Infant neurobehavior was assessed with the NICU Network Neurobehavioral Scale , a measures that strongly correlates with scores on the 12 and 24 month Bayley exam in neonates born <37 weeks’ gestation. We previously reported preliminary data from the IDEAL study demonstrating that exposed neonates have decreased arousal, increased stress, and poor quality of movement at birth. This study reports neurobehavioral findings from the complete cohort of enrolled neonates in the IDEAL study. Further, this report presents findings in one month old infants to determine if the differences reported at birth improved or remained unchanged by early infancy. The IDEAL study is a multi-site, longitudinal study investigating the effects of prenatal MA exposure on child outcome. Detailed recruitment methods for the IDEAL study have been reported previously. In short, from September 2002 – November 2004, subjects were recruited at the time of delivery from seven hospitals in four geographically diverse, collaborating centers in the following areas: Los Angeles, CA; Des Moines, IA; Tulsa, OK; and Honolulu, HI. All women delivering at each of the four clinical sites were approached , screened for eligibility , and consented to participate . A postpartum mother was excluded if she was <18 years of age; used opiates, lysergic acid diethylamide, phencyclidine or cocaine-only during her pregnancy; or was non-English speaking. Further, a mother was excluded if she had a history of hospitalization for intellectual disability or emotional disorders, or was overtly psychotic or had a documented history of psychosis; Exclusion criteria for the infants included: critically ill and unlikely to survive, multiple birth, major life threatening congenital anomaly,indoor vertical farming technology documented chromosomal abnormality associated with mental or neurological deficiency, overt clinical evidence of an intrauterine infection, and sibling previously enrolled in the IDEAL study.
MA exposure was determined by self-reported use during this pregnancy and/or a positive meconium screen and gas chromatography/mass spectroscopy confirmation. Comparison subjects were defined as denial of MA use during this pregnancy and a negative GC/MS for amphetamine and metabolites. The study was approved by the Institutional Review Boards at all participating sites , and signed informed consent was obtained from all subjects. A National Institute on Drug Abuse Certificate of Confidentiality was obtained for the project that assured confidentiality of information regarding the mothers’ drug use, superseding mandatory reporting of illegal substance use.After consent was obtained, a medical chart review and a recruitment Lifestyle Interview were performed to acquire information about prenatal substance use, maternal characteristics and newborn characteristics. Socioeconomic status was determined using Hollingshead scale, an index that ranks SES based on occupation and years of education.Information on the collection procedures and analysis of the meconium samples has been previously published. The NNNS exam was administered to all subjects born at term within the first 5 days of life by certified examiners masked to MA exposure status. Subsequently, the exam was performed again at one month of age. The NNNS is a standardized neurobehavioral exam for both healthy and at-risk infants that provides an assessment of neurological, behavioral, and stress/abstinence neurobehavioral functioning. The neurological component includes active and passive tone, primitive reflexes, and items that reflect the integrity of the central nervous system and maturity of the infant. The behavioral component is based on items from the Neonatal Behavioral Assessment Scale, modified to be sensitive to presumed drug effects. The stress/abstinence component is a checklist of “yes” or “no” items organized by organ system based primarily on the work of Finnegan.
The NNNS items are summarized into the following scales: Habituation, Attention, Arousal, Regulation, Handling, Quality of Movement, Excitability, Lethargy, Nonoptimal Reflexes, Asymmetric Reflexes, Hypertonicity, Hypotonicity, and Stress/Abstinence. The maternal characteristics are shown in Table 1. As expected, there were no differences between the groups in race or maternal education, as these characteristics were matched in our study design. However, despite controlling for maternal education, mothers who used MA were still less likely to have an annual income greater than $10,000. In addition, MAabusing mothers were more likely to be single and older. Furthermore, these mothers also had fewer, as well as later, prenatal visits. Finally, the mothers of exposed infants were more likely to use tobacco, alcohol, and marijuana during their pregnancy, and were more likely to be heavy abusers of these substances in contrast to the mothers of the comparison group. The infant characteristics are presented in Table 2. The exposed infants were generally full term but born 1 week earlier than the comparison infants. There were no differences in gender or birth weight, but the exposed newborns had shorter lengths and smaller head circumferences in contrast to the comparison newborns. The exposed infants were more likely to have a lower 1 minute Apgar score but no differences were noted in Apgar scores by 5 minutes. Lastly, the exposed infants were more likely than the comparisons to be the first born.This is the first prospective investigation reporting the effects of prenatal MA exposure on neurobehavioral outcome at birth and one month. We found presumed maturational changes in all infants, regardless of exposure status, in quality of movement, lethargy, and asymmetric reflexes. In addition, by one month, the MA-exposed infants showed no difference in arousal and total stress relative to the control group. The overall arousal scores in the MA-exposed infants increased over the first month of life, indicating that by one month of age these infants were generally less drowsy.
These findings compliment previous findings regarding drowsiness in exposed infants at birth that resolved by twelve months of age. In contrast, the Maternal Lifestyle Study, which evaluated the neurodevelopmental effects of prenatal cocaine exposure using the NNNS, found lower arousal in the cocaine-exposed infants at one month of age. MA is commonly compared to cocaine due to their similar mechanisms of action as sympathomimetic agents. However, the effects of MA are thought to be potentially greater given its significantly longer half-life and ability to function not only as a dopamine and a norepinephrine reuptake inhibitor, but as a catecholamine release trigger as well. Further, we found a decrease in total stress among the MA-exposed neonates over the first month of life. Our findings in regards to stress have significant implications, particularly in the context of risk factors for non-accidental trauma. Specifically, the association of parental illicit and legal drug abuse as a substantial risk factor for non-accidental trauma is well described; this has significant implications for our exposed infants given the high risk environment into which they are immersed. Likewise, infants who are stressed are at an even higher risk for child abuse given the additional strain placed on their caregivers. The reduction of stress signs in the MA exposed infants alleviates some of the concern that MA exposure affects infant temperament in such a way that,industrial vertical farming compounded with the environmental risk, would increase their risk of non-accidental trauma. No significant differences from newborn to one month were found based solely on exposure status. This is in contrast to studies on other illicit and legal drugs which report differences at birth as well as later in life. Prenatal nicotine exposure has been associated with increased excitability, hypertonicity, need for handling and stress/abstinence scores at birth, with increased need for handling persisting to one month of age. Prenatal cocaine exposure has been associated with increased central nervous system stress, poor visual and auditory following, hypertonicity, and drowsiness at birth, as well as lower arousal, lower regulation, and higher excitability at one month. Our inability to show significant differences based on exposure status may be explained by the overall high risk of both groups. We matched each subject based on SES and race, but our statistical capacity for controlling covariates is not limitless; therefore it is possible that both groups have sufficient risk that affects their functioning. Although differences attributable to MA exposure at birth may resolve at one month of age, it is important to continue following these children as they develop to monitor whether latent neurobehavioral effects emerge during childhood. Our results should be interpreted with caution, as there are limitations to our study. First, the exposed group of subjects was selected primarily based on self-report. However, the reported use of alcohol, tobacco and marijuana is consistent with national surveillance data and only six subjects were ascertained by GC/MS without also having self-reported. Since meconium production begins at 14-16 weeks’ gestation, meconium testing primarily reflects maternal drug use only during the second and third trimesters, but recent evidence show that the assay for MA analytes may not reveal known use until the third trimester. Therefore, information regarding drug use in the first and second trimester could only be obtained by self-report. Additionally, this report does not evaluate for dose-response effects. While we found no significant differences in NNNS summary scores between the two groups overall, if we specifically evaluated the heavily exposed neonates the effects may be augmented.
Similarly, this report also does not evaluate for differences based on exposure timing, although our preliminary report does describe findings of elevated stress abstinence related to first trimester exposure and poorer quality of movement associated wtih versus third trimester exposure. In summary, we found subtle neurobehavioral improvements by one month of age in infants exposed to MA in utero, which has both short and long-term implications. Despite not finding persistent neurobehavioral differences from birth to one month, these exposed infants are susceptible to numerous risk factors related to both direct and indirect effects of MA exposure. These risks include parental abuse, parental neglect, and exposure to chemicals involved in making MA in the home, which may lead to significant neurobehavioral issues in childhood and later in life. These at-risk newborns may require positive caregiving environments and interventions to potentially prevent long-term, permanent insults. Long term follow-up is required to detect and possibly prevent exacerbation of these subtle effects beyond infancy. Alcohol is a known teratogen that causes fetal alcohol syndrome and fetal alcohol spectrum disorders, as well as a range of other harms to fetuses . Alcohol use during pregnancy is common, with approximately 21% of pregnant women reporting any alcohol use and approximately 3% reporting binge drinking in the United States . Since 1974, almost all states have enacted policies targeting alcohol use during pregnancy . These include both supportive and punitive policies. In 2016, Priority Treatment for Pregnant Women and Women with Children was the least common policy and Reporting for Treatment and Data Purposes and Mandatory Warning Signs were the most common. States continue to change their alcohol and pregnancy policies each year . Despite the proliferation of these state-level policies, few studies have assessed what impact, if any, they have . While the purpose of these policies is typically unstated, it is reasonable to assume that a primary intended purpose is to reduce alcohol use during pregnancy and thereby improve birth outcomes and longer term child well-being. For example, a recent study examining the effects of state-level policies that mandate posting of warning signs about harms due to drinking during pregnancy in locations that sell alcohol finds some support for this assumption. Specifically, this study used data from a variety of sources from 1989-2006 for selected states and found that MWS policies may be associated with less alcohol use during pregnancy, and are associated with fewer very low birthweight and very preterm births . However, to our knowledge, this is the only study to have documented a positive effect of a state-level policy targeting alcohol use during pregnancy. Another recent study found that shorter waiting time for substance use disorder treatment is associated with treatment completion for pregnant women , which implies that priority treatment could increase the number of pregnant women in need of treatment that actually receive and complete treatment; this could improve birth outcomes, though this has not yet been studied. Other research suggests that state-level policies targeting alcohol use during pregnancy might not have the intended effects, and might actually have unintended consequences. A qualitative study about barriers to prenatal care for pregnant women who used alcohol and drugs found that women who use drugs during pregnancy avoided prenatal care both out of fear that they would discover that their use had already irreversibly damaged their baby, and out of fear that their providers would report them to Child Protective Services and they would lose their children or go to jail .