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The article discusses the perspectives of two male patients who were concerned about the effects of their medication on reproductive health while planning to conceive. It highlights the importance of preconception counseling for men and the need for further research in this area. Despite theoretical concerns, studies have not shown any association between paternal drug exposure and adverse fetal outcomes, leading to updated guidelines reassuring men about the safety of conceiving while on certain medications. The patients in the cases discussed were able to proceed with their family plans without experiencing any negative effects on their conditions. [Extracted from the article]

Objective The objective of this study is to investigate the effects of maternal perinatal depression symptoms and infant treatment status for neonatal abstinence syndrome (NAS) on maternal perceptions of infant regulatory behavior at 6 weeks of age. Methods Mothers and their infants (N  = 106; 53 dyads) were recruited from a rural, White cohort in Northeast Maine. Mothers in medication-assisted treatment (methadone) and their infants (n  = 35 dyads) were divided based on the infant's NAS pharmacological treatment (n  = 20, NAS+ group; n  = 15, NAS− group) and compared with a demographically similar, nonexposed comparison group (n  = 18 dyads; COMP group). At 6 weeks postpartum, mothers reported their depression symptoms Beck Depression Inventory—2nd Edition) and infant regulatory behaviors [Mother and Baby Scales (MABS)]. Infant neurobehavior was assessed during the same visit using the Neonatal Network Neurobehavioral Scale (NNNS). Results Mothers in the NAS+ group showed significantly higher depression scores than the COMP group (p <.05) while the NAS− group did not. Across the sample, mothers with higher depression scores reported higher infant "unsettled-irregularity" MABS scores, regardless of group status. Agreement between maternal reports of infant regulatory behaviors and observer-assessed NNNS summary scares was poor in both the NAS+ and COMP groups. Conclusions Postpartum women in opioid recovery with infants requiring pharmacological intervention for NAS are more at risk for depression which may adversely influence their perceptions of their infants' regulatory profiles. Unique, targeted attachment interventions may be needed for this population. [ABSTRACT FROM AUTHOR]

Maternal drug use during pregnancy is a significant concern. Drug-exposed newborns are often born premature and may suffer from birth defects, neonatal abstinence syndrome and cognitive and developmental delays. Because of this, testing of neonatal specimens is carried out to assess fetal drug exposure during pregnancy. Umbilical cord tissue (UC) and meconium are commonly used specimens for this purpose. However, comprehensive studies comparing drug positivity rates and concentration in the two specimen types are lacking. To this end, 4,036 paired UC and meconium specimens originating from 13 states within the USA were identified, and retrospective analysis of drug positivity rates and drug concentration was performed for 31 analytes in 5 drug classes. Testing for 11-Nor-9-carboxy-tetrahydrocannabinol (THC-COOH) is a separate orderable for UC specimen at our laboratory, so a second data set was created for evaluation of this drug analyte with 2,112 paired UC and meconium specimens originating from 11 states. Testing of UC was performed by semi-quantitative liquid chromatography–tandem mass spectrometry (LC–MS-MS) assays, whereas, for meconium, an immunoassay-based screening preceded LC–MS-MS confirmation tests. Results generated for UC and meconium specimens were therefore compared for a total of 32 drug analytes from 6 drug classes. Drug concentrations for analytes were higher in meconium compared to UC, with the exception of phencyclidine. Despite this, the positivity rates for individual analytes were higher in UC, with the exception of THC-COOH and cocaine. Furthermore, analysis for multidrug positivity revealed that THC-COOH and opioids were the most common multidrug combination detected in both matrices. In conclusion, this study suggests that for most drug compounds, UC was more analytically sensitive to assess neonatal drug exposure by current methodologies. Additionally, by demonstrating that meconium has higher drug concentrations for most compounds, this study sets the stage for developing more sensitive assays in meconium. [ABSTRACT FROM AUTHOR]

Gabapentin was thought to have low abuse potential, but it is increasingly being abused by people with substance use disorder in an attempt to potentiate the euphoric effects from opioids and other CNS depressants. Additionally, infants co-exposed to gabapentin and opioids during pregnancy tend to exhibit prolonged and more severe neonatal abstinence syndrome. In this study, we describe positivity rates among commonly abused drugs and rates of co-medication with gabapentin in a large dataset of umbilical cord tissue specimens (n  = 25,422) submitted for routine newborn drug testing at a national clinical reference laboratory (ARUP Laboratories, Salt Lake City, UT, USA). Detection of prenatal drug exposure in umbilical cord tissue specimens was accomplished using a semi-quantitative liquid chromatography–tandem mass spectrometry assay designed to detect 47 specific drugs and drug metabolites including opioids, stimulants, sedative-hypnotics and hallucinogens. A positive result for at least one of the measured drugs or drug metabolites was reported in 7,054 (28%) of the umbilical cord tissues analyzed. Gabapentin had a positivity rate of ~2% with 562 positive results. Of the 562 gabapentin-positive samples, 395 (70%) also had a positive result for at least one other drug or drug metabolite, with the highest co-positivity rate observed for norbuprenorphine (32%, n  = 182) followed by amphetamine (15%, n  = 84), buprenorphine (13%, n  = 74), methamphetamine (12%, n  = 68), morphine (11%, n  = 64), fentanyl (10%, n  = 54) and naloxone (10%, n  = 54). Notably, the concentration of gabapentin in gabapentin-positive umbilical cord specimens was higher in buprenorphine-containing specimens as compared to specimens containing other opioids, stimulants or benzodiazepines. Identification of neonatal co-exposure to gabapentin and opioids, particularly buprenorphine, may guide clinicians in rapid initiation of monitoring and intervention for neonatal abstinence syndrome. [ABSTRACT FROM AUTHOR]

Onartuzumab is an engineered single arm, monovalent monoclonal antibody that targets the MET receptor and prevents hepatocyte growth factor (HGF) signaling. Knockout mice have clearly demonstrated that HGF/MET signaling is developmentally critical. A pre- and postnatal development study (enhanced design) was conducted in cynomolgus monkeys to evaluate the potential developmental consequences following onartuzumab administration. Control or onartuzumab, at loading/maintenance doses of 75/50 mg/kg (low) or 100/100 mg/kg (high), was administered intravenously once weekly to 12 confirmed pregnant female cynomolgus monkeys per group from gestation day (GD) 20 through GD 174. Onartuzumab administration resulted in decreased gestation length, decreased birth weight, and increased fetal and perinatal mortality. A GD147 C-section was conducted for a subset of Control and High Dose monkeys, and identified placental infarcts with hemorrhage in the chorionic plate, chorionic villus and/or decidual plate. These findings were limited to placentas from onartuzumab-treated animals. In addition, decreased cellularity of the hepatocytes with dilated hepatic sinusoids was inconsistently observed in the liver of a few fetal or infant monkeys that died in the perinatal period. Surviving offspring had some evidence of developmental delay compared with controls, but no overt teratogenicity. Overall, effects on the perinatal fetuses were consistent with those reported in knockout mice, but not as severe. Onartuzumab concentrations were low or below the level of detection in most offspring, with cord blood concentrations only 1%–2% of maternal levels on GD 147. Malperfusion secondary to onartuzumab-induced placental injury could explain the adverse pregnancy outcomes, fetal growth restriction and relatively low fetal exposures. [ABSTRACT FROM AUTHOR]

This scientific commentary refers to 'Integrative genomics reveals pathogenic mediator of valproate-induced neurodevelopmental disability' by Feleke I et al i . The maximum dose (20 g/kg) administered to rats in the study would be expected to give rise to valproate blood levels of ~180-280 ml/l, which is below the human therapeutic range of valproate (~347-693 ml/l) for antiseizure effects. [Extracted from the article]

The article shares observations and reflections from senior toxicologists on their careers as the British Toxicology Society (BTS) celebrates its 50th anniversary. Among the observed trends in toxicology are changing skill sets, the need to make decisions based on limited data, alignment with fundamental science in other disciplines and diverse routes taken by senior toxicologists. It also highlights changes regarding career progression and workplace culture and increased inclusivity.

Study Question: What is the relationship between maternal paracetamol intake during the masculinisation programming window (MPW, 8-14 weeks of gestation) and male infant anogenital distance (AGD), a biomarker for androgen action during the MPW?Summary Answer: Intrauterine paracetamol exposure during 8-14 weeks of gestation is associated with shorter AGD from birth to 24 months of age.What Is Already Known: The increasing prevalence of male reproductive disorders may reflect environmental influences on foetal testicular development during the MPW. Animal and human xenograft studies have demonstrated that paracetamol reduces foetal testicular testosterone production, consistent with reported epidemiological associations between prenatal paracetamol exposure and cryptorchidism.Study Design, Size, Duration: Prospective cohort study (Cambridge Baby Growth Study), with recruitment of pregnant women at ~12 post-menstrual weeks of gestation from a single UK maternity unit between 2001 and 2009, and 24 months of infant follow-up. Of 2229 recruited women, 1640 continued with the infancy study after delivery, of whom 676 delivered male infants and completed a medicine consumption questionnaire.Participants/materials, Setting, Method: Mothers self-reported medicine consumption during pregnancy by a questionnaire administered during the perinatal period. Infant AGD (measured from 2006 onwards), penile length and testicular descent were assessed at 0, 3, 12, 18 and 24 months of age, and age-specific Z scores were calculated. Associations between paracetamol intake during three gestational periods (<8 weeks, 8-14 weeks and >14 weeks) and these outcomes were tested by linear mixed models. Two hundred and twenty-five (33%) of six hundred and eighty-one male infants were exposed to paracetamol during pregnancy, of whom sixty-eight were reported to be exposed during 8-14 weeks. AGD measurements were available for 434 male infants.Main Results and the Role Of Chance: Paracetamol exposure during 8-14 weeks of gestation, but not any other period, was associated with shorter AGD (by 0.27 SD, 95% CI 0.06-0.48, P = 0.014) from birth to 24 months of age. This reduction was independent of body size. Paracetamol exposure was not related to penile length or testicular descent.Limitations, Reasons For Caution: Confounding by other drugs or endocrine-disrupting chemicals cannot be discounted. The cohort was not fully representative of pregnant women in the UK, particularly in terms of maternal ethnicity and smoking prevalence. There is likely to have been misclassification of paracetamol exposure due to recall error.Wider Implications Of the Findings: Our observational findings support experimental evidence that intrauterine paracetamol exposure during the MPW may adversely affect male reproductive development.Study Funding/competing Interests: This work was supported by a European Union Framework V programme, the World Cancer Research Fund International, the Medical Research Council (UK), the Newlife Foundation for Disabled Children, the Evelyn Trust, the Mothercare Group Foundation, Mead Johnson Nutrition, and the National Institute for Health Research Cambridge Comprehensive Biomedical Research Centre. The authors declare no conflict of interest. [ABSTRACT FROM AUTHOR]

Objectives: Data on fetal exposure to antiretroviral agents during pregnancy are important to estimate their potential for prevention of mother-to-child transmission (PMTCT) and possible toxicity. For the recently developed HIV integrase inhibitor dolutegravir, clinical data on fetal disposition are not yet available. Dual perfusion of a single placental lobule (cotyledon) provides a useful ex vivo model to predict the in vivo maternal-to-fetal transfer of this drug. The aim of this study was to estimate the transfer of dolutegravir across the human term placenta, using a dual-perfusion cotyledon model. Methods After cannulation of the cotyledons (n?=?6), a fetal circulation of 6 mL/min and maternal circulation of 12 mL/min were initiated. The perfusion medium consisted of Krebs-Henseleit buffer (pH?=?7.2-7.4) supplemented with 10.1 mM glucose, 30 g/L human serum albumin and 0.5 mL/L heparin 5000IE. Dolutegravir was administered to the maternal circulation (~4.2 mg/L) and analysed by UPLC-MS/MS. Results After 3 h of perfusion, the mean?±?SD fetal-to-maternal (FTM) concentration ratio of dolutegravir was 0.6?±?0.2 and the mean?±?SD concentrations in the maternal and fetal compartments were 2.3?±?0.4 and 1.3?±?0.3 mg/L, respectively. Conclusions: Dolutegravir crosses the blood-placental barrier with a mean FTM concentration ratio of 0.6. Compared with other antiretroviral agents, placental transfer of dolutegravir is moderate to high. These data suggest that dolutegravir holds clinical potential for pre-exposure prophylaxis and consequently PMTCT, but also risk of fetal toxicity. [ABSTRACT FROM AUTHOR]

This review summarizes available data for lamivudine and tenofovir disoproxil fumarate use during pregnancy and breastfeeding. The data demonstrate that drug exposure to infants is less from breastfeeding than from in utero exposure.Lamivudine and tenofovir disoproxil fumarate (TDF) are both active against hepatitis B virus (HBV). Due to its potency, high genetic barrier to resistance, and safety during pregnancy, TDF may be useful to prevent HBV transmission from mother to child, which is the leading cause of transmission globally. Despite the safety record of lamivudine and TDF in pregnancy, the labels for both of these drugs recommend against their use during breastfeeding. In this review, we discuss the data regarding lamivudine and TDF use during pregnancy and breastfeeding and find that the exposure to the drug is lower from breastfeeding than from in utero exposure. Thus, the data do not support the contraindication to their use during breastfeeding. [ABSTRACT FROM PUBLISHER]

Prenatal infection is an environmental risk factor for schizophrenia while later in life, stressful events have been associated with the onset and severity of psychosis. Recent findings on the impact of stress on the N-methyl-d-aspartate receptor (NMDAR), of which hypofunctioning is implicated in schizophrenia, suggest changes in stress-induced regulation of the glutamatergic system may be related to the pathogenesis of schizophrenia. Our study aimed to test whether prenatal immune activation could interact with stress at adolescence to alter NMDAR function. We used offspring from rat dams administered bacterial lipopolysaccharide (LPS) during pregnancy (gestational days 15 and 16), an animal model expressing schizophrenia-related behavioural phenotypes. Using electrophysiological techniques, we investigated effects of stress and the stress hormone corticosterone (Cort) on NMDAR-mediated synaptic function and long-term depression (LTD) in hippocampal CA1 slices from these adolescent (aged 28–39 d) male offspring. In prenatal LPS offspring, NMDAR-mediated synaptic function and LTD were reduced and abolished, respectively, compared to prenatal saline controls. Notably, in vivo stress and in vitro Cort treatment facilitated LTD in slices from prenatal LPS rats but not prenatal saline controls. Finally, Cort enhanced NMDAR-mediated synaptic function in slices from prenatal LPS rats only. We conclude that prenatal immune activation results in NMDAR hypofunction in the hippocampus of adolescent rats but also increases responsiveness of NMDAR-mediated synaptic function and LTD towards stress. Prenatal infection could confer susceptibility to schizophrenia through modification of hippocampal NMDAR function, with hypofunction in resting conditions and heightened responsiveness to stress, thus impacting the development of the disorder. [ABSTRACT FROM AUTHOR]

Background. The genotoxicity of zidovudine has been established in experimental models. The objective of the study was to identify genotoxicity markers in cord blood cells from newborns exposed in utero to antiretroviral (ARV) combinations containing zidovudine.Methods. Cells were investigated by karyotyping and gene expression analysis of the CD34+ hematopoietic stem/progenitor cell (HPC) compartment.Results. Karyotyping of the cord blood cells from 15 ARV-exposed newborns and 12 controls revealed a higher proportion of aneuploid cells in the exposed group (median, 18.8% [interquartile range, 10.0%–26.7%] vs 6.6% [interquartile range, 3.1%–11.7%]; P < .001). All chromosomes were involved, with a random distribution of these alterations. Gene expression profiling of CD34+ HPCs from 7 ARV-exposed and 6 control newborns revealed that >300 genes were significantly upregulated or downregulated by at least 1.5-fold in the exposed group (P < .05 for all comparisons). Significant alterations of genes involved in cell cycle control, mitotic checkpoints, and DNA repair were identified. Although this study does not allow discrimination between the roles of each of the 3 drugs, both cytogenetic and transcriptional findings are similar to those in cellular experiments that used zidovudine alone.Conclusions. The cord blood cells, including hematopoietic stem cells, from newborns exposed in utero to a zidovudine-based ARV combination present cytogenetic and transcriptional abnormalities compatible with DNA damage. [ABSTRACT FROM AUTHOR]

BackgroundClonidine, a centrally acting antihypertensive agent, has been used successfully in pregnancy. We sought to describe the pharmacodynamic effects of clonidine in pregnancy and the associated impact on fetal growth.MethodsA retrospective cohort study was performed. Maternal hemodynamics were measured before and after treatment. Responses to clonidine were categorized by the predominant hemodynamic effect: decreased vascular resistance, decreased cardiac output (CO), or mixed. Multinomial logistic regression was used to evaluate predictors of hemodynamic response to clonidine and association between response group and birth weight.ResultsSixty-six pregnant women were studied. Treatment was associated with a reduction of mean arterial pressure (MAP) (−9.2 mm Hg, P < 0.001), a reduction in total peripheral resistance (TPR) (−194 dyne·cm·sec−5, P < 0.001), and an increase in CO (+0.5 l/min, P < 0.001). The hemodynamic response was characterized by decreased resistance in 34 women; decreased CO in 22; and mixed effect in 10. No maternal demographic characteristics were associated with a reduction in CO. Mean birth weight percentile was lower in the group that experienced a reduction in CO compared to the group with a reduction in vascular resistance (26.1 vs. 43.6, P = 0.02). The rate of birth weight <10th percentile was also higher in the group experiencing decreased CO (41 vs. 8.8%, P = 0.008).ConclusionsThe hemodynamic effect of clonidine in pregnancy is heterogeneous. The category of effect, reduction in vascular resistance vs. reduction in CO, significantly impacts fetal growth. A reduction in heart rate (HR) after therapy identifies pregnancies at risk for reduced fetal growth.American Journal of Hypertension (2010). doi:10.1038/ajh.2010.159 [ABSTRACT FROM AUTHOR]

Objective To examine the effects of maternal cigarette smoking during pregnancy on the developing infant's autonomic regulation before the possible effects of parturition and neonatal withdrawal could alter outcome measures. Methods Heart rate variability (HRV) was assessed for 10 mm during late gestation for 21 cigarette-exposed (CE) and 22 nonexposed (NE) fetuses. Results HRV was significantly lower in fetuses whose mothers smoked cigarettes during pregnancy. Spectrum analysis of that variability showed temporally organized rhythms at a frequency similar to rhythms previously found in fetal cyclic motility (approximately .3 cycles per mm). Lower powered rhythms—associated with poorer development—at the first, second, and dominant rhythms, as well as lower overall power of the power spectrum, were found for CE fetuses. Pearson correlations showed significant negative correlations between the amount of maternal cigarette smoking during the first trimester of pregnancy and measures of fetal HRV and power of spectral peaks. Conclusions Results show that CE fetuses have lower HRV and disrupted temporal organization of autonomic regulation before effects of parturition, postnatal adaptation, and possible nicotine withdrawal contributes to differences in infant neurobehavioral function. [ABSTRACT FROM AUTHOR]

Multiple binary outcomes are encountered frequently in epidemiologic research. This work was motivated by the Maternal Lifestyle Study, 1993–1995, where newborns exposed prenatally to cocaine and a comparison cohort were examined for the presence of central and autonomic nervous system (CNS/ANS) signs. Thus, each infant contributed to multiple, possibly interrelated, binary outcomes that may collectively constitute one syndrome (even though specific outcomes that are affected by cocaine are of scientific interest). Because it is neither scientifically appropriate nor statistically efficient to fit separate models for each outcome, here we adopt a multivariate repeated measures approach to simultaneously model all the CNS/ANS outcomes as a function of cocaine exposure and other covariates. This formulation has a number of advantages. First, it implicitly recognizes that all the CNS/ANS outcomes may together constitute one syndrome. Second, simultaneous modeling boosts statistical efficiency by allowing for correlations among the outcomes, and it avoids multiple comparisons. Third, it allows for outcome-specific exposure effects, so that the specific signs that are affected by cocaine exposure can be identified. [ABSTRACT FROM AUTHOR]

A systemic lupus erythematosus (SLE) pregnancy is no longer regarded as unacceptable, with an early diagnosis, a mild disease condition, and good interdisciplinary collaboration ensuring intense surveillance of pregnant SLE patients. The key point is a sufficiently long period of disease quiescence before conception. A low dose of prednisone is preferable during pregnancy. Nevertheless, 20% of disease flare-up still happens interpartum or postpartum, even in such well-planned pregnancies, although usually with only mild severity. Pregnancy during an active disease stage, especially active nephritis, should always be avoided. Substantial renal function damage may occur, and there is a relatively high prevalence of preeclampsia, which may further compromise the mother as well as the fetus. It is well documented that antiphospholipid syndrome and antiphospholipid antibodies are strongly associated with fetal wastage. Low-dose aspirin or heparin is indicated for a favorable fetal outcome. Women with positive anti-SSA and/or anti-SSB should be aware of the danger of congenital heart block in their infants. Cytotoxic drugs applied in the early stage of pregnancy are dangerous to the fetus. A rather long-term follow-up is required to make a precise evaluation of the maternal SLE influence on the offspring. [ABSTRACT FROM AUTHOR]

The teratogenic effects of ethanol have been widely studied in a variety of experimental models. In humans, ethanol teratogenicity results from both direct and indirect effects. This paper reviews the differences between direct and indirect effects of ethanol on the developing fetus. Experimental paradigms are discussed that attempt to differentiate between direct and indirect effects. For the purpose of this review, direct effects of ethanol are caused by ethanol interacting with the fetal cell. Indirect effects of ethanol teratogenicity are defined as any perturbation of the developing fetus resulting from ethanol exposure but not caused by ethanol's interacting with the fetal cell. Indirect effects of ethanol teratogenicity include: ethanol-induced maternal undernutrition; ethanol-induced placental dysfunction and acetaldehyde teratogenicity. [ABSTRACT FROM PUBLISHER]

The article presents the authors analysis of data on infants to determine the placement outcomes of prenatally drug-exposed children two years after they had been placed in foster care. It reports on a study of infants referred at birth to the Los Angeles County, California Department of Children and Family Services (DCFS) from July 1989 to March 1991; the study included a two-year follow-up. The DCFS implements the directives of the Juvenile Court of Los Angeles County. Two years after being placed under the court's custody or DCFS supervision, the case status of each child was classified as either "open" or "closed." The subjects for this study included 1,041 infants prenatally exposed to street drugs in utero and a comparison group of 207 infants who had not been prenatally exposed to drugs but who had been removed from their mothers before hospital discharge for other reasons. The small comparison group was included to represent the more traditional foster care population. It is therefore important to contrast them with the new drug-exposed population.