Fetal neuromaturation in late gestation is affected by maternal sleep disordered breathing and sleep disruption in pregnant women with obesity.

OBJECTIVE: Maternal sleep disordered breathing and sleep disruption have adverse effects on pregnancy outcomes through multiple potential pathophysiologic pathways. We hypothesize that disordered maternal sleep also adversely impacts the neuromaturation of the fetus. METHODS: Participants in this prospective observational study included 102 obese pregnant women (pre-pregnancy body mass index [BMI] of 30 or higher) at 36 weeks of pregnancy. Fetal neuromaturation, defined through measures of fetal heart rate variability, motor activity, and motor-cardiac coupling, was quantified through digitized fetal actocardiography during an afternoon recording. Maternal sleep measures were collected overnight through polysomnography. Data analysis focused on multiple regression, controlling for maternal BMI, blood pressure, and diabetes. RESULTS: Indicators of higher sleep disordered breathing were associated with delayed fetal neuromaturation and greater fetal motor activity. Less maternal sleep disruption (shorter rapid eye movement [REM] latency, more REM sleep, and/or fewer transitions) was associated with higher fetal heart rate variability and coupling-based neuromaturation. CONCLUSION: Characteristics of disordered maternal sleep affect the developing fetal nervous system. It is unknown whether these results extend to populations that are not characterized by obesity. The influence of maternal sleep on the developing fetal nervous system has been understudied and may yield effects that persist beyond pregnancy.

Maternal buprenorphine treatment during pregnancy and maternal physiology.

BACKGROUND: Buprenorphine, used for opioid use disorder (OUD) treatment during pregnancy, provides unknown effects on maternal physiological activity. The primary aim of this report is to document acute effects of buprenorphine administration on indicators of maternal autonomic functioning. Effects of maternal buprenorphine dose and other substance exposures on maternal measures were examined, as were neonatal abstinence syndrome (NAS) outcomes. METHODS: Forty-nine pregnant, buprenorphine-maintained women yielded maternal physiologic information (heart rate and variability, electrodermal activity, and respiratory rate) at 24, 28, 32 and 36 weeks gestation. Monitoring at trough and peak maternal medication levels was implemented to ascertain acute physiologic effects of buprenorphine administration. RESULTS: Buprenorphine administration accelerated maternal heart rate and reduced variability at two gestational ages (24 and 36 weeks) and suppressed sympathetic (electrodermal) activation at 24, 28 and 32 weeks at times of peak maternal medication levels. Maternal autonomic parameters were unrelated to polysubstance exposure with the exception of cigarette smoking. Heavier smoking dampened maternal heart rate variability across gestation and potentiated reactivity to buprenorphine at 24 and 36 weeks. Heavier smoking was also associated with reduced electrodermal activity at 36 weeks. Buprenorphine dose was unrelated to observed effects. Larger degree of maternal heart rate reactivity to buprenorphine administration was related to more severe NAS expression. CONCLUSIONS: These findings detail the maternal autonomic response to buprenorphine administration but also illustrate the significant effect of concurrent cigarette use on maternal autonomic regulation. This suggests the importance of smoking-reduction strategies in the comprehensive, medication-assisted treatment of women with OUD.

Maternal buprenorphine treatment and infant outcome.

BACKGROUND AND OBJECTIVES: Maternal buprenorphine maintenance predisposes the infant to exhibit neonatal abstinence syndrome (NAS), but there is insufficient published information regarding the nature of NAS and factors that contribute to its severity in buprenorphine-exposed infants. METHODS: The present study evaluated forty-one infants of buprenorphine-maintained women in comprehensive substance use disorder treatment who participated in an open-label study examining the effects of maternal buprenorphine maintenance on infant outcomes. Modifiers of the infant outcomes, including maternal treatment and substance use disorder parameters, were also evaluated. RESULTS: Fifty-nine percent of offspring exhibited NAS that required pharmacologic management. Both maternal buprenorphine dose as well as prenatal polysubstance exposure to illicit substance use/licit substance misuse were independently associated with NAS expression. Polysubstance exposure was associated with more severe NAS expression after controlling for the effects of buprenorphine dose. Other exposures, including cigarette smoking and SRI use, were not related to outcomes. Maternal buprenorphine dose was positively associated with lower birth weight and length. CONCLUSIONS: Polysubstance exposure was the most potent predictor of NAS severity in this sample of buprenorphine-exposed neonates. This finding suggests the need for interventions that reduce maternal polysubstance use during medication assisted treatment for opioid use disorder, and highlights the necessity of a comprehensive approach, beyond buprenorphine treatment alone, for the optimal care for pregnant women with opioid use disorders.

Maternal salivary testosterone in pregnancy and fetal neuromaturation.

Testosterone exposure during pregnancy has been hypothesized as a mechanism for sex differences in brain and behavioral development observed in the postnatal period. The current study documents the natural history of maternal salivary testosterone from 18 weeks gestation of pregnancy to 6 months postpartum, and investigates associations with fetal heart rate, motor activity, and their integration. Findings indicate maternal salivary testosterone increases with advancing gestation though no differences by fetal sex were detected. High intra-individual stability in prenatal testosterone levels extend into the postnatal period, particularly for pregnancies with male fetuses. With respect to fetal development, by 36 weeks gestation higher maternal prenatal salivary testosterone was significantly associated with faster fetal heart rate and less optimal somatic-cardiac integration. Measurement of testosterone in saliva is a useful tool for repeated-measures studies of hormonal concomitants of pregnancy. Moreover, higher maternal testosterone levels are associated with modest interference to fetal neurobehavioral development.

Maternal buprenorphine treatment and fetal neurobehavioral development.

BACKGROUND: Gestational opioid use/misuse is escalating in the United States; however, little is understood about the fetal effects of medications used to treat maternal opioid use disorders. OBJECTIVE: The purpose of this study was to determine the effect of maternal buprenorphine administration on longitudinal fetal neurobehavioral development. STUDY DESIGN: Forty-nine buprenorphine-maintained women who attended a substance use disorder treatment facility with generally uncomplicated pregnancies underwent fetal monitoring for 60 minutes at times of trough and peak maternal buprenorphine levels. Data were collected at 24, 28, 32, and 36 weeks gestation. Fetal neurobehavioral indicators (ie, heart rate, motor activity, and their integration [fetal movement-fetal heart rate coupling]) were collected via an actocardiograph, digitized and quantified. Longitudinal data analysis relied on hierarchic linear modeling. RESULTS: Fetal heart rate, heart rate variability, and heart rate accelerations were significantly reduced at peak vs trough maternal buprenorphine levels. Effects were significant either by or after 28 weeks gestation and tended to intensify with advancing gestation. Fetal motor activity and fetal movement-fetal heart rate coupling were depressed from peak to trough at 36 weeks gestation. Polysubstance exposure did not significantly affect fetal neurobehavioral parameters, with the exception that fetuses of heavier smokers moved significantly less than those of lighter smokers at 36 weeks gestation. By the end of gestation, higher maternal buprenorphine dose was related to depression of baseline fetal cardiac measures at trough. CONCLUSION: Maternal buprenorphine administration has acute suppressive effects on fetal heart rate and movement, and the magnitude of these effects increases as gestation progresses. Higher dose (≥13 mg) appears to exert greater depressive effects on measures of fetal heart rate and variability. These findings should be balanced against comparisons to gestational methadone effects, relatively good outcomes of buprenorphine-exposed infants, and recognition of the benefits of medication-assisted treatment for pregnant women with opioid use disorders in optimizing pregnancy outcomes.

Maternal distress and child neuroendocrine and immune regulation.

RATIONALE: Neuroendocrine-immune regulation is essential for maintaining health. Early-life adversity may cause dysregulation in the neuroendocrine-immune network through repeated activation of the stress response, thereby increasing disease risk. OBJECTIVE: This paper examined the extent to which maternal psychological well-being moderates neuroendocrine-immune relations in children. METHODS: We used data from a laboratory-based study of mothers and their five-year old children (n = 125 mother-child pairs) conducted from 2011 to 2013 in Baltimore, Maryland. Child saliva was assayed for markers of immune function (i.e., cytokines: interleukin [IL]-1ß, IL-6, IL-8, tumor necrosis factor alpha [TNF-α]) and hypothalamic-pituitary-adrenal activity (i.e., cortisol). A composite score for depressive symptoms, anxiety, and parenting stress characterized maternal psychological distress. Multilevel mixed models examined the relationship between maternal psychological well-being and child neuroendocrine-immune relations. RESULTS: Significant cytokine × maternal distress interactions indicated that as maternal distress increased, expected inverse cytokine-cortisol relations within children became weaker for IL-1ß, IL-6, and TNF-α. Sex-stratified models revealed that these interactions were only significant among girls. Among boys, there were inverse cytokine-cortisol relations for all cytokines, and, while in the same direction as observed among girls, the cytokine × maternal distress interactions were non-significant. CONCLUSION: The findings suggest that maternal distress is associated with child neuroendocrine-immune relations in saliva and may alter the sensitivity of inflammatory immune processes to cortisol's inhibitory effects. This desensitization may place the child at risk for inflammatory diseases. The findings support efforts for the early detection and treatment of at-risk mothers to protect maternal and child health and well-being.

STUDIES IN FETAL BEHAVIOR: REVISITED, RENEWED, AND REIMAGINED.

Among the earliest volumes of this monograph series was a report by Lester Sontag and colleagues, of the esteemed Fels Institute, on the heart rate of the human fetus as an expression of the developing nervous system. Here, some 75 years later, we commemorate this work and provide historical and contemporary context on knowledge regarding fetal development, as well as results from our own research. These are based on synchronized monitoring of maternal and fetal parameters assessed between 24 and 36 weeks gestation on 740 maternal-fetal pairs compiled from eight separate longitudinal studies, which commenced in the early 1990s. Data include maternal heart rate, respiratory sinus arrhythmia, and electrodrmal activity and fetal heartrate, motor activity, and their integration. Hierarchical linear modeling of developmental trajectories reveals that the fetus develops in predictable ways consistent with advancing parasympathetic regulation. Findings also include:within-fetus stability (i.e., preservation of rank ordering over time) for heart rate, motor, and coupling measures; a transitional period of decelerating development near 30 weeks gestation; sex differences in fetal heart rate measures but not in most fetal motor activity measures; modest correspondence in fetal neurodevelopment among siblings as compared to unrelated fetuses; and deviations from normative fetal development in fetuses affected by intrauterine growth restriction and other conditions. Maternal parameters also change during this period of gestation and there is evidence that fetal sex and individual variation in fetal neurobehavior influence maternal physio-logical processes and the local intrauterine context. Results are discussed within the framework of neuromaturation, the emergence of individual differences, and the bidirectional nature of the maternal-fetal relationship.We pose a number of open questions for future research. Although the human fetus remains just out of reach, new technologies portend an era of accelerated discovery of the earliest period of development

Salivary cytokines as a minimally-invasive measure of immune functioning in young children: correlates of individual differences and sensitivity to laboratory stress.

There is growing interest in minimally-invasive measures of environmentally-responsive biological systems in developmental science. Contributing to that endeavor, this study explores the intercorrelations, correlates, and task-sensitivity of proinflammatory salivary cytokines in childhood. Saliva was sampled from 125 healthy five-year old children (49% male) across a series of cognitive and emotional challenge laboratory tasks. Samples were assayed for cytokines (IL-1ß, IL-6, IL-8, TNFα), and markers of hypothalamic-pituitary-adrenal (HPA) and autonomic nervous system (ANS) activation (salivary cortisol and alpha-amylase [sAA]). Cytokines were positively intercorrelated and task-sensitivity varied. Except IL-8, cytokines were elevated in children with oral health issues and tobacco smoke exposure. Among boys, cytokines were positively related to sAA and negatively related to cortisol. The findings suggest that in healthy children, salivary cytokine levels reflect compartmentalized oral immune activity. Associations between ANS and HPA activity and cytokines in saliva may present opportunities for minimally-invasive methods to explore neuroendocrine-immune interactions during development.

Isolated prenatal choroid plexus cysts do not affect child development.

OBJECTIVE: To examine the effect of isolated prenatal choroid plexus cysts (CPCs) on child cognitive, behavioral, motor, and autonomic development at 18 months of age. METHODS: A prospective design was implemented to identify CPC cases and controls in mid-pregnancy. Cases (n = 25) and controls (n = 45) participated in a follow-up visit when children were 18 months of age. Child mental and motor development was assessed using standard developmental assessments, socioemotional and behavioral functioning during testing was rated by examiners, and accelerometers provided measures of motor activity and energy expenditure. Cardiac patterns were collected using a three-lead electrocardiogram (ECG) and quantified as indicators of autonomic control of the heart, including vagal tone. RESULTS: No significant differences were found in any outcome measure between children with prenatal CPC detection and those without. CONCLUSION: Findings should provide reassurance to practitioners and parents that isolated CPCs in fetuses with normal karyotypes do not affect child development after birth.

Maternal zinc supplementation during pregnancy affects autonomic function of Peruvian children assessed at 54 months of age.

Maternal prenatal zinc supplementation improved fetal autonomic regulation in a nutrient-deficient population in Peru. To evaluate whether differences in autonomic regulation existed in early childhood, we studied 165 children from a zinc supplementation trial (80% of original sample) as part of a comprehensive evaluation at age 54 mo. Electrocardiogram (ECG) data were collected from the children at rest and while they underwent a cognitive testing battery following a standardized protocol. Of these, 79 were born to mothers receiving 25 mg/d zinc in addition to 60 mg/d iron and 250 µg/d folic acid during pregnancy, and 86 were born to mothers receiving iron and folic acid only. Derived cardiac measures included heart period (HP), range, HP variability (HPV), mean square of successive differences (MSSD), and a measure of vagal tone (V). Children in the zinc supplementation group had greater HP (i.e. slower heart rate), greater range, higher time-independent (HPV) and time-dependent (MSSD) variability in HP, and higher V (P < 0.05) during baseline. Analyses conducted across the cognitive testing period revealed similar effects of prenatal zinc supplementation on cardiac patterns. Concurrent child zinc plasma concentration was also associated with longer HP, greater variability, and marginally higher range and V (P < 0.10). Differences in cardiac patterns due to prenatal zinc supplementation were detectable in children at 54 mo of age during conditions of both rest and challenge, indicating that supplementing zinc-deficient pregnant women has beneficial long-term consequences for neural development associated with autonomic regulation.

Infant autonomic functioning and neonatal abstinence syndrome.

BACKGROUND: Neonatal abstinence syndrome (NAS) expression is widely variable among affected infants and the reasons for this variability are largely unknown; mechanisms that predispose infants to NAS expression are not understood. It has been postulated that the regulatory problems of prenatally drug exposed infants are manifested in dysfunctional vagal regulation of autonomic processes. The current study examines whether cardiac vagal tone, an indicator of parasympathetic neuroregulation, provides a marker for autonomic dysregulation subsequently expressed as NAS in prenatally opioid-exposed newborns. METHODS: Heart period (HP) and cardiac vagal tone (V) were derived from electrocardiogram data collected from 64 methadone-exposed infants on postnatal days 1 and 3. The postpartum NAS course was assessed serially. RESULTS: Infants with lower V on day 1 had significantly higher NAS symptomatology on day 3. Boys had more severe NAS symptoms than girls through the first 4 days of life and, among infants receiving pharmacologic treatment for NAS, boys required longer treatment course and hospitalizations. Greater poly-drug exposure, detected through toxicology screening throughout pregnancy, and cocaine use in particular, were associated with lower V and shorter HP (faster heart rate) in newborns. Multiple regression models accounted for 25-35% of the variance in NAS symptoms and duration of hospitalization in methadone-exposed infants. Significant predictors included infant sex, SSRI/SNRI use, and cigarette smoking. CONCLUSIONS: Results support the hypothesis of a biologic vulnerability of autonomic regulatory functioning in methadone-exposed infants and greater male infant vulnerability to maternal methadone use.

Maternal psychophysiological change during the second half of gestation.

This study investigated the trajectory of physiological and psychological functioning during the second half of pregnancy and compared responsiveness to a laboratory stressor between pregnant and non-pregnant women. Monitoring of 137 pregnant women at 20, 24, 28, 32, 36, and 38 weeks of pregnancy included measures of heart period (HP), heart period variability (HPV), skin conductance (SCL), respiratory period (RP), respiratory sinus arrhythmia (RSA), and self-report of mood disturbance. HP and RSA declined during this period; SCL and mood disturbance increased. Parity was a significant moderator. HP and SCL responsiveness to the Stroop color-word task was assessed twice in pregnant participants and compared to a sample of 27 non-pregnant women. Physiologic responsiveness was reduced in pregnant women. Pregnant women perceived the Stroop to be more difficult, but performance was unaffected. Despite buffered responsivity to stressful stimuli during pregnancy, advancing gestation is associated with escalating sympathetic tone and declining parasympathetic tone.