Evaluation of Three-year Neurodevelopmental Outcomes in Infants Prenatally Exposed to Substance Use
Abstract
Introduction
Prenatal exposure to substance use is associated with long-term deficits in the neurodevelopment of children. The objective was to investigate the association between cognitive, motor, and language neurodevelopment at three years of age in infants prenatally exposed to substance use.
Material and methods
A prospective matched case-control study was conducted. Biomarkers of fetal exposure were measured in meconium samples. The Bayley Scales of Infant and Toddler Development (BSID-III) were used to calculate neurodevelopment scores.
Results
32 non-exposed and 32 exposed infants were evaluated, of which 16 were exposed to cannabis, 8 to ethanol, 2 to cocaine and 6 to more than one substance. Normal BSID-III scores ≥85 in all domains, were detected in 23 exposed infants to any substance and 29 infants non-exposed. Neurodevelopmental delay was detected in the language domain, specifically in male infants exposed to cannabis. Two infants exposed to cannabis had a severe developmental delay (score<70). Infants exposed to any substance obtained significantly lower total scores than control infants in all domains. Infants exposed to cannabis obtained significantly lower composite scores in the cognitive and motor domains. Infants exposed to more than one substance had lower scores in motor skills. By gender, only males exposed obtained significantly lower composite scores than non-exposed males in the cognitive domain.
Conclusions
The most common and severe neurodevelopmental delay at 36 months was detected in the domain of language in male infants prenatally exposed to cannabis. Neurodevelopmental disorders detected can enable an early intervention and plan therapeutic strategies.
Introduction
Prenatal substance use is associated with harmful effects on maternal, neonatal, and infant health. This includes prematurity, low birth weight, neonatal withdrawal syndrome, and long-term deficits in the physical, cognitive, behavioral, and emotional development of children (Behnke et al., 2013, Cook et al., 2017, Etemadi-Aleagha and Akhgari, 2022, Ross et al., 2015). Indeed, neonates exposed to substance use during pregnancy have a higher risk of admission to a Neonatal Intensive Care Unit and Neonatal Intermediate Care Unit (NICU and NIMCU) (Avalos et al., 2023, Dumbhare and Taksande, 2023, Sarkar and Donn, 2006) hence, early identification of newborns exposed to substance use guarantees an accurate clinical evaluation, promotes early intervention, and mitigates signs of withdrawal in the neonate if they appear (Jarque et al., 2021, Roca et al., 2021). Meconium has become the “gold standard” for the detection of newborns exposed to substance use during the pregnancy (Jones, 2023). Since its formation starts around the 12th week of gestation and it accumulates until birth, it was considered that it reflected pregnant women with substance use disorder during the second and third trimesters.
Drug and alcohol biomarkers detection in neonatal biological matrices is a useful tool to objectively detect prenatal exposure (Jarque et al., 2021, Roca et al., 2021). Research on the consequences of prenatal substance use has largely focused on short-term obstetric and neonatal outcomes, including low birth weight, stillbirth, and preterm birth. However, knowledge of long-term neurobehavioral consequences is limited, and furthermore, there are other environmental factors associated with substance consumption that can affect the development of children. For example, maternal substance use disorder has been shown to negatively impact mother-child bonding and interaction and increase the risk of childhood exposure to stress, trauma, and/or violence (Guille and Aujla, 2019). Additionally, many studies investigating the relationship between prenatal exposure to substance use and child development do not consider other variables that are often associated with substance use and can affect child development. These variables are prenatal care, childbirth, premature birth, low birth weight, poverty, nutrition, perinatal psychiatric comorbidities, multiple substance use, and the child’s family situation (Guille and Aujla, 2019).
Prematurity or low birth weight is associated with poor academic performance, inattention, behavioral disorders, and anxiety in school-age children, including a 2.6-fold increased risk of attention-deficit/hyperactivity disorder, independently of the type of substance use (Bhutta et al., 2002, Villar et al., 2012). Therefore, it is important to determine if prenatal drug exposure contributes to any neurodevelopmental impairments linked to prematurity, low birth weight, or other perinatal morbidities.
Although there are different tools and scales, which can lead to different results that are barely comparable to each other (Guille and Aujla, 2019), the Bayley Scales of Infant and Toddler Development (BSID), developed in the United States, is one of the most used tests to evaluate the neurodevelopment of children under three years of age, and, for many, it is considered the reference standard for measuring the development in early childhood (Weiss et al., 2010). Performance of 3-year-old children on the Bayley-III scale might indicate their future cognitive, language and motor function (Nishijima et al., 2022).
The objective of this study was to investigate cognitive, motor, and language development at 3 years of age using BSID-III cut-off scores as a clinical outcome in a cohort of newborns requiring admission to the NICU and NIMCU at birth who were prenatally exposed to substance use, which were detected using biomarkers in neonatal meconium.
Study design
A prospective matched case-control study of the neurodevelopment of infants prenatally exposed to substance use requiring admission at birth to a NICU and NIMCU.
Participants
The starting point was a cohort of controls (323 infants) and infants prenatally exposed to substance use (49 newborns) (Jarque et al., 2021, Roca et al., 2021) that required admission at birth to the same NICU and NIMCU classified as a IIIB reference center between March 2018 and December 2019.
From this cohort, all efforts were made to
Results
64 infants were evaluated (30 males and 34 females): 32 unexposed controls and 32 infants exposed to substance use (16 (50.0%) to cannabis, 8 (25.0%) to ethanol, 2 (6.2%) to cocaine, and 6 (18.8%) to more than one substance use).
Discussion
The results of this case-control study show the association between prenatal exposure to substance use and a deficit in neurodevelopment at 36 months in patients who required admission to the NICU and NIMCU at birth. The clinical value of the Bayley Scales results lies in their ability to facilitate early developmental intervention and early detection of developmental delay.
One of the strengths of this study, unlike others, is that uses the analysis of biomarkers of substance use in meconium
Conclusions
Infants who required admission to the NICU and NIMCU exposed to any substance use during pregnancy show neurodevelopmental deficits (cognitive, language, and motor skills) compared to non-exposed infants at 36 months. The most common and severe neurodevelopmental delay at 36 months was detected in the domain of language in male infants prenatally exposed to cannabis. Infants who were exposed to more than one substance use had lower scores in motor skills. Male infants, but not females, who were
Funding
This work was supported by the National Plan on Drugs (grant number 2017I033); Ministry of Health, Social Services and Equality, Spain.
Credit authorship contribution statement
Antonia Roca: Investigation, Funding acquisition, Conceptualization. Miguel Carmona:Investigation, Funding acquisition, Conceptualization. Simona Pichini: Writing – review & editing, Writing – original draft. Bernardino Barcelo: Writing – review & editing, Writing – original draft, Resources, Investigation, Funding acquisition, Conceptualization. Pilar Jarque: Investigation, Funding acquisition, Conceptualization. Pilar Sanchis: Data curation. Miguel Angel Elorza: Investigation, Funding
Declaration of Competing Interest
The authors declare no conflict of interest.
Acknowledgments
We thank the participating infants and their families.
Institutional review board statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the research ethics committee of the Balearic Islands (CEI-IB, project number IB 3538/17 IP).
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