Persistent Organic Pollutants in Austrian Human Breast Milk Collected between 2013 and 2016.

Breast milk holds an immense nutritional value as it contains health-promoting substances in a unique, optimal form. Additionally, breast milk's significance extends to health and environmental protection, as it serves as an indicator of both maternal and infant exposure. In this study, breast milk samples collected in 2013 and in 2014-2016 from mothers in Vienna (Austria) were analysed for polybrominated diphenyl ethers (PBDE) and per- and polyfluoroalkyl substances (PFAS), as well as further substances which have been listed under the Stockholm Convention on Persistent Organic Pollutants (POPs) due to their persistent, bioaccumulative and toxic properties. The total concentration of the PBDE congeners in the samples (n = 18, sampled 2013) ranged from 0.055 to 52 ng/g lipid, and from 0.002 to 2.5 ng/g breast milk. In the pooled sample, the sum of PBDEs was detected at a level of 4.4 ng/g lipid. Based on the 2014-2016 study population, certain PFAS were detected in all samples (n = 40). Exposure to the sum of four specific PFAS including perfluorooctanesulphonate (PFOS), perfluorooctanoic acid (PFOA), perfluoro-n-nonanoic acid (PFNA) and perfluoro-1-hexanesulfonate (PFHxS) ranged between 0.014 and 0.12 ng/L breast milk. In the pooled sample, PFOS and PFOA were found in concentrations of 0.025 ng/g and of 0.045 ng/g, respectively. In addition, the first generation of POPs, mainly organochlorine compounds, was measured in a pooled sample of breast milk from participants sampled in 2014-2016 as part of the WHO/UNEP breast milk monitoring program and compared to the POPs measured in pooled samples collected in 1987/1988 and 1992/1993, respectively. Therefore, this paper demonstrates the effectiveness of the Stockholm Convention on POPs by comparing the Austrian results from the WHO/UNEP global breast milk study from 1987 to 2016. However, the data also show that, despite these reductions, health-relevant levels are still being reached, particularly in terms of children's health when the presence of the new generation of POPs, such as PBDEs and PFAS, in human breast milk is taken into account.

Gene Variants Determine Placental Transfer of Perfluoroalkyl Substances (PFAS), Mercury (Hg) and Lead (Pb), and Birth Outcome: Findings From the UmMuKi Bratislava-Vienna Study.

Prenatal exposure to perfluoroalkyl substances (PFAS), bisphenol A (BPA), lead (Pb), total mercury (THg), and methylmercury (MeHg) can affect fetal development. Factors influencing placental transfer rate of these toxins are poorly investigated. Whether prenatal exposure to pollutants has an effect on birth weight is incompletely understood. We therefore aimed (1) to determine placental transfer rates of PFAS, BPA, Pb, THg, and MeHg, (2) to analyze relationships between fetal exposure and birth outcome and (3) to analyze gene variants as mediators of placental transfer rates and birth outcome. Two hundred healthy pregnant women and their newborns participated in the study. BPA, 16 PFAS, THg, MeHg, and Pb were determined using HPLCMS/MS (BPA, PFAS), HPLC-CV-ICPMS (MeHg), CV-AFS (THg), and GF-AAS (Pb). Questionnaires and medical records were used to survey exposure sources and birth outcome. 20 single nucleotide polymorphisms and two deletion polymorphisms were determined by real-time PCR from both maternal and newborn blood. Genotype-phenotype associations were analyzed by categorical regression and logistic regression analysis. Specific gene variants were associated with altered placental transfer of PFAS (ALAD Lys59Asn, ABCG2 Gln141Lys), THg (UGT Tyr85Asp, GSTT1del, ABCC1 rs246221) and Pb (GSTP1 Ala114Val). A certain combination of three gene polymorphisms (ABCC1 rs246221, GCLM rs41303970, HFE His63Asp) was over-represented in newborns small for gestational age. 36% of Austrian and 75% of Slovakian mothers had levels exceeding the HBM guidance value I (2 µg/L) of the German HBM Commission for PFOA. 13% of newborns and 39% of women had Ery-Pb levels above 24 µg/kg, an approximation for the BMDL01 of 12 µg/L set by the European Food Safety Authority (EFSA). Our findings point to the need to minimize perinatal exposures to protect fetal health, especially those genetically predisposed to increased transplacental exposure.

Lessons learned from a comparison of evidence-based research in pregnant opioid-dependent women.

OBJECTIVES: Lessons learned in research and treatment of opioid dependence demonstrate the need to include pregnant women in clinical trials. METHODS: Two double-blind, double-dummy, randomized controlled trials (Pilot study, European sample(†) of MOTHER-trial) comparing buprenorphine and methadone in opioid-dependent pregnant women were conducted. In both studies, participants received voucher-based incentives for attendance and completion of study assessments. In the MOTHER trial, participants additionally received escalating voucher incentives for drug-free urine samples. Neonatal abstinence syndrome was treated with oral morphine solution based on standardized modified Finnegan scores. RESULTS: After a mean treatment period of 13.79 weeks in the Pilot study (PS, n = 18) and 20.78 weeks in the MOTHER-trial (MT, n = 41), respectively (p < 0.001), PS patients delivered at mean doses of 14.00 mg buprenorphine/52.50 mg methadone and MT participants at 13.44 mg buprenorphine/63.68 mg methadone. Nonsignificant differences regarding dropout rates were found (22% in PS versus 10% in MT), but dropout was significantly earlier in the MT (p = 0.013). Significantly higher rates of concomitant consumption of opioids and benzodiazepines occurred in the PS compared with the MT (p < 0.001), however, with no significant differences in neonatal data between both settings. CONCLUSIONS: Early treatment enrolment combined with contingency management contributes to reduced illicit drug use throughout pregnancy, surprisingly without influencing neonatal outcome parameters.

Neonatal neurobehavior effects following buprenorphine versus methadone exposure.

AIM: To determine the effects of in utero exposure to methadone or buprenorphine on infant neurobehavior. DESIGN: Three sites from the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study, a double-blind, double-dummy, randomized clinical trial participated in this substudy. SETTING: Medical Centers that provided comprehensive maternal care to opioid-dependent pregnant women in Baltimore, MD, Providence, RI and Vienna, Austria. PARTICIPANTS: Thirty-nine full-term infants. MEASUREMENTS: The Neonatal Intensive Care Unit (NICU) Network Neurobehavioral Scale (NNNS) was administered to a subgroup of infants on postpartum days 3, 5, 7, 10, 14-15 and 28-30. FINDINGS: While neurobehavior improved for both medication conditions over time, infants exposed in utero to buprenorphine exhibited fewer stress-abstinence signs (P < 0.001), were less excitable (P < 0.001) and less over-aroused (P < 0.01), exhibited less hypertonia (P < 0.007), had better self-regulation (P < 0.04) and required less handling (P < 0.001) to maintain a quiet alert state relative to in utero methadone-exposed infants. Infants who were older when they began morphine treatment for withdrawal had higher self-regulation scores (P < 0.01), and demonstrated the least amount of excitability (P < 0.02) and hypertonia (P < 0.02) on average. Quality of movement was correlated negatively with peak NAS score (P < 0.01), number of days treated with morphine for NAS (P < 0.01) and total amount of morphine received (P < 0.03). Excitability scores were related positively to total morphine dose (P < 0.03). CONCLUSION: While neurobehavior improves during the first month of postnatal life for in utero agonist medication-exposed neonates, buprenorphine exposure results in superior neurobehavioral scores and less severe withdrawal than does methadone exposure.

Are male neonates more vulnerable to neonatal abstinence syndrome than female neonates?

BACKGROUND: Prior studies have shown an increased vulnerability among males to adverse outcomes during the postnatal period. Most children exposed to opioids and other medications in utero develop neonatal abstinence syndrome (NAS), yet individual predisposition for NAS is poorly understood. OBJECTIVE: This investigation examined the role of neonatal sex in the postnatal period for neonates exposed to standardized opioid maintenance treatment in utero with a focus on NAS regarding severity, medication requirements, and duration. METHODS: This was a secondary analysis of data collected in a prospective randomized, double-blind, double-dummy, multicenter trial (MOTHER study) that examined the comparative safety and efficacy of methadone and buprenorphine during pregnancy. A total of 131 neonates born to opioid-dependent women randomized at 6 US sites (n = 74) and 1 European site (n = 37) were analyzed. Sex-based differences in birth weight, length, head circumference, NAS duration, NAS severity, and treatment parameters of full-term neonates were assessed. RESULTS: Males had a significantly higher birth weight (P = 0.027) and head circumference (P = 0.017) compared with females, with no significant sex difference in rates of preterm delivery. No significant sex-related differences were found for NAS development, severity, or duration, or medication administered, and there were no significant differences in concomitant drug consumption during pregnancy (P = 0.959). CONCLUSIONS: This unique prospective study shows similar postnatal vulnerability for both sexes, suggesting that factors other than sex are the major determinants of clinically significant NAS. ClinicalTrials.gov identifier: NCT 00271219.

Randomized controlled trials in pregnancy: scientific and ethical aspects. Exposure to different opioid medications during pregnancy in an intra-individual comparison.

BACKGROUND: Chronic medical conditions such as opioid dependence require evidence-based treatment recommendations. However, pregnant women are under-represented in clinical trials. We describe the first within-subject comparison of maternal and neonatal outcomes for methadone- versus buprenorphine-exposed pregnancies. Although methadone is the established treatment of pregnant opioid-dependent women, recent investigations have shown a trend for a milder neonatal abstinence syndrome (NAS) under buprenorphine. However, it is not only the choice of maintenance medication that determines the occurrence of NAS; other factors such as maternal metabolism, illicit substance abuse and nicotine consumption also influence its severity and duration and represent confounding factors in the assessment of randomized clinical trials. CASE SERIES DESCRIPTION: Three women who were part of the European cohort of a randomized, double-blind multi-center trial with a contingency management tool [the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study], each had two consecutive pregnancies and were maintained on either methadone or buprenorphine for their first and then the respective opposite, still-blinded medication for their second pregnancy. Birth measurements, the total neonatal abstinence score, the total amounts of medication used to treat NAS and the days of NAS treatment duration were assessed. RESULTS: Both medications were effective and safe in reducing illicit opioid relapse and avoiding preterm labor. Methadone maintenance yielded to a significantly higher neonatal birth weight. Data patterns suggest that buprenorphine exposure was associated with lower neonatal abstinence syndrome (NAS) scores. Findings from this unique case series are consistent with earlier reports using between-group analyses. CONCLUSIONS: Buprenorphine has the potential to become an established treatment alternative to methadone for pregnant opioid-dependent women. Under special consideration of ethical boundaries, psychopharmacological treatment during pregnancy must be addressed as an integral part of clinical research projects in order to optimize treatment for women and neonates.

Perinatal lead and mercury exposure in Austria.

OBJECTIVE: The heavy metals lead (Pb) and mercury (Hg) are ubiquitous environmental pollutants with high neurotoxic potential. We aimed to compare perinatal Pb and Hg concentrations and to explore the potential association between Pb and Hg exposure and newborn anthropometry. STUDY DESIGN: Pregnant women were recruited in 2005 at the General Hospital Vienna for participation in this longitudinal study. Pb and Hg concentrations were measured in maternal blood and hair, placenta, cord blood, meconium, and breast milk of 53 mother-child pairs by CV-AAS, GF-AAS, and HPLC-CV-ICPMS. We conducted bivariate analyses and categorical regression analysis (CATREG) to evaluate the determinants of Pb and Hg exposure, and of infant anthropometry. RESULTS: Median Pb and total Hg contents were low, i.e., 25 µg/L (maternal blood-Pb), 13 µg/L (cord blood-Pb), 0.7 µg/L (maternal blood-Hg), and 1.1 µg/L (cord blood-Hg). Hg levels in maternal and fetal tissues were frequently correlated (r>0.3, P<0.05, respectively). Regarding Pb, only maternal blood and cord blood concentrations correlated (P=0.043). Cord blood levels indicated higher Hg exposure but lower Pb exposure relative to maternal blood contents. Adjusted CATREG models indicated the significant predictors of birth length (placenta-Pb, gestational length, meconium-Pb), birth weight (placenta-Pb, gestational length, maternal blood-Pb), and head circumference (maternal education, maternal height). Besides one significant correlation between maternal hair Hg and birth length, the mercury levels were not associated with newborn anthropometry. CONCLUSIONS: Our data implicate that different modes of action may exist for placentar transfer of Pb and Hg as well as that low Pb exposure levels can result in lower birth weight. The findings related to newborn anthropometry need to be confirmed by the examination of larger study groups. Further research is needed to clarify the mechanisms of Pb and Hg transfer via the placenta, and to explore how prenatal Pb exposure is related to intrauterine growth.

Association between prenatal tobacco exposure and outcome of neonates born to opioid-maintained mothers. Implications for treatment.

BACKGROUND: Prenatal nicotine exposure is associated with increased neonatal mortality, low birth weight, and smaller head circumference. Opioid-dependent pregnant women show a particularly high prevalence of tobacco smoking and are at greater risk for additional adverse events. However, little is known about the impact of tobacco smoking on opioid-maintained pregnant women and neonatal outcomes. PATIENTS AND METHODS: This study examined the effect of cigarette smoking on 139 opioid-maintained pregnant women and their neonates. Forty-five percent of the participants were maintained on slow-release oral morphine (SROM), 39% received methadone maintenance, and 16% received buprenorphine. Participants were divided into two groups: (1) women who reported a low cigarette consumption of < or =10 cigarettes/day (56.8%) and (2) those reporting heavy consumption of > or =20 cigarettes/day (43.2%). Neonatal outcome measures were assessed, and a standardized Finnegan score was applied to determine the neonatal abstinence syndrome (NAS). RESULTS: Fifty-two percent of the newborns did not require treatment for NAS (54% of neonates born to methadone-maintained mothers, 30% born to SROM-maintained mothers, and 95% born to buprenorphine-maintained mothers; p < 0.001). Heavy cigarette consumption was associated with significantly lower neonatal birth weight (p < 0.001), smaller birth length (p = 0.017) as well as with the severity of NAS (p = 0.03). With regard to concomitant consumption of opioids (p = 0.54), cocaine (p = 0.25), amphetamines (p = 0.90) or benzodiazepines (p = 0.09), no significant differences between heavy or low nicotine consumption were noted. CONCLUSION: Heavy tobacco smoking in opioid-maintained pregnant women is associated with adverse medical and developmental consequences for the newborn. Future treatment programs for this target group should focus on an individualized approach to opioid maintenance therapy in addition to offering specially tailored counseling for smoking cessation.

Small volume enemas do not accelerate meconium evacuation in very low birth weight infants.

We hypothesized that small volume enemas accelerate meconium evacuation in very low birth weight (VLBW) infants. In a randomized controlled trial, VLBW infants (n = 81) received either repeated daily small volume enemas if complete spontaneous meconium passage failed within 24 h or no intervention. Small volume enemas did not accelerate complete meconium evacuation, which occurred after 6.0 to 9.6 (95% CI) d in the intervention group and after 7.7 to 11.0 (95% CI) d in the control group. No adverse events were observed. Daily administration of small volume enemas had no effect on total meconium evacuation defined by the time of last meconium passage.

Management of neonatal abstinence syndrome in neonates born to opioid maintained women.

Neonates born to opioid-maintained mothers are at risk of developing neonatal abstinence syndrome (NAS), which often requires pharmacological treatment. This study examined the effect of opioid maintenance treatment on the incidence and timing of NAS, and compared two different NAS treatments (phenobarbital versus morphine hydrochloride). Fifty-three neonates born to opioid-maintained mothers were included in this study. The mothers received methadone (n=22), slow-release oral morphine (n=17) or buprenorphine (n=14) throughout pregnancy. Irrespective of maintenance treatment, all neonates showed APGAR scores comparable to infants of non-opioid dependent mothers. No difference was found between the three maintenance groups regarding neonatal weight, length or head circumference. Sixty percent (n=32) of neonates required treatment for NAS [68% in the methadone-maintained group (n=15), 82% in the morphine-maintained group (n=14), and 21% in the buprenorphine-maintained group (n=3)]. The mean duration from birth to requirement of NAS treatment was 33 h for the morphine-maintained group, 34 h for the buprenorphine-maintained group and 58 h for the methadone-maintained group. In neonates requiring NAS treatment, those receiving morphine required a significantly shorter mean duration of treatment (9.9 days) versus those treated with phenobarbital (17.7 days). Results suggest that morphine hydrochloride is preferable for neonates suffering NAS due to opioid withdrawal.

Methadone versus buprenorphine in pregnant addicts: a double-blind, double-dummy comparison study.

AIMS: To evaluate the efficacy and safety of methadone versus buprenorphine treatment in pregnant opioid-dependent women. DESIGN: Randomized, double-dummy, double-blind, flexible-dosing comparison study. SETTING: Addiction Clinic at the Medical University of Vienna, Austria. PARTICIPANTS: Eighteen women were assigned randomly to receive either methadone (n = 9) or buprenorphine (n = 9) during weeks 24-29 of pregnancy. After dropouts, data were available from 14 cases (six in the methadone and eight in the buprenorphine group). INTERVENTION: Sublingual buprenorphine tablets (8-24 mg/day) or oral methadone solution (40-100 mg/day), with matched placebos. MEASUREMENTS: Mothers: retention in treatment, urine toxicology and nicotine use. Neonates: Routine birth data, neonatal abstinence syndrome (NAS) in severity and duration. FINDINGS: There was somewhat greater retention in the buprenorphine group but significantly lowered use of additional opioids in the methadone group (P = 0.047).Neonates: There was earlier onset of NAS in neonates born to the methadone (mean 60 hours) than to the buprenorphine groups (mean 72 hours after last medication); 43% did not require NAS-treatment with short treatment duration in both groups (mean 5 days). CONCLUSION: This preliminary study had limited power to detect differences but the trends observed suggest this kind of research is practicable and that further studies are warranted.

Monocyte toll-like receptor 4 expression and LPS-induced cytokine production increase during gestational aging.

Premature newborns are highly susceptible to severe bacterial infections. This is partially due to their immature innate immune system, characterized by decreased neutrophil and monocyte activity as well as by reduced concentrations of complement factors. However, additional mechanisms might be important for innate immunity and are still the subject of considerable debate. The importance of pattern recognition domains such as Toll-like receptors (TLR) has been fully acknowledged within the last few years. Therefore, we investigated age-related monocyte TLR4 expression and lipopolysaccharide-induced cytokine secretion from very low birth weight infants (VLBWI) and from newborns after wk 30 of gestation in comparison to healthy adults. In VLBWI, expression of TLR4 surface protein, detected by flow cytometry, and TLR4-specific mRNA, quantified by real time-PCR, were significantly reduced in comparison to mature infants and to adults. Reduced TLR4 expression was paralleled by significantly diminished ex vivo LPS stimulated IL-1beta, IL-6, and tumor necrosis factor-alpha secretion into whole blood. We conclude that, in VLBWI, the minimized expression of TLR4 contributes to the susceptibility of VLBWI to infections with Gram-negative bacteria due to the lack of cytokines to boost initial immune response.

3-D ultrasonographic imaging of the cerebral ventricular system in very low birth weight infants.

The purpose of the study was to assess reference ranges for lateral ventricular volume of very low birth weight (VLBW) infants using 3-D ultrasound (US). A total of 108 patients with birth weights < or =1500 g or mother's postmenstrual age < or =32 weeks were examined prospectively in a longitudinal study. Infants in conditions considered being potential confounders such as intraventricular haemorrhage (IVH) and periventricular leukomalacia (PVL) were not included in the calculations. Hence, 77 subjects remained for final statistical analysis. Mean postmenstrual age at birth was 194.5 (27 weeks and 5.5 days) +/- 14 SD days, mean birth weight was 972.5 +/- 236.3 SD g. Reference ranges for lateral ventricle volume were established from serial images. The exponential regression analyses revealed a weekly increase in volume of 6.3% (95% CI 4.4%-8.3%) and 6.6% (95% CI 4.7%-8.6%) in respect to the left and the right ventricle (p < 0.001). Postmenstrual age correlated significantly (p < or = 0.015) with ventricle volume. No significant association to head circumference could be determined. Establishment of reference values for the lateral ventricle volume of VLBW infants should facilitate application of 3-D US in routine diagnostics in neonatal intensive care units and detection of ventricular enlargement as a prediction of risk for poor neurodevelopmental outcome in high-risk cohorts.

Pain and stress management in the Neonatal Intensive Care Unit--a national survey in Austria.

UNLABELLED: Neonates are sensitive to pain and vulnerable to both its short-term and long-term effects. Management of analgesia is thought to be hampered by lack of awareness that newborns are capable of experiencing pain and by fears about adverse effects associated with analgesics. The purpose of this study was to assess current medical practice in preventive analgesia and sedation in the neonate throughout Austria. This report details the results of a survey in 28 neonatal intensive care units (NICUs) in Austria. Data collection took place from October to December 2001. All NICUs reported the capability of newborns to experience and express pain and nearly all stated the possibility of pain affecting morbidity. Validated scores for pain assessment were used by 11% of NICUs, standardized protocols for analgesia existed in 75%, and 100% practiced non-pharmacological treatment strategies. The use of preventive measures in routinely performed painful procedures ranged from 8% to 96%. For example, only 8% of NICUs prevent distress and pain prior to umbilical vessel catheterization, 29% prior to subcutaneous injections and 46% prior to heel lancing. Nearly all NICUs apply analgesia before lumbar puncture and thoracic-drain placement, and all use analgesic and/or sedative medication in elective intubation. CONCLUSION: There is widespread awareness among neonatologists of the importance and effects of distress caused by pain in newborns. However, the necessity of providing sufficient analgesia is underestimated. Further information on the safety of analgesic drugs in neonatology is imperative.

Neonatal outcome following buprenorphine maintenance during conception and throughout pregnancy.

AIMS: To assess the effects of maternal buprenorphine treatment at conception and during pregnancy on neonates in terms of birth outcomes and neonatal abstinence syndrome (NAS). DESIGN AND SETTING: Prospective, open-label, out-patient maintenance, case report study, conducted at the drug addiction out-patient clinic at the University Hospital Vienna. PARTICIPANTS: Two buprenorphine-maintained pregnant women who had conceived during buprenorphine treatment. Both patients had previously given birth to healthy neonates following induction on to buprenorphine maintenance therapy in the second trimester. MEASUREMENTS: Mothers: urinalysis. Neonates: gestational age at delivery, Apgar scores, birth weight, length and NAS (Finnegan Scale). FINDINGS: Urinalyses were negative for both women for 25 and 38 months, respectively, during the pregnancy period. There were no complications during the course of the pregnancy. The newborns delivered by both women were healthy, birth outcomes were within normal ranges and there were no NAS symptoms requiring treatment. CONCLUSIONS: To our knowledge this is the first report detailing the pregnancies of women treated with buprenorphine at the time of conception and investigated in a prospective study. The NAS noted in neonates born to buprenorphine-maintained mothers appears to be less severe than the NAS observed in neonates born to methadone-maintained mothers. These preliminary data indicate that, in our patient cohort, buprenorphine maintenance at the time of conception and during pregnancy did not seem to affect birth outcome measurements such as pregnancy complications, week of delivery, birth weight, length, umbilical pH or neurodevelopmental progress. Future prospective studies with larger study populations are warranted.

Serratia marcescens in the neonatal intensive care unit: re-emphasis of the potentially devastating sequelae.

BACKGROUND: It is known that infections with Serratia marcescens can take a progressive course in preterm infants and that meningoencephalitis with this pathogen exhibits an extremely bad neurologic prognosis. METHODS AND RESULTS: We report on five cases of septicemia with Serratia marcescens in preterm infants during a nosocomial outbreak. Three patients developed meningoencephalitis with brain abscesses. Mild clinical and laboratory findings of infection contrasted with destructive findings on MRI scan. All five patients survived, those with isolated bacteremia without neurologic sequelae. CONCLUSION: When Serratia marcescens is isolated from any source in a neonatal intensive care unit, preventive measures including strict hygiene and cohorting of infants must be implemented immediately since this pathogen seems to exhibit specific affinity for the central nervous system and Serratia marcescens meningoencephalitis takes a progressive and destructive course despite antibiotic therapy.