Growing together: Optimization of care through quality improvement for the mother/infant dyad affected by perinatal opioid use.

The care of the dyad affected by opioid use disorder (OUD) requires a multi-disciplinary approach that can be challenging for institutions to develop and maintain. However, over the years, many institutions have developed quality improvement (QI) initiatives aimed at improving outcomes for the mother, baby, and family. Over time, QI efforts targeting OUD in the perinatal period have evolved from focusing separately on the mother and baby to efforts addressing care of the dyad and family during pregnancy, delivery, and postpartum. Here, we review recent and impactful QI initiatives that serve as examples of work improving outcomes for this population. Further, we advocate that this work be done through a racial equity lens, given ongoing inequities in the care of particularly non-white populations with substance use disorders. Through QI frameworks, even small interventions can result in meaningful changes to the care of babies and families and improved outcomes.

Prenatal opioid exposure by likelihood of exposure and risk to prenatal development: Medicaid-covered births in Wisconsin, 2010-2019.

Prenatal opioid exposure is an established public health problem, in particular among Medicaid-covered births. Yet, existing prevalence rates are plausibly underestimated. We leverage extensive linked longitudinal administrative data for all Medicaid-covered live births in Wisconsin from 2010 to 2019 to estimate a range of prevalence rates using an innovative strategy that jointly accounts for both likelihood of exposure and potential risk to prenatal development. We find that 20.8% of infants may have been prenatally exposed to opioids, with 1.7% diagnosed with neonatal abstinence syndrome and an additional 1.2% having a high combined likelihood of exposure and potential risk to prenatal development, 2.6% a moderate combined likelihood and risk, and 15.3% a low or uncertain combined likelihood and risk. We assess improvements in prevalence estimates based on our nuanced classification relative to those of prior studies. Our strategy could be broadly used to quantify the scope of the opioid crisis for pregnant populations, target interventions, and promote child health and development.

Transitioning Care Approach for Neonatal Opioid Withdrawal Syndrome and Neonatal Abstinence Syndrome.

The increase in substance use during pregnancy results in a higher incidence of neonatal abstinence syndrome/neonatal opioid withdrawal syndrome (NAS/NOWS), straining health care and social systems and creating an economic burden. There is a paradigm shift in transitioning the care approach for NAS/NOWS from a medical model of care to a family-centered individualized non-pharmacological care approach with non-pharmacological interventions as the first line of treatment. Supporting families after birth with a nurturing environment and providing them with a toolbox of non-pharmacological interventions prepares them for the transition from hospital to home.

Neonatal Abstinence Syndrome/Neonatal Opioid Withdrawal Syndrome: An Ecological View of Non-Pharmacologic Interventions for Feeding Success.

The number of infants diagnosed with neonatal abstinence syndrome (NAS) or neonatal opioid withdrawal syndrome (NOWS) has increased. The expression of NAS/NOWS symptoms differs and typically begins within the first few days of life, considered a critical period for feeding skill establishment, nourishment, and attachment. Non-pharmacologic interventions may be deployed to reduce or eliminate the need for replacement opioids while targeting outcomes like feeding dysfunction. Critical care providers can benefit from a structured examination of disordered feeding experiences to inform their selection of non-pharmacologic interventions. This structure can be provided using the Ecology of Human Performance model.

Comparison of the effect of phenobarbital & levetiracetam in the treatment of neonatal abstinence syndrome (NAS) as adjuvant treatment in neonates admitted to the neonatal intensive care unit: a randomized clinical trial.

BACKGROUND: Infants who are born from mothers with substance use disorder might suffer from neonatal abstinence syndrome (NAS) and need treatment with medicines. One of these medicines is phenobarbital, which may cause side effects in long-term consumption. Alternative drugs can be used to reduce these side effects. This study seeks the comparison of the effects of phenobarbital & levetiracetam as adjuvant therapy in neonatal abstinence syndrome. METHODS: This randomized clinical trial was performed in one year from May 2021 until May 2022. The neonates who were born from mothers with substance use disorder and had neonatal abstinence syndrome in Afzalipoor Hospital of Kerman were studied. The treatment started with morphine initially and every four hours the infants were checked. The infants who were diagnosed with uncontrolled symptoms After obtaining informed consent from the parents were randomly divided into two groups and treated with secondary drugs, either phenobarbital or levetiracetam. RESULTS: Based on the obtained results, it was clear that there was no significant difference between the hospitalization time of the two infant groups under therapy (phenobarbital: 18.59 days versus Levetiracetam 18.24 days) (P-value = 0.512). Also, there was no significant difference between both groups in terms of the frequency of re-hospitalization during the first week after discharge, the occurrence of complications, and third treatment line prescription (P-value = 0.644). CONCLUSIONS: Based on the obtained results, like hospitalization duration time (P-value = 0.512) it seems that levetiracetam can be used to substitute phenobarbital in treating neonatal abstinence syndrome. TRIAL REGISTRATION: The current study has been registered in the Iran registry of clinical trials website (fa.irct.ir) on the date 25/2/2022 with registration no. IRCT20211218053444N2.

Weaning buprenorphine in pregnant patients.

OBJECTIVE: Evaluate maternal and neonatal outcomes after buprenorphine wean compared to patients maintained on buprenorphine throughout pregnancy. METHODS: Prospective cohort study of pregnant patients with opioid use disorder enrolled in a multidisciplinary treatment program between 2015 and 2022. All patients were offered Medications to treat Opioid Use Disorder (MOUD) primarily with buprenorphine. Patients had at least 2 prenatal visits and negative urine drug tests (UDT) prior to weaning. The experimental group underwent a buprenorphine wean greater than 20% of their baseline dose. The control group was maintained on buprenorphine throughout the pregnancy. Relapse was defined as patient reported use or positive UDT during weekly assessments. Mass spectrophotometer was used for detection of drugs in samples. Fisher's exact tests were used to compare outcomes in weaned and control groups. RESULTS: 334 of 456 (73%) patients were treated with buprenorphine during pregnancy, with 39 in the experimental group and 295 in the control group. The mean dose for buprenorphine was similar between the groups (wean: 10.6 mg ± 5.6 vs. control: 10.3 mg ± 4.6, p = 0.76) but was significantly lower at delivery (wean: 4.4 ± 4.6 mg vs. control: 13.0 ± 4.7, p < 0.0001). Mean gestational age at initiation of the buprenorphine wean was 22.7 weeks. 10 of 39 (26%) who weaned were able to completely discontinue buprenorphine prior to delivery. Demographic data was similar between the groups, including overdose history. Overdose history at time of enrollment had a higher trend in the non-weaning group. neonatal opioid withdrawal syndrome (NOWS) treatment was significantly lower in the wean group (23 vs. 47%, p = 0.006), as was highest Finnegan score (9.6 ± 4.5 vs. 12.3 ± 4.0, p = 0.0003). Birthweight percentile was significantly higher in the wean group (44.3 ± 29.9 vs. 34.8 ± 24.4, p = 0.03). Gestational age at delivery, mode of delivery, and complications (HTN, DM, preterm labor, or short cervix) at delivery did not significantly differ between the groups. CONCLUSION: Despite counseling to stay on buprenorphine, there are patients who desire to wean. The NOWS rate in the weaned cohort was significantly lower than the controls with no observed increase in maternal or neonatal morbidity. There were no maternal overdoses or deaths during the pregnancy. Larger studies are needed to evaluate this approach.

Evaluating a web-based training curriculum for disseminating best practices for the care of newborns with neonatal opioid withdrawal syndrome in a rural hospital, the NOWS-NM Program.

BACKGROUND: The incidence of neonatal opiate withdrawal syndrome (NOWS) in the US has grown dramatically over the past two decades. Many rural hospitals not equipped to manage these patients transfer them to hospitals in bigger cities. METHODS: We created a curriculum, the NOWS-NM Program, a web-based curriculum training in best practices. To evaluate the curriculum, we conducted pre- and post-surveys of NOWS knowledge, attitudes, and care practices, plus post-curriculum interviews and focus groups. RESULTS: Fourteen participants completed both pre- and post-curriculum surveys. They indicated an increase in knowledge and care practices. A small number of respondents expressed negative attitudes about parents of infants with NOWS at pre-test, the training curriculum appeared to have no impact on such attitudes at post-test. Sixteen participants participated in focus groups or interviews. Qualitative data reinforced the positive quantitative results and contradicted the negative survey results, respondents reported that the program did reduce stigma and improve provider/staff interactions with patients. CONCLUSIONS: This curriculum demonstrated positive impacts on NOWS knowledge and care practices. Incorporating focus on core concepts of trauma-informed care and self-regulation in future iterations of the curriculum may strengthen the opportunity to change attitudes and address the needs expressed by participants and improve care of families and babies with NOWS.

Neonatal Abstinence Syndrome and Corresponding Pharmacotherapy Approaches from 2 University-affiliated Neonatal Intensive Care Units in Puerto Rico (2018-2020).

OBJECTIVE: Neonatal abstinence syndrome (NAS) is a set of drug withdrawal symptoms suffered by neonates exposed to drugs in utero. Several studies have widely described NAS incidence and treatment approach; however, little is known regarding the incidence and manifestations of this disease in Puerto Rico (PR). The principal aim of this study was to describe NAS incidence in the neonatal units of hospitals affiliated with the University of PR in terms of occurrence, clinical manifestations, and treatment approaches. METHODS: Our study evaluated the medical records of NAS babies diagnosed from 2018 through 2020 at 2 hospitals affiliated with the University of PR Medical Sciences Campus. Descriptive and inferential statistics were employed to analyze trends. RESULTS: We identified 12 neonates diagnosed with NAS, 5 with low birthweights (<2500 g); for a NAS incidence of 2 cases per 1000 admitted for the 3 years of recollected data. The urine toxicology results revealed that 9 had experienced intrauterine polydrug exposure. Phenobarbital loading dose were determined on the day of diagnosis (indicated by Finnegan score). The first manifestation of NAS symptoms varied: 8 neonates showed symptoms within 48 hours after birth, whereas 4 had withdrawal symptoms within 72-120 hours of their births. Differences between dosing practices and guidelines were observed, ranging from a 0.69% to a 25% difference during treatment initiation. CONCLUSION: Further research on the incidence of NAS in PR (national level) is needed for a deeper understanding that we hope will lead to the development of enhanced treatment protocols in PR.

COVID-19 Pandemic-Related Changes in Rates of Neonatal Abstinence Syndrome.

This cross-sectional study examines COVID-19 pandemic­related changes in rates of neonatal abstinence syndrome (NAS) and whether infants in urban or rural areas and those with low socioeconomic status were disproportionately affected.

Popular media misinformation on neonatal abstinence syndrome, 2015-2021.

BACKGROUND: As the overdose crisis unfolded, narratives mischaracterizing neonatal abstinence syndrome (NAS) as "addicted babies" with echoes to the "crack babies" panic proliferated in mainstream media. his study examines NAS misinformation dynamics and characteristics over a seven-year period. METHODS: Based on a comprehensive query, Media Cloud was used to compile mainstream media content relating to NAS between 2015 and 2021. Articles were redundantly coded on key parameters such as speakers represented, publication source, and scientific accuracy. RESULTS: Of the 348 articles meeting search criteria, 264 (76 %) featured misinformed narratives, 70 (20 %) featured informed narratives, and 14 (4 %) featured both informed and misinformed content. Most frequent misinformation elements related to misrepresentation of babies as "addicted" at birth and exaggeration of NAS symptomatology and long-term harms. Least represented voices were people most affected, with just 11 (2 %) featuring mothers who used opioids prepartum. DISCUSSION: Since misinformation contributes to punitive legal responses and harms patient care, efforts to prevent, monitor, and address inaccurate and stigmatizing narratives are essential to improving policy and practice.

Cost of Care for Newborns With Neonatal Abstinence Syndrome in a State Medicaid Program.

Importance: Neonatal abstinence syndrome (NAS) is a medical condition among neonates experiencing substance withdrawal due to the mother's substance use during pregnancy. While previous studies suggest that the overall incidence and annual costs of NAS are increasing, to date, the long-term costs have yet to be demonstrated in Medicaid populations. Objective: To examine the demographic differences and long-term costs of care for neonates diagnosed with vs not diagnosed with NAS. Design, Setting, and Participants: This cohort study used claims data from the Alabama Medicaid Agency for neonates born to Medicaid-eligible mothers between January 1, 2010, and December 31, 2020. Data were analyzed in June 2022. Exposure: A diagnosis of NAS within 30 days of birth. Main Outcomes and Measures: Rate of NAS by demographic and birth characteristics, long-term costs attributable to NAS status and demographic and birth characteristics, and distribution of this expenditure over the enrollment period. Results: A total of 346 259 neonates with Medicaid eligibility were born during the study period (mean [SD] gestational age, 38.4 [2.2] weeks; 50.5%, male), 4027 (1.2%) of whom had an NAS diagnosis within 30 days of birth. A larger percentage of neonates with an NAS diagnosis were male (52.7%) than in the group without NAS (50.5%). Neonates with NAS also weighed less at birth (mean difference, -212.0 g; 95% CI, -231.1 to -192.8 g) and had older mothers (mean difference, 3.4 years; 95% CI, 2.6-4.2 years). An NAS diagnosis had an estimated additional cost of $17 921 (95% CI, $14 830-$21 012) over the enrollment period, and this cost was not evenly distributed over that period. Conclusions and Relevance: In this cohort study of neonates born into the Alabama Medicaid population, those with an NAS diagnosis had a different demographic profile and a higher cost to state Medicaid agencies than those without NAS. These findings warrant further effort to reduce the occurrence of NAS.

Maternal opioid use disorder and infant mortality in Wisconsin, United States, 2010-2018.

OBJECTIVE: The difference in infant health outcomes by maternal opioid use disorder (OUD) status is understudied. We measured the association between maternal OUD during pregnancy and infant mortality and investigated whether this association differs by infant neonatal opioid withdrawal syndrome (NOWS) or maternal receipt of medication for OUD (MOUD) during pregnancy. METHODS: We sampled 204,543 Medicaid-paid births from Wisconsin, United States (2010-2018). The primary exposure was any maternal OUD during pregnancy. We also stratified this exposure on NOWS diagnosis (no OUD; OUD without NOWS; OUD with NOWS) and on maternal MOUD receipt (no OUD; OUD without MOUD; OUD with <90 consecutive days of MOUD; OUD with 90+ consecutive days of MOUD). Our outcome was infant mortality (death at age <365 days). Demographic-adjusted logistic regressions measured associations with odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Maternal OUD was associated with increased odds of infant mortality (OR 1.43; 95% CI 1.02-2.02). After excluding infants who died <5 days post-birth (i.e., before the clinical presentation of NOWS), regression estimates of infant mortality did not significantly differ by NOWS diagnosis. Likewise, regression estimates did not significantly differ by maternal MOUD receipt in the full sample. CONCLUSIONS: Maternal OUD is associated with an elevated risk of infant mortality without evidence of modification by NOWS nor by maternal MOUD treatment. Future research should investigate potential mechanisms linking maternal OUD, NOWS, MOUD treatment, and infant mortality to better inform clinical intervention.

Prenatal Opioid Exposure and Immune-Related Conditions in Children.

Importance: Prenatal opioid exposure (POE) may alter with fetal development of the immune system, which may influence long-term health and susceptibility to immune-related conditions. Objective: To compare the risk of hospitalization and emergency department presentation for immune-related conditions in children with and without POE. Design, Setting, and Participants: This retrospective, population-based cohort study used linked administrative health records of all children born in Western Australia between January 1, 2003, and December 31, 2018 (N = 401 462). Exposure: Prenatal exposure to prescription opioids (overall and by trimester), neonatal abstinence syndrome diagnosis, and opioid indication (pain or opioid use disorder [OUD]). Main Outcomes and Measures: The main outcome was hospital admissions and emergency department presentations during which a child was diagnosed with an immune-related condition, including infections, conditions associated with an overactive immune system (eg, asthma, eczema, and allergy and anaphylaxis), and autoimmune diseases diagnosed before age 5 years or June 30, 2020. Data were analyzed between August 30, 2022, and February 27, 2023. Results: Neonates with POE (1656 [0.4%]; mean [SD] gestational age, 37.7 [2.1] weeks; 836 females [50.5%]; 820 males [49.5%]) were more likely to be born preterm, have low birth weight for gestational age, and be coexposed to cigarette smoke compared with nonexposed neonates. Perinatal opioid exposure was associated with an increased risk of perinatal infection (adjusted odds ratio [AOR], 1.62; 95% CI, 1.38-1.90) and eczema and dermatitis (AOR, 11.91; 95% CI, 9.84-14.41) compared with nonexposure. Neonatal abstinence syndrome was also associated with both conditions (AOR, 2.91 [95% CI, 2.36-3.57] and 31.11 [95% CI, 24.64-39.28], respectively). Prenatal opioid exposure was also associated with an increased risk of childhood asthma (adjusted hazard ratio [AHR], 1.44; 95% CI, 1.16-1.79), but not allergies and anaphylaxis. It was also associated with an increased risk of childhood eczema and dermatitis, but only in children with POE from opioids used to treat OUD (AHR, 1.47; 95% CI, 1.08-1.99) rather than pain. In contrast, POE from opioids used for pain was associated with an increased risk of infection (AHR, 1.44; 95% CI, 1.32-1.58), but POE to opioids used to treat OUD was not. Autoimmune conditions were rare and were not observed to be associated with POE. Conclusions and Relevance: In this cohort study, POE was associated with an increased risk of infection, eczema and dermatitis, and asthma, but not allergies and anaphylaxis or autoimmune conditions. These findings highlight the importance of further study of opioid-induced immune changes during pregnancy, the potential impact on long-term health in exposed children, and the mechanisms of opioid-induced immune dysregulation.

Advances in the Care of Infants With Prenatal Opioid Exposure and Neonatal Opioid Withdrawal Syndrome.

A significant number of advances have been made in the last 5 years with respect to the identification, diagnosis, assessment, and management of infants with prenatal opioid exposure and neonatal opioid withdrawal syndrome (NOWS) from birth to early childhood. The primary objective of this review is to summarize major advances that will inform the clinical management of opioid-exposed newborns and provide an overview of NOWS care to promote the implementation of best practices. First, advances with respect to standardizing the clinical diagnosis of NOWS will be reviewed. Second, the most commonly used assessment strategies are discussed, with a focus on presenting new quality improvement and clinical trial data surrounding the use of the new function-based assessment Eat, Sleep, and Console approach. Third, both nonpharmacologic and pharmacologic treatment modalities are reviewed, highlighting clinical trials that have compared the use of higher calorie and low lactose formula, vibrating crib mattresses, morphine compared with methadone, buprenorphine compared with morphine or methadone, the use of ondansetron as a medication to prevent the need for NOWS opioid pharmacologic treatment, and the introduction of symptom-triggered dosing compared with scheduled dosing. Fourth, maternal, infant, environmental, and genetic factors that have been found to be associated with NOWS severity are highlighted. Finally, emerging recommendations on postdelivery hospitalization follow-up and developmental surveillance are presented, along with highlighting ongoing and needed areas of research to promote infant and family well-being for families impacted by opioid use.

Neonatal Opioid Withdrawal Syndrome Following Prenatal Use of Supplements Containing Tianeptine.

Tianeptine is an opioid receptor agonist that is prescribed as an antidepressant in many countries. In the United States, tianeptine is not approved for medical use because of its potential for abuse and addiction. Nonetheless, products containing tianeptine are easily obtainable and are marketed as dietary supplements. There are increasing reports of adverse effects and fatal toxicities resulting from tianeptine use among adolescents and adults. This emerging public health threat could escalate the opioid epidemic and drive increased newborn perinatal exposure. The impact of in utero exposure to tianeptine has not been studied, and to our knowledge, the authors of only 1 report have documented possible neonatal effects. Here, we describe a case of chronic prenatal exposure to tianeptine in the setting of maternal dependence on dietary supplements. This infant developed signs of severe withdrawal shortly after birth that were refractory to treatment with oral phenobarbital but responded to subsequent oral morphine therapy. On further questioning, the mother revealed the use of a tianeptine-containing dietary supplement. We did not perform confirmatory toxicology testing because tianeptine is not assayed by usual urine drug screening tests. For infants with clinical signs of opioid withdrawal without known etiology, we suggest that the maternal interview should inquire about the use of neurotropic over-the-counter drugs.

Considerations and Determinants of Discharge Decisions among Prenatal Substance Exposed Infants.

Limited research has examined a comprehensive set of predictors when evaluating discharge placement decisions for infants exposed to substances prenatally. Using a previously validated medical record data extraction tool, the current study examined prenatal substance exposure, infant intervention (i.e., pharmacologic, or non-pharmacologic), and demographic factors (e.g., race and ethnicity and rurality) as predictors of associations with discharge placement in a sample from a resource-poor state (N = 136; 69.9% Non-Hispanic White). Latent class analysis (LCA) was used to examine whether different classes emerged and how classes were differentially related to discharge placement decisions. Logistic regressions were used to determine whether each predictor was uniquely associated with placement decisions. Results of the LCA yielded a two-class solution comprised of (1) a Low Withdrawal Risk class, characterized by prenatal exposure to substances with low risk for neonatal abstinence syndrome (NAS) and non-pharmacologic intervention, and (2) a High Withdrawal Risk class, characterized by a high risk of NAS and pharmacologic intervention. Classes were not related to discharge placement decisions. Logistic regressions demonstrated that meth/amphetamine use during pregnancy was associated with greater odds of out of home placement above other substance types. Future research should replicate and continue examining the clinical utility of these classes.

Inclusion of Sex and Gender Differences in U.S. State Action Plans for Opioid Use and Opioid Use Disorder.

Background: States have developed action plans to address the "opioid crisis" over the past several years. While sex- and gender-based differences have been identified in complications of opioid use, risks of addiction to opioids, barriers to treatment of opioid use disorder, and associated stigma, it is unknown if or to what extent opioid plans consider or account for these differences. The objectives of this study were to analyze U.S. state opioid action plans and their inclusion of sex- and gender-specific concerns. Methods: A content analysis of 49 state plans was conducted in June 2020, assessing their inclusion of 14 variables covering provider education, pregnancy-related, and sex- or gender-based differences in opioid addiction and treatment. Results: Neonatal opioid withdrawal syndrome was the most common variable, noted in 57% of plans. Only 14% included pregnancy-related stigma, and 4% identified gender-specific stigma. Contraceptives and family-planning were included in 12% and 10% of plans, respectively. Two states included more than half of the variables and five plans made no mention of sex or gender differences. Conclusions: Few state plans contained sex- or gender-specific information, and those that did focused almost exclusively on childbearing, excluding other unique considerations of opioid-using-women of all ages. The results of this study could improve the care of women using opioids by informing the strategies of state agencies and impacting legislative efforts for prevention initiatives, substance use disorder treatment, and law enforcement programs.

Trends in Neonatal Opioid Withdrawal Syndrome and Opioid Exposure Diagnoses Among Infants With Private Health Insurance, 2016-2021: Introduction of the P04.14 ICD-10-CM Code.

OBJECTIVE: The opioid epidemic has led to a surge in diagnoses of neonatal opioid withdrawal syndrome (NOWS). Many states track the incidence of NOWS by using the P96.1 International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) code for "neonatal withdrawal symptoms from maternal use of drugs of addiction." In October 2018, an ICD-10-CM code for neonatal opioid exposure (P04.14) was introduced. This code can be used when an infant is exposed to opioids in utero but does not have clinically significant withdrawal symptoms. We analyzed the effect of the P04.14 code on the incidence rate of NOWS (P96.1) and "other" neonatal drug exposure diagnoses (P04.49). METHODS: We used private health insurance data collected for infants in the United States from the first quarter of 2016 through the third quarter of 2021 to describe incidence rates for each code over time and examine absolute and percentage changes before and after the introduction of code P04.14. RESULTS: The exclusive use of code P96.1 declined from an incidence rate per 1000 births of 1.08 in 2016-2018 to 0.70 in 2019-2021, a -35.7% (95% CI, -47.6% to -23.8%) reduction. Use of code P04.49 only declined from an incidence rate of 2.34 in 2016-2018 to 1.64 in 2019-2021, a -30.0% (95% CI, -36.4% to -23.7%) reduction. Use of multiple codes during the course of treatment increased from an average incidence per 1000 births of 0.56 in 2016-2018 to 0.79 in 2019-2021, a 45.5% (95% CI, 24.8%-66.1%) increase. CONCLUSION: The introduction of ICD-10-CM code P04.14 altered the use of other neonatal opioid exposure codes. The use of multiple codes increased, indicating that some ambiguity may exist about which ICD-10-CM code is most appropriate for a given set of symptoms.

Impaired vision in children prenatally exposed to methadone: an observational cohort study.

BACKGROUND/OBJECTIVES: To examine prevalence of failed visual assessment at 8-10 years in children born to methadone-maintained opioid dependent (MMOD) mothers and relate this to known in utero substance exposure. SUBJECTS/METHODS: Follow up of observational cohort study of methadone-exposed and comparison children matched for birthweight, gestation and postcode of residence at birth. Participants were 144 children (98 exposed, 46 comparison). Prenatal drug exposure was previously established via comprehensive maternal and neonatal toxicology. Children were invited to attend for visual assessment and casenotes were reviewed. Presence of acuity poorer than 0.2 logMAR, strabismus, nystagmus and/or impaired stereovision constituted a 'fail'. Fail rates were compared between methadone-exposed and comparison children after adjusting for known confounding variables. RESULTS: 33 children attended in person: data were also derived from casenote review for all children. After controlling for maternal reported tobacco use, methadone-exposed children were more likely to have a visual 'fail' outcome, adjusted odds ratio 2.6, 95% CI 1.1-6.2; adjusted relative risk 1.8 (95% CI 1.1-3.4). Visual 'fail' outcome rates did not differ between methadone-exposed children who had (n = 47) or had not (n = 51) received pharmacological treatment for neonatal abstinence/opioid withdrawal syndrome (NAS/NOWS); fail rate 62% vs 53% (95% CI of difference-11-27%). CONCLUSIONS: Children born to MMOD mothers are almost twice as likely as unexposed peers to have significant visual abnormalities at primary school age. Prenatal methadone exposure should be considered in the differential diagnosis of nystagmus. Findings support visual assessment prior to school entry for children with any history of prenatal opioid exposure. TRIAL REGISTRATION: The study was prospectively registered on ClinicalTrials.gov (NCT03603301), https://clinicaltrials.gov/ct2/show/NCT03603301 .

Transplacental methadone exposure and risk of Neonatal Opioid Withdrawal Syndrome.

STUDY OBJECTIVE: Neonatal opioid withdrawal syndrome (NOWS) is a condition that often occurs in neonates born to mothers who received methadone treatment for opioid use disorder during pregnancy. Early identification and treatment of infants at risk of NOWS may improve clinical outcomes. The purpose of this study was to evaluate whether maternal and umbilical cord plasma concentrations of methadone and its metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), could predict the need for NOWS treatment. DESIGN: Single-center prospective study. SETTING: University of Michigan Neonatal Intensive Care Unit. PATIENTS: The study included 11 opioid-dependent mother-infant dyads, where the mothers were treated with methadone at 34 weeks' gestation or later. INTERVENTION: Maternal and cord blood samples were collected from the study participants. MEASUREMENTS AND MAIN RESULTS: Maternal and cord plasma concentrations of methadone and EDDP were determined. Six out of the 11 infants required treatment for NOWS. Maternal methadone plasma concentrations were comparable between infants requiring and not requiring NOWS treatment (329.1 ± 229.7 ng/mL vs. 413.2 ± 329.8 ng/mL). However, the average cord plasma methadone concentration in infants who did not require NOWS treatment was 2.9-fold higher than in those who required the treatment (120.0 ± 88.6 ng/mL vs. 40.9 ± 24.4 ng/mL), although the difference was not statistically significant. The ratios of maternal-to-cord methadone plasma concentrations were significantly higher in patients who required treatment for NOWS compared with those who did not (7.7 ± 1.9 vs. 3.5 ± 1.6, p = 0.003). Maternal and cord plasma EDDP concentrations and the maternal-to-cord plasma EDDP concentration ratios did not differ between patients who required and did not require treatment for NOWS. CONCLUSIONS: The results suggest that methadone permeability across the blood-placental barrier may affect in utero exposure to methadone, and the maternal-to-cord methadone plasma concentration ratio could be a potential biomarker for predicting the need for NOWS treatment.