electroencephalography recordings in infants participating in a randomized controlled trial of Family Nurture Intervention (FNI). Our results identify several large-scale, frequency-specific network effects of FNI, most extensively in the alpha frequency in fronto-central cortical regions. The connectivity strength in this network was correlated to later neurocognitive performance, and it was comparable to healthy term-born infants rather than the infants receiving standard care. These findings suggest that preterm neurodevelopmental care can be improved by a biologically driven environmental enrichment, such as early facilitation of direct human connection.

A Novel Method for ECG Artifact Removal from EEG without Simultaneous ECG.

The electrocardiogram (ECG) is a common source of electrical artifact in electroencephalogram (EEG). Here, we present a novel method for removing ECG artifact that requires neither simultaneous ECG nor transformation of the EEG signals. The approach relies upon processing a subset of EEG channels that contain ECG artifact to identify the times of each R-wave of the ECG. Within selected brief epochs, data in each EEG channel is signal-averaged ± 60 ms around each R-wave to derive an ECG template specific to each channel. This template is subtracted from each EEG channel which are aligned with the R-waves. The methodology was developed using two cohorts of infants: one with 128-lead EEG including an ECG reference and another with 32-lead EEG without ECG reference. The results for the first cohort validated the methodology the ECG reference and the second demonstrated its feasibility when ECG was not recorded. This method does not require independent, simultaneous recording of ECG, nor does it involve creation of an artifact template based on a mixture of EEG channel data as required by other methods such as Independent Component Analysis (ICA). Spectral analysis confirms that the method compares favorably to results using simultaneous recordings of ECG. The method removes ECG artifact on an epoch by epoch level and does not require stationarity of the artifact. Clinical Relevance - This approach facilitates the removal of ECG noise in frequency bands known to play a central role in brain mechanisms underlying cognitive processes.

Family nurture intervention increases term age forebrain EEG activity: A multicenter replication trial.

OBJECTIVE: This trial (RCT-2) sought to replicate the EEG findings of a randomized controlled trial of Family Nurture Intervention in the NICU (FNI-NICU) (RCT-1) comparing infants receiving standard care (SC) with infants receiving SC plus FNI . METHODS: RCT-2 (NCT02710474) was conducted at two NICUs. Subjects were randomly assigned to receive SC or FNI during their NICU stay. The primary outcome was EEG power in the frontal polar region at 39-41 weeks gestational age (GA). Sixty preterm infants (26-34 weeks GA; 33 SC, 27 FNI) were assessed. FNI-NICU consisted of repeated calming sessions (∼4 times/week) facilitated by Nurture Specialists during which mothers engaged in emotional expression during clothed or skin-to-skin holding, vocal soothing, and eye contact. EEGs were collected from 128 leads. EEG power was computed using Fast Fourier Transforms. RESULTS: RCT-2 replicated RCT-1 results; FNI-NICU led to significantly increased frontal polar power at frequencies > 12 Hz. Effects were spatially more widespread than in RCT-1, with substantial effect sizes (∼0.50) in frontal and parietal regions. CONCLUSIONS: RCT-2 results provide further evidence that FNI-NICU increases term age brain activity. SIGNIFICANCE: FNI-NICU is designed to facilitate autonomic emotional connection and coregulation between mothers and infants in the NICU resulting in profound effects on early brain development.

Effects of Family Nurture Intervention in the NICU on Theory of Mind Abilities in Children Born Very Preterm: A Randomized Controlled Trial.

Preterm infants are at risk for socioemotional deficits, neurodevelopmental disorders, and potentially theory of mind (ToM) deficits. Preterm infants enrolled in a randomized controlled trial in the neonatal intensive care unit (NICU) received Standard Care (SC) or Family Nurture Intervention (FNI). Children (N = 72; median age 61.8 ± 2.6 months; FNI: 35 (55%), SC:2 9 (45%)) completed a ToM task, of whom 64 (54% male; born to White (43.8%), Black (18.7%), and Hispanic (25.0%) mothers) contributed to this analysis. FNI and SC infants born extremely preterm to very preterm differed significantly: 78% (14 of 18) of FNI children passed vs. 30% (3 of 10) SC children (p = 0.01, effect size = 1.06). This large effect size suggests that FNI in the NICU may ameliorate deficits in social-cognitive skills of extreme to very preterm infants by school age.

Increased Heart Rate Variability Response Among Infants with Reported Rhinorrhea and Watery Eyes: A Pilot Study.

INTRODUCTION: 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.

Prenatal Exposure to Tobacco and Alcohol Alters Development of the Neonatal Auditory System.

Prenatal exposures to alcohol (PAE) and tobacco (PTE) are known to produce adverse neonatal and childhood outcomes including damage to the developing auditory system. Knowledge of the timing, extent, and combinations of these exposures on effects on the developing system is limited. As part of the physiological measurements from the Safe Passage Study, Auditory Brainstem Responses (ABRs) and Transient Otoacoustic Emissions (TEOAEs) were acquired on infants at birth and one-month of age. Research sites were in South Africa and the Northern Plains of the U.S. Prenatal information on alcohol and tobacco exposure was gathered prospectively on mother/infant dyads. Cluster analysis was used to characterize three levels of PAE and three levels of PTE. Repeated-measures ANOVAs were conducted for newborn and one-month-old infants for ABR peak latencies and amplitudes and TEOAE levels and signal-to-noise ratios. Analyses controlled for hours of life at test, gestational age at birth, sex, site, and other exposure. Significant main effects of PTE included reduced newborn ABR latencies from both ears. PTE also resulted in a significant reduction of ABR peak amplitudes elicited in infants at 1-month of age. PAE led to a reduction of TEOAE amplitude for 1-month-old infants but only in the left ear. Results indicate that PAE and PTE lead to early disruption of peripheral, brainstem, and cortical development and neuronal pathways of the auditory system, including the olivocochlear pathway.

Association of Prenatal Exposure to Maternal Drinking and Smoking With the Risk of Stillbirth.

Importance: Prenatal smoking is a known modifiable risk factor for stillbirth; however, the contribution of prenatal drinking or the combination of smoking and drinking is uncertain. Objective: To examine whether prenatal exposure to alcohol and tobacco cigarettes is associated with the risk of stillbirth. Design, Setting, and Participants: The Safe Passage Study was a longitudinal, prospective cohort study with data collection conducted between August 1, 2007, and January 31, 2015. Pregnant women from Cape Town, South Africa, and the Northern Plains region of the US were recruited and followed up throughout pregnancy. Data analysis was performed from November 1, 2018, to November 20, 2020. Exposure: Maternal consumption of alcohol and tobacco cigarettes in the prenatal period. Main Outcomes and Measures: The main outcomes were stillbirth, defined as fetal death at 20 or more weeks' gestation, and late stillbirth, defined as fetal death at 28 or more weeks' gestation. Self-reported alcohol and tobacco cigarette consumption was captured at the recruitment interview and up to 3 scheduled visits during pregnancy. Participants were followed up during pregnancy to obtain delivery outcome. Results: Of 11663 pregnancies (mean [SD] gestational age at enrollment, 18.6 [6.6] weeks) in 8506 women for whom the pregnancy outcome was known by 20 weeks' gestation or later and who did not terminate their pregnancies, there were 145 stillbirths (12.4 per 1000 pregnancies) and 82 late stillbirths (7.1 per 1000 pregnancies). A total of 59% of pregnancies were in women from South Africa, 59% were in multiracial women, 23% were in White women, 17% were in American Indian women, and 0.9% were in women of other races. A total of 8% were older than 35 years. In 51% of pregnancies, women reported no alcohol or tobacco cigarette exposure (risk of stillbirth, 4 per 1000 pregnancies). After the first trimester, 18% drank and smoked (risk of stillbirth, 15 per 1000 births), 9% drank only (risk of stillbirth, 10 per 1000 pregnancies), and 22% smoked only (risk of stillbirth, 8 per 1000 pregnancies). Compared with the reference group (pregnancies not prenatally exposed or without any exposure after the first trimester), the adjusted relative risk of late stillbirth was 2.78 (98.3% CI, 1.12-6.67) for pregnancies prenatally exposed to drinking and smoking, 2.22 (98.3% CI, 0.78-6.18) for pregnancies prenatally exposed to drinking only after the first trimester, and 1.60 (98.3% CI, 0.64-3.98) for pregnancies prenatally exposed to smoking only after the first trimester. The adjusted relative risk for all stillbirths was 1.75 (98.3% CI, 0.96-3.18) for dual exposure, 1.26 (98.3% CI, 0.58-2.74) for drinking only, and 1.27 (98.3% CI, 0.69-2.35) for smoking only compared with the reference group. Conclusions and Relevance: These results suggest that combined drinking and smoking after the first trimester of pregnancy, compared with no exposure or quitting before the end of the first trimester, may be associated with a significantly increased risk of late stillbirth.

Effects of Prenatal Exposure to Alcohol and Smoking on Fetal Heart Rate and Movement Regulation.

Negative associations of prenatal tobacco and alcohol exposure (PTE and PAE) on birth outcomes and childhood development have been well documented, but less is known about underlying mechanisms. A possible pathway for the adverse fetal outcomes associated with PTE and PAE is the alteration of fetal autonomic nervous system development. This study assessed PTE and PAE effects on measures of fetal autonomic regulation, as quantified by heart rate (HR), heart rate variability (SD-HR), movement, and HR-movement coupling in a population of fetuses at ≥ 34 weeks gestational age. Participants are a subset of the Safe Passage Study, a prospective cohort study that enrolled pregnant women from clinical sites in Cape Town, South Africa, and the Northern Plains region, United States. PAE was defined by six levels: no alcohol, low quit early, high quit early, low continuous, moderate continuous, and high continuous; while PTE by 4 levels: no smoking, quit early, low continuous, and moderate/high continuous. Linear regression analyses of autonomic measures were employed controlling for fetal sex, gestational age at assessment, site, maternal education, household crowding, and depression. Analyses were also stratified by sleep state (1F and 2F) and site (South Africa, N = 4025, Northern Plains, N = 2466). The final sample included 6491 maternal-fetal-dyad assessed in the third trimester [35.21 ± 1.26 (mean ± SD) weeks gestation]. PTE was associated with a decrease in mean HR in state 2F, in a dose dependent fashion, only for fetuses of mothers who continued smoking after the first trimester. In state 1F, there was a significant increase in mean HR in fetuses whose mother quit during the first trimester. This effect was driven by the Norther Plains cohort. PTE was also associated with a significant reduction in fetal movement in the most highly exposed group. In South Africa a significant increase in mean HR both for the high quit early and the high continuous group was observed. In conclusion, this investigation addresses a critical knowledge gap regarding the relationship between PTE and PAE and fetal autonomic regulation. We believe these results can contribute to elucidating mechanisms underlying risk for adverse outcomes.

Nicotinic Receptors in the Brainstem Ascending Arousal System in SIDS With Analysis of Pre-natal Exposures to Maternal Smoking and Alcohol in High-Risk Populations of the Safe Passage Study.

Pre-natal exposures to nicotine and alcohol are known risk factors for sudden infant death syndrome (SIDS), the leading cause of post-neonatal infant mortality. Here, we present data on nicotinic receptor binding, as determined by 125I-epibatidine receptor autoradiography, in the brainstems of infants dying of SIDS and of other known causes of death collected from the Safe Passage Study, a prospective, multicenter study with clinical sites in Cape Town, South Africa and 5 United States sites, including 2 American Indian Reservations. We examined 15 pons and medulla regions related to cardiovascular control and arousal in infants dying of SIDS (n = 12) and infants dying from known causes (n = 20, 10 pre-discharge from time of birth, 10 post-discharge). Overall, there was a developmental decrease in 125I-epibatidine binding with increasing postconceptional age in 5 medullary sites [raphe obscurus, gigantocellularis, paragigantocellularis, centralis, and dorsal accessory olive (p = 0.0002-0.03)], three of which are nuclei containing serotonin cells. Comparing SIDS with post-discharge known cause of death (post-KCOD) controls, we found significant decreased binding in SIDS in the nucleus pontis oralis (p = 0.02), a critical component of the cholinergic ascending arousal system of the rostral pons (post-KCOD, 12.1 ± 0.9 fmol/mg and SIDS, 9.1 ± 0.78 fmol/mg). In addition, we found an effect of maternal smoking in SIDS (n = 11) combined with post-KCOD controls (n = 8) on the raphe obscurus (p = 0.01), gigantocellularis (p = 0.02), and the paragigantocellularis (p = 0.002), three medullary sites found in this study to have decreased binding with age and found in previous studies to have abnormal indices of serotonin neurotransmission in SIDS infants. At these sites, 125I-epibatidine binding increased with increasing cigarettes per week. We found no effect of maternal drinking on 125I-epibatidine binding at any site measured. Taken together, these data support changes in nicotinic receptor binding related to development, cause of death, and exposure to maternal cigarette smoking. These data present new evidence in a prospective study supporting the roles of developmental factors, as well as adverse exposure on nicotinic receptors, in serotonergic nuclei of the rostral medulla-a finding that highlights the interwoven and complex relationship between acetylcholine (via nicotinic receptors) and serotonergic neurotransmission in the medulla.

Family nurture intervention in the NICU increases autonomic regulation in mothers and children at 4-5 years of age: Follow-up results from a randomized controlled trial.

BACKGROUND: Maturation of multiple neurobehavioral systems, including autonomic regulation, is altered by preterm birth. The purpose of this study was to determine the long-term effects of Family Nurture Intervention (FNI) in the NICU on autonomic regulation of preterm infants and their mothers. METHOD: A subset of infants and mothers (48% of infants, 51% of mothers) randomly assigned to either standard are (SC), or SC plus the FNI in the NICU in a prior RCT (ClincalTrials.gov; NCT01439269) returned for follow-up assessments when the children were 4 to 5 years corrected age (CA). ECGs were collected for 10 minutes in mothers and their children while children were in their mothers' laps. Heart rate, standard deviation for heart rate, respiratory sinus arrhythmia (RSA)-an index of parasympathetic regulation, and a measure of vagal efficiency were quantified. RESULTS: Both children and mothers in the FNI group had significantly greater levels of RSA compared to the SC group (child: mean difference = 0.60, 95% CI 0.17 to 1.03, p = 0.008; mother: mean difference = 0.64, 95% CI 0.07 to 1.21, p = 0.031). In addition, RSA increased more rapidly in FNI children between infancy and the 4 to 5-year follow-up time point (SC = +3.11±0.16 loge msec2, +3.67±0.19 loge msec2 for FNI, p<0.05). These results show that the rate of increase in RSA from infancy to childhood is more rapid in FNI subjects. CONCLUSION: Although these preliminary follow-up results are based on approximately half of subjects originally enrolled in the RCT, they suggest that FNI-NICU led to healthier autonomic regulation in both mother and child, when measured during a brief face-to-face socioemotional interaction. A Pavlovian autonomic co-conditioning mechanism may underly these findings that can be exploited therapeutically.

Family nurture intervention alters relationships between preterm infant EEG delta brush characteristics and term age EEG power.

OBJECTIVE: Family Nurture Intervention (FNI) facilitates mother/infant emotional connection, improves neurodevelopmental outcomes and increases electroencephalogram (EEG) power at term age. Here we explored whether delta brushes (DB), early EEG bursts that shape brain development, are altered by FNI and mediate later effects of FNI on EEG. METHODS: We assessed DB characteristics in EEG data from a randomized controlled trial comparing infants with standard care (SC, n = 31) versus SC + FNI (n = 33) at ~35 and ~40 weeks GA. RESULTS: Compared to SC infants, FNI infant DB amplitude increased more from ~35 to ~40 weeks, and FNI infants had longer duration DBs. DB parameters (rate, amplitude, brush frequency) at ~35 weeks were correlated with power at ~40 weeks, but only in SC infants. FNI effects on DB parameters do not mediate FNI effects on EEG power or coherence at term. CONCLUSIONS: DBs are related to subsequent brain activity and FNI alters DB parameters. However, FNI's effects on electrocortical activity at term age are not dependent on its earlier effects on DBs. SIGNIFICANCE: While early DBs can have important effects on later brain activity in preterm infants, facilitating emotional connection with FNI may allow brain maturation to be less dependent on early bursts.

Association Between Prenatal Exposure to Alcohol and Tobacco and Neonatal Brain Activity: Results From the Safe Passage Study.

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 < .05; 95% CI, -0.379 to -0.045; P < .05), quit (95% CI, -0.419 to -0.127; P < .001; 95% CI, -0.398 to -0.106; P < .005), and moderate or high continuous (95% CI, -0.430 to -0.124; P < .001; 95% CI, -0.420 to -0.119; P < .005) PAE clusters had increased 4- to 6-Hz and 7- to 9-Hz left-temporal EEG power. Newborns with moderate or high continuous PTE had decreased 19- to 21-Hz (95% CI, 0.034 to 0.327; P < .05) and 22- to 24-Hz (95% CI, 0.022 to 0.316; P < .05) right-central EEG compared with newborns with no PTE. Newborns with moderate or high continuous PTE had significantly decreased 22- to 36-Hz right-central EEG power compared with the quit smoking group (22-24 Hz, 95% CI, 0.001 to 0.579; P < .05; 25-27 Hz, 95% CI, 0.008 to 0.586; P < .05; 28-30 Hz, 95% CI, 0.028 to 0.607; P < .05; 31-33 Hz, 95% CI, 0.038 to 0.617; P < .05; 34-36 Hz, 95% CI, 0.057 to 0.636; P < .05). Conclusions and Relevance: These findings suggest that even low levels of PAE or PTE are associated with changes in offspring brain development.

Concurrent prenatal drinking and smoking increases risk for SIDS: Safe Passage Study report.

BACKGROUND: Sudden infant death syndrome (SIDS) is the leading cause of postneonatal mortality. Although the rate has plateaued, any unexpected death of an infant is a family tragedy thus finding causes and contributors to risk remains a major public health concern. The primary objective of this investigation was to determine patterns of drinking and smoking during pregnancy that increase risk of SIDS. METHODS: The Safe Passage Study was a prospective, multi-center, observational study with 10,088 women, 11,892 pregnancies, and 12,029 fetuses, followed to 1-year post delivery. Subjects were from two sites in Cape Town, South Africa and five United States sites, including two American Indian Reservations. Group-based trajectory modeling was utilized to categorize patterns of drinking and smoking exposure during pregnancy. FINDINGS: One-year outcome was ascertained in 94·2% infants, with 28 SIDS (2·43/1000) and 38 known causes of death (3·30/1000). The increase in relative risk for SIDS, adjusted for key demographic and clinical characteristics, was 11·79 (98·3% CI: 2·59-53·7, p < 0·001) in infants whose mothers reported both prenatal drinking and smoking beyond the first trimester, 3.95 (98·3% CI: 0·44-35·83, p = 0·14), for drinking only beyond the first trimester and 4·86 (95% CI: 0·97-24·27, p = 0·02) for smoking only beyond the first trimester as compared to those unexposed or reported quitting early in pregnancy. INTERPRETATION: Infants prenatally exposed to both alcohol and cigarettes continuing beyond the first trimester have a substantially higher risk for SIDS compared to those unexposed, exposed to alcohol or cigarettes alone, or when mother reported quitting early in pregnancy. Given that prenatal drinking and smoking are modifiable risk factors, these results address a major global public health problem. FUNDING: National Institute on Alcohol Abuse and Alcoholism, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute on Deafness and Other Communication Disorders.

Assessment of autonomic function in the late term fetus: The effects of sex and state.

Researchers have reported associations between fetal sex and heart rate (FHR) and heart rate variability (FHRV) but rarely in the context of fetal behavioral sleep state. We examined differences in measures of fetal autonomic function by sex and sleep state. Fetal abdominal ECG monitoring technology was used to measure FHR and two measures of FHRV-standard deviation of FHR (SD) and beat-to-beat variability (RMSSD). FHR and movement patterns were also recorded with standard Doppler ultrasound monitor technology employed to code sleep states. Data were collected from 82 healthy fetuses ranging from 36 to 39 weeks gestation. A one-way MANOVA showed that FHR was significantly lower and SD was significantly higher for males than females. Independent samples t tests found that these sex differences were only in the active sleep state. There were no significant differences in RMSSD by sex. Repeated measures MANOVA for a subset that exhibited more than one state (N = 22) showed that SD was significantly different by state. RMSSD showed a marginally significant sleep state difference. In conclusion, fetal sex differences in HR and HRV may indicate more mature autonomic functioning in near-term males than females and fetal sleep state can influence abdominal fECG derived measures of FHR and FHRV.