Association of prenatal substance exposure and the development of the amygdala, hippocampus, and parahippocampus

Substance use

Prenatal opioid exposure was determined through the biological parent’s self-report of prescribed medication or illicit drug use. Within the medication history, prenatal opioid exposure was determined from questions asking about illicit Oxycontin or Morphine use of the biological mother during pregnancy, or if the mother had been prescribed any of the following drugs during pregnancy: Oxycontin, Oxycodone, Oxymorphone, Lortab, Percocet, Codeine, Vicodin, Morphine, Hydrocodone, Fentanyl, Norco, and Methadone. Prenatal alcohol and tobacco exposure was assessed through reported use during pregnancy – regardless whether the use was before or after the pregnancy and was known to the mother. Prenatal alcohol exposure was then split into three categories (none [0], 1–3, or 4+) based on alcohol consumption, measured as the average number of drinks per week. Tobacco use was coded as a binary variable as having utilized or not during pregnancy.

Magnetic resonance imaging (MRI)

MRI within the ABCD Study was harmonized across 22 sites to allow for multi-site collaboration, as extensively discussed in a previous publication [31]. Quality control variables were utilized to exclude participants with indeterminable or corrupt MRI data. Then we extracted variables to assess the volumetric size (mm³) of the amygdala, hippocampus, and parahippocampal gyrus. The variable names within the dataset are smri_vol_scs_amygdalalh (left) and smri_vol_scs_amygdalarh (right) for the amygdala, mrisdp_476 and mrisdp_550 for the parahippocampal gyrus (Destrieux parcellation) [32], and smri_vol_scs_hpuslh and smri_vol_scs_hpusrh for the hippocampus, whereas total brain volume, utilized as a control for these analyses, was assessed utilizing the variable smri_vol_scs_wholeb.

Demographics

Volumetric differences in both the amygdalar and hippocampal regions in children have been noted on poverty level [33] and among adults and nonhuman animals who were exposed to chronic stress. Given these differences, we extracted data regarding household financial stability to assess the financial risk – a cumulative measure of seven items assessed as the number of affirmative responses to the following prompts: In the past 12 months, has there been a time when you and your immediate family experienced any of the following:

1. Needed food but couldn’t afford to buy it or couldn’t afford to go out and get it?

2. Were without telephone service because you could not afford it?

3. Didn’t pay the full amount of the rent or mortgage because you could not afford it?

4. Were evicted from your home for not paying the rent or mortgage?

5. Had services turned off by the gas or electric company, or the oil company wouldn’t deliver oil because payments were not made?

6. Had someone who needed to see a doctor or go to the hospital but didn’t because you could not afford it?

7. Had someone who needed a dentist but couldn’t go because you could not afford it?

Additionally, the interaction of age, sex assigned at birth, and race/ethnicity could influence variations in growth. Therefore, we utilized these variables, along with brain volume (mentioned previously) and financial risk as controls within the adjusted models. Age (in months at the time of the survey), sex, and race/ethnicity were are collected by parent report.

Statistical analysis

We applied the complex design of the survey data to stratify for recruitment sites and family units. We reported the sociodemographic characteristics of the sample overall and by children who were prenatally exposed to alcohol, tobacco, or prenatal opioids. Next, we calculated and reported the means of each brain region by substance exposure type utilizing the sum of the left and right measures for each of the brain structures – amygdala, parahippocampal gyrus, and hippocampus. We then constructed multivariable regression models to measure the associations between different PSE, controlling each of the other types, as well as the demographic characteristics described previously, total brain volume, and the volumes of each brain structure. Data collection for the ABCD Study was approved by the central Institutional Review Board (cIRB) at the University of California, San Diego, CA, USA. Results were reported according to Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.

Prevention

Given the cumulative neurodevelopmental effects associated with PSE, risk assessment for substance use among pregnant individuals is increasingly important because they are at increased risk for adverse health and social outcomes [40]. Research indicates that a substantial number of pregnant women cared for during the prenatal period have unrecognized or untreated substance use patterns [41]. Tools for identifying prenatal substance use outside of biological sample testing include validated screening tools such as the 4 P’s Plus (parents, partner, past, and pregnancy substance use screen) [42], National Institute on Drug Abuse (NIDA) Quick Screen-ASSIST (Modified Alcohol, Smoking, and Substance Involvement Screening Test), and the SURP-P (Substance Use Risk Profile-Pregnancy) scales. Although the 4 P’s Plus and the NIDA Quick Screen-ASSIST [43] have been shown to have high sensitivity and negative predictive values, a 2010 survey of obstetrician-gynecologists (OB/GYNs) found 58 % did not utilize a validated screening tool to assess alcohol risk despite there being several validated tools available [44]. This may relate to both tobacco screening and opioid use.

In addition to identifying substance use, the intervention methods following identification play an important role in patient outcomes. Studies have found that many women recognize that there are risks associated with drinking during pregnancy, but they do not receive individual advice from health professionals – revealing a lack of clear and consistent advice regarding safe drinking levels from health professionals [45]. Primary care studies have provided evidence that physician intervention and counseling through advice, education, and contracting information significantly reduces the amount of alcohol use, episodes of binge drinking, and frequency of excessive drinking [46]. However, there may be less motivation or perceived barriers for healthcare workers to implement interventions after screening – especially for tobacco use. Among a 2014 study of 252 OB/GYNs, 88 % reported always asking about tobacco use during an initial visit; however, the sample also reported that only 25 % asked about smoking status if it was suspected but not marked on the patient intake, which may under-report smoking status. Further, if tobacco use was identified, the most frequent action was to advise abstinence and the least frequent was to refer to counseling [47], despite the United States Preventive Services Task Force (USPSTF) advising to “provide behavioral interventions for cessation” in addition to advising to stop [48]. The respondents in the study reported the most perceived barriers to offering intervention being a lack of referral resources for prenatal tobacco use, expecting patient denial or treatment resistance, and most commonly, time limitations [47].

Recommendations

While our first recommendation is for healthcare providers to increase screening rates, detection, and referrals for cessation, also noted by Zou et al. [49], we also recommend that medical associations lobby policymakers to address upstream barriers to the effective identification of at-risk pregnant individuals, specifically eliminating or significantly reducing punitive legal consequences stemming from state laws concerning prenatal substance use – particularly from opioids and other controlled drugs [50, 51]. These laws discourage disclosure of substance use behaviors to providers and ultimately delay intervention and treatment – which also disproportionately affects individuals with low socioeconomic status and people of color [52]. Further, these laws also propagate public stigma surrounding substance use among pregnant individuals. A qualitative study of individuals who utilized substances during pregnancy not only highlighted this stigma to the point of self-isolation and avoidance of seeking care, but it also highlighted the lack of knowledge of treatment options for them and the gaps in services after pregnancy [52]. For instance, among a group of mothers who were on methadone during pregnancy, they often reported having long periods after pregnancy when they were not able to continue treatment and had desires to resume drug use [52]. Thus, increasing both the public messaging surrounding substance use and postnatal services may reduce the long-term impact of prenatal substance use and therefore outcomes from prenatal exposure.

A 2022 study evaluating the consumption of alcohol during pregnancy found that some of the most commonly reported reasons for alcohol use during pregnancy were due to the lack of awareness of adverse effects for the fetus, a belief that only “strong” alcohol or alcohol in large quantities would be harmful, and advice from medical practitioners [53]. Additionally, a study evaluating tobacco use in pregnancy identified risk factors such as a lower education status, clinically relevant anxiety symptoms, and exposure to environmental tobacco smoke [54]. This information further supports the previously mentioned need for physician intervention and counseling through advice, education, and contracting information regarding alcohol and tobacco use in pregnancy. Opioid use during pregnancy is due to a variety of reasons, and commonly is due to the pain associated with pregnancy – with the prevalence of low back and pelvic pain during pregnancy ranging from 68 to 72 % [55]. Osteopathic manipulative treatments (OMTs) prove to be an effective tool to reduce the acute pain of the lower back and pelvis during pregnancy [56]. Additionally, these treatments have also been found to improve the mental health and emotional aspects of the patients receiving treatments [56]. Therefore, osteopathic manipulative medicine (OMM) may provide an approach to care for pregnant individuals that can reduce both opioid and tobacco use during pregnancy.

Limitations

One of the limitations of the ABCD Study was that maternal medical history was performed via self-survey by the patient rather than collected from a medical chart, leading to subjectivity in the responses, and it may also be subject to recall bias given that the surveys were collected 9–10 years following the pregnancy. The use of prescription opioids may also have been underreported during the height of the opioid pandemic. Along these lines, the report of substance use during pregnancy, or even right after pregnancy, may have been skewed due to the stigma surrounding tobacco, alcohol, and opioid use during pregnancy. It is worth noting that substance use groupings may have overlap between columns – some individuals may be exposed to more than one substance – and therefore caution should be taken when interpreting the data. It is also important to note that this study is conducted on children ages 9 and 10, which may not yield the most precise results regarding prenatal exposure due to the inherent plasticity of the infant/pediatric brain. However, given the large sample size and robust methodology within the ABCD Study across all 23 sites, we believe that these limitations are minimized. Given the previous research linking MRI measurements of the parahippocampal gyrus-orbitofrontal cortex to memory loss and cognitive impairment among individuals with Alzheimer’s disease, a future cohort study to investigate the relationship between changes in the brain structure of individuals who were exposed to prenatal tobacco and their likelihood of developing Alzheimer’s disease may be warranted. Another research initiative, The HEALthy Brain and Child Development Study, may be another avenue to investigate linkages between PSE and infant brain development, as this study is following cohorts of pregnant women to better understand substance use, PSE, and pre- and postnatal outcomes [57].