Long-Term Neurodevelopmental Impacts of Prenatal Opioid Exposure

Amit Akirov, MD 

February 7, 2020

Article published here

Opioid use disorder is on the rise among women of reproductive age, contributing markedly to the opioid epidemic and increasing the incidence of adverse health outcomes in pregnant women and children. It is estimated that up to 14.4% of pregnant women have opioids dispensed during pregnancy. Perinatal exposure to opioids may have significant immune, neural, and behavioral effects that can alter central nervous system (CNS) development, as well as induce long-term changes in brain structure and function, according to a preclinical animal model study published in Brain, Behavior, and Immunity.

In light of the marked increase in the use of prescription opioids among women of childbearing age, there is evidence for a rapid increase in the rates of opioid use disorder during pregnancy and the risk for neonatal opioid withdrawal syndrome. Opioid exposure includes the use and misuse of various opioids, including oxycodone, morphine, codeine, illicit opioids, and medications used to manage opioid use disorders, such as methadone and buprenorphine.

Limited data are available on the direct effects of perinatal opioid exposure on developing neural circuitry and neurodevelopment outcomes. Because opioids rapidly cross the placenta, perinatal opioids can have a direct impact on the CNS.

The researchers completed a literature review to assess the effects of opioids on the developing brain. They used an animal model that included 200 male and female rat pups; 86 saline-exposed and 114 methadone-exposed offspring were used for outcome measures.

Similar to what was previously observed in human neonates after methadone exposure, rat pups of both sexes born to methadone-exposed mothers with methadone exposure in utero, and continuing through the perinatal and neonatal periods, had significantly reduced body weight. Methadone concentration in the urine also increased proportionally to maternal dose.

Methadone was found to induce systemic inflammatory response syndrome that persisted for weeks postnatally, with evidence for increased inflammatory proinflammatory cytokines in peripheral circulation, including a 19-fold (1954%) increase in interleukin (IL)-1β, 36% increase in tumor necrosis factor (TNF)-α, and more than 2-fold (225%) increase in IL-6 at approximately 17 days of methadone exposure. Although at a later time point there was no difference in TNFα, IL-6, and CXCL1, levels of IL-1β remained significantly increased (188%), compared with the saline-exposed pups.

Compared with peripheral bone marrow cells (PMBCs) from saline-exposed pups, PMBCs from methadone-exposed pups hypersecreted proinflammatory cytokines, including TNF-α and IL-1β. These findings support enhanced immune activation and lymphocyte hyperreactivity after methadone exposure. This sustained peripheral immune hyperreactivity was blocked by pretreatment of PMBCs with naloxone.

Perinatal methadone exposure leads to an increase in several cerebral molecular and cellular inflammatory mediators, including a 42% increased cerebral cortical Toll-like receptor 4 (TLR4) mRNA expression and an 87% increased MyD88 mRNA expression in the brains of methadone-exposed pups, compared with saline-exposed rats. Furthermore, there was an increase in cortical IL-1β and cortical CXCL1 among methadone-exposed rats, but brain levels of TNFα and IL-6 were unchanged with methadone exposure.  Perinatal methadone exposure was also associated with increased microglial activation.  

Regarding structural effects of methadone exposure in the CNS, there was a significant reduction in axonal integrity and myelin expression in methadone-exposed pups compared with saline-exposed pups. Diffusion tensor imaging was used to examine the brain ex vivo, with evidence for decreased fractional anisotropy in methadone-exposed rat offspring compared with saline-exposed pups, an indication for abnormal diffusion in the corpus callosum and external capsule.

After the data pointed to structural and microstructural brain injury, the researchers used a touchscreen operant platform to assess cognition and executive function. Methadone exposure during the perinatal period was associated with widespread associative learning and executive control dysfunction among adult rats. Importantly, these impairments were not secondary to sensorimotor-related problems or lack of motivation, as the data showed normal response reaction times and reward retrieval latencies.

The researchers acknowledged several study limitations, including lack of power to assess for sex differences in outcome measures and limitations secondary to the use of an ELISA kit to perform urinalysis for methadone levels.

“We provide evidence that methadone exposure in the perinatal period leads to a unique immune, neural and behavioral phenotype, associated with a systemic pro-inflammatory signature indicative of widespread brain and immune system injury. This signature reflects a significantly altered cerebral and immune microenvironment concomitant with dysregulated developmental homeostasis in the perinatal period,” concluded the researchers.

Reference

Jantzie LL, Maxwell JR, Newville JC, et al. Prenatal opioid exposure: the next neonatal neuroinflammatory disease[published online ahead of print, 2019 Nov 22]. Brain Behav Immun. doi: 10.1016/j.bbi.2019.11.007

METH, OPIOID USE IN PREGNANCY ON RISE

THURSDAY, Nov. 29, 2018 (HealthDay News) -- Methamphetamine and opioid use has soared among pregnant American women, putting the health of baby and mother at risk, a new study finds. 

While addiction among pregnant women has dramatically increased across the country, it disproportionally affects women living in rural America, where access to addiction treatment and prenatal care is limited, the researchers added.

"Use of both substances represents worsening public health crises," said lead researcher Dr. Lindsay Admon, an assistant professor of obstetrics and gynecology at the University of Michigan in Ann Arbor.

Although government efforts to curb methamphetamine use have been effective in the past, its use has spiked once more, she said.

Some data suggests that stopping amphetamine use in pregnancy can improve outcomes, Admon said. "But as clinicians, we need clear guidance on how to best promote cessation among pregnant patients with amphetamine use disorders."

Moreover, doctors need ways to guide patients to treatment services, particularly in rural areas where obstetric and addiction treatment services may be harder to access. In addition, addicted women may not tell their doctors about their drug use for fear of the legal consequences, Admon noted.

Another women's health expert agreed with the findings.

"This study confirms what I have been hearing clinically from providers and patients in the West that there is an unrecognized problem with amphetamines, and that the opioid crisis is now coupled with an amphetamine crisis that desperately needs monetary, treatment and recovery infrastructure support to reduce it," said Hendree Jones, a professor of obstetrics and gynecology at the University of North Carolina in Chapel Hill.

Furthermore, the study provides compelling data that underscores the lack of addiction treatment resources for women of childbearing age, said Jones, who wasn't involved with the research.

For the study, Admon and colleagues collected data on 47 million births in U.S. hospitals over 12 years. 

They found that the number of births among women addicted to amphetamine, mostly methamphetamine, doubled from 2008 to 2015, from 1.2 per 1,000 births to 2.4 per 1,000 births.

In addition, opioid use more than quadrupled from 1.5 per 1,000 births between 2004 and 2005 to 6.5 per 1,000 between 2014 and 2015. 

Using amphetamine during pregnancy increases the odds of moms dying or having serious medical complications by nearly two times of that of women using opioids, the researchers found. 

Also the risk of preterm delivery, preeclampsia or eclampsia, heart failure or heart attack, and the need for a blood transfusion were higher among moms using amphetamine, compared with those using opioids, according to the study. 

The main risk to infants born to addicted mothers is neonatal abstinence syndrome. Basically, the infants are born addicted to the drug mom was using and they go through withdrawal, much as an adult does when they stop taking the drug.

Symptoms such as body shakes, tremors, breathing problems, diarrhea or throwing up and fever and sweating can last up to six months, according to the March of Dimes. 

Often these babies need to be in neonatal intensive care units for an extended period.

Between 2014 and 2015, amphetamine use caused delivery complications in roughly 1 percent of all births in the rural West (11 per 1,000 deliveries), which was higher than the number of complications among women using opioids in most areas. 

Opioid use during pregnancy was highest in rural areas of the Northeast, causing complications in nearly 3 percent of all births (29 per 1,000 deliveries).

Poor, white women on public assistance were the ones most likely to be using amphetamine and opioids, the researchers found.

In addition to using amphetamine and opioids, many of these women are also using marijuana and tobacco, said Dr. Rahul Gupta, chief medical and health officer at the March of Dimes.

"It's very troubling that of all the times in the lifecycle of an individual during pregnancy, women who are using opioids are also using tobacco," he said. "That almost seals the fate of the infant, as well as the health of the mother and the ability of the mother to take care of the child," Gupta said.

The report was published Nov. 29 in the American Journal of Public Health

Full article here

Neonatal Abstinence Syndrome: Stringent Weaning Protocol Best

Lara C. Pullen, PhD

July 29, 2014

Use of a stringent protocol to treat neonatal narcotic abstinence syndrome (NAS) reduces the duration of opioid exposure as well as the length of hospital stay, according to a new study. The benefits of a stringent protocol are significant, regardless of the opioid used for treatment.

NAS is increasing in prevalence in the United States, and yet there is currently no consensus with regard to the best treatment drug or best taper strategy for NAS management. The study advances medical understanding of the "best practice" for NAS management.

Eric S. Hall, PhD, from the Prenatal Institute at Cincinnati Children's Hospital in Ohio, and colleagues present the results of their cohort analysis in an article July 28 in Pediatrics. The multicenter cohort includes charted data from 547 pharmacologically treated infants and is larger than any other previously published study or meta-analysis.

"Our study identified key differences in NAS management strategies that translated into shorter opioid exposures and reduced length of hospital stay. Results indicate that the use of a stringent weaning protocol, rather than the particular opioid chosen for treatment, was the most important predictor of length of hospital stay and duration of opioid treatment,” the authors write.

“Consistent with previous literature describing improvements in pediatric outcomes through standardization of care, study results suggest that the greatest impact on outcomes is achieved through implementation and adherence to a formalized NAS treatment protocol with agreed-upon starting doses, explicit instruction about dose escalation, and strict weaning parameters," the authors explain.

The study included only infants who required opioid therapy (417 managed with an established weaning protocol and 130 managed without an established weaning protocol). After the researchers accounted for hospital variation, infants who received protocol-based weans had a significantly shorter duration of opioid treatment (17.7 vs 32.1 days; P < .0001) and shorter hospital stay (22.7 vs 32.1 days; P = .004).

Among those who received protocol-based weaning, the duration of opioid treatment and length of stay were no different in infants treated with morphine compared with those treated with methadone.

When the authors analyzed the data from patients who were treated with phenobarbital, they found a longer duration of phenobarbital administration in patients treated with morphine compared with those treated with methadone (P ≤ .002).

The protocol-driven wean described in the current study has the advantage of reducing the length of drug treatment. Such a reduction will likely improve patient safety. In addition, a stringent protocol should reduce length of hospitalization, and therefore reduce cost of care for management of NAS.