Gestational buprenorphine-naloxone exposure and fetal neurobehavior.

BACKGROUND: Buprenorphine-naloxone treatment may confer substantial benefits for the treatment of opioid use disorder (OUD) during pregnancy including lower risk for overdose/death, less diversion potential and reduced use of other substances. Treatment may also result in less severe Neonatal Abstinence Syndrome (NAS), but little is known about the effects of this medication on fetal neurodevelopment. METHODS: The purpose of the current study is to evaluate neurobehaviors among fetuses exposed to buprenorphine-naloxone at four time points over the second and third trimesters of gestation in pregnant women with OUD on buprenorphine-naloxone therapy. Sixty minutes of continuous fetal monitoring via fetal actocardiograph with a single wide array abdominal transducer took place at times of peak and trough buprenorphine-naloxone levels in 24 pregnant women. Data collection, which included measures of fetal heart rate and motor activity, was conducted between 24 and 36 weeks gestation, with the majority (84.6%) monitored at two or more gestational ages. Medication dose and other substance use was monitored throughout the study and infant NAS severity was assessed. RESULTS: Fetal heart rate (FHR), FHR variability, accelerations in FHR, and motor activity were suppressed when buprenorphine-naloxone levels were at pharmacologic peak as compared to trough concentrations at 36 weeks, but not earlier in gestation. Maternal medication dose was unrelated to infant NAS severity. CONCLUSIONS: Conclusions: There were evident subclinical fetal neurophysiological responses at times of peak maternal buprenorphine/naloxone levels in later gestation, similar to those previously described for buprenorphine only. Further studies evaluating the effects of these changes in fetal neurobehaviors on the longer-term infant development are needed.

Women Living with Human Immunodeficiency Virus with Intended and Unintended Pregnancy: Characteristics and Patient Outcomes.

Background: Rates of unintended pregnancy may be higher in women living with human immunodeficiency virus (WLWH) than in the general population, and it is unclear how populations of WLWH with intended and unintended pregnancy differ. We compared baseline characteristics and outcomes between WLWH with intended and unintended pregnancy. Materials and Methods: We conducted a retrospective analysis of WLWH enrolled in a human immunodeficiency virus (HIV) and Pregnancy clinic from 2003 to 2014. Data were analyzed using descriptive statistics, chi-square test, Student's t-test, one-way analysis of variance, and linear and logistic regression analysis. Two-tailed p-value <0.05 was considered significant. The study was approved by the Johns Hopkins University School of Medicine Institutional Review Board. Results: Sixty-nine (27.1%) of 255 women reported an intended pregnancy. Women with intended pregnancy (WWIP) were more likely to be older, White, married, privately insured, and college educated. WWIP were less likely to use tobacco (15.9% vs. 44.2%, p < 0.001), alcohol (2.9% vs. 11.1%, p = 0.041), opiates (0.0% vs. 19.3%, p < 0.001), or cocaine (2.9% vs. 21.0%, p < 0.001) during pregnancy, more likely to disclose their HIV status to the father of the baby by delivery (100.0% vs. 15.8%, p < 0.001), and more likely to receive less effective contraception at delivery (condoms 14.9% vs. 4.8%, p = 0.024; sterilization 11.9% vs. 22.1%, p = 0.028). In multivariate regression analysis, pregnancy intendedness was an important predictor of nondetectable viral load at pregnancy entry but not at delivery. Conclusions: WLWH vary in their baseline characteristics and pregnancy outcomes depending on pregnancy intendedness, highlighting the need to improve pregnancy timing in WLWH and intensify interventions for women with unintended pregnancy.

Pregnancy in an Urban Cohort of Adolescents Living with Human Immunodeficiency Virus: Characteristics and Outcomes in Comparison to Adults.

Adolescents (13-24 years of age) account for more than one-fifth of new HIV diagnoses yearly, and the United States has one of the highest rates of adolescent pregnancy among high resource countries. However, there is limited information on the characteristics and outcomes of adolescents living with HIV (ALWHIV) during pregnancy and differences with pregnancy in adults living with HIV. We performed a retrospective cohort study to compare demographic characteristics, HIV viral suppression, and pregnancy outcomes in adolescents (n = 90) as compared with adults (n = 250) in an urban HIV pregnancy clinic from 2003 to 2015. Seventy-one women overall were diagnosed with HIV during pregnancy (adolescents, 25/90; adults, 46/250). One-fifth of adolescents acquired HIV perinatally. Adolescents were more likely than adults to have unintended pregnancy (83.6% vs. 68.7%, p = 0.016) and were less likely to be virally suppressed at delivery (50.0% vs. 69.7% overall, p = 0.001; 48.0% vs. 78.2% in postuniversal antiretroviral therapy era, p = 0.007%). Over one-third of adolescents reported a history of any illicit substance use, and adolescents were more likely than adults to use marijuana during pregnancy (29.2% vs. 16.9%, p = 0.013). Adolescents were less likely to experience preterm labor (11.0% vs. 24.1%, p = 0.012) or preterm premature rupture of membranes (3.7% vs. 16.7%, p = 0.003). There was one case of maternal-fetal transmission, which occurred in an adult pregnancy. Despite the high rate of unintended pregnancy, one-third of adolescents were discharged without an identified contraception plan. We identify several opportunities for intervention to improve reproductive health outcomes in ALWHIV.

Association of Patient Sex and Pregnancy Status With Naloxone Administration During Emergency Department Visits.

OBJECTIVE: To evaluate the association of sex and pregnancy status with rates of naloxone administration during opioid overdose-related emergency department (ED) visits by using the Nationwide Emergency Department Sample. METHODS: A retrospective cohort study was conducted using the Nationwide Emergency Department Sample 2016 and 2017 data sets. Eligible records included men and women, 15-49 years of age, with an opioid overdose-related ED visit; records for women were stratified by pregnancy status (International Classification of Diseases, Tenth Revision O codes). A multivariable logistic regression model was used to assess the primary outcome of naloxone administration (Current Procedural Terminology code: J2310). Secondary outcomes included subsequent admission and mortality. A subgroup analysis compared pregnant women who did receive naloxone compared with those who did not receive naloxone. RESULTS: Records from 443,714 men, 304,364 nonpregnant women, and 25,056 pregnant women were included. Nonpregnant women had lower odds for naloxone administration (1.70% vs 2.10%; adjusted odds ratio [aOR] 0.86 [95% CI 0.83-0.89]) and mortality (2.21% vs 2.99%; aOR 0.71 [95% CI 0.69-0.73]) but higher odds of subsequent admission (30.22% vs 27.18%; aOR 1.04 [95% CI 1.03-1.06]) compared with men. Pregnant women had lower odds for naloxone administration (0.27% vs 1.70%; aOR 0.16 [95% CI 0.13-0.21]) and mortality (0.41% vs 2.21%; aOR 0.28 [95% CI 0.23-0.35]) but higher odds of subsequent admission (40.50% vs 30.22%; aOR 2.04 [95% CI 2.00-2.10]) compared with nonpregnant women. Pregnant women who received naloxone had higher odds of mortality (14% vs 0.39%; aOR 6.30 [95% CI 2.11-18.78]) compared with pregnant women who did not receive naloxone. Pregnant women who did not receive naloxone were more likely to have Medicaid as their expected insurance payer, be in the lowest quartile of median household income for residence ZIP codes, and have a concurrent mental health diagnosis compared with pregnant women who did receive naloxone. CONCLUSION: Reproductive-aged women who are nonpregnant and pregnant were less likely to receive naloxone during opioid overdose-related ED visits compared with reproductive-aged men. Naloxone administration for reproductive-aged women should be prioritized in the efforts to reduce opioid- and pregnancy-related morbidity and mortality in the United States.

Prenatal opioid exposure: The next neonatal neuroinflammatory disease.

The rates of opioid use disorder during pregnancy have more than quadrupled in the last decade, resulting in numerous infants suffering exposure to opioids during the perinatal period, a critical period of central nervous system (CNS) development. Despite increasing use, the characterization and definition of the molecular and cellular mechanisms of the long-term neurodevelopmental impacts of opioid exposure commencing in utero remains incomplete. Thus, in consideration of the looming public health crisis stemming from the multitude of infants with prenatal opioid exposure entering school age, we undertook an investigation of the effects of perinatal methadone exposure in a novel preclinical model. Specifically, we examined the effects of opioids on the developing brain to elucidate mechanisms of putative neural cell injury, to identify diagnostic biomarkers and to guide clinical studies of outcome and follow-up. We hypothesized that methadone would induce a pronounced inflammatory profile in both dams and their pups, and be associated with immune system dysfunction, sustained CNS injury, and altered cognition and executive function into adulthood. This investigation was conducted using a combination of cellular, molecular, biochemical, and clinically translatable biomarker, imaging and cognitive assessment platforms. Data reveal that perinatal methadone exposure increases inflammatory cytokines in the neonatal peripheral circulation, and reprograms and primes the immune system through sustained peripheral immune hyperreactivity. In the brain, perinatal methadone exposure not only increases chemokines and cytokines throughout a crucial developmental period, but also alters microglia morphology consistent with activation, and upregulates TLR4 and MyD88 mRNA. This increase in neuroinflammation coincides with reduced myelin basic protein and altered neurofilament expression, as well as reduced structural coherence and significantly decreased fractional anisotropy on diffusion tensor imaging. In addition to this microstructural brain injury, adult rats exposed to methadone in the perinatal period have significant impairment in associative learning and executive control as assessed using touchscreen technology. Collectively, these data reveal a distinct systemic and neuroinflammatory signature associated with prenatal methadone exposure, suggestive of an altered CNS microenvironment, dysregulated developmental homeostasis, complex concurrent neural injury, and imaging and cognitive findings consistent with clinical literature. Further investigation is required to define appropriate therapies targeted at the neural injury and improve the long-term outcomes for this exceedingly vulnerable patient population.

Maternal buprenorphine treatment during pregnancy and maternal physiology.

BACKGROUND: Buprenorphine, used for opioid use disorder (OUD) treatment during pregnancy, provides unknown effects on maternal physiological activity. The primary aim of this report is to document acute effects of buprenorphine administration on indicators of maternal autonomic functioning. Effects of maternal buprenorphine dose and other substance exposures on maternal measures were examined, as were neonatal abstinence syndrome (NAS) outcomes. METHODS: Forty-nine pregnant, buprenorphine-maintained women yielded maternal physiologic information (heart rate and variability, electrodermal activity, and respiratory rate) at 24, 28, 32 and 36 weeks gestation. Monitoring at trough and peak maternal medication levels was implemented to ascertain acute physiologic effects of buprenorphine administration. RESULTS: Buprenorphine administration accelerated maternal heart rate and reduced variability at two gestational ages (24 and 36 weeks) and suppressed sympathetic (electrodermal) activation at 24, 28 and 32 weeks at times of peak maternal medication levels. Maternal autonomic parameters were unrelated to polysubstance exposure with the exception of cigarette smoking. Heavier smoking dampened maternal heart rate variability across gestation and potentiated reactivity to buprenorphine at 24 and 36 weeks. Heavier smoking was also associated with reduced electrodermal activity at 36 weeks. Buprenorphine dose was unrelated to observed effects. Larger degree of maternal heart rate reactivity to buprenorphine administration was related to more severe NAS expression. CONCLUSIONS: These findings detail the maternal autonomic response to buprenorphine administration but also illustrate the significant effect of concurrent cigarette use on maternal autonomic regulation. This suggests the importance of smoking-reduction strategies in the comprehensive, medication-assisted treatment of women with OUD.

Maternal buprenorphine treatment and fetal neurobehavioral development.

BACKGROUND: Gestational opioid use/misuse is escalating in the United States; however, little is understood about the fetal effects of medications used to treat maternal opioid use disorders. OBJECTIVE: The purpose of this study was to determine the effect of maternal buprenorphine administration on longitudinal fetal neurobehavioral development. STUDY DESIGN: Forty-nine buprenorphine-maintained women who attended a substance use disorder treatment facility with generally uncomplicated pregnancies underwent fetal monitoring for 60 minutes at times of trough and peak maternal buprenorphine levels. Data were collected at 24, 28, 32, and 36 weeks gestation. Fetal neurobehavioral indicators (ie, heart rate, motor activity, and their integration [fetal movement-fetal heart rate coupling]) were collected via an actocardiograph, digitized and quantified. Longitudinal data analysis relied on hierarchic linear modeling. RESULTS: Fetal heart rate, heart rate variability, and heart rate accelerations were significantly reduced at peak vs trough maternal buprenorphine levels. Effects were significant either by or after 28 weeks gestation and tended to intensify with advancing gestation. Fetal motor activity and fetal movement-fetal heart rate coupling were depressed from peak to trough at 36 weeks gestation. Polysubstance exposure did not significantly affect fetal neurobehavioral parameters, with the exception that fetuses of heavier smokers moved significantly less than those of lighter smokers at 36 weeks gestation. By the end of gestation, higher maternal buprenorphine dose was related to depression of baseline fetal cardiac measures at trough. CONCLUSION: Maternal buprenorphine administration has acute suppressive effects on fetal heart rate and movement, and the magnitude of these effects increases as gestation progresses. Higher dose (≥13 mg) appears to exert greater depressive effects on measures of fetal heart rate and variability. These findings should be balanced against comparisons to gestational methadone effects, relatively good outcomes of buprenorphine-exposed infants, and recognition of the benefits of medication-assisted treatment for pregnant women with opioid use disorders in optimizing pregnancy outcomes.

Association between depression and nonadherence to antiretroviral therapy in pregnant women with perinatally acquired HIV.

Women with perinatally acquired HIV (PAH) face unique psychosocial challenges due to the presence of a lifelong chronic illness and often unstable living situations. With advances in HIV treatment, an increasing number of those with PAH are reaching childbearing age and becoming pregnant. Depression may be an important and common factor that complicates both treatment and pregnancy outcomes in this group. We conducted a retrospective cohort study in pregnant patients with PAH to determine if history of depression is associated with nonadherence to antiretroviral therapy (ART). We reviewed charts of women with PAH receiving prenatal care at a single institution from March 1995 to December 2012. ART nonadherence was measured by patient self-report of any missed doses in the third trimester. Demographic, obstetric, and HIV infection characteristics of patients with a history of depression (dPAH) were compared to patients without a history of depression. Nine pregnancies among 6 dPAH women and 14 pregnancies among 12 PAH women without a history of depression were identified. None of the dPAH women reported 100% adherence to ART in the third trimester while 57% of women without a history of depression reported strict adherence (p = 0.04). The mean HIV RNA level at delivery was higher among dPAH women (17,399 vs. 2966 copies/Ml; p = 0.03) and fewer reached an undetectable HIV RNA level (<400 copies/mL) at delivery (p = 0.03). We concluded that a history of depression may contribute to poor medication adherence and treatment outcomes among pregnant women with PAH. Focused attention on diagnosis and treatment of depression in the preconception period may lead to more optimal medication adherence.

Fetal neurobehavioral effects of exposure to methadone or buprenorphine.

As part of a double-blind study of medication treatment for opioid dependence during pregnancy, 17 opioid-dependent pregnant women maintained on either buprenorphine or methadone underwent fetal monitoring at 24, 28, 32, and 36 weeks gestation. Maternal demographic information and infant outcomes did not significantly differ by medication group. Earlier in gestation (24 and 28 weeks), buprenorphine-exposed fetuses had higher levels of fetal heart rate variability, more accelerations in fetal heart rate and greater coupling between fetal heart rate and fetal movement than the methadone-exposed group (all ps < .05). Later in gestation (32 and 36 weeks), buprenorphine-exposed fetuses displayed less suppression of motor activity and longer duration of movements than the methadone-exposed group (all ps < .05). These results may have implications for the optimal treatment of the opioid-dependent pregnant woman.

Intrahepatic vein for fetal blood sampling: one center's experience.

OBJECTIVE: The objective of the study was to examine 1 center's experience with fetal blood sampling via the fetal intrahepatic vein (IHV) and cordocentesis. STUDY DESIGN: Consecutive IHV and cordocentesis procedures between July 1987 and February 2006 were compared with respect to success rates, streaming at the sampling site, nonreassuring fetal heart rate (NRFHR), or need for urgent delivery post procedure. A subanalysis of cases with fetal thrombocytopenia was performed. Data were analyzed using Fisher's exact and Student t tests. RESULTS: Two hundred ten procedures (130 IHV samplings and 110 cordocenteses) were identified. Success rates were significantly higher with IHV sampling than with cordocentesis (84.6% vs 69.1%, P = .004). Streaming from the sampling site occurred after 0.79% of IHV procedures vs 30.8% of cordocenteses (P < .0001). There was no difference between IHV and cordocentesis in the incidence of NRFHR or need for immediate delivery. Twenty-five cases of fetal thrombocytopenia (20 sampled via IHV, 5 by cordocentesis) were identified. Streaming from the sampling site occurred in 0 of 20 IHV cases vs 2 of 5 cordocentesis cases (40%) (P = .03). CONCLUSION: IHV has a significantly lower rate of streaming from the sampling site, compared with cordocentesis. Our data suggest that IHV sampling conveys a particular advantage when fetal thrombocytopenia is suspected.

Dosing adjustments in postpartum patients maintained on buprenorphine or methadone.

Scant scientific attention has been given to examining the need for agonist medication dose changes in the postpartum period. Study objectives were: 1) to determine the need for medication dose adjustments in participants stabilized on buprenorphine or methadone 3 weeks before and 4 weeks after delivery, and 2) to evaluate the need for methadone dose adjustments during the first 7 days in participants transferred from buprenorphine to methadone at 5 weeks postpartum. Participants were opioid-dependent pregnant women who had completed a randomized, double-blind, double-dummy, flexible dosing comparison of buprenorphine to methadone. Participants received a stable dose of methadone (N = 10) or buprenorphine (N = 8) before and 4 weeks after delivery. Buprenorphine-maintained participants were transferred to methadone at 5 weeks postpartum. There were no significant differences predelivery and/or postdelivery between the buprenorphine and methadone conditions in the mean ratings of dose adequacy, "liking," "hooked," and "craving" of heroin or cocaine. Patient response to the conversion from buprenorphine to methadone seems variable. Buprenorphine-maintained participants required dose changes postpartum only after they transferred to methadone. Regardless of type of medication, postpartum patients should be monitored for signs of overmedication.

Buprenorphine versus methadone in the treatment of pregnant opioid-dependent patients: effects on the neonatal abstinence syndrome.

This study was designed to compare the neonatal abstinence syndrome (NAS) in neonates of methadone and buprenorphine maintained pregnant opioid-dependent women and to provide preliminary safety and efficacy data for a larger multi-center trial. This randomized, double-blind, double-dummy, flexible dosing, parallel-group controlled trial was conducted in a comprehensive drug-treatment facility that included residential and ambulatory care. Participants were opioid-dependent pregnant women and their neonates. Treatment involved daily administration of either sublingual buprenorphine or oral methadone using flexible dosing of 4-24 mg or 20-100 mg, respectively. Primary a priori outcome measures were: (1) number of neonates treated for NAS; (2) amount of opioid agonist medication used to treat NAS; (3) length of neonatal hospitalization; and (4) peak NAS score. Two of 10 (20%) buprenorphine-exposed and 5 of 11 (45.5%) methadone-exposed neonates were treated for NAS (p=.23). Total amount of opioid-agonist medication administered to treat NAS in methadone-exposed neonates was three times greater than for buprenorphine-exposed neonates (93.1 versus 23.6; p=.13). Length of hospitalization was shorter for buprenorphine-exposed than for methadone-exposed neonates (p=.021). Peak NAS total scores did not significantly differ between groups (p=.25). Results suggest that buprenorphine is not inferior to methadone on outcome measures assessing NAS and maternal and neonatal safety when administered starting in the second trimester of pregnancy.

Randomized controlled study transitioning opioid-dependent pregnant women from short-acting morphine to buprenorphine or methadone.

This study compared the safety and withdrawal discomfort associated with transitioning pregnant opioid-dependent women from short-acting morphine onto buprenorphine or methadone under well-controlled double-blind conditions. Participants (n=18) were patients in a comprehensive treatment setting and were part of a larger randomized controlled trial comparing the neonatal abstinence syndrome in mothers treated with individualized doses of sublingual buprenorphine or oral methadone. Methadone was first given to all patients within 24h of treatment admission. After written informed consent was signed (3-5 days post-admission), methadone was discontinued and Immediate Release Morphine (IRM) was initiated. The initial total daily dose of IRM was six times the last daily methadone dose. The daily dose of IRM was divided in four daily doses. Induction onto double-blind, double dummy (i.e., two medications were administered with only one being active) methadone or buprenorphine was accomplished over 3 days (i.e., induction). Withdrawal scores during the IRM and induction onto randomized medication were judged mild and not statistically different for both methadone (mean dose 53.5 mg) and buprenorphine (mean dose 10.9 mg). No significant differences between medication groups were observed when individual withdrawal items were examined. No observed differences in safety measures including fetal movement, maternal physiological parameters of body temperature, heart rate and blood pressure were observed between groups. Transitioning opioid-dependent pregnant women from IRM to methadone or buprenorphine during the second trimester of pregnancy can be conducted with similar comfort and safety.