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.

Prenatal methadone exposure, meconium biomarker concentrations and neonatal abstinence syndrome.

AIMS: Methadone is standard pharmacotherapy for opioid-dependent pregnant women, yet the relationship between maternal methadone dose and neonatal abstinence syndrome (NAS) severity is still unclear. This research evaluated whether quantification of fetal methadone and drug exposure via meconium would reflect maternal dose and predict neonatal outcomes. DESIGN: Prospective clinical study. SETTING: An urban drug treatment facility treating pregnant and post-partum women and their children. PARTICIPANTS: Forty-nine opioid-dependent pregnant women received 30-110 mg methadone daily. MEASUREMENTS: Maternal methadone dose, infant birth parameters and NAS assessments were extracted from medical records. Thrice-weekly urine specimens were screened for opioids and cocaine. Newborn meconium specimens were quantified for methadone, opioid, cocaine and tobacco biomarkers. FINDINGS: There was no relationship between meconium methadone concentrations, presence of opioids, cocaine and/or tobacco in meconium, maternal methadone dose or NAS severity. Opioid and cocaine were also found in 36.7 and 38.8 of meconium specimens, respectively, and were associated with positive urine specimens in the third trimester. The presence of opioids other than methadone in meconium correlated with increased rates of preterm birth, longer infant hospital stays and decreased maternal time in drug treatment. CONCLUSIONS: Methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) concentrations in meconium did not predict infant birth parameters or NAS severity. Prospective urine testing defined meconium drug detection windows for opiates and cocaine as 3 months, rather than the currently accepted 6 months. The presence of opioids in meconium could be used as a biomarker for infants at elevated risk in the newborn period.

Infant autonomic functioning and neonatal abstinence syndrome.

BACKGROUND: Neonatal abstinence syndrome (NAS) expression is widely variable among affected infants and the reasons for this variability are largely unknown; mechanisms that predispose infants to NAS expression are not understood. It has been postulated that the regulatory problems of prenatally drug exposed infants are manifested in dysfunctional vagal regulation of autonomic processes. The current study examines whether cardiac vagal tone, an indicator of parasympathetic neuroregulation, provides a marker for autonomic dysregulation subsequently expressed as NAS in prenatally opioid-exposed newborns. METHODS: Heart period (HP) and cardiac vagal tone (V) were derived from electrocardiogram data collected from 64 methadone-exposed infants on postnatal days 1 and 3. The postpartum NAS course was assessed serially. RESULTS: Infants with lower V on day 1 had significantly higher NAS symptomatology on day 3. Boys had more severe NAS symptoms than girls through the first 4 days of life and, among infants receiving pharmacologic treatment for NAS, boys required longer treatment course and hospitalizations. Greater poly-drug exposure, detected through toxicology screening throughout pregnancy, and cocaine use in particular, were associated with lower V and shorter HP (faster heart rate) in newborns. Multiple regression models accounted for 25-35% of the variance in NAS symptoms and duration of hospitalization in methadone-exposed infants. Significant predictors included infant sex, SSRI/SNRI use, and cigarette smoking. CONCLUSIONS: Results support the hypothesis of a biologic vulnerability of autonomic regulatory functioning in methadone-exposed infants and greater male infant vulnerability to maternal methadone use.

Maternal methadone dosing schedule and fetal neurobehaviour.

OBJECTIVE: Daily methadone maintenance is the standard of care for opiate dependency during pregnancy. Previous research has indicated that single-dose maternal methadone administration significantly suppresses fetal neurobehaviours. The purpose of this study was to determine if split-dosing would have less impact on fetal neurobehaviour than single-dose administration. METHODS: Forty methadone-maintained women were evaluated at peak and trough maternal methadone levels on single- and split-dosing schedules. Monitoring sessions occurred at 36- and 37-weeks gestation in a counterbalanced study design. Fetal measures included heart rate, variability, accelerations, motor activity and fetal movement-heart rate coupling (FM-FHR). Maternal measures included heart period, variability, skin conductance, respiration and vagal tone. Repeated measure analysis of variance was used to evaluate within-subject changes between split- and single-dosing regimens. RESULTS: All fetal neurobehavioural parameters were suppressed by maternal methadone administration, regardless of dosing regimen. Fetal parameters at peak were significantly lower during single versus split methadone administration. FM-FHR coupling was less suppressed from trough to peak during split-dosing versus single-dosing. Maternal physiologic parameters were generally unaffected by dosing condition. CONCLUSION: Split-dosed fetuses displayed less neurobehavioural suppression from trough to peak maternal methadone levels as compared with single-dosed fetuses. Split-dosing may be beneficial for methadone-maintained pregnant women.

Maternal vagal tone change in response to methadone is associated with neonatal abstinence syndrome severity in exposed neonates.

OBJECTIVE: Though methadone pharmacotherapy is the treatment of choice for opiate-dependence during pregnancy in the USA, most methadone-exposed neonates develop neonatal abstinence syndrome (NAS). NAS expression is widely variable among methadone-exposed neonates and only a subset requires pharmacotherapy. This study explores the potential predictors of NAS severity, including aspects of maternal substance use and methadone maintenance histories, concomitant exposure to other licit substances, and individual differences in intrinsic maternal or infant factors that may affect the infant's vulnerability to NAS expression. METHODS: Fifty methadone-maintained pregnant women attending a comprehensive substance abuse treatment facility, received electrocardiogram monitoring at 36 weeks of gestation at the times of trough and peak maternal methadone levels. Vagal tone, an estimate of the magnitude of an individual's respiratory sinus arrhythmia and an indicator of autonomic control, was derived. RESULTS: NAS expression was unrelated to maternal substance abuse history, methadone maintenance history, or psychotropic medication exposure. Male infants displayed more profound NAS symptoms and received more pharmacotherapy to treat NAS (all p < 0.05). NAS expression was related to maternal vagal reactivity; both suppression and activation of maternal vagal tone in response to methadone administration were positively and significantly associated with NAS symptomatology (F (2,44) = 4.15, p < 0.05) and treatment (F (2,44) = 3.39, p < 0.05). Infants of vagal non-responder mothers showed substantially lower NAS expression. CONCLUSIONS: NAS severity is associated with maternal vagal tone change in response to methadone administration.

Fetal response to maternal methadone administration.

OBJECTIVE: The purpose of this study was to investigate the effect of methadone on fetal neurobehavioral functions and maternal physiologic indicators. STUDY DESIGN: Forty women attending a substance abuse treatment facility with otherwise uncomplicated pregnancies were evaluated at peak and trough methadone levels. Fetal measures included heart rate, variability, periodic accelerations/decelerations, motor activity, and fetal movement-heart rate coupling. Maternal measures included maternal heart period, variability, electrodermal skin conductance, respiration, and respiratory sinus arrhythmia (RSA). Repeated measure analysis of variance was used to evaluate within-subject changes. RESULTS: At peak methadone, fetal heart rate was slower, less variable, and displayed fewer accelerations. Fetuses displayed less motor activity, and the integration between heart rate and motor activity was attenuated. Maternal heart rate and skin conductance were unchanged, but methadone administration was associated with lower respiratory rate and RSA, an indicator of parasympathetic tone. CONCLUSION: Maternal methadone administration has significant effects on fetal behavioral functions that are independent of maternal effects.

Spontaneous regression of high-grade cervical dysplasia: effects of human papillomavirus type and HLA phenotype.

PURPOSE: Persistent infection with oncogenic human papillomaviruses (HPV) plays a central etiologic role in the development of squamous carcinomas of the cervix and their precursor lesions, cervical intraepithelial neoplasias (CIN). We carried out a prospective observational cohort study evaluating known, quantifiable prognostic variables of clinical behavior in women with high-grade cervical lesions. EXPERIMENTAL DESIGN: Our study cohort included healthy women with high-grade cervical lesions (CIN2/3) with residual visible lesions after colposcopically directed biopsy. We prospectively followed 100 women over 15 weeks before standard resection. HPV typing was done using PCR and a reverse line blot detection method. RESULTS: The rate of spontaneous histologic regression, defined as (CIN1 or less at resection) was 28%. The overall rate of HPV infection was 100%. HPV16 was identified in 68% of the lesions. Women with HPV16 only were significantly less likely to regress, compared with women with HPV types other than HPV16 (odds ratio, 0.342; 95% confidence interval, 0.117-0.997; P = 0.049). In the cohort with HPV16 only, patients who had an HLA*A201 allele had similar outcomes to those who did not carry A201. However, among patients with HPV types other than HPV16, the HLA*A201 allele interaction was significant; patients with HLA*A201 were the least likely to resolve. CONCLUSIONS: CIN2/3 lesions associated with HPV16 alone are significantly less likely to resolve spontaneously than those caused by other types. Interactions among HPV type, HLA type, and regression rate support a role for HLA-restricted HPV-specific immune responses in determining disease outcome.