Determining the exposure of maternal medicines through breastfeeding:the UmbrelLACT study protocol - a contribution from the ConcePTION project

Introduction:Breastfeeding is beneficial for the health of the mother and child. However, at least 50% of postpartum women need pharmacotherapy, and this number is rising due to the increasing prevalence of chronic diseases and pregnancies at a later age. Making informed decisions on medicine use while breastfeeding is often challenging, considering the extensive information gap on medicine exposure and safety during lactation. This can result in the unnecessary cessation of breastfeeding, the avoidance of pharmacotherapy or the off-label use of medicines. The UmbrelLACT study aims to collect data on human milk transfer of maternal medicines, child exposure and general health outcomes. Additionally, the predictive performance of lactation and paediatric physiologically based pharmacokinetic (PBPK) models, a promising tool to predict medicine exposure in special populations, will be evaluated. Methods and analysis:Each year, we expect to recruit 5-15 breastfeeding mothers using pharmacotherapy via the University Hospitals Leuven, the BELpREG project (pregnancy registry in Belgium) or external health facilities. Each request and compound will be evaluated on relevance (ie, added value to available scientific evidence) and feasibility (including access to analytical assays). Participants will be requested to complete at least one questionnaire on maternal and child's general health and collect human milk samples over 24 hours. Optionally, two maternal and one child's blood samples can be collected. The maternal medicine concentration in human milk will be determined along with the estimation of the medicine intake (eg, daily infant dose and relative infant dose) and systemic exposure of the breastfed child. The predictive performance of PBPK models will be assessed by comparing the observed concentrations in human milk and plasma to the PBPK predictions. Ethics and dissemination:This study has been approved by the Ethics Committee Research UZ/KU Leuven (internal study number S67204). Results will be published in peer-reviewed journals and presented at (inter)national scientific meetings. Trial registration number NCT06042803.</p

Case Report:Bosentan and Sildenafil Exposure in Human Milk - A Contribution From the ConcePTION Project

Introduction: Quantitative information on disposition of maternal medicines in human milk remains a major knowledge gap. This case report presents the clinical and pharmacokinetic data of a single mother-infant pair exposed to bosentan and sildenafil for the treatment of pulmonary arterial hypertension (PAH) during lactation. Case presentation: A 43-year old mother was treated with sildenafil (20 mg, 3x/day) and bosentan (125 mg, 2x/day) for PAH. Her 21-months old infant received breastfeeding in combination with adequate complementary foods. Milk samples were collected over 24 h, at day 637 and 651 after delivery. The observed average steady-state concentrations of sildenafil (2.84 μg/L) and bosentan (49.0 μg/L) in human milk were low. The Daily Infant Dosage ingested by the nursing infant through human milk was 0.02 μg/kg/day for sildenafil and 0.29 μg/kg/day for bosentan at day 637, and 0.03 μg/kg/day and 0.60 μg/kg/day at day 651. The Relative Infant Dose calculated for an exclusively breastfed infant with an estimated milk intake of 150 ml/kg/day, was 0.06% for sildenafil and 0.24% for bosentan. General health outcome of the infant, reported by the mother, was uneventful until the sampling days. Conclusion: Low medicine concentrations were found in human milk expressed 21 months after delivery after maternal intake of 20 mg sildenafil three times daily and 125 mg bosentan twice daily. General health of the nursing infant until sampling was reported as optimal by the mother

Determining the exposure of maternal medicines through breastfeeding:the UmbrelLACT study protocol - a contribution from the ConcePTION project

Introduction:Breastfeeding is beneficial for the health of the mother and child. However, at least 50% of postpartum women need pharmacotherapy, and this number is rising due to the increasing prevalence of chronic diseases and pregnancies at a later age. Making informed decisions on medicine use while breastfeeding is often challenging, considering the extensive information gap on medicine exposure and safety during lactation. This can result in the unnecessary cessation of breastfeeding, the avoidance of pharmacotherapy or the off-label use of medicines. The UmbrelLACT study aims to collect data on human milk transfer of maternal medicines, child exposure and general health outcomes. Additionally, the predictive performance of lactation and paediatric physiologically based pharmacokinetic (PBPK) models, a promising tool to predict medicine exposure in special populations, will be evaluated. Methods and analysis:Each year, we expect to recruit 5-15 breastfeeding mothers using pharmacotherapy via the University Hospitals Leuven, the BELpREG project (pregnancy registry in Belgium) or external health facilities. Each request and compound will be evaluated on relevance (ie, added value to available scientific evidence) and feasibility (including access to analytical assays). Participants will be requested to complete at least one questionnaire on maternal and child's general health and collect human milk samples over 24 hours. Optionally, two maternal and one child's blood samples can be collected. The maternal medicine concentration in human milk will be determined along with the estimation of the medicine intake (eg, daily infant dose and relative infant dose) and systemic exposure of the breastfed child. The predictive performance of PBPK models will be assessed by comparing the observed concentrations in human milk and plasma to the PBPK predictions. Ethics and dissemination:This study has been approved by the Ethics Committee Research UZ/KU Leuven (internal study number S67204). Results will be published in peer-reviewed journals and presented at (inter)national scientific meetings. Trial registration number NCT06042803.</p

Pasteurization of mother's own milk for preterm infants does not reduce the incidence of late-onset sepsis

Feeding preterm infants human milk has a beneficial effect on the risk of late-onset sepsis (LOS). Due to lack of microbiological standards, practices such as pasteurization of mother's own milk differ widely among neonatal intensive care units worldwide.status: publishe

Evolution of circulating thyroid hormone levels in preterm infants during the first week of life: perinatal influences and impact on neurodevelopment

Background For several decades, transient hypothyroxinemia of prematurity (THOP) has been a topic of debate. The pathophysiology is incompletely understood and consensus on the therapeutic approach is lacking. This study aimed at gaining a better insight into the pathogenesis by studying the trends in thyroid hormone (TH) levels during the first week of life. Methods This single-center prospective observational study analyzed the plasma levels of total thyroxine (T4) and free thyroxine (fT4), total triiodothyronine (T3), thyroid-stimulating hormone (TSH) and T4-binding globulin (TBG) in cord blood and at the end of the first week of life in 120 preterm infants (gestational age [GA] <37 weeks). The change over time was calculated (delta, ∆). The impact of perinatal and subsequently postnatal variables on ∆ was studied by hierarchical multiple regression. The impact of ∆ on the neurodevelopmental outcome at the corrected ages of 9 and 24 months, measured by the Bayley Scales of Infant Development (BSID)-II, was assessed by logistic regression. Results ∆fT4 levels were negatively affected by GA and use of dopamine, whereas only GA was associated with low ∆T3 levels. Negative ∆fT4 levels were present in 75% of the extremely low-for-gestational-age infants, whereas 23.5% had a negative ∆T3 level. There was an increased risk for an abnormal mental developmental score (<85) with decreasing ∆T3 at 9 months, corrected age, but not at 24 months. Conclusions A negative evolution in circulating TH levels is principally an immaturity phenomenon, whereas dopamine can further suppress the hypothalamic-pituitary-thyroid axis. There is at least a temporary negative effect of this evolution on the infants' neurodevelopment.status: publishe

Clinical and Biomechanical Progression after Ankle Joint Distraction in a Young Adolescent Patient with Haemophilia.

Ankle joint distraction (AJD) has been described to be a valuable joint-sparing alternative to arthrodesis or arthroplasty; however, clinical endpoints associated to this surgical intervention are lacking. The current case report describes clinical and biomechanical outcome measures of ankle joint distraction in a 14-year-old patient with severe haemophilia A. Because of persistent and incapacitating pain and the poor response to conservative and invasive treatment options, ankle joint distraction was performed in this 14-year-old patient using an external fixator encompassing two Ilizarov full rings in the tibia and a foot ring fixed to the foot by four K-wires. State-of-the-art medical imaging and non-invasive skin marker-based 3D multi-segment foot modelling were performed in a pre- and post-operative stage. From a structural viewpoint, this AJD was a success since it improved and stabilised the osteo-cartilaginous lesions of the ankle. Biomechanical outcome measures associated with the 18-month follow-up were found to be suboptimal, showing an early plantarflexion pattern at the ankle joint during midstance and a tendency towards increased power absorption at the midfoot with peak power absorption being almost two times higher when compared to boys of the same age. From a functional viewpoint, we observed a clear reduction in the patients' physical activities until one year after AJD. Despite these functional and structural improvements, recurrent painful phenomena, including the development of a complex regional pain syndrome (CRPS) and a stress fracture of the third metatarsal bone, were observed which are probably related with the development of recurrent subchondral oedema

Chronic renal failure: an unexpected presentation

Chronic renal failure in childhood is mostly caused by a congenital disorder or an acquired form of glomerulonephritis. We describe a case of a 13-year-old boy from Africa who presented with a cerebrovascular accident, malignant hypertension and renal insufficiency. Aetiological workup of his hypertension revealed underlying chronic renal failure due to histologically confirmed haemolytic uraemic syndrome. This case serves to remind clinicians of the serious complications of undiagnosed chronic renal failure in a child

SARS-CoV-2 Infections and Impact of the COVID-19 Pandemic in Pregnancy and Breastfeeding: Results from an Observational Study in Primary Care in Belgium

COVID-19 also affects pregnant and breastfeeding women. Hence, clinicians and policymakers require reliable evidence on COVID-19 epidemiology and consequences in this population. We aimed to assess the susceptibility of pregnant women to SARS-CoV-2 and women's perceived impact of the pandemic on their breastfeeding practices, medical counseling and social support. We performed a cross-sectional study using an online survey in primary care in Belgium. Pregnant and breastfeeding women and women who breastfed in the preceding four weeks were eligible to participate. The survey was distributed through social media in April 2020. In total, 6470 women participated (i.e., 2647 pregnant and 3823 breastfeeding women). Overall, 0.3% of all respondents reported to have tested positive for SARS-CoV-2, not indicating a higher susceptibility of pregnant women to contracting COVID-19. More than 90% refuted that the pandemic affected their breastfeeding practices, nor indicated that the coronavirus was responsible for breastfeeding cessation. Half of the women even considered giving longer breastmilk because of the coronavirus. In contrast, women's medical counseling and social support were negatively affected by the lockdown. Women without previous breastfeeding experience and in the early postpartum period experienced a higher burden in terms of reduced medical counseling and support. In the future, more consideration and alternative supportive measures such as tele-visits by midwives or perinatal organizations are required for these women.status: publishe

Review shows that thyroid hormone substitution could benefit transient hypothyroxinaemia of prematurity but treatment strategies need to be clarified

AIM: Thyroid hormones are crucial for foetal and neonatal brain development. This paper provides an overview of the normal role of thyroid hormones in foetal brain development and the pathophysiology of transient hypothyroxinaemia of prematurity (THOP). It also discusses the diagnostic and therapeutic controversies around THOP and looks at directions for future research. METHODS: We used the PubMed and Embase databases to identify papers published in English from 1969 to June 2018. This identified 20 papers about the impact of THOP on neurodevelopment and seven randomised controlled trials about therapeutic approaches from 1981-2016. RESULTS: THOP has been researched for more than three decades. The impact of temporarily low thyroxine levels, without any increase in pituitary-secreted thyroid-stimulating hormone at a critical timeframe in an infant's brain development, is still debated. Heterogeneity in THOP definitions, difficulties with thyroid hormone assessment, identifying patients at risk and a clear lack of sufficiently powered studies add to the current controversy. There are indications that thyroid hormone substitution might be useful in extremely low gestational age neonates with THOP. CONCLUSION: Some preterm infants could benefit from THOP treatment, but more studies are needed to clarify further treatment strategies, including the optimal timing of initiation and duration.status: publishe