• Activation of a TLR9 mediated innate immune response in preeclampsia.

      Williamson, Rachel D; McCarthy, Fergus P; Kenny, Louise C; McCarthy, Cathal M (Scientific Reports, 2019-04-11)
      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 specifc 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 signifcantly increased at time of disease in women with preeclampsia. Furthermore, we show activation of neutrophil markers, Calprotectin, Myeloperoxidase (MPO), and IL-8 are signifcantly 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.
    • Compliance with National Institute of Health and Care Excellence risk-based screening for gestational diabetes mellitus in nulliparous women.

      Murphy, Nicolai M; McCarthy, Fergus P; Khashan, Ali S; Myers, Jenny E; Simpson, Nigel A B; Kearney, Patricia M; Greene, Richard A; Poston, Lucilla; Kenny, Louise C (European journal of obstetrics, gynecology, and reproductive biology, 2016-04)
      To investigate compliance with risk-based screening for Gestational Diabetes Mellitus (GDM) in a nulliparous cohort.
    • Gitelman's syndrome in pregnancy: case report and review of the literature.

      McCarthy, Fergus P; Magee, Ciara N; Plant, William D; Kenny, Louise C; The ANU Research Centre, Department of Obstetrics and Gynaecology, University, College Cork, Cork University Maternity Hospital, Wilton, Cork., Fergus.mccarthy@ucc.ie (2012-01-31)
      Gitelman's syndrome (GS), a rare renal disorder, results in hypokalaemia, hypomagnesaemia, hypocalciuria and a metabolic alkalosis. It is unclear if an alteration in management is necessary or beneficial during pregnancy. A 32-year-old woman with GS was managed in her second pregnancy. Antenatally, the patient required 39 (principally day case) admissions to the hospital for intravenous (IV) therapy and received a cumulative total of 47 l of IV 0.9% saline solution, 47 doses of 20 mmol magnesium chloride and 46 doses of 80 mmol potassium chloride. She delivered a 2940-g female infant in excellent condition by caesarean section. We would suggest that close attention to maternal weight gain during pregnancy is an easily available clinical tool to assess adequacy of fluid and electrolyte repletion in this condition.
    • Metabolic profiling uncovers a phenotypic signature of small for gestational age in early pregnancy.

      Horgan, Richard P; Broadhurst, David I; Walsh, Sarah K; Dunn, Warwick B; Brown, Marie; Roberts, Claire T; North, Robyn A; McCowan, Lesley M; Kell, Douglas B; Baker, Philip N; et al. (2012-01-31)
      Being born small for gestational age (SGA) confers increased risks of perinatal morbidity and mortality and increases the risk of cardiovascular complications and diabetes in later life. Accumulating evidence suggests that the etiology of SGA is usually associated with poor placental vascular development in early pregnancy. We examined metabolomic profiles using ultra performance liquid chromatography-mass spectrometry (UPLC-MS) in three independent studies: (a) venous cord plasma from normal and SGA babies, (b) plasma from a rat model of placental insufficiency and controls, and (c) early pregnancy peripheral plasma samples from women who subsequently delivered a SGA baby and controls. Multivariate analysis by cross-validated Partial Least Squares Discriminant Analysis (PLS-DA) of all 3 studies showed a comprehensive and similar disruption of plasma metabolism. A multivariate predictive model combining 19 metabolites produced by a Genetic Algorithm-based search program gave an Odds Ratio for developing SGA of 44, with an area under the Receiver Operator Characteristic curve of 0.9. Sphingolipids, phospholipids, carnitines, and fatty acids were among this panel of metabolites. The finding of a consistent discriminatory metabolite signature in early pregnancy plasma preceding the onset of SGA offers insight into disease pathogenesis and offers the promise of a robust presymptomatic screening test.
    • Peroxisome proliferator-activated receptor-gamma as a potential therapeutic target in the treatment of preeclampsia.

      McCarthy, Fergus P; Drewlo, Sascha; Kingdom, John; Johns, Edward J; Walsh, Sarah K; Kenny, Louise C; Anu Research Centre, University College Cork, Cork University Maternity Hospital,, Wilton, Cork, Ireland. fergusmccarthy@gmail.com (2012-01-31)
      Preeclampsia is a multisystemic disorder of pregnancy characterized by hypertension, proteinuria, and maternal endothelial dysfunction. It is a major cause of maternal and perinatal morbidity and mortality and is thought to be attributable, in part, to inadequate trophoblast invasion. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a ligand-activated transcription factor expressed in trophoblasts, and the vasculature of which activation has been shown to improve endothelium-dependent vasodilatation in hypertensive conditions. We investigated the effects of the administration of a PPAR-gamma agonist using the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia. The selective PPAR-gamma agonist, rosiglitazone, was administered to pregnant rats that had undergone RUPP surgery. To investigate whether any observed beneficial effects of PPAR-gamma activation were mediated by the antioxidant enzyme, heme oxygenase 1, rosiglitazone was administered in combination with the heme oxygenase 1 inhibitor tin-protoporphyrin IX. RUPP rats were characterized by hypertension, endothelial dysfunction, and elevated microalbumin:creatinine ratios. Rosiglitazone administration ameliorated hypertension, improved vascular function, and reduced the elevated microalbumin:creatinine ratio in RUPP rats. With the exception of microalbumin:creatinine ratio, these beneficial effects were abrogated in the presence of the heme oxygenase 1 inhibitor. Administration of a PPAR-gamma agonist prevented the development of several of the pathophysiological characteristics associated with the RUPP model of preeclampsia, via a heme oxygenase 1-dependent pathway. The findings from this study provide further insight into the underlying etiology of preeclampsia and a potential therapeutic target for the treatment of preeclampsia.
    • Placental FKBP51 mediates a link between second trimester maternal anxiety and birthweight in female infants.

      Togher, Katie L; O'Keeffe, Gerard W; Khashan, Ali S; Clarke, Gerard; Kenny, Louise C; Cork University Maternity Hospital and University College Cork (Scientific Reports, 2018-10-11)
      Prenatal distress is associated with adverse outcomes in affected offspring. Alterations in placental glucocorticoid signalling and subsequent foetal overexposure to glucocorticoids have been implicated as an underlying mechanism. Infant sex is emerging as an important factor in disease susceptibility. This study aimed to examine the effects of maternal distress across pregnancy on birth outcomes and placental glucocorticoid genes in a sex-dependent manner. Participants completed psychological distress questionnaires throughout pregnancy. Placental HSD11B2, NR3C1 and FKBP51 were analysed by real time PCR and cortisol was measured in new-born hair. Second trimester stress was negatively correlated with birthweight in males and positively correlated with placental NR3C1 mRNA in females. Second trimester anxiety was negatively correlated with birthweight and placental FKBP51 mRNA in females. In mediation analysis, placental FKBP51 mRNA expression was found to mediate the link between prenatal anxiety and birthweight. New-born cortisol was negatively correlated with second trimester anxiety and positively correlated with female placental FKBP51 mRNA levels. Again, FKBP51 mRNA was found to mediate the link between anxiety and new-born cortisol. These results highlight a role for FKBP51 in the placental response to prenatal distress in females. The precise role that placental FKBP51 has in foetal and infant development has not been extensively studied and warrants further investigations.
    • Plasma-mediated vascular dysfunction in the reduced uterine perfusion pressure model of preeclampsia: a microvascular characterization.

      Walsh, Sarah K; English, Fred A; Johns, Edward J; Kenny, Louise C; Anu Research Centre, Department of Obstetrics and Gynaecology, University College, Cork, Cork University Maternity Hospital, Wilton, Cork, Ireland. S.Walsh@ucc.ie (2012-01-31)
      Preeclampsia is associated with widespread maternal vascular dysfunction, which is thought to be mediated by circulating factor(s). The aim of the study was to characterize vascular function in the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia and to investigate the role of plasma factors in mediating any observed changes in vascular reactivity. Mean arterial blood pressure and vascular function were measured in RUPP and control rats. Mesenteric vessels from both virgin and pregnant rats were exposed for 1 hour or overnight to plasma from both RUPP and control rats and their vascular function assessed. RUPP rats were characterized by severe hypertension, restricted fetal growth, and reduced placental weight (P<0.001). Vasorelaxation was impaired in resistance vessels from RUPP compared with control rats (acetylcholine: R(max) 70+/-3 versus 92+/-1 [NP] and 93+/-3% [sham], P<0.01; bradykinin: 40+/-2 versus 62+/-2 [NP] and 59+/-4% [sham], P<0.001). Incubation of vessels from pregnant (but not virgin) animals with RUPP plasma overnight resulted in an attenuation of vasorelaxant responses (acetylcholine: 63+/-7 versus 86+/-2%, P<0.05; bradykinin: 35+/-5 versus 55+/-6%, P<0.001). The residual relaxant response in RUPP plasma-treated vessels was not further attenuated after treatment with N(omega)-nitro-l-arginine methyl ester (acetylcholine: 57+/-7 versus 63+/-7%, ns; bradykinin: 37+/-5 versus 35+/-5%, ns). The RUPP rat model is characterized by an impaired response to vasodilators which may be attributable to one or more circulating factors. This plasma-mediated endothelial dysfunction appears to be a pregnancy-dependent effect. Furthermore, nitric oxide-mediated vasorelaxation appears to be absent in RUPP plasma-treated vessels.
    • Pregnancy and the risk of autoimmune disease.

      Khashan, Ali S; Kenny, Louise C; Laursen, Thomas M; Mahmood, Uzma; Mortensen, Preben B; Henriksen, Tine B; O'Donoghue, Keelin; Anu Research Centre, Department of Obstetrics and Gynaecology, Cork University, Maternity Hospital, University College Cork, Wilton, Cork, Republic of Ireland. (2012-01-31)
      Autoimmune diseases (AID) predominantly affect women of reproductive age. While basic molecular studies have implicated persisting fetal cells in the mother in some AID, supportive epidemiological evidence is limited. We investigated the effect of vaginal delivery, caesarean section (CS) and induced abortion on the risk of subsequent maternal AID. Using the Danish Civil Registration System (CRS) we identified women who were born between 1960 and 1992. We performed data linkage between the CRS other Danish national registers to identify women who had a pregnancy and those who developed AID. Women were categorised into 4 groups; nulligravida (control group), women who had 1st child by vaginal delivery, whose 1st delivery was by CS and who had abortions. Log-linear Poisson regression with person-years was used for data analysis adjusting for several potential confounders. There were 1,035,639 women aged >14 years and 25,570 developed AID: 43.4% nulligravida, 44.3% had their first pregnancy delivered vaginally, 7.6% CS and 4.1% abortions. The risk of AID was significantly higher in the 1st year after vaginal delivery (RR = 1.1[1.0, 1.2]) and CS (RR = 1.3[1.1, 1.5]) but significantly lower in the 1st year following abortion (RR = 0.7[0.6, 0.9]). These results suggest an association between pregnancy and the risk of subsequent maternal AID. Increased risks of AID after CS may be explained by amplified fetal cell traffic at delivery, while decreased risks after abortion may be due to the transfer of more primitive fetal stem cells. The increased risk of AID in the first year after delivery may also be related to greater testing during pregnancy.
    • A prospective cohort study investigating associations between hyperemesis gravidarum and cognitive, behavioural and emotional well-being in pregnancy.

      McCarthy, Fergus P; Khashan, Ali S; North, Robyn A; Moss-Morris, Rona; Baker, Philip N; Dekker, Gus; Poston, Lucilla; Kenny, Louise C; Department of Obstetrics and Gynecology, The Anu Research Centre, Cork University, Maternity Hospital, University College Cork, Cork, Ireland., Fergus.mccarthy@ucc.ie (2012-01-31)
      OBJECTIVES: To investigate the association between hyperemesis gravidarum and altered cognitive, behavioural and emotional well-being in pregnancy. METHODS: The study cohort consisted of 3423 nulliparous women recruited in the Screening for Pregnancy Endpoints (SCOPE) study performed in Auckland, New Zealand; Adelaide, Australia; Cork, Ireland; Manchester and London, United Kingdom between November 2004 and August 2008. Women were interviewed at 15+/-1 weeks' gestation and at 20+/-1weeks' gestation. Women with a diagnosis of hyperemesis gravidarum (HG) were compared with women who did not have a diagnosis of HG. Main outcome measures included the Short form State- Trait Anxiety Inventory (STAI) score (range 6-24), Perceived Stress Scale score (PSS, range 0-30), Edinburgh Postnatal Depression Scale (EPDS) score (range 0-30 or categories a-c) and behavioural responses to pregnancy score (limiting/resting [range 0-20] and all-or-nothing [range 0-28]). RESULTS: During the study period 164 women suffered from HG prior to their 15 week interview. Women with HG had significantly higher mean STAI, PSS, EPDS and limiting response to pregnancy scores compared to women without HG. These differences were observed at both 15+/-1 and 20+/-1 weeks' of gestation. The magnitude of these differences was greater in women with severe HG compared to all women with HG. Women with severe HG had an increased risk of having a spontaneous preterm birth compared with women without HG (adjusted OR 2.6 [95% C.I. 1.2, 5.7]). CONCLUSION: This is the first large prospective study on women with HG. Women with HG, particularly severe HG, are at increased risk of cognitive, behavioural and emotional dysfunction in pregnancy. Women with severe HG had a higher rate of spontaneous preterm birth compared to women without HG. Further research is required to determine whether the provision of emotional support for women with HG is beneficial.
    • Risk of affective disorders following prenatal exposure to severe life events: a Danish population-based cohort study.

      Khashan, Ali S; McNamee, Roseanne; Henriksen, Tine B; Pedersen, Marianne G; Kenny, Louise C; Abel, Kathryn M; Mortensen, Preben B; Anu Research Centre, Department of Obstetrics and Gynecology, University College , Cork, Cork University Maternity Hospital, Cork, Ireland. a.khashan@ucc.ie (2012-01-31)
      OBJECTIVE: To examine the effect of prenatal exposure to severe life events on risk of affective disorders in the offspring. METHODS: In a cohort of 1.1 million Danish births from May 1978 until December 1997, mothers were considered exposed if one (or more) of their close relatives died or was diagnosed with serious illness up to 6 months before conception or during pregnancy. Offspring were followed up from their 10th birthday until their death, migration, onset of affective disorder or 31 December 2007; hospital admissions were identified by linkage to the Central Psychiatric Register. Log-linear Poisson regression was used for data analysis. RESULTS: The risk of affective disorders was increased in male offspring whose mothers were exposed to severe life events during the second trimester (adjusted RR 1.55 [95% CI 1.05-2.28]). There was an increased risk of male offspring affective disorders in relation to maternal exposure to death of a relative in the second trimester (adjusted RR 1.74 [95% CI 1.06-2.84]) or serious illness in a relative before pregnancy (adjusted RR 1.44 [95% CI 1.02-2.05]). There was no evidence for an association between prenatal exposure to severe life events and risk of female offspring affective disorders. CONCLUSIONS: Our population-based study suggests that prenatal maternal exposure to severe life events may increase the risk of affective disorders in male offspring. These findings are consistent with studies of populations exposed to famine and earthquake disasters which indicate that prenatal environment may influence the neurodevelopment of the unborn child.
    • Robust early pregnancy prediction of later preeclampsia using metabolomic biomarkers.

      Kenny, Louise C; Broadhurst, David I; Dunn, Warwick; Brown, Marie; North, Robyn A; McCowan, Lesley; Roberts, Claire; Cooper, Garth J S; Kell, Douglas B; Baker, Philip N; et al. (2012-01-31)
      Preeclampsia is a pregnancy-specific syndrome that causes substantial maternal and fetal morbidity and mortality. The etiology is incompletely understood, and there is no clinically useful screening test. Current metabolomic technologies have allowed the establishment of metabolic signatures of preeclampsia in early pregnancy. Here, a 2-phase discovery/validation metabolic profiling study was performed. In the discovery phase, a nested case-control study was designed, using samples obtained at 15+/-1 weeks' gestation from 60 women who subsequently developed preeclampsia and 60 controls taking part in the prospective Screening for Pregnancy Endpoints cohort study. Controls were proportionally population matched for age, ethnicity, and body mass index at booking. Plasma samples were analyzed using ultra performance liquid chromatography-mass spectrometry. A multivariate predictive model combining 14 metabolites gave an odds ratio for developing preeclampsia of 36 (95% CI: 12 to 108), with an area under the receiver operator characteristic curve of 0.94. These findings were then validated using an independent case-control study on plasma obtained at 15+/-1 weeks from 39 women who subsequently developed preeclampsia and 40 similarly matched controls from a participating center in a different country. The same 14 metabolites produced an odds ratio of 23 (95% CI: 7 to 73) with an area under receiver operator characteristic curve of 0.92. The finding of a consistent discriminatory metabolite signature in early pregnancy plasma preceding the onset of preeclampsia offers insight into disease pathogenesis and offers the tantalizing promise of a robust presymptomatic screening test.
    • Trial of labour after caesarean section and the risk of neonatal and infant death: a nationwide cohort study.

      O'Neill, Sinéad M; Agerbo, Esben; Khashan, Ali S; Kearney, Patricia M; Henriksen, Tine Brink; Greene, Richard A; Kenny, Louise C (BMC Pregnancy and Childbirth, 2017-02-27)
      Caesarean section (CS) rates are increasing worldwide and as a result repeat CS is common. The optimal mode of delivery in women with one previous CS is widely debated and the risks to the infant are understudied. The aim of the current study was to evaluate if women with a trial of labour after caesarean (TOLAC) had an increased odds of neonatal and infant death compared to women with an elective repeat CS (ERCS).
    • Undiagnosed coeliac disease in a father does not influence birthweight and preterm birth.

      Khashan, Ali S; Kenny, Louise C; McNamee, Roseanne; Mortensen, Preben B; Pedersen, Marianne G; McCarthy, Fergus P; Henriksen, Tine B; Anu Research Centre, Department of Obstetrics and Gynaecology, University College, Cork, Cork University Maternity Hospital, Ireland. a.khashan@ucc.ie (2012-01-31)
      There is conflicting evidence regarding the effect of coeliac disease (CD) in the father on birthweight and preterm birth. We investigated the association between paternal CD and birthweight and preterm birth. Medical records of all singleton live-born children in Denmark between 1 January 1979 and 31 December 2004 were linked to information about parents' diseases. Fathers who were diagnosed with CD were then identified. Fathers with CD were considered treated if they were diagnosed before pregnancy and untreated if they were diagnosed after the date of conception. The outcome measures were: birthweight, small-for-gestational age (birthweight<10th centile for gestational age) and preterm birth (<37 weeks). We compared the offspring of men without CD (n = 1 472 352) and offspring of those with CD [untreated (n = 138) and treated (n = 473)]. There was no significant association between untreated CD in the father and birthweight (adjusted mean difference = -3 g; [95% CI -46, 40]) or preterm birth (adjusted odds ratio (OR) = 0.86, [95% CI 0.53, 1.37]) (compared with no CD). There was some evidence for an association between treated paternal CD and birthweight (adjusted mean difference = -81 g; [95% CI -161, -3]), but not preterm birth (adjusted OR = 1.76, [95% CI 0.95, 3.26]). Untreated paternal CD was not associated with an increased risk of reduced birthweight, or of preterm birth. There was some evidence that diagnosis and presumed treatment of paternal CD with a gluten-free diet is associated with reduced birthweight.