Advances in science allow researchers to understand how prenatal exposures affect health and disease outcomes later in life. Studying DNA from the umbilical cord blood of babies revealed differences in those whose mothers used methadone for their opioid use disorder.

This pilot study found that there are changes in cells involving multiple areas of body function. Keep reading to learn which systems are affected.

The Study:

Title: DNA methylation patterns in umbilical cord blood from infants of methadone maintained opioid dependent mothers

Published in Nature, July 2024

The Science in Plain English :

Data from this study of 16 infants (8 infants in the Methadone group and 8 infants in the Control group) may explain neonatal outcomes seen from prenatal methadone exposure. DNA changes were observed in a variety of systems within the methadone-exposed infants.

Brain and Behavior

Babies born to mothers who used methadone during pregnancy may have changes in brain function, behavior, and growth. Methadone can affect genes that can lead to issues with how the brain develops and functions.

Research also shows that babies might be born early, smaller than expected, or have developmental problems, such as difficulty with learning or behavior.

Vision and Thinking

Methadone exposure can affect genes involved in vision problems and cognitive delays. Some babies have issues with seeing clearly or with intellectual development.

Immune System

Babies of mothers who use methadone may be at a higher risk of developing immune problems like asthma or eczema.

Heart Problems

Methadone exposure is linked to heart issues, like heart failure, arrhythmias (irregular heartbeats), and other cardiac problems in babies. Genes related to how the heart functions can be affected.

Liver and Kidney

Methadone can also affect the liver and kidneys, causing inflammation or other damage. This could lead to liver problems or kidney failure in some babies.

Growth Problems

Babies exposed to methadone in the womb may not grow as expected, especially in the later stages of pregnancy. This could be due to problems with the hormones that control growth.

Damage to Brain Development

Exposure to methadone can increase stress on the brain cells, which can harm brain development and make it harder for babies to develop the right connections in the brain. This can lead to problems with myelination (the process of covering nerve fibers with protective layers) and overall brain function.

Changes in DNA

Methadone exposure causes changes in the DNA of babies, affecting genes that control brain function, heart health, and the body’s stress response. These changes could explain why babies of mothers using methadone have problems with development, heart function, and growth.

In short, this study shows that methadone use during pregnancy affects the development of babies in many ways, including their brain, immune system, heart, liver, kidneys, and growth. More research is needed to fully understand how these changes affect babies in the long run.

Many thanks to the authors of this article: Oluwatobi Adegboyega, Suhita Gayen nee’ Betal, Pedro Urday, Rachel Huang, Katherine Bodycot, Huda B. Al-Kouatly, Kolawole Solarin, Joanna S. Y. Chan, Sankar Addya, Rupsa C. Boelig & Zubair H. Aghai 

Pain impacts the life of any parent whose kiddo suffers the bumps, scratches, and other boo-boos of childhood. Do opioid-exposed children have the same pain sensitivity as their non-exposed peers?

The researchers conducting this study were interested in this question, as well as how adults with prenatal opioid exposure perceive pain. It was the treatment of pain, after all, that started our country’s opioid epidemic. If opioid-exposed children experience stronger levels of pain, will they turn to opioids for relief?

The Study:

Title: Opioid-induced dysbiosis of maternal gut microbiota during gestation alters offspring gut microbiota and pain sensitivity

Published in Gut Microbes, December 2023

The Science in Plain English :

To answer the author’s questions, researchers took the following steps;

• female mice were exposed to regular methadone use

• poop from these mice was examined to determine the balance of bacteria (harmful or beneficial) in their gut

• male mice were introduced

• children of the methadone-using mice were subjected to heat, and their feet were poked

• measurements of pain sensitivity in these mice children were compared to mice without opioid exposure

• mice children were given a specialized probiotic mix

• following the probiotics, the pain tolerance of these mice was remeasured 

• mice children brains were examined to detect genes and neural pathways

• mice children poop was also examined for gut bacterial balance, both before and after probiotics were introduced

Mice Mom Results

Pregnant mice who use opioids disrupt the balance of bacteria in their gut microbiomes. This, in turn, disrupts the composition of of their child’s gut microbiome.

Mice Children Results

• Prenatal methadone exposure increased sensitivity to both thermal pain (heat) and mechanical pain (poking).

• Blood samples taken from the methadone-exposed mice children had higher levels of a protein that plays a role in tissue inflammation.

• Analysis of their poop showed prenatal opioid exposure resulted in significant change to the balance of bacteria in their guts; necessary bacteria strains were depleted and harmful bacteria was overgrown.

After supplementing these mice with probiotics, which reset the balance of bacteria in their guts, their previous hypersensitivity to pain was gone. 

• Some mice children nursed from female mice who were not exposed to methadone. Exposure to a healthy balance of gut bacteria in this way also reset the mice children and relieved their pain sensitivity.

• Brain examinations showed that providing probiotics to rebalance the gut resulted in gene changes related to pain signaling. This is evidence of the gut-brain-axis mediating pain sensitivity in the mice children.

Conclusions

“Prenatal methadone exposure increases sensitivity to thermal and mechanical pain…, which is mediated by the microbiome”

The higher levels of specific proteins generated, that play a role in tissue inflammation, are made better with probiotic administration.

Prenatal opioid exposure alters a total of 3,516 genes. These genes provide pathways with key roles in neurological and immune function as well as behavior. Other altered genes activate pain and inflammation signals, sensation, and sensory system development. Significant decreases were seen in neurotransmission, learning, memory, and cognition compared to control mice. However, after administering probiotics, the effects in hundreds of these same genes were reversed. This provided significant increases in lost neurotransmission, learning, memory and cognition, and significant decreases in anxiety and sensation.

The benefits of probiotics given to pregnant mom mice affect the growing offspring’s physiology and brain function. This suggests that the deficits associated with prenatal methadone exposure may in part be mediated by the gut microbiome. If not done during pregnancy, resetting the gut bacteria balance immediately after birth may induce a permanent shift.

“…[We] suggest the importance of maintaining a balanced gut microbiome during pregnancy as one arm of a comprehensive treatment strategy to help mitigate downstream effects of prenatal opioid exposure.”

Questions

Are there more answers in the gut underlying the adverse neurodevelopmental outcomes of prenatal opioid exposure? 

Yes. Scientific knowledge of the gut microbiome and it’s role in the gut-brain-axis has significantly grown in recent years. As connections are made there is sure to be knowledge gained regarding the effects of prenatal opioid exposure.

Do these findings in mice apply to humans?

Yes. Mice are used for research when it’s known that the systems and processes measured in mice mimic human systems and processes. This does not mean there is always a 100% match. However, much can be gained from doing experiments with mice models when human experimentation is not viable.

Note: Opioid and methadone are used interchangeably in this summary. Methadone was the substance administered to the mice. Methadone is an opioid.

Many thanks to the authors of this article: Abu, Y. F., Singh, S., Tao, J., Chupikova, I., Singh, P., Meng, J., & Roy, S.

Let’s break it down into plain English…

Title: Medication-assisted treatment vs. detoxification for women who misuse opioids in pregnancy: Associations with dropout, relapse, neonatal opioid withdrawal syndrome (NOWS), and childhood sexual abuse.

Published in Addict Behav Rep. Nov 12, 2020

Summary in plain English :

The American College of Obstetricians and Gynecologists advises using medication-assisted treatment (MAT) for pregnant women who misuse opioids instead of detoxification due to the risks of relapse and treatment dropout. In a study of 55 pregnant women with opioid use disorder, those who chose MAT had a lower dropout rate, but higher rates of neonatal opioid withdrawal syndrome (NOWS) in their infants compared to those who chose detoxification. Relapse was more common among women on MAT (26%) than those who detoxified (0%).

What happens when the infant experiences NOWS?

• The average cost of delivery increases from $3,500 to $93,400

• Baby’s first experience outside of the womb is the frightening stress of detoxification

• Significant effects on cognitive and motor development are likely

• Inhibitory control and working memory abilities are damaged

• Head circumference at birth is smaller (30% are below or equal to the 10th percentile, and 8% are below or equal to the 3rd percentile)

Full detoxification from opioids during pregnancy offers the potential to eliminate NOWS and the lifelong effects of prenatal opioid exposure. This is not the first study showing that detoxifying from opioids during pregnancy doesn’t appear to harm the fetus. In this study, no participants dropped out and there was minimal relapse (all within the MAT cohort). Lowering MAT doses reduced neonatal opioid withdrawal syndrome (NOWS), and detoxification eliminated it. Women with a history of sexual abuse were more successful in tapering or detoxifying than those on MAT. Different causes of opioid misuse might affect treatment outcomes. More research is needed to confirm these findings and to identify which pregnant women are most likely to benefit from detoxification, along with postpartum follow-up for relapse vulnerability.

Many thanks to the authors of this article: Macfie J, Towers CV, Fortner KB, Stuart GL, Zvara BJ, Kurdziel-Adams G, Kors SB, Noose SK, Gorrondona AM, Cohen CT

The full report is accessible here: https://pmc.ncbi.nlm.nih.gov/articles/PMC7752716/

• Opioids in Pregnancy ‘Not Linked’ to High Risk of Child Disorders

• Prenatal Opioid Exposure Not Tied to Neuropsychiatric Disorders in Offspring

Could this be true? An exploration of the data is necessary to confirm or deny this broad-reaching statement.

Title: Prenatal opioid exposure and subsequent risk of neuropsychiatric disorders in children: nationwide birth cohort study in South Korea

Published in BMJ, April 24, 2024

Summary in plain English :

This study of over 3 million children is one of the largest to track prenatal opioid exposure. In the sample of nearly all infants born in South Korea, from January 2009 to December 2017, there were 216,000 iopioid-exposed infants. The study ended in December 2020, allowing the researchers to follow children who had aged 3 to 10 years. Capping the age at 10 years is the first flaw in relating the study results to the study headlines. The majority of neuropsychiatric disorders, such as depression, anxiety, mood disorders and eating disorders, are diagnosed after the age of 10. Is declaring opioid-exposed children not at an increased risk even accurate?

The infants in this study were exposed only to prescription opioids. These opioids were taken to alleviate pain and 97% were either Hydrocodone or Tramadol. None of the babies in this study were exposed to illicit opioids. The data showed which part of the pregnancy moms were in when prescribed opioid medications. It cannot be known whether prescriptions were filled or taken, so babies deemed opioid-exposed may include unexposed babies as well. This can underestimate the adverse effects of opioid exposure to the fetus.

The conclusion of the article states; “Opioid use during pregnancy was not associated with a substantial increase in the risk of neuropsychiatric disorders in the offspring. A slightly increased risk of neuropsychiatric disorders was observed, but this should not be considered clinically meaningful given the observational nature of the study, and limited to high opioid dose, more than one opioid used, longer duration of exposure, opioid exposure during early pregnancy, and only to some neuropsychiatric disorders.”

While a substantial increase in risk was not seen with lower opioid doses taken after the first trimester of pregnancy, wouldn’t a more informative and truthful headline read, “Opioid use during pregnancy is associated with neuropsychiatric disorders when taken at high doses, over 60 days, or when taken during the first trimester.”

When examining the risk to benefit ratio, let’s think carefully about what the risk actually is. The study states, “Prenatal opioid exposure modestly increased the risk of severe neuropsychiatric disorders [including,] mood disorders, attention deficit hyperactivity disorder, and intellectual disability in the child.” While the risk may be modest, is a severe disorder afflicting your child preferred to the relief during pregnancy of pain?That’s a decision no mom wants to make, but when forced to choose, she should be fully educated on the science. Reading just the article headline communicates a different picture.

This robust study can be helpful to many within the medical field. Much new information is accessible when read in its entirety. However, in a fast-paced world where headlines can be the only way people get their news, misleading summaries can cause life-long harm.

Many thanks to the authors of this article: Kang J, Kim H J, Kim T, Lee H, Kim M, Lee S W et al.

The full report is accessible here: https://doi.org/10.1136/bmj-2023-077664

Key Points

• Recent trends in caring for babies exposed to opioids focus more on non-drug methods and less on giving them medicine after birth for withdrawal symptoms.

• It's hard to separate how opioids affect a baby's brain from other things in their environment like economics, where they live, and their genes.

• Babies who were exposed to opioids before birth are at higher risk for developmental and behavioral concerns and poorer school performance.

• Taking care of these babies and their families should be multi-disciplinary and comprehensive. A non-judgmental focus on strengthening the caregiver–child relationship is important.

Title: Neonatal Opioid Withdrawal Syndrome: An Update on Developmental Outcomes

Published in Clinics in Perinatology, March 2023

Summary in plain English :

After discussing the importance of prenatal opioid exposure, the authors addressed changes in brain development seen in the lab. Studies done with rodents and models of organs show how prenatal opioid exposure can change how the brain develops and how a person behaves. In tests with mice, being exposed to opioids affects how the brain cells grow, how the brain's support cells grow, and how the brain's protective covering forms, as well as memory and behavior. The're not sure if these changes also happen in humans, but studies using brain imaging show differences in brain sizes, small spots of damage in the white matter, changes in the structure of the white matter, changes in how different parts of the brain connect, and more blood flow to the brain in babies and kids who were exposed to opioids before birth.

Cognitive Outcomes

Infants :
In one study, babies with opioid exposure did as well as others on tests at 5 to 8 months. Another study found moms on opioid treatment had babies with normal development scores. But another study showed babies exposed to opioids had lower scores on tests at 6 months. Babies treated for opioid withdrawal or exposed to other drugs did worse on tests too. In a small group, babies treated for withdrawal had lower scores than usual.

Toddlers :
In two studies, babies treated for withdrawal from opioids had lower cognitive scores at 15 to 24 months, but still within the normal range. Another small study showed babies exposed to methadone before birth had lower scores at 18 to 24 months compared to others. But in a recent study, there was no difference in scores between babies treated with morphine or methadone for withdrawal at 18 months. Babies given phenobarbital had lower scores than those who didn't get it. In another study, babies exposed to opioids at birth had lower cognitive scores at 2 years compared to others, with many showing cognitive delay.

Preschool to School Age :
In a study from New Zealand, at 4.5 years old, children exposed to opioids had more problems in areas like language, hearing, thinking, and understanding compared to those who weren't exposed. Their overall IQ scores were lower too. They were three times more likely to have trouble learning or thinking and to have delays in thinking compared to others. In another study, at 4 years old, both groups of children did okay on thinking tests, but those exposed to opioids had more trouble with memory, paying attention, and doing tasks that needed planning.

Speech and Language Outcomes

Infants :
In one study, babies exposed to medication for opioid use disorder (MOUD) or treated for NOWS had similar language scores at 5 to 8 months compared to those not exposed. Another study found that communication scores were normal in babies exposed to MOUD at 3 and 6 months. However, in a different study, babies treated for NOWS had lower language scores compared to typical scores for their age group.

Toddlers :
In studies, babies treated for NOWS had lower language scores at 15 to 24 months but still within normal levels. Another big study showed babies exposed to opioids before birth were more likely to have speech problems than those not exposed. However, a small study found that babies exposed to methadone had similar language scores as others at 18 to 24 months. In a different study, there was no difference in language scores between babies treated with morphine or methadone for NOWS at 18 months, but many had lower scores than usual, indicating a higher risk of language delays. In another study, babies exposed to opioids at birth initially had lower language scores at 2 years, but after considering other factors, the differences disappeared.

Preschool to School Age :
In the New Zealand study, at 4.5 years old, children exposed to opioids had lower scores on language tests compared to the control group. They were also three times more likely to have language delays or problems. Even after considering other factors, like home environment and education, opioid exposure still affected how well they could speak.

Motor Outcomes

In studies from the last 10 years, findings on motor skills in kids with prenatal opioid exposure are mixed. Some studies show these kids have lower motor scores than usual, but still within the normal range. For example, in one study, babies with NOWS had lower motor scores at 1 to 3 months. Another study found that at 6 months, babies exposed to opioids before birth scored lower on motor tests compared to others. However, some studies suggest that the dose of opioids might affect motor scores, with higher doses possibly leading to lower scores. In toddlers, similar findings were seen, with opioid-exposed children having lower motor scores but still falling in the normal range. Only one study looked at motor skills in older children with prenatal opioid exposure, finding they scored lower on motor tests compared to other kids their age.

Behavioral Outcomes

Several studies have shown that children with prenatal opioid exposure are more likely to have behavior problems. One study found that they were more likely to have diagnoses of behavioral or emotional problems compared to children not exposed to opioids before birth. In another study, researchers used a questionnaire to assess behavior in children with prenatal opioid exposure at different ages. They found that these children had higher scores indicating more difficulties, especially with attention, hyperactivity, and peer relationships, and these problems tended to get worse over time compared to children who weren't exposed to opioids before birth. Children with more risk factors in their biology, their mother's social situation, and their upbringing had more behavior problems.

Visual Outcomes

Visual Evoked Potentials :

The Visual Evoked Potentials (VEPs) test checks how well the brain processes visual information by measuring electrical changes. A slower VEP latency suggests slower visual development. In one study, infants exposed to methadone had slower processing times at 6 months compared to others. Another study found that at 4 months, these infants took longer to process visual information, but by 36 months, they caught up, showing that visual development continues into childhood.

Visual Acuity :

There aren't many studies on how well children see if they were exposed to opioids before birth. One study found that at 4.5 years old, children exposed to opioids before birth had lower vision in their left eye compared to others. There was also a hint that their overall vision might be lower too.

Strabismus/Eye Muscle/Binocular Movement :

Many reports on eye muscle and movement problems in children exposed to opioids before birth talk about nystagmus and strabismus. In a big study, babies exposed to opioids who needed medicine for NOWS had the highest rates of strabismus compared to those not needing medicine and babies not exposed to opioids. In another study, babies exposed to opioids had a higher chance of being hospitalized for eye problems and were more likely to have issues with their eye muscles compared to babies exposed to other substances or those not exposed at all. Smoking during pregnancy, which is also linked to strabismus, is an important factor in some studies.

Visual Attention and Smooth Pursuit :

The way our eyes smoothly follow moving objects can be affected by things babies are exposed to before they're born. In one study, researchers found that 4-year-old children exposed to opioids didn't have different numbers of quick eye movements or problems following slow-moving objects compared to others. But when they looked at fast-moving objects, these children's eye movements were slower. However, this difference went away when they considered other factors like how much education their moms had or their birth weight. Another study found that children exposed to opioids had trouble ignoring distractions when doing a special attention test, especially if they were also treated for Neonatal Opioid Withdrawal Syndrome (NOWS) or if their moms used marijuana during pregnancy.

Medical Comorbidities

Babies exposed to opioids before birth often need more medical care and may end up back in the hospital more than other babies, even after they're born. Some studies show they're more likely to go back to the hospital for infections. However, a study from Nordic countries found no difference in antibiotic use or infections between babies exposed to opioids and those who weren't. Two studies found that babies treated for Neonatal Opioid Withdrawal Syndrome (NOWS) were more likely to have torticollis, a condition where the neck muscles cause the head to tilt or turn. Most cases were due to tight muscles and the way babies were positioned.

Recommendations

It's crucial to keep track of how babies with Neonatal Opioid Withdrawal Syndrome are developing to make sure they get the support they need. This means checking in regularly to watch how they're growing, behaving, and learning, and getting them help early if needed. The authors of this study suggest a schedule for visits and what to pay attention to during these visits.

Summary

Exposure to opioids before birth, whether or not it leads to NOWS, is linked to developmental impacts. Yet, it's uncertain if this exposure directly causes these effects or if it's just a correlation, given the many other factors involved like exposure to multiple substances, family challenges, mental health issues, and environmental influences. Nevertheless, children exposed to opioids before birth appear to face greater risks of developmental and behavioral problems and should receive close monitoring.

Many thanks to the authors of this article: Benninger KL, McAllister JM, and Merhar SL

The full report is accessible here: https://doi.org/10.1016/j.clp.2022.10.007

What started in 2010, with an 82% increase in Neonatal Abstinence Syndrome (NAS) from the rate just two years earlier, is still at a crazy high level. Recent data from the Healthcare Cost and Utilization Project (HCUP) show that by 2020 over 6 newborn babies per every 1000 in the U.S. were hospitalized for NAS. That’s close to 1% of overall births!

After the substantial increase in the early years of the opioid epidemic, HCUP reports continued consistent growth through 2017. While 2018 saw the first downturn in the incidence of NAS, the decline has been minimal. NAS levels are still significantly higher than pre-crisis numbers.

Depending on where you live, it may be easier to forget how much damage prenatal opioid exposure is still causing. Cases of NAS are not evenly distributed. Eastern states like Delaware, Maine, and Vermont consistently care for over 20 babies per thousand with NAS. During peak years of the opioid crisis, these states had numbers as high as 36 per 1000 newborns, or 3.6% of all hospital births. West Virginia takes the notorious title of largest per capita cases of NAS with an all-time high in 2017 of 56 babies per 1000. The incidence of autism diagnoses in the U.S. that same year was under 20 per 1000.

I use the comparison to autism diagnoses to contrast the knowledge and attention of the general public. We all know families with members who have autism. We've seen fundraising campaigns and can identify the puzzle piece symbol for this condition. Babies with a Neonatal Abstinence Syndrome diagnosis have long-term outcomes too; disabilities that require governmental and school system services and the need for funding to cover these services. Yet most people are unaware that members of this population live among them.

So how many actual kids is this? HCUP data shows that 15,085-27,085 children per year were hospitalized at birth with NAS since 2010. Those 27,085 born in 2017, at the peak of this problem, are in first grade now. It’s likely their caregivers are yet unaware of the learning challenges they are saddled with. In Junior High/Middle School (grades 6-8) our nation is educating 48,000 of these children. I suspect their caregivers are now aware of the academic and behavioral struggles that are often seen by this age.

Our 1% is still hidden. As researchers continue to study these kids and learn precisely how trauma and opioids changed their neurons and brain chemical systems, we will be able to harness the tools necessary to support them. Caregivers who are aware of their child’s newborn diagnosis can better understand them and society can recognize the children who emerged from this scarring epidemic. Overdose deaths are not the only news to report in this continued epidemic.

Access the Healthcare Cost and Utilization Project data, which is managed by the U.S. Agency for Healthcare Research and Quality, here: https://datatools.ahrq.gov/hcup-fast-stats/

Beginning at conception, a timeline of creation builds the ANS as well as the organs, muscles and other parts of the body it connects to. The authors of this study were able to shed light on what happens when opioids are introduced to this process.

Title: A Review on the Vagus Nerve and Autonomic Nervous System During Fetal Development: Searching for Critical Windows

Published in Frontiers in Neuroscience , September 2021

Summary in plain English :

Synopsis

The autonomic nervous system (ANS) is a vital system in our bodies that controls various functions automatically. It starts working even before we're born, helping in the development of the fetus. One important part of this system is the vagus nerve, which plays a crucial role in many processes, from keeping inflammation in check to producing hormones for energy. It's also the main way our organs communicate with the brain.

This article explores how the ANS, especially the vagus nerve, develops in babies before and after birth. It looks at factors like the baby's characteristics, the mother's lifestyle and health, the health of the placenta, the conditions during birth, and exposure to medications to see how they might affect the vagus nerve's development during these crucial periods.

Understanding this can help doctors and other healthcare professionals create better guidelines for caring for babies, especially to reduce the chances of long-term problems related to the development of the ANS.

The timeline below, provided for reference, shows the main events related to ANS development.

CAN, central autonomic network; fHRV, fetal heart rate variability; FM, fetal movement; GM, general movement; PNS, parasympathetic nervous system.

Findings

The full article (link below) provides a detailed description of development during the 1st, 2nd and 3rd trimesters. There are even important developments during labor and in postnatal life. For the purpose of this summary, focus will be on findings relevant to prenatal opioid exposure. And since many opioid exposed babies are born prematurely, it's important to point out how that may affect the baby as well.

Premature Birth and the Autopilot System: When infants transition from being inside the womb to being born, their bodies need a hormone called cortisol to help with this change. But in cases of premature birth. or when labor doesn't happen naturally, the release of cortisol is significantly reduced. If there's not enough cortisol, it can affect the development of the Central Autonomic Network (CAP). And when cortisol levels are low, it can also lead to problems in controlling inflammation after birth. For example, it could contribute to conditions like necrotizing enterocolitis (NEC), which can harm the cells in certain parts of the brain related to the vagus nerve.

It takes about 37 weeks in the womb for the ANS to fully develop. So, when babies are born too early, they may struggle to handle changes in their body caused by the outside world. Additionally, premature babies often need intense medical care, like help with breathing or various drugs, which can put extra stress on their immature autonomic nervous system. In fact, it seems that even when premature babies catch up to the age when they should have been born, their ANS response is quite low in comparison to full-term babies.

Issues after 40 Weeks: Although premature babies can develop a reasonably healthy autonomic nervous system after 2-3 years, issues with the ANS often persist into later life. These issues can come with problems in regulating the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis, both when they're awake and when they're asleep.

Problems with the ANS during a baby's first year of life can lead to issues with how the heart and blood vessels work. This means it's really important to watch how the ANS develops during the first two years of life to identify babies who might be at risk. If the ANS doesn't mature properly due to things like inflammation, being born prematurely, or being smaller than usual, it can also increase the chances of developing conditions like type 2 diabetes later in life. These conditions, along with others related to metabolism and the immune system, may be linked to how the ANS regulates inflammation.

Additionally, problems with the ANS in newborns can cause issues with the brain and how it functions, and can even lead to conditions like cerebral palsy by the time a child is 2 years old. Since the development of the ANS is connected to the development of the fetal movements, ANS issues can also affect the growth of the central nervous system and behavior. On one hand, fetal movements are linked to the body's fight-or-flight response, which influences how we react to stress. On the other hand, problems with the ANS maturation are linked to changes in how the brain and motor skills develop, which can affect cognitive abilities, language, play, and social skills.

The immaturity of the autonomic nervous system, due to complications that occur before or after birth, such as maternal health issues or difficult births, can affect the overall development of the brain. This, in turn, can influence behavior, the ability to handle stress, and mood regulation. In some cases, it can even lead to serious neurological or psychological problems in infants, adolescents, and adults. Even medical procedures that cause pain during hospital stays can disrupt the regulation of stress and the development of the brain in newborns.

What can be done: Given the potential long-term harm caused by ANS problems, it's crucial to focus on protective measures that support the maturation of the ANS. Breastfeeding, stress reduction during pregnancy, skin-to-skin contact, and social interactions between newborns and parents or caregivers can help babies develop a well-functioning ANS, reduce stress, build resilience, and enhance their brain's adaptability.

Opioid-specific: Overexposure to opioids during pregnancy can harm various fetal systems, including the cardiovascular, respiratory, neurobehavioral, metabolic, and neuroendocrine systems. Early exposure to buprenorphine can lead to higher fetal heart rate variability. Fetuses exposured later in pregnancy (32-36 weeks), display less suppression of motor activity, possibly involving the vagus nerve system. Opioid dependence is also linked to an increased risk of Neonatal Abstinence Syndrome (NAS) and Neonatal Opioid Withdrawal Syndrome (NOWS).

Newborns with NOWS show changes in the levels of various neurotransmitters and hormones, suggesting a potential disruption in vagal and central autonomic pathway activity. Prenatal opioid exposure might program the stress response systems, possibly leading to long-term consequences.

Conclusion

When opioids are involved in building the body’s autopilot system, the opportunity for construction mishaps is high.

Many thanks to the authors of this article: Cerritelli F, Frasch MG, Antonelli MC, Viglione C, Vecchi S, Chiera M and Manzotti A

The full report is accessible here: https://doi.org/10.3389/fnins.2021.721605

Title: Developmental implications of prenatal opioid exposure among school-aged children: a mixed methods and community-initiated analysis

Published in BMC Public Health, September 2023

Summary in plain English :

Results of this study, which included 163 opioid exposed children, indicate the following:

• almost half of them have multiple developmental delays, behavioral health conditions, and specific learning difficulties

• about 85% face behavioral challenges

• negative outcomes in their development were not linked to the type of opioid their mothers used during pregnancy or whether their mothers used multiple substances

• more than 80% of the families mentioned positive qualities in their children, including, empathy, being socially friendly, and being able to bounce back from tough situations

The authors concluded, children born with prenatal opioid exposure may continue to face difficulties as they grow and start school. These findings align with previous research involving younger children, emphasizing the importance of developing effective ways to support and care for these children as they progress beyond the early stages of life.

Methodology:

This research project was initiated by the non-profit organization, "To The Moon And Back" (TTMAB). This community organization has been helping children and families affected by prenatal opioid exposure in Massachusetts and West Virginia since 2017. Child Trends partnered with TTMAB to gather data from the families they support.

To do this, a mixed methods approach was used, specifically a method that gives equal importance to both quantitative (numbers-based) and qualitative (descriptive) data. This approach helps avoid letting one type of data influence or limit the other. Data was collected through surveys and focus groups involving families in West Virginia and Massachusetts. The research aimed to answer several questions, including:

1. What are the effects of prenatal opioid exposure on a child's development, both positive and negative?

2. Do the developmental outcomes connected to prenatal opioid exposure differ based on the type of opioids or multiple substances used, while taking into account adverse childhood experiences?

3. What services do families with children affected by POE use, which ones are beneficial, and what services do they wish were available? (Question #3 data is not presented in this study)

Substance Exposures:

The children studied were exposed to various types of opioids, including illegal ones (74%), methadone or buprenorphine for medication assisted therapy (43%), opioids not prescribed to them (34%), and opioids prescribed by a doctor (11%).

A majority of these children (85%) were also exposed to other substances before they were born, typically around four additional substances on average. These additional substances included nicotine (94%), marijuana (89%), alcohol (76%), tranquilizers (71%), methamphetamines (66%), other stimulants (61%), and hallucinogens (24%).

When asked which trimester of pregnancy the child was exposed to these substances, most respondents said it was throughout the entire pregnancy. Only a few reported exposure during the first and second trimesters for alcohol, nicotine, and/or marijuana.

The rates of using multiple substances did not differ between pregnant individuals using legally prescribed opioids, methadone, or buprenorphine and those using non-prescribed or illegal opioids. Moreover, many pregnant individuals using methadone or buprenorphine were also exposed to illegal opioids.

Behavioral Issues and Tantrums:

The results from the survey's behavioral questions, give a better understanding of the complex behavioral and symptom profiles of the children in this study. They are based on what parents and caregivers have noticed and their opinions. Here's what the survey revealed:

• More than half of the respondents mentioned that their children exhibited behaviors like being impulsive (67%), having tantrums (60%), struggling with transitions (58%), showing aggression (57%), seeking or avoiding sensory input (57%), and having difficulty with changes in routine (55%).

• Among those who reported tantrums, nearly half (45%) said that the frequency of tantrums had increased in the past year.

• Children with sensory processing issues showed varying preferences for different sensory inputs. For instance, when it came to sensitivity to light, 60% of children avoided it, while 40% actively sought out light.

• There were more consistent patterns of sensory avoidance when it came to sound and clothing, and more consistent patterns of sensory-seeking behavior for physical touch.

• For smells and tastes, an equal number of children were reported to seek and avoid them.

In the focus group discussions, parents shared how these behavioral issues could manifest in their children. They described their children bouncing while sitting or banging their heads against walls to seek physical sensory input. Parents also mentioned that their children sometimes struggle to regulate their own behavior.

In responses to open-ended survey questions, parents mentioned that their children's tantrums were triggered by unusual things, such as feeling overwhelmed (for example, during baths, haircuts, or loud noises) and when their child couldn't complete a task. Some parents linked these tantrums to past experiences their children might have had.

About one-third of parents also reported that their children's tantrums could be aggressive or violent, involving actions like pushing, hitting, spitting, biting, kicking, head banging, hair pulling, breaking toys, or throwing things. Some parents even mentioned physical damage to their homes, like "the bedroom door has noticeable dents" and "my child has left bruises on me more than once."

Additionally, over 10% of parents described these tantrums as intense and unpredictable, with sudden shifts in mood from happiness to extreme anger in just seconds, and a complete loss of reasoning during tantrums, which made it necessary to ensure everyone's safety.

Conclusions:

As the use of opioids during pregnancy continues to increase, and research shows that children exposed to opioids before birth can face developmental challenges that extend into their school years, it's crucial for states to invest in services for these children and their families. This investment is essential as we await further medical research to provide clearer guidance.

While there are established best practices for caring for newborns with prenatal opioid exposure, there's currently a lack of such guidance for toddlers, preschoolers, and school-age children with this exposure, who often encounter significant difficulties. Without a clear roadmap for supporting these children throughout their growth, they are at risk of facing disparities in education and healthcare.

Parents have shared stories of their kindergartners being referred to juvenile justice programs for their behavior, children being diagnosed with oppositional defiance disorder, and caregivers mistreating them out of frustration. Instead of punishing these children for challenges beyond their control, we should focus on providing them and their families with support to help these resilient young individuals succeed. The more that educators and healthcare providers understand these children and how to assist them, the better it is for everyone involved.

Many thanks to the authors of this article: Wilkinson, A., Rackers, H.S. & Harmon, T.M.

The full report is accessible here: https://doi.org/10.1186/s12889-023-16702-8

Title: Eat, Sleep, Console Approach or Usual Care for Neonatal Opioid Withdrawal

Published in The New England Journal of Medicine, June 2023

Summary in plain English :

In the United States, a newborn is diagnosed with neonatal opioid withdrawal syndrome every 18 minutes due to exposure to opioids during pregnancy. This syndrome causes symptoms like stomach issues, fussiness, muscle stiffness, and seizures, leading to longer hospital stays. Current care for these babies varies because there's no standard approach, especially when it comes to using medications, which affects how long they stay in the hospital.

For nearly half a century, subjective scales have been used to assess the severity of this syndrome and decide when to use drugs. Despite concerns that this approach might lead to unnecessary treatment, it's still the main method because there hasn’t been a better alternative.

In 2014, a new approach called "Eat, Sleep, Console" was suggested for assessing these babies. More recently, this approach has gained popularity and is used alongside the Finnegan Neonatal Abstinence Scoring Tool. It focuses on evaluating the baby's ability to eat, sleep, and be comforted and promotes non-medical treatments first, like creating a calm environment, skin-to-skin contact, clustered care, and breastfeeding. Several quality-improvement programs have found this approach better than the old one, and it's being adopted in medical practice.

However, some people worry about its rapid adoption without solid evidence to support its safety and effectiveness across different situations and patient groups. There's concern that it might lead to undertreatment with medication and early discharge, putting babies at risk for readmission, harm, or even death.

To address these concerns, the Advancing Clinical Trials in Neonatal Opioid Withdrawal (ACT NOW) collaborative, part of the National Institutes of Health's Helping to End Addiction Long-term (HEAL) Initiative, was formed. They conducted a controlled trial called "Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW)" to see how safe, effective, and applicable the "Eat, Sleep, Console" approach is compared to the usual approach with the Finnegan tool.

Primary Outcome:

On average, babies in the "Eat, Sleep, Console" group were ready to go home 8.2 days after they were born, while those in the usual-care group took longer, 14.9 days. This is a difference of almost a full week.

Secondary Outcomes:

In the usual-care group, 52.0% of babies received opioid treatment, whereas in the "Eat, Sleep, Console" group, only 19.5% did. This is a substantial difference of 32.5 percentage points.

When looking at the safety of the infants up to 3 months of age, both groups had similar rates of adverse outcomes, with 16.1% in the "Eat, Sleep, Console" group and 15.8% in the usual-care group.

Result:

In this study conducted across multiple medical centers, a randomized and controlled trial found that use of the Eat, Sleep, Console care approach significantly decreased the number of days until infants with neonatal opioid withdrawal syndrome were medically ready for discharge, compared to the usual-care approach, without increasing specified adverse outcomes

Many thanks to the authors of this article: Young LW et al.

The full report is accessible here: https://doi.org/10.1056/NEJMoa2214470

Title: Visual function in Norwegian children aged 5–13 years with prenatal exposure to opioid maintenance therapy: A case–control study

Published in Acta Ophthalmologica, September 2024

Summary in plain English :

The goal of this study is to check how well the eyes and vision work in kids who were exposed to opioid medications during gestation. The researchers were particularly interested in differences dependent on whether the women took methadone or buprenorphine during pregnancy.

The scientists worked with 63 kids who were between 5 and 13 years old. These kids were exposed to opioid medications before they were born. They compared them to another group of 63 kids who were the same age and gender but were not exposed to opioids before they were born. They checked how well their eyes worked by looking at things like how clearly they could see, the alignment of their eyes, the need for glasses, how they saw colors, and their peripheral vision.

Here's what they found:

1. Kids who were exposed to opioid medications before they were born had worse eyesight. This means they couldn't see as clearly as kids who weren't exposed to opioids, whether they were using their best eye, worst eye, or both eyes together.

2. Some of the kids exposed to opioids had a condition where their eyes didn't align properly (strabismus). This was more common in the group exposed to opioids (30%) compared to the group that wasn't exposed (4.8%).

3. Some of the kids exposed to opioids had a condition called nystagmus, where their eyes moved involuntarily. This was more common in the exposed group, too.

4. The kids exposed to opioids had a harder time adjusting their focus, like when they switch between looking at something up close and something far away, compared to the other kids.

5. Even when they considered other factors like the use of multiple drugs and being smaller at birth, the differences in eyesight, strabismus and nystagmus, still existed between the two groups.

6. Among the kids exposed to opioids, those whose moms took methadone had worse eyesight, more eye alignment issues, more nystagmus, and more issues with being farsighted and having astigmatism compared to those whose moms took buprenorphine.

Many thanks to the authors of this article: Anne Kathinka Aslaksen, Gro Horgen Vikesdal, Marit Torbergsen Voie, Megan Rowlands, Jon Skranes, Olav H. Haugen

The full report is accessible here: https://doi.org/10.1111/aos.15764

Title: Neonatal abstinence syndrome and the gastrointestinal tract

Published in Medical Hypotheses, December 2016

Summary in Plain English:

In the NICU, your NAS baby may have suffered from diarrhea, vomiting and reflux. The high-pitched crying may have been due to intolerable abdominal pain and cramping. These are all symptoms of gastrointestinal distress.

This study asks what happens in the intestinal tract of a fetus exposed to opioids. While exposure during gestation, and development of NAS at birth, are well known to be associated with gastrointestinal distress, the authors did not see data to confirm this exposure lead to a dysbiotic gut microbiome.

Since 2016, when this article was published, it has been proven that in utero exposure to opioids does indeed cause a dysbiotic gut microbiome. This means that the balance of bacteria and other microorganisms in the digestive system is not healthy or normal. It suggests that there might be an overgrowth of harmful bacteria or a lack of beneficial ones, which can lead to various health issues through the child’s life. Without a healthy gut microbiome, newborns can struggle to establish strong immunity and protection from pathogens.

Although this article was published as a hypothesis, or question to future researchers, it is included here due to the important science the hypothesis is based on.

Many thanks to the authors of this article: Denise Maguire PhD, RN, CNL and Maureen Gröer PhD, RN, FAAN

The full report is accessible here: https://doi.org/10.1016/j.mehy.2016.10.006

Title: Global Brain Functional Network Connectivity in Infants With Prenatal Opioid Exposure

Published in Frontiers in Pediatrics, March 2022

Summary in Plain English:

The research team conducing this study began with the following knowledge; Babies exposed to opioids and other substances before birth are more likely to have problems with their behavior as they grow up. They reasoned that by taking pictures of the infant brains when they are still very young, they may be able to find out if there are any differences in how the brains are developed. Finding differences can help predict how the infants will behave in the future.

This study was designed to use special brain scans on babies that can detect changes in how their brains are connected compared to babies who were not exposed to opioids or substances before they were born. They included 23 babies who were exposed to opioids before birth and 29 babies who were not exposed to opioids. Pictures of their brains were taken using a special MRI when they were less than three months old.

The research team found four important brain network components that were different in babies exposed to opioids compared to the healthy ones. Among these four, two were related to the mother's mental health. Additionally, the way the brain's networks are connected is different in babies exposed to opioids compared to those who weren't.

The affected brain networks are located in various parts of the brain, including the front, sides, back, top, and insides, suggesting that substances taken by the mother during pregnancy can affect the entire developing brain. These brain networks included regions associated with different functions like paying attention, making decisions, processing rewards, and more. Two of the networks showed stronger connections within themselves in babies exposed to opioids, while two other networks had weaker connections.

In conclusion, the research found important changes in how different parts of the brains of babies exposed to opioids before birth communicate with each other. These changes were significant and differed from the brains of babies who were not exposed to opioids during pregnancy.

Many thanks to the authors of this article: Radhakrishnan R, Vishnubhotla RV, Zhao Y, Yan J, He B, Steinhardt N, Haas DM, Sokol GM and Sadhasivam S

The full report is accessible here: https://doi.org/10.3389/fped.2022.847037

Title: Neonatal Abstinence Syndrome and High School Performance

Published in Pediatrics, February 2017

Summary in plain English :

There were 2234 children with NAS diagnoses and a control group of 4330 kids matched for gestation, socioeconomic status and gender. A third group of almost 600,000 kids made up the rest of the population of school kids who took Australia’s National Reading and Math tests in 3rd, 5th and 7th grades.

Results showed test scores for the NAS group were significantly lower in 3rd grade. Out of a maximum score of 1000, the 3 groups scored as follows;

NAS 359

Control 410

Remaining Population 421

The deficit was progressive. By 7th grade, the NAS group scored lower than the 5th graders in the general population.

Conclusions included:

A NAS diagnosis is strongly associated with poor and deteriorating school performance.

Children with NAS and their families must be identified early and provided with support to minimize the consequences of poor educational outcomes. This is because school performance is one of the most important outcomes of childhood. And the ability to do well in school is consistently related to adult success. Also, learning problems may not be recognized until a child enters school. However, simple and cost-effective strategies are strikingly beneficial in improving outcomes.

More about test scores:

Children with NAS had significantly lower scores than either the control group or the New South Wales general population in EVERY GRADE and EVERY DOMAIN of testing.

By 7th grade, 38% of NAS kids did not meet the minimum requirements to advance to the next grade, in at least 1 subject. This compares to only 18% of the control group and 15% of the larger population.

Why is this report, the first to measure academic outcomes at a population level for children with a history of NAS, important? Results show that a diagnosis of NAS is associated with poor performance in standardized testing from as early as 3rd grade (age 8 or 9). And school failure is of great concern as it increases risk of poor adult outcomes including depression in women, criminal activity and drug use.

What can we do? The research team stated we must take advantage of the fact that many children with NAS can be identified from birth. Interventions are much more effective when they are started early.

Many thanks to the authors of this article: Oei JL, Melhuish E, Uebel H, Azzam N, Breen C, Burns L, Hilder L, Bajuk B, Abdel-Latif ME, Ward M, Feller JM, Falconer J, Clews S, Eastwood J, Li A, Wright IM.

The full report is accessible here: https://doi.org/10.1542/peds.2016-2651

To watch a video summary of this report, click here: https://youtu.be/quIGGZuS1dU