Behavioral epigenetics and the developmental origins of child mental health disorders.

Advances in understanding the molecular basis of behavior through epigenetic mechanisms could help explain the developmental origins of child mental health disorders. However, the application of epigenetic principles to the study of human behavior is a relatively new endeavor. In this paper we discuss the 'Developmental Origins of Health and Disease' including the role of fetal programming. We then review epigenetic principles related to fetal programming and the recent application of epigenetics to behavior. We focus on the neuroendocrine system and develop a simple heuristic stress-related model to illustrate how epigenetic changes in placental genes could predispose the infant to neurobehavioral profiles that interact with postnatal environmental factors potentially leading to mental health disorders. We then discuss from an 'Evo-Devo' perspective how some of these behaviors could also be adaptive. We suggest how elucidation of these mechanisms can help to better define risk and protective factors and populations at risk.

Cocaine exposure is associated with subtle compromises of infants' and mothers' social-emotional behavior and dyadic features of their interaction in the face-to-face still-face paradigm.

Prenatal cocaine and opiate exposure are thought to subtly compromise social and emotional development. The authors observed a large sample of 236 cocaine-exposed and 459 nonexposed infants (49 were opiate exposed and 646 nonexposed) with their mothers in the face-to-face still-face paradigm. Infant and maternal behaviors were microanalytically coded. No opiate-exposure effects were detected. However, mothers of cocaine-exposed infants showed more negative engagement than other mothers. The cocaine-exposed dyads also showed higher overall levels of mismatched engagement states than other dyads, including more negative engagement when the infants were in states of neutral engagement. Infants exposed to heavier levels of cocaine showed more passive-withdrawn negative engagement and engaged in more negative affective matching with their mothers than other infants. Although effect sizes were small, cocaine exposure, especially heavy cocaine exposure, was associated with subtly negative interchanges, which may have a cumulative impact on infants' later development and their relationships with their mothers.

Prenatal drug exposure and maternal and infant feeding behaviour.

OBJECTIVE: To evaluate feeding difficulties and maternal behaviour during a feeding session with 1 month old infants prenatally exposed to cocaine and/or opiates. METHODS: The study is part of the maternal lifestyle study, which recruited 11 811 subjects at four urban hospitals, then followed 1388 from 1 to 36 months of age. Exposure to cocaine and opiates was determined by maternal interview and meconium assay. At the 1 month clinic visit, biological mothers were videotaped while bottle feeding their infants. This sample included 364 exposed to cocaine, 45 exposed to opiates, 31 exposed to both drugs, and 588 matched comparison infants. Mothers were mostly black, high school educated, and on public assistance. Videotapes were coded without knowledge of exposure status for frequency, duration and quality of infant sucking, arousal, feeding problems, and maternal feeding activity and interaction. RESULTS: No cocaine effects were found on infant feeding measures, but cocaine-using mothers were less flexible (6.29 v 6.50), less engaged (5.77 v 6.22), and had shorter feeding sessions (638 v 683 seconds). Opiate exposed infants showed prolonged sucking bursts (29 v 20 seconds), fewer pauses (1.6 v 2.2 per minute), more feeding problems (0.55 v 0.38), and increased arousal (2.59 v 2.39). Their mothers showed increased activity (30 v 22), independent of their infants' feeding problems. CONCLUSIONS: Previous concerns about feeding behaviour in cocaine exposed infants may reflect the quality of the feeding interaction rather than infant feeding problems related to prenatal exposure. However, opiate exposed infants and their mothers both contributed to increased arousal and heightened feeding behaviour.

Buprenorphine treatment of pregnant opioid--dependent women: maternal and neonatal outcomes.

This open-label prospective study examined maternal and neonatal safety and efficacy outcome measures during and following prenatal buprenorphine exposure. Three opioid-dependent pregnant women received 8 or 12 mg sublingual buprenorphine tablets daily for 15-16 weeks prior to delivery. Results showed that buprenorphine in combination with comprehensive prenatal care was safe and effective in these women. Prenatal exposure to buprenorphine resulted in normal birth outcomes, a mean of 4.33 days (minimum possible=4) hospitalization, and a 'relatively mild' neonatal abstinence syndrome comprised primarily of tremors (disturbed), hyperactive moro and shortened sleep after feeding. The infants required no pharmacological treatment. Onset of neonatal abstinence signs occurred within the first 12 h after birth, peaked by 72 h and returned to below pre-12 h levels by 120 h. It is concluded that buprenorphine has potential utility for the treatment of pregnant opioid-dependent women.

The Maternal Lifestyle Study: drug use by meconium toxicology and maternal self-report.

OBJECTIVE: The objective of this study was to describe drug use by pregnant women participating in the 4-site Maternal Lifestyle Study of in utero cocaine and/or opiate exposure. METHODS: Meconium specimens of 8527 newborns were analyzed by immunoassay with GC/MS confirmation for metabolites of cocaine, opiates, cannabinoids, amphetamines, and phencyclidine. Maternal self-report of drug use was determined by hospital interview. RESULTS: The prevalence of cocaine/opiate exposure in the 4 sites was 10.7% with the majority (9.5%) exposed to cocaine based on the combination of meconium analysis and maternal self-report. However, exposure status varied by site and was higher in low birth weight infants (18.6% for very low birth weight and 21.1% for low birth weight). Gas chromatography/mass spectrometry (GC/MS) confirmation of presumptive positive cocaine screens was 75.5%. In the cocaine/opiate-exposed group, 38% were cases in which the mother denied use but the meconium was positive. There was 66% agreement between positive meconium results and positive maternal report. Only 2% of mothers reported that they used only cocaine during pregnancy and mothers were 49 times more likely to use another drug if they used cocaine. CONCLUSION: Accurate identification of prenatal drug exposure is improved with GC/MS confirmation and when the meconium assay is coupled with a maternal hospital interview. However, the use of GC/MS may have different implications for research than for public policy. We caution against the use of quantitative analysis of drugs in meconium to estimate the degree of exposure. Our study also highlights the polydrug nature of what used to be thought of as a cocaine problem.

The effects of maternal depression on fetal heart rate response to vibroacoustic stimulation.

To better understand the effects of untreated maternal depression on the fetus, this study examined fetal heart rate (FHR) and FHR reactivity to vibroacoustic stimulation in pregnant women with untreated depression. The 20 participants were 32- to 36-week pregnant women divided into groups with depression (N = 10) and without depression (N = 10) based on the Beck Depression Inventory (BDI; Beck, 1977; Beck & Steer, 1987). Participants were attached to a fetal heart monitor, and 10 min of baseline FHR were recorded. A vibroacoustic stimulus (VAS) was presented, and an additional 10 min of FHR were recorded. Fetuses of mothers with depression had an elevated baseline FHR and a 3.5-fold delay in return to baseline FHR after VAS presentation. Additionally, mothers with depression had significantly higher anxiety levels and took fewer prenatal vitamins during pregnancy. Delayed habituation of FHR in the fetuses of mothers with depression may be due to alterations in the internal hormonal environment and could have implications for postnatal information processing.

Prenatal cocaine exposure and child outcome: a model for the study of the infant at risk.

The problem of cocaine use by pregnant women and the effects on the developing child has become major focus of research, treatment and public policy in the United States. The purpose of this article is to summarize our knowledge base in this area including methodological issues, discuss the drug exposed infant as a prototype of the infant at risk, and to consider issues that impact on public policy and treatment.

Biology versus environment in the extremely low-birth weight infant.

This article examines the role of biologic and environmental factors in determining the long-term outcomes of extremely low-birth weight infants. Research focusing on follow-up to at least 4 years of age is reviewed. Methodologic issues related to sampling, the use of control groups, and diagnostic criteria are also discussed. The use of cumulative models of risk for examining the relative contribution of environmental and biologic factors is presented.

Longitudinal neurologic follow-up in neonatal intensive care unit survivors with various neonatal morbidities.

OBJECTIVE: The purpose of this prospective longitudinal study was to examine neurocognitive and school performance outcomes of low birth weight infants with reference to neonatal morbidity and socioeconomic status. We further evaluated the cognition and school performance based on their neurologic status at the time of assessment. METHODS: One hundred eighty-eight children (39 healthy full-term and 149 preterm infants) were classified into 4 subgroups based on their neonatal medical status: healthy, sick (without neurologic complications), small for gestational age, and neurologically compromised infants. Neurologic status was classified as normal, suspect, or abnormal at hospital discharge, 18 months, 30 months, 4 years, and 8 years of age. Socioeconomic status, cognitive, and school performances were assessed. RESULTS: Neurologically, both full-term and healthy preterm groups did well during the 8-year period. There were significant fluctuations between suspect and abnormal neurologic classifications among the 3 preterm groups with neonatal complications. Preterms with neurologic abnormality during the neonatal period did the poorest with 45% of the group remaining abnormal at 8 years of age. Children who were neurologically normal had higher cognitive scores at ages 4 and 8 than those categorized as suspect or abnormal. Preterm infants with neurologic abnormality required significantly more academic resources in the school. Reading and math achievement scores were the lowest for the preterm groups classified as neurologically suspect or abnormal. CONCLUSIONS: Neonatal morbidities exert a significant impact in neurologic outcomes among preterm children during the 8 years of assessment. Compromised neurologic status adversely affects cognitive and school performances. Neonatal medical status is an important variable indicating neurocognitive and school performance outcomes in low birth weight infants.

Immunoassay and GC-MS procedures for the analysis of drugs of abuse in meconium.

The analysis of meconium specimens for metabolites of substances of abuse is a relatively accurate method for the detection of fetal exposure to drugs. Most of the methods reported in the literature before the early 1990s relied on radioimmunoassays. The purpose of this study was to develop and validate methods for meconium sample preparation for the screening and gas chromatography-mass spectrometry (GC-MS) confirmation of meconium extracts for cannabinoids, cocaine, opiates, amphetamines, and phencyclidine. EMIT and TDx immunoassays were evaluated as screening methods. The sample preparation method developed for screening included extraction and purification prior to analysis. Cutoff levels were administratively set at 20 ng/g for 11-nor-delta9-THC-9-COOH (THCCOOH) and phencyclidine and at 200 ng/g for benzoylecgonine, morphine, and amphetamines, although lower levels could be detected in meconium using the EMIT-ETS system. Ninety-five meconium specimens were subjected to the screening procedure with GC-MS confirmation of presumptive positives. In addition, 30 (40 for cocaine) meconium specimens were subjected to GC-MS analysis for all analytes regardless of the screening results to determine the false-negative rate, if any, of the immunoassay. Although there were no false negatives detected, the GC-MS confirmation rate for the immunoassay-positive specimens was generally low, ranging from 0% for amphetamines to 75% for opiates. The lowest rate of confirmed positives was found with the cannabinoids, suggesting that tetrahydrocannabinol (THC) metabolites other than free 11-nor-9-carboxy-delta9-THC may be major contributors to the immunoassay response in meconium.

Interpreting research on prenatal substance exposure in the context of multiple confounding factors.

Fetal exposure to specific drugs often occurs in the context of polydrug use, medical complications, and social/environmental risks. Early reports of severe developmental consequences of fetal exposure to illicit drugs, for example, cocaine, have largely been unsupported by recent studies that take these factors into account. Using a database of published studies on cocaine exposure, this article examines how confounding factors are controlled by recruitment and statistical strategies. Rather than attempting to reduce the impact of these factors, it is suggested that multiple risks in children's lives should be included in models of developmental outcomes along with drug exposure. Understanding the complexity of multiple risks in the child's environment and the subtlety of drug exposure effects can guide the choice of clinical treatment and intervention.

The NICU Network Neurobehavioral Scale. Clinical use with drug exposed infants and their mothers.

The NNNS provides a comprehensive assessment of the at-risk and drug-exposed infant. The examination was developed for research and has now been extended to clinical practice. It is routinely used in our hospital in several clinical programs. In this article we detailed how the examination is used with substance-involved mothers and their infants. As we continue to develop assessment procedures based on understanding the capacities of the infant and understanding the parenting capacities of mothers, we will improve our ability to secure the welfare of drug-exposed infants.

Prenatal cocaine exposure and child development: what do we know and what do we do?

The literature remains unclear about the effects of prenatal cocaine exposure on child development. Meanwhile, the implications for public policy and treatment and for our scientific understanding of the toxicity of cocaine are substantial. In this article we describe; (1) our current understanding of the effects of prenatal cocaine use and child outcome, (2) the issues that need to be investigated, and (3) implications for treatment of cocaine exposed children. Findings from our database of the published literature shows that our knowledge is still limited, scattered, and compromised by methodological problems that mitigate any conclusions about whether or not or how prenatal cocaine exposure affects child outcome. The cocaine problem is more complicated than first envisioned--it is a multifactorial problem including the use of other drugs, parenting, and environmental lifestyle issues. However, we also show that, even though the effects may be more subtle than initially anticipated, prenatal cocaine exposure will substantially increase in the number of school age children who will need special education services. Clinicians working with these children and families need to be prepared to address psychosocial and environmental issues, as well as developmental performance, in order to optimize their assessment and intervention.

Cardiorespiratory reactivity during the Brazelton Scale in term and preterm infants.

Determined the relationship between behaviour measured with the Brazel zelton Scale and simultaneously recorded cardiorespiratory activity. The Brazelton Scale was administered and videotaped in a sample of 22 term and 22 preterm infants at term conceptional age. The videotapes were coded off line with a computer interface to time lock behavior and physiological activity for the duration of four alert, non-crying conditions. Term infants showed increases in heart rate and breathing rate when unswaddled and cuddled following cry and increases in respiratory sinus arrhythmia (RSA) during orientation and swaddling. Preterm infants showed the same general trend as term infants in heart rate and breathing rate. However, RSA decreased during orientation in preterm infants. On behavioral scores, preterm infants showed lower scores on self-regulation and a higher cost of attention. Correlations between behavior and physiological activity showed lower RSA associated with enhanced behavioral scores for the preterm infants. Results of this study are consistent with the hypothesis that attentional responsivity in the preterm infant may be at the expense of physiological stability.

Behavioral intervention and post-natal growth in full-term intrauterine growth retarded (IUGR) infants.

The purpose of this study was twofold: (1) to describe the patterns of post-natal growth in full-term infants as a function of IUGR and (2) to assess the impact of an individualized behavioral feeding intervention with the mothers on these patterns of infant growth. Eighty-eight (88) full-term infants, including 54 with IUGR, half of whom received behavioral intervention were included. Weight, length, skinfold thickness, head circumference and Ponderal Index were measured at birth and at 1, 4, 8, 12, and 18 months. Results show positive intervention effects between birth and 1 month in weight, length, skinfold thickness, and Ponderal Index. However, there were no intervention effects at subsequent ages. No evidence was found for catch-up growth in full-term IUGR infants in weight, length, and head circumference. We conclude that an individualized behavioral feeding intervention can accelerate early growth in IUGR infants, but the positive effects on growth are only seen while the intervention lasts (between birth and 1 month). On most parameters of physical growth, there is no lasting catch-up growth over the first 18 months in IUGR full-term infants.