INFANT Research Centre

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INFANT A research centre focused entirely on pregnancy, birth and early childhood. Hosted at University College Cork (UCC), Cork, Ireland, The Irish Centre for Maternal and Child Health Research has local impact with a global reach. INFANT is answering the international need for research and innovation to improve health outcomes for mothers and babies. Across pregnancy, birth, infancy and childhood, INFANT is solving challenges through its key research themes

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Accurate wearable heart rate monitoring during physical exercises using PPG
(IEEE, 2017-03-01) Temko, Andriy; Science Foundation Ireland
Objective: The challenging task of heart rate (HR) estimation from the photoplethysmographic (PPG) signal, during intensive physical exercises is tackled in this paper. Methods: The study presents a detailed analysis of a novel algorithm (WFPV) that exploits a Wiener filter to attenuate the motion artifacts, a phase vocoder to refine the HR estimate and user-adaptive postprocessing to track the subject physiology. Additionally, an offline version of the HR estimation algorithm that uses Viterbi decoding is designed for scenarios that do not require online HR monitoring (WFPV+VD). The performance of the HR estimation systems is rigorously compared with existing algorithms on the publically available database of 23 PPG recordings. Results: On the whole dataset of 23 PPG recordings, the algorithms result in average absolute errors of 1.97 and 1.37 BPM in the online and offline modes, respectively. On the test dataset of 10 PPG recordings which were most corrupted with motion artifacts, WFPV has an error of 2.95 BPM on its own and 2.32 BPM in an ensemble with 2 existing algorithms. Conclusion: The error rate is significantly reduced when compared with the state-of-the art PPG-based HR estimation methods. Significance: The proposed system is shown to be accurate in the presence of strong motion artifacts and in contrast to existing alternatives has very few free parameters to tune. The algorithm has a low computational cost and can be used for fitness tracking and health monitoring in wearable devices. The Matlab implementation of the algorithm is provided online.
Activation of a TLR9 mediated innate immune response in preeclampsia
(Nature Publishing Group, 2019-04-11) Williamson, Rachel D.; McCarthy, Fergus P.; Kenny, Louise C.; McCarthy, Cathal M.; Science Foundation Ireland; Health Research Board
Preeclampsia is a multisystemic disorder leading to the development of a placental ischemic microenvironment with a resultant increase in oxidative stress. There is evidence that mitochondrial dysfunction and the innate immune system both play a role in the pathophysiology of this disease. Mitochondrial DAMPs such as mtDNA bind specific pattern recognition receptors such as Toll-like receptor 9 (TLR9) on the endosomal surface of immune cells, in particular neutrophils, subsequently activating them and triggering an innate response. We hypothesised that the exaggerated innate immune response seen in preeclampsia is provoked by dysfunctional mitochondria. Here we provide evidence that TLR9 activity is significantly increased at time of disease in women with preeclampsia. Furthermore, we show activation of neutrophil markers, Calprotectin, Myeloperoxidase (MPO), and IL-8 are significantly increased at time of disease compared to uncomplicated pregnancies. This research supports a potential role of TLR9 activation of an innate immune response evident in preeclampsia which may possibly be initially triggered by dysfunctional mitochondria.
Adherence to the infant vitamin D supplementation policy in Ireland
(Springer Nature Switzerland AG, 2020-07-17) Hemmingway, Andrea; Fisher, Dawn; Berkery, Teresa; Murray, Deirdre M.; Kiely, Mairead E.; Science Foundation Ireland; European Regional Development Fund; National Children’s Research Centre, Ireland
Purpose: From September 2010 until November 2019, Ireland’s infant vitamin D supplementation policy recommended administration of 5 μg/day of vitamin D3 from birth to 12 months to all infants, regardless of feeding method. This study aims to examine policy adherence. Methods: In the prospective COMBINE birth cohort study (recruited 2015–2017), detailed longitudinal supplement data were examined in 364 infants across the first year of life, according to product type, dose, frequency, and duration. Vitamin D supplement use at 2, 6, and 12 months in COMBINE was compared with the BASELINE cohort (recruited 2008–2011, n = 1949). Results: In COMBINE, 92% of infants initiated supplementation at birth. The median supplementation duration was 51 (40, 52) weeks, with a range of 3–52 weeks. While supplementing, most parents (92%) used an exclusive vitamin D supplement as recommended and 88% gave 5 µg/day. Half (51%) gave vitamin D daily and a further 33% supplemented at least 3–6 times/week. Overall, 30% adhered fully to the policy, providing 5 µg vitamin D3 daily from birth to 12 months. A further 16% were broadly compliant, giving 5 µg frequently for the full 12 months. Vitamin D supplement use at 2, 6, and 12 months in COMBINE was 93%, 89%, and 72%, considerably higher than our earlier BASELINE cohort at 49%, 64%, and 44% at the same time points (all P < 0.001). Conclusions: We report a high level of vitamin D supplementation initiation at birth, with full to broad policy adherence among more than half of infants. There is scope to improve overall compliance by focusing on supplementation frequency.
Adverse pregnancy outcomes and long-term risk of maternal renal disease: a systematic review and meta-analysis protocol
(BMJ Publishing Group, 2019-05-05) Barrett, Peter M.; McCarthy, Fergus P.; Kublickiene, Karolina; Evans, Marie; Cormican, Sarah; Judge, Conor; Perry, Ivan J.; Kublickas, Marius; Stenvinkel, Peter; Khashan, Ali S.; Health Research Board; Wellcome Trust; Health Service Executive; Health and Social Care, Research and Development, Northern Ireland
Introduction: Adverse pregnancy outcomes, such as hypertensive disorders of pregnancy (HDP), gestational diabetes (GDM) and preterm birth have been linked to maternal cardiovascular disease in later life. Pre-eclampsia (PE) is associated with an increased risk of postpartum microalbuminuria, but there is no clear consensus on whether HDP increases the risk of maternal chronic kidney disease (CKD) and end-stage kidney disease (ESKD). Similarly, it is uncertain whether GDM, preterm birth and delivery of low birth-weight infants independently predict the risk of maternal renal disease in later life. The aims of this proposed systematic review and meta-analysis are to summarise the available evidence examining the association between adverse outcomes of pregnancy (HDP, GDM, preterm birth, delivery of low birth-weight infant) and later maternal renal disease and to synthesise the results of relevant studies. Methods and analysis: A systematic search of PubMed, EMBASE and Web of Science will be undertaken using a detailed prespecified search strategy. Two authors will independently review the titles and abstracts of all studies, perform data extraction and appraise the quality of included studies using a bias classification tool. Original case–control and cohort studies published in English will be considered for inclusion. Primary outcomes of interest will be CKD and ESKD; secondary outcomes will be hospitalisation for renal disease and deaths from renal disease. Meta-analyses will be performed to calculate the overall pooled estimates using the generic inverse variance method. The systematic review will follow the Meta-analyses Of Observational Studies in Epidemiology guidelines. Ethics and dissemination: This systematic review and meta-analysis will be based on published data, and thus there is no requirement for ethics approval. The results will be shared through publication in a peer reviewed journal and through presentations at academic conferences. PROSPERO registration number CRD42018110891
Adverse pregnancy outcomes and the long-term risk of maternal kidney disease
(University College Cork, 2021-01-06) Barrett, Peter M.; Khashan, Ali; McCarthy, Fergus; Kublickiene, Karolina; Wellcome Trust; Health Research Board
Background: Adverse pregnancy outcomes, including hypertensive disorders of pregnancy (HDP), preterm delivery, foetal growth restriction, gestational diabetes (GDM), and pregnancy loss, have been associated with the risk of maternal chronic disease, particularly cardiovascular disease. Less is known about the long-term risk of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) in women who have experienced pregnancy complications. This thesis aims to examine associations between adverse pregnancy outcomes and the risk of maternal CKD and ESKD in later life. Structure and methods: This thesis begins with an introductory chapter (Chapter 1) followed by a systematic review and meta-analysis of the published literature, based on a pre-specified protocol (Chapter 2). A detailed methods chapter outlines the data sources, study design, exposure and outcome variables, and statistical approach used in each of the original observational studies conducted for this research (Chapter 3). Four population-based cohort studies are presented, and they focus on the risk of maternal kidney disease following preterm delivery (Chapter 4), stillbirth (Chapter 5), HDP (preeclampsia and gestational hypertension) (Chapter 6) and GDM (Chapter 7) respectively. In each study, data from the Swedish national registers are used, and analyses are based on Cox proportional hazard regression models with time-dependent covariates, adjusted for a wide range of medical, obstetric, and socio-demographic factors. In Chapter 8, an updated systematic review and meta-analysis is presented to reflect newly published literature on this topic. This is followed by a discussion and interpretation of the key findings, including consideration of the public health implications arising from this work (Chapter 9). Finally, conclusions of the thesis are presented in Chapter 10. Results: (i) Updated systematic review and meta-analysis - Overall, the published literature on this topic was sparse and most meta-analyses were based on small numbers (<5) of original studies. HDP and preterm delivery were associated with higher risk of long-term kidney disease in parous women. Preeclampsia was associated with a strongly increased risk of ESKD (adjusted risk ratio (aRR) 4.90; 95% CI, 3.56-6.74) and a modest increased risk of CKD (aRR 1.73, 95% CI 1.42-2.12). Gestational hypertension was associated with a strongly increased risk of ESKD (aRR, 3.64, 95% CI, 2.34-5.66), and more modest increased risk of CKD (aRR 1.48, 95% CI 1.38-1.58). Preterm delivery was associated with an increased risk of ESKD (aRR 2.19, 95% CI 1.93-2.47), but there were too few studies to determine the risk of CKD, or to separate the effects of iatrogenic vs. spontaneous preterm deliveries. No significant association was observed between GDM and CKD (aRR 1.04, 95% CI 0.76-1.41), but this meta-analysis was based on pooled estimates from just two studies. (ii) Original population-based cohort studies - Preterm delivery was associated with increased risk of both CKD and ESKD in our study. This association was strongest in women who experienced iatrogenic preterm delivery (due to preeclampsia or small for gestational age (SGA)), but the risk persisted in women who only had spontaneous preterm deliveries compared to women who delivered at term (for CKD, aHR 1.32, 95% CI 1.25-1.39; for ESKD, aHR 1.99, 95% CI 1.67-2.38). Separately, stillbirth was alsoassociated with an increased risk of both CKD (aHR 1.26, 95% CI 1.09–1.45) and ESKD (aHR 2.25, 95% CI 1.55-3.25) compared to women who only experienced live births. These associations persisted independent of preeclampsia, SGA or congenital malformations. Preeclampsia was associated with a higher risk of CKD during follow-up (vs. no preeclampsia, aHR 1.92, 95% CI 1.83–2.03), but this risk differed by CKD subtype and was greater for hypertensive CKD, diabetic CKD, and glomerular/proteinuric CKD. Women who experienced preterm preeclampsia, recurrent preeclampsia, or preeclampsia complicated by antenatal obesity were at particularly high risk of CKD. There was also a modest risk of CKD among women who experienced gestational hypertension (vs. none, aHR 1.49, 95% CI 1.38–1.61). GDM-diagnosed women were at increased risk of CKD and ESKD overall. However, when GDM was stratified according to those who developed post-pregnancy type 2 diabetes (T2DM), the associations between GDM alone (without later T2DM) and maternal kidney disease were non-significant (for CKD, 1.11, 95% CI 0.89-1.38; for ESKD, aHR 1.58, 95% CI 0.70-3.60). By contrast, strong associations were observed with CKD and ESKD in those who had GDM followed by subsequent T2DM. Conclusion: Adverse pregnancy outcomes, specifically preeclampsia, gestational hypertension, preterm delivery and stillbirth, are associated with increased risk of maternal CKD and ESKD. These associations persisted in a nationwide cohort after controlling for a wide range of confounders. Although the relative risk of future kidney disease is highest for ESKD, associations with CKD are likely to be of greater importance from a population perspective, given the high prevalence of CKD. Women who experience adverse pregnancy outcomes may warrant systematic follow-up to prevent onset or progression of future kidney disease, but the optimal format and timing of this follow-up requires further research.
All Island Congenital Heart Network brings diagnosis closer to home
(Irish Medical Organisation, 2022-12) Finn, Daragh; Allawendy, S.A.A.; Dempsey, Eugene M.; McMahon, C. J.
Aim: The All-Island congenital heart network appointed paediatricians with expertise in cardiology in regional centres. Prior to these appointments children with suspected congenital heart disease were referred to the national children’s heart centre for investigation. The aim of this study is to quantify paediatric cardiology activity in a regional Irish centre over the first year of service provision. Methods: Data was collected retrospectively on all inpatient neonatal referrals over a 12-month period (January 2019 to January 2020). Results: There were 268 neonatal referrals. Premature infants (< 37 weeks gestation) accounted for 26% (n= 69) of total neonatal referrals. Congenital cardiac disease was identified in 58.5% (n= 113) of referrals. Cardiac intervention in the first year of life was required in 24 infants, 12.2% of referrals (5.6% catheter and 6.6% surgery). Discussion: Our report displays how clinical networks of care can reduce hospital transfers from regional neonatal centres for non-invasive cardiology investigations.
Altered inflammasome activation in neonatal encephalopathy persists in childhood
(John Wiley and Sons Ltd, 2021-07) Kelly, Lynne A.; O'Dea, Mary I.; Zareen, Zunera; Melo, A. M.; McKenna, Ellen; Strickland, Tammy; McEneaney, V.; Donoghue, Veronica; Boylan, Geraldine B.; Sweetman, Deirdre; Butler, J.; Vavasseur, Claudine; Miletin, Jan; El-Khuffash, Afif; O'Neill, Luke; O'Leary, John; Molloy, Eleanor J.; National Children's Research Centre; Health Research Board
Neonatal encephalopathy (NE) is characterized by altered neurological function in term infants and inflammation plays an important pathophysiological role. Inflammatory cytokines interleukin (IL)-1 beta, IL-1ra and IL-18 are activated by the nucleotide-binding and oligomerization domain (NOD)-, leucine-rich repeat domain (LRR)- and NOD-like receptor protein 3 (NLRP3) inflammasome; furthermore, we aimed to examine the role of the inflammasome multiprotein complex involved in proinflammatory responses from the newborn period to childhood in NE. Cytokine concentrations were measured by multiplex enzyme-linked immunosorbent assay (ELISA) in neonates and children with NE in the absence or presence of lipopolysaccharide (LPS) endotoxin. We then investigated expression of the NLRP3 inflammasome genes, NLRP3, IL-1 beta and ASC by polymerase chain reaction (PCR). Serum samples from 40 NE patients at days 1 and 3 of the first week of life and in 37 patients at age 4-7 years were analysed. An increase in serum IL-1ra and IL-18 in neonates with NE on days 1 and 3 was observed compared to neonatal controls. IL-1ra in NE was decreased to normal levels at school age, whereas serum IL-18 in NE was even higher at school age compared to school age controls and NE in the first week of life. Percentage of LPS response was higher in newborns compared to school-age NE. NLRP3 and IL-1 beta gene expression were up-regulated in the presence of LPS in NE neonates and NLRP3 gene expression remained up-regulated at school age in NE patients compared to controls. Increased inflammasome activation in the first day of life in NE persists in childhood, and may increase the window for therapeutic intervention.
Amniotic fluid C-reactive protein as a predictor of infection in caesarean section: a feasibility study
(Nature Publishing Group, ) Marchocki, Zbigniew; Vinturache, Angela; Collins, Kevin; O'Reilly, Paddy; O'Donoghue, Keelin
This study evaluated the feasibility of maternal C-reactive protein (CRP) in amniotic fluid (AF) as a predictor of post-partum infection in women who undergo emergency or elective caesarean section (CS). AF bacterial culture and levels of hs-CRP in maternal serum and AF were evaluated in Day 0 and three days thereafter (Day 3) in 79 women undergoing CS. Univariate analyses assessed the clinical and demographic characteristics, whereas the ROC curves assessed the feasibility of hs-CRP as marker of inflammation in women who undergo CS. There was no difference in AF, Day 0, and Day 3 serum hs-CRP levels between women with sterile compared to those with bacterial growth in AF. Among women with positive AF cultures, AF and Day 0 serum hs-CRP levels were higher in women who underwent emergency compared to those who had elective CS (p = 0.04, and p = 0.02 respectively). hs-CRP in Day 0 and Day 3 serum but not in AF has a fair predictor value of infection in emergency CS only (AUC 0.767; 95% CI 0.606-0.928, and AUC 0.791; 95% CI 0.645-0.036, respectively). We conclude that AF hs-CRP is not feasible in assessing the risk of post-cesarean inflammation or infection.
Anakinra for recalcitrant pyoderma gangrenosum
(John Wiley & Sons, Inc., 2021-06-16) O'Connor, Cathal; Gallagher, Catriona; Hollywood, Aoife; Paul, Lindsay; O'Connell, Michael
Pyoderma gangrenosum (PG) is an autoinflammatory neutrophilic dermatosis characterized by rapidly enlarging, painful ulcers. Anakinra is a recombinant interleukin-1 (IL-1) receptor antagonist that blocks the activity of IL-1α and IL-1β by competitively inhibiting IL-1 binding to the IL-1 type I receptor. We present a series of two patients with recalcitrant PG, who had limited therapeutic options due to multiple previous treatment failures and multiple co-morbidities, who obtained 100% healing with anakinra. Compared to conventional first-line therapies for PG, the safety profile of anakinra may be preferable for patients with multiple co-morbidities. Further research is needed to assess the safety and efficacy of anakinra for PG.
Analysis of a low-cost EEG monitoring system and dry electrodes toward clinical use in the neonatal ICU
(MDPI, 2019-06-11) O'Sullivan, Mark; Temko, Andriy; Bocchino, Andrea; O'Mahony, Conor; Boylan, Geraldine B.; Popovici, Emanuel M.; Irish Research Council; Science Foundation Ireland; Health Research Board; Wellcome Trust
Electroencephalography (EEG) is an important clinical tool for monitoring neurological health. However, the required equipment, expertise, and patient preparation inhibits its use outside of tertiary care. Non-experts struggle to obtain high-quality EEG due to its low amplitude and artefact susceptibility. Wet electrodes are currently used, which require abrasive/conductive gels to reduce skin-electrode impedance. Advances in dry electrodes, which do not require gels, have simplified this process. However, the assessment of dry electrodes on neonates is limited due to health and safety barriers. This study presents a simulation framework for assessing the quality of EEG systems using a neonatal EEG database, without the use of human participants. The framework is used to evaluate a low-cost EEG acquisition system and compare performance of wet and dry (Micro Transdermal Interface Platforms (MicroTIPs), g.tec-g.SAHARA) electrodes using accurately acquired impedance models. A separate experiment assessing the electrodes on adult participants was conducted to verify the simulation framework’s efficacy. Dry electrodes have higher impedance than wet electrodes, causing a reduction in signal quality. However, MicroTIPs perform comparably to wet electrodes at the frontal region and g.tec-g.SAHARA performs well at the occipital region. Using the simulation framework, a 25dB signal-to-noise ratio (SNR) was obtained for the low-cost EEG system. The tests on adults closely matched the simulated results.
Antenatal vitamin D status is not associated with standard neurodevelopmental assessments at age 5 Years in a well-characterized prospective maternal-infant cohort
(Oxford University Press, 2018-08-30) McCarthy, Elaine K.; Malvisi, Lucio; Kiely, Mairead E.; Murray, Deirdre M.; Hourihane, Jonathan O'B.; Irvine, Alan D.; Kenny, Louise C.; Seventh Framework Programme; National Children’s Research Centre, Ireland; Health Research Board; Science Foundation Ireland
Background: Although animal studies show evidence for a role of vitamin D during brain development, data from human studies show conflicting signals. Objective: We aimed to explore associations between maternal and neonatal vitamin D status with childhood neurodevelopmental outcomes. Methods: Comprehensive clinical, demographic, and lifestyle data were collected prospectively in 734 maternal-infant dyads from the Cork BASELINE Birth Cohort Study. Serum 25-hydroxyvitamin D [25(OH)D] concentrations were quantified at 15 weeks of gestation and in umbilical cord sera at birth via a CDC-accredited liquid chromatography-tandem mass spectrometry method. Children were assessed at age 5 y through the use of the Kaufman Brief Intelligence Test (2nd Edition, KBIT-2) and the Child Behaviour Checklist (CBCL). Linear regression was used to explore associations between 25(OH)D and neurodevelopmental outcomes. Results: 25(OH)D concentrations were <30 nmol/L in 15% of maternal and 45% of umbilical cord sera and <50 nmol/L in 42% of mothers and 80% of cords. At age 5 y, the mean ± SD KBIT-2 intelligence quotient (IQ) composite score was 104.6 ± 8.6; scores were 107.2 ± 10.0 in verbal and 99.8 ± 8.8 in nonverbal tasks. Developmental delay (scores <85) was seen in <3% of children across all domains. The mean ± SD CBCL total problem score was 21.3 ± 17.5; scores in the abnormal/clinical range for internal, external, and total problem scales were present in 12%, 4%, and 6% of participants, respectively. KBIT-2 and CBCL subscale scores at 5 y were not different between children exposed to low antenatal vitamin D status, either at 30 or 50 nmol/L 25(OH)D thresholds. Neither maternal nor cord 25(OH)D (per 10 nmol/L) were associated with KBIT-2 IQ composite scores [adjusted β (95% CI): maternal –0.01 (−0.03, 0.02); cord 0.01 (−0.03, 0.04] or CBCL total problem scores [maternal 0.01 (−0.04, 0.05); cord 0.01 (−0.07, 0.09)]. Conclusion: In this well-characterized prospective maternal-infant cohort, we found no evidence that antenatal 25(OH)D concentrations are associated with neurodevelopmental outcomes at 5 y. The BASELINE Study was registered at www.clinicaltrials.gov as NCT01498965; the SCOPE Study was registered at http://www.anzctr.org.au as ACTRN12607000551493
The anti-inflammatory compound candesartan cilexetil improves neurological outcomes in a mouse model of neonatal hypoxia
(Frontiers Media, 2019-07-24) Quinlan, Sean; Merino-Serrais, Paula; Di Grande, Alessandra; Dussmann, Heiko; Prehn, Jochen H. M.; Ní Chonghaile, Tríona; Henshall, David C.; Jimenez-Mateos, Eva M.; Science Foundation Ireland; European Regional Development Fund; FutureNeuro; Svenska Sällskapet för Medicinsk Forskning; Ministerio de Ciencia, Innovación y Universidades
Recent studies suggest that mild hypoxia-induced neonatal seizures can trigger an acute neuroinflammatory response leading to long-lasting changes in brain excitability along with associated cognitive and behavioral deficits. The cellular elements and signaling pathways underlying neuroinflammation in this setting remain incompletely understood but could yield novel therapeutic targets. Here we show that brief global hypoxia-induced neonatal seizures in mice result in transient cytokine production, a selective expansion of microglia and long-lasting changes to the neuronal structure of pyramidal neurons in the hippocampus. Treatment of neonatal mice after hypoxia-seizures with the novel anti-inflammatory compound candesartan cilexetil suppressed acute seizure-damage and mitigated later-life aggravated seizure responses and hippocampus-dependent learning deficits. Together, these findings improve our understanding of the effects of neonatal seizures and identify potentially novel treatments to protect against short and long-lasting harmful effects.
Aplasia cutis congenita in dizygotic twin infants
(John Wiley & Sons, Inc., 2021-05-28) Bowe, S.; O'Connor, Cathal; Kenosi, M.; Murphy, L. A.
Aplasia cutis congenita (ACC) is a rare heterogenous group of disorders characterized by the absence of a portion of skin in a localized or widespread area at birth. 1 ACC is often sporadic but familial cases have been reported. 1,2 We report a case of a dichorionic diamniotic (DCDA) twin pregnancy in which both the male and female twins had matching areas of aplasia cutis on their scalps.
Application of a physiologically-based pharmacokinetic model for the prediction of bumetanide plasma and brain concentrations in the neonate
(Wiley, 2018-01-10) Donovan, Maria D.; Abduljalil, Khaled; Cryan, John F.; Boylan, Geraldine B.; Griffin, Brendan T.; Irish Research Council for Science, Engineering and Technology; Health Research Board; Science Foundation Ireland; Seventh Framework Programme
Bumetanide is a loop diuretic that is proposed to possess a beneficial effect on disorders of the central nervous system, including neonatal seizures. Therefore, prediction of unbound bumetanide concentrations in the brain is relevant from a pharmacological prospective. A physiologically‐based pharmacokinetic (PBPK) model was developed for the prediction of bumetanide disposition in plasma and brain in adult and paediatric populations. A compound file was built for bumetanide integrating physicochemical data and in vitro data. Bumetanide concentration profiles were simulated in both plasma and brain using the Simcyp PBPK model. Simulations of plasma bumetanide concentrations were compared against plasma levels published in the literature. The model performance was verified with data from adult studies before predictions in the paediatric population were undertaken. The adult and paediatric intravenous models predicted pharmacokinetic factors, namely area under the concentration–time curve, maximum concentration in plasma and time to maximum plasma concentration, within two‐fold of observed values. However, predictions of plasma concentrations within the neonatal intravenous model did not produce a good fit with the observed values. The PBPK approach used in this study produced reasonable predictions of plasma concentrations of bumetanide, except in the critically ill neonatal population. This PBPK model requires more information regarding metabolic intrinsic clearance and transport parameters prior to further validation of drug disposition predictions in the neonatal population. Given the lack of information surrounding certain parameters in this special population, the model is not appropriately robust to support the recommendation of a suitable dose of bumetanide for use as an adjunct antiepileptic in neonates.
Applications of metabolomics to study the pathophysiology of adverse pregnancy outcomes
(University College Cork, 2020) Morillon, Aude-Claire; McCarthy, Fergus; English, Jane; Yakkundi, Shirish; Kenny, Louise; Baker, Philip; Science Foundation Ireland; Waters Corporation
Background: Clinical metabolomics is a growing field of research aiming to use metabolomic techniques to gain further knowledge into diseases, the use of biomarkers to predict their onset, or the effect of a potential therapeutic agent on the metabolome. Adverse pregnancy outcomes, such as small for gestation age (or fetal growth restriction), spontaneous preterm birth, and pre-eclampsia, lead to high maternal and fetal mortality and morbidity rates. However, despite research efforts to date, their pathophysiology remains poorly understood. Aim: The aims of this thesis was to determine the accuracy of metabolomics to predict small for gestation age (SGA) babies, to explore the metabolic pathways involved in the pathophysiology of SGA and spontaneous preterm birth (sPTB), to identify potential predictive biomarkers of sPTB, and investigate the use of a potential therapeutic agent in an animal model of pre-eclampsia. Methods: Firstly, a systematic review was undertaken to examine the predictive accuracy of metabolomics for the prediction of small for gestational age babies. The original search was conducted in February 2018 and the results are presented in Chapter 2. Secondly, we investigated the metabolic pathways involved in the pathophysiology of small for gestation age (SGA) using untargeted ultra-performance liquid chromatography coupled to quadrupole time of flight mass spectrometry (UPLC-Q-TOF-MS). Plasma (Cork) and urine (Cork, Auckland) samples were collected at 20 weeks of gestation from pregnant women participating in the SCreening fOr Pregnancy Endpoints (SCOPE) study, an international study that recruited 5,628 nulliparous women, with a singleton low-risk pregnancy. Cases were women with SGA (customised birthweight ≤ 10th centile) matched to controls who had uncomplicated pregnancies, according to age (±5 years), body mass index (BMI, ±3.5 kg/m2), and ethnicity. All samples were analysed in untargeted positive and negative ion modes, using UPLC-Q-TOF-MS. Data were processed, features were ranked based on p-values from empirical Bayes analysis adjusted for multiple testing, and significant features (adjusted p-values <0.05 were searched for identification (HMDB, LipidMaps)). Thirdly, we aimed to decipher the lipidomics pathways involved in pathophysiology of spontaneous preterm birth (sPTB). Our analysis focused on plasma samples from SCOPE in Cork, collected at 20 weeks of gestation. Samples were profiled using semi-targeted liquid chromatography-mass spectrometry lipidomics, and lipids significantly altered between sPTB (n=16) and Control (n=32) groups were identified using empirical Bayes testing, adjusting for multiple comparisons. Significantly altered lipids (adj. p-values <0.05) were database searched for identifications (HMDB, LipidMaps). Fourthly, in Chapter 5, we performed a discovery lipidomics experiment to determine potential biomarkers of sPTB, in plasma samples taken at 15 weeks of gestation in women who participated in SCOPE in Cork and Auckland. Selected participants were women who has sPTB before 34 weeks of gestation (n=16 from Cork, and n=23 from Auckland), matched to women who had an uncomplicated pregnancy (n=39) according to age (±5 years) and BMI (± 3 kg/m2). Lipidomics analysis was performed using UPLC-Q-TOF-MS. Statistical analysis using empirical Bayes, adjusted for multiple testing was used to create a list of potential biomarkers. Five potential biomarkers were selected for validation based on statistical analysis, and their identification was validated using standard mix and UPLC coupled to triple quadrupole mass spectrometer (TQ-MS) analyses. Their prediction potential was tested using samples taken at 15 and 20 weeks of gestation from women from SCOPE Cork who had sPTB before 37 weeks of gestation (n=54) matched to women who had an uncomplicated pregnancy (controls, n=108). In addition, plasma collected at time of delivery (ToD) was also analysed for six cases and their 12 matching controls. Cases were matched to controls according to age (±5 years) and BMI (± 3 kg/m2). Samples were analysed using UPLC-TQ-MS, and statistical analysis was performed using independent T tests on normalised data. In addition, independent T tests were performed to determine if the levels of each target were significantly different between cases and controls at each time point (15 or 20 weeks). We defined significance as p-value <0.05. Finally, in chapter 6 we performed metabolomics analysis of plasma from experiments examining L-Ergothioneine treatment in the Reduced Uterine Perfusion Pressure (RUPP) rat model of pre-eclampsia. The effect of L-Ergothioneine (ET) treatment was explored using in vivo treatment in rats: Sham control (SC, n=5), RUPP control (RC, n=5), Sham + ET (ST, n=5), RUPP + ET (RT, n=5). Metabolic profiles of plasma samples were obtained using UPLC-Q-TOF-MS, and statistical analysis of the data was performed on normalised data, using independent T tests adjusted with false discovery rate (FDR) to compare RC to SC, RT to RC and RT to ST. Metabolites significantly altered (FDR <0.05) were putatively identified through database search (HMDB). Results: The systematic review presented in Chapter 2 examining the predictive accuracy of metabolomics for small for gestational age babies showed that to date no combination of metabolites are able to predict small for gestational age accurately. However, the review revealed the potential of investigating lipids pathways, their involvement in the pathophysiology of small for gestational age, and their high predictive potential. The metabolomic studies performed on urine samples and reported in Chapter 3, showed lower levels of 4 metabolites of interest (sulfolithocholic acid, estriol-16-Glucuronide, Neuromedin N (1-4), and 4-Hydroxybenzaldehyde) in Cork were associated with SGA at 20 weeks of gestation, but not in Auckland samples. These urinary metabolites are associated with detoxification, nutrient transport and absorption pathways. The lipidomics analysis performed on plasma samples showed that higher levels of several glycerophospholipids (3 phosphatidylethanolamines, 5 phosphatidylserines, 3 phosphatidylcholines, 1 lyso phosphatidylcholine, 1 phosphatidylglycerophosphate, 1 lyso phosphatidylglycerophosphate, 2 phosphatidylinositols, 2 phosphatidylglycerophosphates, and 3 phosphatidylglycerols) in at 20 weeks of gestation were associated with the development of SGA in the Cork participants of the SCOPE pregnancy cohort. Chapter 4 demonstrated that twenty-six lipids showed lower levels in sPTB compared to controls (adjusted p <0.05), including 20 glycerophospholipids (12 phosphatidylcholines, 7 phosphatidylethanolamines, 1 phosphatidylinositol) and 6 sphingolipids (2 ceramides and 4 sphingomyelines). In addition, a diaglyceride, DG (34:4), was detected in higher levels in sPTB compared to controls. In Chapter 4, we reported that reduced levels of phospholipids (glycerophospholipids and sphingolipids) are associated with the pathophysiology of sPTB. In the UPLC-Q-TOF-MS discovery phase of the study presented in Chapter 5, a list of 120 potential lipid biomarkers were reported. Most were tentatively identified as glycerophospholipids and detected in lower levels in sPTB. From this list of features, 5 potential biomarkers predictive of sPTB were selected and used in a targeted UPLC-TQ-MS analysis. The results obtained showed that two of the targets showed significant differences between cases and controls and over time (between 15 and 20 weeks of gestation), PC (15:0/22:6) and TG (18:3/18:2/18:3). In Chapter 6, using untargeted UPLC-Q-TOF-MS, we tested the effect of L-Ergothioneine (ET) as a potential therapeutic agent for the treatment of pre-eclampsia in the RUPP rat model. We reported significantly higher levels of L-palmitoylcarnitine, fatty acyl substrate involved in beta-oxidation in the mitochondria, in RUPP rats compared to Sham rats. When comparing plasma metabolic profiles of RUPP + ET rats to RUPP rats, we reported 10 metabolites associated with inflammation significantly altered (FDR <0.05, e.g. 20-COOH-leukotriene E4). Glutamylcysteine, a metabolite associated with oxidative stress, was detected at significantly higher levels (FDR <0.05) when comparing RUPP + ET rats to RUPP rats, and RUPP + ET rats to Sham + ET rats. These results show that the therapeutic properties of L-Ergothioneine might be related to mitochondrial function preservation, by attenuating inflammatory response evident in pre-eclampsia in addition to increasing antioxidant levels. Conclusions: Overall, these results show that glycerophospholipids appear to play a key role in the pathophysiology of SGA and sPTB, and dysregulated glycerophospholipids are potential makers of adverse pregnancy outcomes. Further research is needed to understand their precise associations, whether they are a cause or effect of SGA and sPTB, as well as to validate their potential as predictive biomarkers in independent pregnancy cohorts. In addition, we have shown that the use of L-Ergothioneine for the treatment of pre-eclampsia in the RUPP rat model reduces the oxidative stress induced by pre-eclampsia, via amino acid and glycerophospholipids metabolism pathways. Future work should focus on a testing L-Ergothioneine as a treatment for pre-eclampsia in a clinical trial. This thesis has demonstrated the potential for metabolomics to help understand the pathophysiology of adverse pregnancy outcomes and has explored its use in assessing biological pathways, predictive biomarkers and potential therapeutic pharmacological interventions. To date results are limited with significant further validation required.
Applying design thinking
(2016-06-30) O'Raghallaigh, Paidi
The association between caesarean section and cognitive ability in childhood
(Springer, 2019-10-22) Hanrahan, Michael; McCarthy, Fergus P.; O'Keeffe, Gerard W.; Khashan, Ali S.
Purpose: Global rates of caesarean section (CS) rates have increased rapidly in recent years. This is a growing public health concern as it has been proposed that CS may impact cognitive outcomes in childhood. However, the evidence for this association is limited and inconsistent. Therefore, the aim of this study was to investigate the relationship between obstetric mode of delivery and longitudinal cognitive outcomes in childhood. Methods: We examined this question using data from a longitudinal cohort study of 8845 participants from the Millennium Cohort Study, a nationally representative UK cohort, who completed a range of verbal and visual-spatial cognitive assessments at ages 3, 5, 7 and 11 years. Results: We found a statistically significant association between planned CS and visual-spatial cognitive delay in the pattern construction assessment at age 5 (OR 1.31, 95% CI 0.99–1.72) and age 7 (OR 1.42, 95% CI 1.12–1.81). Additionally planned CS was also associated with increased odds of “early childhood delay” (OR 1.70, 95% CI 1.15–2.50) and borderline increased odds of “persistent delay” (OR 1.37, 95% CI 0.99–1.89) in visual-spatial cognitive tests. Mode of delivery was not associated with verbal ability or with patterns of delay at any age point in verbal cognitive tests. Conclusion: We have reported a small association between planned CS and visual-spatial cognitive delay in childhood. However, while this result should be interpreted with caution, it highlights the need to further explore this potential relationship and the causal basis of such an association.
Association between caesarean section delivery and obesity in childhood: a longitudinal cohort study in Ireland
(BMJ Publishing Group, 2019-03-15) Masukume, Gwinyai; McCarthy, Fergus P.; Baker, Philip N.; Kenny, Louise C.; Morton, Susan M. B.; Murray, Deirdre M.; Hourihane, Jonathan O'B.; Khashan, Ali S.; Health Research Board; National Children’s Research Centre, Ireland; Food Standards Agency, United Kingdom
Objectives: To investigate the association between caesarean section (CS) birth and body fat percentage (BF%), body mass index (BMI) and being overweight or obese in early childhood. Design: Prospective longitudinal cohort study. Setting: Babies After Screening for Pregnancy Endpoints: Evaluating the Longitudinal Impact on Neurological and Nutritional Endpoints cohort. Participants: Infants born to mothers recruited from the Screening for Pregnancy Endpoints study, Cork University Maternity Hospital between November 2007 and February 2011.Outcome measure: Overweight or obese defined according to the International Obesity Task Force criteria.Results: Of the 1305 infants, 362 (27.8%) were delivered by CS. On regression analysis, BF% at 2 months did not differ significantly by delivery mode. Infants born by CS had a higher mean BMI at 6 months compared with those born vaginally (adjusted mean difference=0.24; 95% CI 0.06 to 0.41, p value=0.009). At 2 years, no difference was seen across the exposure groups in the risk of being overweight or obese. At 5 years, the association between prelabour CS and the risk of overweight or obesity was not statistically significant (adjusted relative risk ratio, aRRR=1.37; 95% CI 0.69 to 2.69) and the association remained statistically nonsignificant when children who were macrosomic at birth were excluded from the model (aRRR=0.86; 95% CI 0.36 to 2.08).Conclusion: At 6 months of age, children born by CS had a significantly higher BMI but this did not persist into future childhood. There was no evidence to support an association between mode of delivery and long-term risk of obesity in the child.
The association between hypertensive disorders of pregnancy and neurodevelopmental disorders in the offspring
(University College Cork, 2020-03) Maher, Gillian M.; Khashan, Ali; O'Keeffe, Gerard W.; Kearney, Patricia M.; Kenny, Louise C.; Health Research Board
Background and aims: Hypertensive disorders of pregnancy (HDP) are one of the most common gestational complications. HDP may be chronic (pre-dating pregnancy or diagnosed before 20 weeks’ gestation) or arise de novo (either preeclampsia or gestational hypertension). Of these, preeclampsia is one of the leading cause of maternal mortality and morbidity. Evidence suggests an association between HDP and neurodevelopmental outcomes; however, results are limited and inconsistent. The aim of the current thesis was to examine the association between HDP (in particular, preeclampsia) and neurodevelopmental disorders in the offspring, including autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), child development and behavioural outcomes. This would be achieved by systematically reviewing existing literature, and conducting a range of robust analyses using Swedish National Registry data, and data from a nationally representative study of children living in Ireland. Structure and methods: This thesis includes a brief introductory chapter (Chapter 1), and a detailed methods chapter describing study designs, data sources, exposure and outcome variables, statistical modelling, and the role of bias, confounding and chance in epidemiology (Chapter 2). Published literature on the relationship between HDP and neurodevelopmental disorders in the offspring were synthesised using a systematic review and meta-analysis, based on a pre-prepared protocol (Chapters 3 and 4). This was followed by a narrative literature review to provide a perspective on how maternal inflammation may lead to altered neurodevelopmental outcomes in preeclampsia-exposed offspring (Chapter 5). Data from Swedish National Registers were analysed to examine the association between preeclampsia and ASD and ADHD, using Cox proportional hazards regression analysis, adjusting for several perinatal and sociodemographic factors. Sibling-matched analysis was used to also control for shared genetic and familial confounding (Chapters 6 and 7). These associations were further explored by examining the intergenerational association between preeclampsia and ASD and ADHD (Chapter 8). Data from Growing Up in Ireland (GUI), a nationally representative study of children living in Ireland, were analysed to examine the association between preeclampsia and child development using the Ages and Stages Questionnaire (ASQ) at age 9-months, and behavioural outcomes using the Strengths and Difficulties Questionnaire (SDQ) at age 3 years, 5 years and 7-8 years. Multivariate logistic regression, linear regression and linear spline multilevel modelling were applied for this analysis (Chapter 9). Finally, the systematic review and meta-analysis was updated and included in this thesis (Chapter 10), along with discussion of findings, strengths and limitations of the thesis, and recommendations for future research (Chapter 11). Results: Updated systematic review and meta-analysis: Among ASD studies, adjusted pooled results indicated that exposure to HDP is associated with a 33% increased odds of ASD when compared to those unexposed (OR: 1.33, 95% CI: 1.17, 1.52). Results of a subgroup analysis, examining a preeclampsia-ASD relationship in isolation provided an OR of 1.36 (95% CI: 1.18, 1.58), while the other HDP-ASD relationship was statistically non-significant with an OR of 1.29 (95% CI: 0.97, 1.71). Among ADHD studies, adjusted pooled results suggested that offspring exposed to HDP are 26% more likely to have ADHD compared to those unexposed (OR: 1.26, 95% CI: 1.15, 1.38). For the subgroup analysis examining the preeclampsia-ADHD relationship, the OR was 1.23 (95% CI: 1.13, 1.35), and for other HDP-ADHD relationship, the OR was 1.80 (95% CI: 1.25, 2.59). Swedish National Registers: The adjusted Cox model suggested that preeclampsia was associated with 25% increased odds of ASD (Hazard ratio (HR): 1.25, (95% CI: 1.19, 1.30). The sibling-matched analysis reduced the HR to 1.17 (95% CI: 1.06, 1.28). The HR for preeclampsia and SGA combined (used as a crude proxy for preeclampsia with placental dysfunction) was 1.66 (95% CI: 1.49, 1.85) in the adjusted Cox model and 1.95 (95% CI: 1.53, 2.48) in the sibling-matched analysis. In the adjusted Cox model, preeclampsia was associated with a 15% increase in likelihood of ADHD (HR: 1.15, 95% CI: 1.12, 1.19), while the HR for preeclampsia and SGA combined was 1.43 (95% CI: 1.31, 1.55) in the adjusted model, compared to those unexposed to preeclampsia/SGA. The sibling-matched analysis did not materially change these associations. Similar to the findings outlined above, the intergenerational analysis suggested that exposure to preeclampsia was associated with an increased likelihood of ASD and ADHD in offspring. In addition to this, results suggested that preeclampsia in both the child’s mother and grandmother was associated with a 58% increased likelihood of ASD (HR: 1.58, 95% CI: 1.02, 2.46) and 34% increased likelihood of ADHD (HR: 1.34, 95% CI: 1.01, 1.80) in the child. GUI study: Multivariate logistic regression suggested that preeclampsia was not associated with failing any ASQ domain. Preeclampsia was associated with abnormal SDQ cut-off of Emotional (score of ≥5) and Hyperactivity (score of ≥7) domains at age 5 years only. In the linear spline model, mean SDQ score was higher at age 3, 5 and 7-8 years in exposed groups, however did not always reach statistical significance. Conclusions: This thesis rigorously investigates the association between HDP (in particular, preeclampsia) and neurodevelopmental disorders in offspring using a range of analytic approaches, and adjusting for a wide variety of potential confounders. Pooled estimates from previous literature suggested an association between HDP and ASD and ADHD. Furthermore, the data from Swedish National Registers indicate that exposure to preeclampsia or preeclampsia and SGA combined (i.e. SGA baby exposed to preeclampsia) was associated with ASD and ADHD. The stronger association with preeclampsia and SGA combined than preeclampsia alone suggests that placental pathology may be a mechanism for the increased likelihood of ASD and ADHD. Results of the current thesis also suggest that preeclampsia may be associated with adverse neurodevelopmental outcomes across generations. While we did not find strong evidence of associations between preeclampsia and child developmental and behavioural outcomes overall in the GUI study, exposure to preeclampsia was associated with an increased likelihood of subtle behavioural issues in the emotional and hyperactivity domain of the SDQ. The overall conclusion of this thesis suggests an association between HDP and neurodevelopmental outcomes in offspring. It is important to note however, that we cannot rule out the presence of residual confounding in observational studies.
Association between hypertensive disorders of pregnancy and the risk of asthma, eczema and allergies in offspring: A systematic review and meta-analysis
(John Wiley & Sons, Inc., 2020-10-09) Conlan, Nicola; Maher, Gillian M.; Al Khalaf, Sukainah; McCarthy, Fergus P.; Khashan, Ali S.; Health Research Board
Objective: Conduct a systematic review and meta‐analysis examining the association between hypertensive disorders of pregnancy (HDP) and risk of asthma, eczema, food allergies and allergic rhinitis in the offspring. Design: A systematic review and random‐effects meta‐analyses were used to synthesize the published literature. PRISMA guidelines were followed throughout. Two independent reviewers carried out data extraction and quality assessment of included studies. Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to assess certainty of findings. Data Sources: A systematic search of PubMed, Embase, Web of Science and CINAHL was performed from inception of databases‐21 April 2020, supplemented by hand‐searching reference lists of included articles. Eligibility Criteria: Two reviewers independently reviewed titles, abstracts and full‐text articles. English language, cohort, case‐control and cross‐sectional published studies examining the association between HDP (primary exposure: pre‐eclampsia; secondary exposures: all other HDP) and asthma, eczema, food allergies and allergic rhinitis were included. Results: Of the 2833 studies retrieved, 14 studies met inclusion criteria. Of these, 11 studies reported evidence of association between HDP and atopic disorders. Thirteen studies reported estimates for asthma. Seven of these included adjusted estimates (including 3 645 773 participants) for a pre‐eclampsia‐asthma relationship resulting in a pooled odds ratio (OR) of 1.14 (95% CI: 1.04, 1.26) (I2 = 62%). However, this OR was reduced to 1.08 (95% CI: (0.78, 1.48) when the large registry‐based cohort studies were excluded, and only studies using parent‐reported measures to determine a diagnosis of asthma were included. Four studies included adjusted estimates (including 254 998 participants) for other HDP and asthma (pooled OR: 1.02, 95% CI: 0.96, 1.09) (I2 = 0%). Two studies provided adjusted estimates (including 1 699 663 participants) for a pre‐eclampsia‐eczema relationship (pooled OR: 1.06, 95% CI: 0.98, 1.14) (I2 = 0%). One study including pre‐eclampsia‐food allergies was identified (OR: 1.28, 95% CI: 1.11, 1.46). Three studies examined a HDP (including pre‐eclampsia) and allergic rhinitis relationship, with effect estimates ranging from 1.14 to 2.10. Studies were classified as low or low‐moderate risk of bias, while GRADE certainty of findings were low to very low. Conclusions: While pre‐eclampsia was associated with a possible increased risk of asthma in offspring, there was no evidence for a relationship between other HDP and asthma. There is a lack of published literature examining the association between HDP and eczema, food allergy and allergic rhinitis. Further primary research is warranted to gain a better understanding of the association between HDP and the risk of childhood atopic disease.

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