Search Results (22)

Background/Objectives: While breastfeeding is highly recommended, breastfed infants may be exposed to drugs by milk due to maternal pharmacotherapy, resulting in a risk of adverse drug events (ADE) or reactions (ADRs). The U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) is an online pharmacovigilance database, while the Drugs and Lactation Database (LactMed^®) includes accurate and evidence-based information on levels of substances in breast milk and infant blood, and possible ADRs in nursing infants. We aimed to explore the FAERS database and compare ADE/ADR information patterns between both databases. Methods: The FAERS database was explored (29 July 2024) for ADEs related to drug exposure during lactation to determine annual trends, infant outcomes, and regions of reporting. The active pharmaceutical ingredients (APIs) associated with these ADEs were categorized based on the Anatomical Therapeutic Chemical (ATC, first level) classification. The top five APIs in each ATC group were explored in terms of the type of ADEs reported and compared to information in LactMed^®. Results: In total, 2628 ADEs were obtained from the FAERS database, with increased reporting over time. In the FAERS database, 68.4% of the patients were under 2 months old, 5.5% had life threatening ADEs, and 3.6% died, while 84.70% of the cases were categorized as serious. Most ADEs were from North America (44.9%). Most drugs (50.9%) were nervous system drugs. The most frequent reported outcome was “other outcomes (without additional subdivision or information)” (58.2%), reflecting the diversity in outcomes reported. When related to the same drug, the FAERS database and LactMed^® resource exhibited both similarities and differences in the types of reported ADE/ADR. Conclusions: The FAERS database is a useful tool to detect potential ADEs (rather sensitive), without ADR assessment, while LactMed^® provides guidance driven by relevant ADRs (rather specific). The FAERS database is useful to obtain exploratory information about ADEs during lactation to increase the knowledge about drug safety during breastfeeding and the awareness of the possible risks in nursing infants, while LactMed^® translates all available information into guidance. Full article

The Vietnam Ministry of Health (MOH) has intensified efforts in its aim to eliminate AIDS by 2030. Expanding the program for prevention of mother-to-child transmission (PMTCT) is a significant step towards achieving this goal. However, there are still HIV-exposed children who do not have access to PMTCT services, and some who have participated in the program but still contracted HIV. This study focused on assessing the prevalence and profile of HIV mutations among children under 18 months of age who had recently tested positive for HIV, while gaining insights into the implementation of early infant diagnostic (EID) tests. Between 2017 and 2021, 3.43% of 5854 collected dry blood spot (DBS) specimens from Vietnam’s Central and Southern regions showed positive EID results. This study identified a high prevalence of resistance mutations in children, totaling 62.9% (95% CI: 53.5–72.3). The highest prevalence of mutations was observed for NNRTIs, with 57.1% (95% CI: 47.5–66.8). Common mutations included Y181C and K103N (NNRTI resistance), M184I/V (NRTI resistance), and no major mutations for PI. The percentage of children with any resistance mutation was significantly higher among those who received PMTCT interventions (69.2%; 95% CI: 50.5–92.6%) compared with those without PMTCT (45.0%; 95% CI: 26.7–71.1%) with χ2 = 6.06, p = 0.0138, and OR = 2.75 (95% CI: 1.13–6.74). Mutation profiles revealed that polymorphic mutations could be present regardless of whether PMTCT interventions were implemented or not. However, non-polymorphic drug resistance mutations were predominantly observed in children who received PMTCT measures. Regarding PMTCT program characteristics, this study highlights the issue of late access to HIV testing for both mothers and their infected children. Statistical differences were observed between PMTCT and non-PMTCT children. The proportion of late detection of HIV infection and breastfeeding rates were significantly higher among non-PMTCT children (p < 0.05). Comparative analysis between children with low viral load (≤200 copies/mL) and high viral load (>200 copies/mL) showed significant differences between the mothers’ current ART regimens (p = 0.029) and the ARV prophylaxis regimen for children (p = 0.016). These findings emphasize the need for comprehensive surveillance to assess the effectiveness of the PMTCT program, including potential transmission of HIV drug-resistance mutations from mothers to children in Vietnam. Full article

Dolutegravir (DTG) is one of the most prescribed antiretroviral drugs for treating people with HIV infection, including women of child-bearing potential or pregnant. Nonetheless, neuropsychiatric symptoms are frequently reported. Early reports suggested that, probably in relation to folic acid (FA) shortage, DTG may induce neural tube defects in infants born to women taking the drug during pregnancy. Subsequent reports did not definitively confirm these findings. Recent studies in animal models have highlighted the association between DTG exposure in utero and congenital anomalies, and an increased risk of neurologic abnormalities in children exposed during in utero life has been reported. Underlying mechanisms for DTG-related neurologic symptoms and congenital anomalies are not fully understood. We aimed to deepen our knowledge on the neurodevelopmental effects of DTG exposure and further explore the protective role of FA by the use of zebrafish embryos. We treated embryos at 4 and up to 144 h post fertilization (hpf) with a subtherapeutic DTG concentration (1 μM) and observed the disruption of the anterior–posterior axis and several morphological malformations in the developing brain that were both prevented by pre-exposure (2 hpf) and rescued by post-exposure (10 hpf) with FA. By whole-mount in situ hybridization with riboprobes for genes that are crucial during the early phases of neurodevelopment (ntl, pax2a, ngn1, neurod1) and by in vivo visualization of the transgenic Tg(ngn1:EGFP) zebrafish line, we found that DTG induced severe neurodevelopmental defects over time in most regions of the nervous system (notochord, midbrain–hindbrain boundary, eye, forebrain, midbrain, hindbrain, spinal cord) that were mostly but not completely rescued by FA supplementation. Of note, we observed the disruption of ngn1 expression in the dopaminergic regions of the developing forebrain, spinal cord neurons and spinal motor neuron projections, with the depletion of the tyrosine hydroxylase (TH)⁺ dopaminergic neurons of the dorsal diencephalon and the strong reduction in larvae locomotion. Our study further supports previous evidence that DTG can interfere with FA pathways in the developing brain but also provides new insights regarding the mechanisms involved in the increased risk of DTG-associated fetal neurodevelopmental defects and adverse neurologic outcomes in in utero exposed children, suggesting the impairment of dopaminergic pathways. Full article

Maintenance of remission during pregnancy is vital for women with inflammatory bowel disease (IBD). The antenatal safety of novel small molecules for IBD is yet to be ascertained. We aimed to describe the current evidence on reproductive data regarding small-molecule drugs. We performed a systematic review searching Embase Classic + Embase and Ovid MEDLINE for reproductive outcomes for tofacitinib, filgotinib, upadacitininb, and ozanimod. Additionally, we asked the manufacturers for available data on file regarding reproduction. We analysed data from 10 sources; six studies and four manufacturer reports were identified from our search. Significant malformation risks were reported for tofacitinib, filgotinib, upadacitininb, and ozanimod in animal studies. In 126 tofacitinib-exposed pregnancies, there were 55 live births with 2 congenital malformations and 1 serious infant infection, 14 terminations, 15 miscarriages, and 42 outcomes unknown. In 50 filgotinib-exposed pregnancies, there were 20 healthy babies, 1 congenital malformation, 9 terminations, 10 miscarriages, and 10 outcomes unknown. In 78 upadacitinib-exposed pregnancies, there were 30 healthy babies, 15 terminations, 15 miscarriages, and 18 outcomes unknown. In 60 ozanimod-exposed pregnancies, there were 31 live births with 1 congenital malformation, 1 case of intra-uterine growth restriction, 1 case of neonatal icterus, 13 terminations, 9 miscarriages, and 8 unknown outcomes. Animal data suggest significant risks of malformations for tofacitinib, filgotinib, upadacitininb, and ozanimod. Human data from clinical trials and real-world observations do not show concerning data so far, but these are very limited. Currently, alternative treatments should be used for IBD during pregnancy. Full article

Sertoli cells are essential for germ cell development and function. Their disruption by endocrine disrupting chemicals (EDCs) or drugs could jeopardize spermatogenesis, contributing to male infertility. Perinatal exposure to EDCs and acetaminophen (APAP) disrupts male reproductive functions in animals and humans. Infants can be exposed simultaneously to the dietary soy phytoestrogen genistein (GEN) and APAP used for fever or pain relief. Our goal was to determine the effects of 10–100 µM APAP and GEN, alone or mixed, on immature Sertoli cells using mouse TM4 Sertoli cell line and postnatal-day 8 rat Sertoli cells, by measuring cell viability, proliferation, prostaglandins, genes and protein expression, and functional pathways. A value of 50 µM APAP decreased the viability, while 100 µM APAP and GEN decreased the proliferation. Sertoli cell and eicosanoid pathway genes were affected by GEN and mixtures, with downregulation of Sox9, Cox1, Cox2, and genes relevant for Sertoli cell function, while genes involved in inflammation were increased. RNA-seq analysis identified p53 and TNF signaling pathways as common targets of GEN and GEN mixture in both cell types. These results suggest that APAP and GEN dysregulate immature Sertoli cell function and may aid in elucidating novel EDC and drug targets contributing to the etiology of male infertility. Full article

Neonatal abstinence syndrome (NAS) has been of increasing concern. Studies suggest that prenatal exposure to buprenorphine may be preferred to methadone in regard to neonatal withdrawal. Our aim was to determine whether the incidence and severity of NAS are different between babies prenatally exposed to methadone or buprenorphine in pregnancy. This retrospective analysis of infants ≥ 35-weeks-old exposed to methadone/buprenorphine alone or in conjunction with other substances in utero. They were divided into four groups: 1—methadone alone (Met), 2—buprenorphine alone (Bup), 3 and 4—those exposed to methadone and buprenorphine, respectively, in conjunction with other drugs (Met+ and Bup+). The frequency of NAS treatment, duration of treatment (LOT) and length of stay (LOS) were compared between groups. Of the 290 mothers, 59% were in the Met group, 18% in the Bup group, 14% in the Met or Bup and another opiate group, and 9% took methadone or buprenorphine plus various other substances. Infants born to Met/Met+ mothers had a four-times higher likelihood of developing NAS (p < 0.001). There was no difference in the LOS (p = 0.08) or LOT (p = 0.11) between groups. The buprenorphine treatment in pregnancy decreased the risk of babies developing NAS. However, once the NAS required pharmacological treatment, the type of maternal prenatal exposure did not affect the LOS or LOT. Full article

Infants of mothers treated for tuberculosis might be exposed to drugs via breast milk. The existing information on the exposure of breastfed infants lacks a critical review of the published data. We aimed to evaluate the quality of the existing data on antituberculosis (anti-TB) drug concentrations in the plasma and milk as a methodologically sound basis for the potential risk of breastfeeding under therapy. We performed a systematic search in PubMed for bedaquiline, clofazimine, cycloserine/terizidone, levofloxacin, linezolid, pretomanid/pa824, pyrazinamide, streptomycin, ethambutol, rifampicin and isoniazid, supplemented with update references found in LactMed^®. We calculated the external infant exposure (EID) for each drug and compared it with the recommended WHO dose for infants (relative external infant dose) and assessed their potential to elicit adverse effects in the breastfed infant. Breast milk concentration data were mainly not satisfactory to properly estimate the EID. Most of the studies suffer from limitations in the sample collection, quantity, timing and study design. Infant plasma concentrations are extremely scarce and very little data exist documenting the clinical outcome in exposed infants. Concerns for potential adverse effects in breastfed infants could be ruled out for bedaquiline, cycloserine/terizidone, linezolid and pyrazinamide. Adequate studies should be performed covering the scenario in treated mothers, breast milk and infants. Full article

Introduction: A significant increase in psychoactive drugs use was observed in women of childbearing age and during the perinatal period worldwide. Yet, the use of illicit drugs, alcohol and tobacco during pregnancy is a serious health risk for the mother, developing fetus and newborn. Methods: This review of current trends and consequences of psychoactive substance use in the general population and in pregnant women was conducted using the English and French literature published during the years 2000 to 2022, supplemented by guidelines, meta-analyses and reviews. Results: According to current rates of prenatal substances use, it was calculated that 380,000 offspring were exposed to illicit substances, more than 500,000 to alcohol and over one million to tobacco during uterine life. Alarmingly, drug-related pregnancy-associated mortality has shown a staggering 190% rise between 2010 and 2019 in the USA. Different drugs of abuse, when used during pregnancy, increase the risk of stillbirth, neonatal abstinence syndrome and sudden infant death. Adverse effects on pregnancy include premature rupture of membranes, placental abruption, preterm birth, low birth space? weight and small-for-gestational-age infants. There is also an increased risk of morbidity and mortality for the pregnant women. Long-term negative adverse effects of perinatal exposure to substances also include a number of neurocognitive, behavioral and emotional dysfunctions in infants. Each type of substance has its own specificities, which will be briefly summarized. Conclusion: All childbearing age women must be informed about the potential harm of the prenatal use of psychoactive substances and should be encouraged to stop their use when pregnancy is planned and, at least, when pregnancy is known. Questioning women about their alcohol consumption should be systematic at the first prenatal visit and then at every prenatal visit until delivery. Multidisciplinary prevention approaches as well as intervention measures targeted to each type of psychoactive substance can save mothers’ lives and mitigate serious adversities to the offspring. Full article

Infants might be exposed to pain during their admissions in the neonatal intensive care unit [NICU], both from their underlying conditions and several invasive procedures required during their stay. Considering the particularities of this population, recognition and adequate management of pain continues to be a challenge for neonatologists and investigators. Diverse therapies are available for treatment, including non-pharmacological pain management measures and pharmacological agents (sucrose, opioids, midazolam, acetaminophen, topical agents…) and research continues. In recent years one of the most promising drugs for analgesia has been dexmedetomidine, an alpha-2 adrenergic receptor agonist. It has shown a promising efficacy and safety profile as it produces anxiolysis, sedation and analgesia without respiratory depression. Moreover, studies have shown a neuroprotective role in animal models which could be beneficial to neonatal population, especially in preterm newborns. Side effects of this therapy are mainly cardiovascular, but in most studies published, those were not severe and did not require specific therapeutic measures for their resolution. The main objective of this article is to summarize the existing literature on neonatal pain management strategies available and review the efficacy of dexmedetomidine as a new therapy with increasing use in the NICU. Full article

As most new medications, Cabotegravir (CAB) was recently approved as an antiretroviral treatment of HIV infection without in-depth safety information on in utero exposure. Although no developmental toxicity in rats and rabbits was reported, recent studies demonstrated that CAB decreases pluripotency of human embryonic stem cells. CAB exposure effects during development were assessed in zebrafish embryos by the Fish Embryo Toxicity test after exposure at subtherapeutic concentrations up to 25× the human C_max. Larvae behavior was assessed by the light–dark locomotion test. The expression of factors involved in neurogenesis was evaluated by whole-mount in situ hybridization. CAB did not cause gross morphological defects at low doses, although pericardial edema, uninflated swim bladder, decreased heartbeats, growth delay, and decreased hatching rate were observed at the highest concentrations. Decreased locomotion was observed even at the subtherapeutic dose, suggesting alterations of nervous system integrity. This hypothesis was supported by the observation of decreased expression of crucial factors involved in early neuronal differentiation in diencephalic and telencephalic dopaminergic areas, midbrain/hindbrain boundary, and craniofacial ganglia. These findings support CAB effects on neurogenesis in zebrafish embryos and suggest long-term follow-up of exposed infants to provide data on drug safety during pregnancy. Full article

Premature infants are exposed to increased generation of reactive oxygen species, and on the other hand, they have a deficient antioxidant defense system. Oxidative insult is a salient part of lung injury that begins as acute inflammatory injury in respiratory distress disease and then evolves into chronic and structural scarring leading to bronchopulmonary dysplasia. Oxidative stress is also involved in the pathogenesis of pulmonary hypertension in newborns through the modulation of the vascular tone and the response to pulmonary vasodilators, with consequent decrease in the density of the pulmonary vessels and thickening of the pulmonary arteriolar walls. Oxidative stress has been recognized as both a trigger and an endpoint for several events, including inflammation, hypoxia, hyperoxia, drugs, transfusions, and mechanical ventilation, with impairment of pulmonary function and prolonged lung damage. Redoxomics is the most fascinating new measure to address lung damage due to oxidative stress. The new challenge is to use omics data to discover a set of biomarkers useful in diagnosis, prognosis, and formulating optimal and individualized neonatal care. The aim of this review was to examine the most recent evidence on the relationship between oxidative stress and lung diseases in preterm newborns. What is currently known regarding oxidative stress-related lung injury pathogenesis and the available preventive and therapeutic strategies are also discussed. Full article

Neonatal sepsis is a leading cause of death among newborns and infants, especially in the developing world. The problem is compounded by the delays in pinpointing the causative agent of the infection. This is reflected in increasing mortality associated with these cases and the spread of multi-drug-resistant bacteria. In this work, we deployed bioinformatics and proteomics analyses to determine a promising target that could be used for the identification of a major neonatal sepsis causative agent, Klebsiella pneumoniae. A 19 amino acid peptide from a hypothetical outer membrane was found to be very specific to the species, well conserved among its strains, surface exposed, and expressed in conditions simulating infection. Antibodies against the selected peptide were conjugated to gold nanoparticles and incorporated into an immunochromatographic strip. The developed strip was able to detect as low as 10⁵ CFU/mL of K. pneumoniae. Regarding specificity, it showed negative results with both Escherichia coli and Enterobacter cloacae. More importantly, in a pilot study using neonatal sepsis cases blood specimens, the developed strip selectively gave positive results within 20 min with those infected with K. pneumoniae without prior sample processing. However, it gave negative results in cases infected with other bacterial species. Full article

Pregnancy-related cancer management represents a real challenge for both the patients and the physicians. The long-term neurodevelopmental outcome of children in utero exposed to chemotherapeutic agents has only recently been addressed. This review aims to systematically integrate and highlight all existing data from the literature regarding the effect of prenatal exposure to chemotherapy on fetal brain growth and child development. All eligible studies are based on validated neurodevelopmental testing scales (e.g., Bayley Scales of Infant Development, Wechsler Preschool and Primary Scale of Intelligence) and/or well-defined questionnaires. Our systematic review including 17 studies demonstrates that no major consequences on the neurodevelopment of children after in utero exposure to anti-cancer drugs have been reported; nevertheless, longer and more thorough follow-up with large-scale multicenter prospective studies is certainly required in order to draw firm conclusions. Full article

Infant antiretroviral (ARV) prophylaxis given to children who are human immunodeficiency virus (HIV)-exposed but uninfected (CHEU) to prevent HIV transmission through breastfeeding previously proved its efficacy in the fight against the pediatric epidemic. However, few studies have investigated the short- and long-term safety of prophylactic regimens. We previously reported a decrease of mitochondrial DNA (mtDNA) content among CHEU who received one year of lamivudine (3TC) or lopinavir-boosted ritonavir (LPV/r) as infant prophylaxis. We aimed to describe mtDNA content at six years of age among these CHEU, including those for whom we identified mtDNA depletion at week 50 (decrease superior or equal to 50% from baseline), and to compare the two prophylactic drugs. We also addressed the association between mtDNA depletion at week 50 with growth, clinical, and neuropsychological outcomes at year 6. Quantitative PCR was used to measure mtDNA content in whole blood of CHEU seven days after birth, at week 50, and at year 6. Among CHEU with identified mtDNA depletion at week 50 (n = 17), only one had a persistent mtDNA content decrease at year 6. No difference between prophylactic drugs was observed. mtDNA depletion was not associated with growth, clinical, or neuropsychological outcomes at year 6. This study brought reassuring data concerning the safety of infant 3TC or LPV/r prophylaxis. Full article

Respiratory syncytial virus (RSV) causes substantial lower respiratory tract disease in children and at-risk adults. Though there are no effective anti-viral drugs for acute disease or licensed vaccines for RSV, palivizumab prophylaxis is available for some high risk infants. To support anti-viral and vaccine development efforts, we developed an RSV virus-like particle (VLP) platform to explore the role RSV F and G protein interactions in disease pathogenesis. Since VLPs are immunogenic and a proven platform for licensed human vaccines, we also considered these VLPs as potential vaccine candidates. We developed two RSV VLP platforms, M+P and M+M2-1 that had F and G, F and a G peptide, or a truncated F and G on their surface. Immunoblots of sucrose gradient purified particles showed co-expression of M, G, and F with both VLP platforms. Electron microscopy imaging and immunogold labeling confirmed VLP-like structures with surface exposed projections consistent with F and G proteins. In mice, the VLPs induced both anti-F and -G protein antibodies and, on challenge, reduced lung viral titer and inflammation. These data show that these RSV VLP platforms provide a tool to study the structure of F and G and their interactions and flexible platforms to develop VLP vaccines in which all components contribute to RSV-specific immune responses. Full article