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1. The health and educational costs of preterm birth to 18 years of age in Australia.

Author

Newnham, JP, Schilling, C, Petrou, S, Morris, JM, Wallace, EM, Brown, K, Edwards, L, Skubisz, MM, White, SW, Rynne, B, Arrese, CA, Doherty, DA, Newnham, JP, Schilling, C, Petrou, S, Morris, JM, Wallace, EM, Brown, K, Edwards, L, Skubisz, MM, White, SW, Rynne, B, Arrese, CA, and Doherty, DA

Abstract

BACKGROUND: Preterm birth is the greatest cause of death up to five years of age and an important contributor to lifelong disability. There is increasing evidence that a meaningful proportion of early births may be prevented, but widespread introduction of effective preventive strategies will require financial support. AIMS: This study estimated the economic cost to the Australian government of preterm birth, up to 18 years of age. MATERIALS AND METHODS: A decision-analytic model was developed to estimate the costs of preterm birth in Australia for a hypothetical cohort of 314 814 children, the number of live births in 2016. Costs to Australia's eight jurisdictions included medical expenditures and additional costs to educational services. RESULTS: The total cost of preterm birth to the Australian government associated with the annual cohort was estimated at $1.413 billion (95% CI 1047-1781). Two-thirds of the costs were borne by healthcare services during the newborn period and one-quarter of the costs by educational services providing special assistance. For each child, the costs were highest for those born at the earliest survivable gestational age, but the larger numbers of children born at later gestational ages contributed heavily to the overall economic burden. CONCLUSION: Preterm birth leaves many people with lifelong disabilities and generates a significant economic burden to society. The costs extend beyond those to the healthcare system and include additional educational needs. Assessments of economic costs should inform economic evaluations of interventions aimed at the prevention or treatment of preterm birth.

Published
2022

2. The Relationship Between Fetal Growth and Retinal Nerve Fiber Layer Thickness in a Cohort of Young Adults

Author

Dyer, KIC, Sanfilippo, PG, Yazar, S, Craig, JE, Hewitt, AW, Newnham, JP, Mackey, DA, Lee, SSY, Dyer, KIC, Sanfilippo, PG, Yazar, S, Craig, JE, Hewitt, AW, Newnham, JP, Mackey, DA, and Lee, SSY

Abstract

PURPOSE: To explore relationships between patterns of fetal anthropometric growth, as reflective of fetal wellbeing, and global retinal nerve fiber layer (RNFL) thickness measured in young adulthood. METHODS: Participants (n = 481) from within a Western Australian pregnancy cohort study underwent five serial ultrasound scans during gestation, with fetal biometry measured at each scan. Optic disc parameters were measured via spectral-domain optical coherence tomography imaging at a 20-year follow-up eye examination. Generalized estimating equations were used to evaluate differences in global RNFL thickness between groups of participants who had undergone similar growth trajectories based on fetal head circumference (FHC), abdominal circumference (FAC), femur length (FFL), and estimated fetal weight (EFW). RESULTS: Participants with consistently large FHCs throughout gestation had significantly thicker global RNFLs than those with any other pattern of FHC growth (P = 0.023), even after adjustment for potential confounders (P = 0.037). Based on model fit statistics, FHC growth trajectory was a better predictor of global RNFL thickness than birth weight or head circumference at birth. RNFL thickness did not vary significantly between groups of participants with different growth trajectories based on FAC, FFL, or EFW. CONCLUSIONS: FHC growth is associated with RNFL thickness in young adulthood and, moreover, is a better predictor than either birth weight or head circumference at birth. TRANSLATIONAL RELEVANCE: This research demonstrates an association between intrauterine growth and long-term optic nerve health, providing a basis for further exploring the extent of the influence of fetal wellbeing on clinical conditions linked to RNFL thinning.

Published
2022

3. Associations between Prenatal Exposure to Phthalates and Timing of Menarche and Growth and Adiposity into Adulthood: A Twenty-Years Birth Cohort Study

Author

Berman, YE, Doherty, DA, Main, KM, Frederiksen, H, Hickey, M, Keelan, JA, Newnham, JP, Hart, RJ, Berman, YE, Doherty, DA, Main, KM, Frederiksen, H, Hickey, M, Keelan, JA, Newnham, JP, and Hart, RJ

Abstract

Phthalates are ubiquitous environmental chemicals with endocrine disrupting properties and potentially obesogenic effects. We hypothesised that antenatal phthalate exposure may influence growth and adiposity patterns in girls through childhood into adolescence. Among 1342 Raine Study singleton females, 462 had maternal serum and at least one outcome available up to 20 years of age. Individuals' maternal serum collected at 18 and 34 weeks gestation was pooled and analyzed for concentrations of 32 metabolites of 15 phthalate diesters. Cox regression and linear models were used to determine associations between maternal phthalate levels and age at menarche, change in height and weight z-scores between birth and two years, height from birth to 20 years, BMI from two to 20 years, deviation from mid-parental height at age 20 and DEXA scan measures at age 20. Weak negative associations were detected with some phthalate metabolites and change in height and weight z-score during infancy. Weak positive associations between some of the high molecular weight phthalate metabolites and height z-score were detected during childhood. While still within the normal range, age at menarche was slightly delayed in girls with higher prenatal exposure to the higher molecular weight phthalate metabolites. We derived some associations between prenatal phthalate exposure with early growth patterns and age at menarche.

Published
2021

4. A multi-centre, open label, randomised, parallel-group, superiority Trial to compare the efficacy of URsodeoxycholic acid with RIFampicin in the management of women with severe early onset Intrahepatic Cholestasis of pregnancy: the TURRIFIC randomised trial

Author

Hague, WM, Callaway, L, Chambers, J, Chappell, L, Coat, S, de Haan-Jebbink, J, Dekker, M, Dixon, P, Dodd, J, Fuller, M, Gordijn, S, Graham, D, Heikinheimo, O, Hennessy, A, Kaaja, R, Khong, TY, Lampio, L, Louise, J, Makris, A, Markus, C, Marschall, H-U, Middleton, P, Mol, BW, Morris, J, Newnham, JP, Ovadia, C, Peek, M, Shand, A, Stark, M, Thornton, J, Timonen, S, Walker, S, Warrilow, D, Williamson, C, Hague, WM, Callaway, L, Chambers, J, Chappell, L, Coat, S, de Haan-Jebbink, J, Dekker, M, Dixon, P, Dodd, J, Fuller, M, Gordijn, S, Graham, D, Heikinheimo, O, Hennessy, A, Kaaja, R, Khong, TY, Lampio, L, Louise, J, Makris, A, Markus, C, Marschall, H-U, Middleton, P, Mol, BW, Morris, J, Newnham, JP, Ovadia, C, Peek, M, Shand, A, Stark, M, Thornton, J, Timonen, S, Walker, S, Warrilow, D, and Williamson, C

Abstract

BACKGROUND: Severe early onset (less than 34 weeks gestation) intrahepatic cholestasis of pregnancy (ICP) affects 0.1% of pregnant women in Australia and is associated with a 3-fold increased risk of stillbirth, fetal hypoxia and compromise, spontaneous preterm birth, as well as increased frequencies of pre-eclampsia and gestational diabetes. ICP is often familial and overlaps with other cholestatic disorders. Treatment options for ICP are not well established, although there are limited data to support the use of ursodeoxycholic acid (UDCA) to relieve pruritus, the main symptom. Rifampicin, a widely used antibiotic including in pregnant women, is effective in reducing pruritus in non-pregnancy cholestasis and has been used as a supplement to UDCA in severe ICP. Many women with ICP are electively delivered preterm, although there are no randomised data to support this approach. METHODS: We have initiated an international multicentre randomised clinical trial to compare the clinical efficacy of rifampicin tablets (300 mg bd) with that of UDCA tablets (up to 2000 mg daily) in reducing pruritus in women with ICP, using visual pruritus scores as a measuring tool. DISCUSSION: Our study will be the first to examine the outcomes of treatment specifically in the severe early onset form of ICP, comparing "standard" UDCA therapy with rifampicin, and so be able to provide for the first-time high-quality evidence for use of rifampicin in severe ICP. It will also allow an assessment of feasibility of a future trial to test whether elective early delivery in severe ICP is beneficial. TRIAL IDENTIFIERS: Australian New Zealand Clinical Trials Registration Number (ANZCTR): 12618000332224p (29/08/2018). HREC No: HREC/18/WCHN/36. EudraCT number: 2018-004011-44. IRAS: 272398. NHMRC registration: APP1152418 and APP117853.

Published
2021

5. Associations Between Fetal Growth Trajectories and the Development of Myopia by 20 Years of Age

Author

Dyer, KIC, Sanfilippo, PG, White, SW, Guggenheim, JA, Hammond, CJ, Newnham, JP, Mackey, DA, Yazar, S, Dyer, KIC, Sanfilippo, PG, White, SW, Guggenheim, JA, Hammond, CJ, Newnham, JP, Mackey, DA, and Yazar, S

Abstract

PURPOSE: To evaluate the contribution of genetic and early life environmental factors, as reflected by fetal anthropometric growth trajectories, toward the development of myopia during childhood and adolescence. METHODS: This analysis included 498 singleton Caucasian participants from the Raine Study, a pregnancy cohort study based in Western Australia. Serial fetal biometric measurements of these participants were collected via ultrasound scans performed at 18, 24, 28, 34, and 38 weeks' gestation. At a 20-year follow-up, the participants underwent a comprehensive ophthalmic examination, including cycloplegic autorefraction and ocular biometry measurements. Using a group-based trajectory modeling approach, we identified groups of participants with similar growth trajectories based on measurements of fetal head circumference (HC), abdominal circumference, femur length (FL), and estimated fetal weight (EFW). Differences between trajectory groups with respect to prevalence of myopia, axial length (AL), and corneal radius of curvature measured at the 20-year follow-up were evaluated via logistic regression and analysis of variance. RESULTS: Prevalence of myopia was highest among participants with consistently short or consistently long FLs (P = 0.04). There was also a trend toward increased prevalence with larger HC in late gestation, although not at a statistically significant level. Trajectory groups reflecting faster HC, FL, or EFW growth correlated with significantly flatter corneas (P = 0.03, P = 0.04, and P = 0.01, respectively) and a general, but not statistically significant, increase in AL. CONCLUSIONS: Environmental or genetic factors influencing intrauterine skeletal growth may concurrently affect ocular development, with effects persisting into adulthood.

Published
2020

8. Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: findings from the pregnancy and childhood epigenetics (PACE) consortium

Author

Sharp, GC, Salas, LA, Monnereau, Claire, Allard, C, Yousefi, P, Everson, TM, Bohlin, J, Xu, ZL, Huang, RC, Reese, SE, Xu, CJ, Baiz, N, Hoyo, C, Agha, G, Roy, R, Holloway, JW, Ghantous, A, Merid, SK, Bakulski, KM, Kupers, LK, Zhang, HM, Richmond, Rebecca, Page, CM, Duijts, Liesbeth, Lie, RT, Melton, PE, Vonk, JM, Nohr, EA, Williams-DeVane, C, Huen, K, Rifas-Shiman, SL, Ruiz-Arenas, C, Gonseth, S, Rezwan, FI, Herceg, Z, Ekstrom, S, Croen, L, Falahi, F, Perron, P, Karagas, MR, Quraishi, BM, Suderman, M, Magnus, MC, Jaddoe, Vincent, Taylor, JA, Anderson, D, Zhao, SS, Smit, HA, Josey, MJ, Bradman, A, Baccarelli, AA, Bustamante, M, Haberg, SE, Pershagen, G, Hertz-Picciotto, I, Newschaffer, C, Corpeleijn, E, Bouchard, L, Lawlor, DA, Maguire, RL, Barcellos, LF, Smith, GD, Eskenazi, B, Karmaus, W, Marsit, CJ, Hivert, MF, Snieder, H, Fallin, MD, Melen, E, Munthe-Kaas, MC, Arshad, H, Wiemels, JL, Annesi-Maesano, I, Vrijheid, M, Oken, E, Holland, N, Murphy, SK, Sorensen, TIA, Koppelman, GH, Newnham, JP, Wilcox, AJ, Nystad, W, London, SJ, Felix, Janine, Relton, CL, Sharp, GC, Salas, LA, Monnereau, Claire, Allard, C, Yousefi, P, Everson, TM, Bohlin, J, Xu, ZL, Huang, RC, Reese, SE, Xu, CJ, Baiz, N, Hoyo, C, Agha, G, Roy, R, Holloway, JW, Ghantous, A, Merid, SK, Bakulski, KM, Kupers, LK, Zhang, HM, Richmond, Rebecca, Page, CM, Duijts, Liesbeth, Lie, RT, Melton, PE, Vonk, JM, Nohr, EA, Williams-DeVane, C, Huen, K, Rifas-Shiman, SL, Ruiz-Arenas, C, Gonseth, S, Rezwan, FI, Herceg, Z, Ekstrom, S, Croen, L, Falahi, F, Perron, P, Karagas, MR, Quraishi, BM, Suderman, M, Magnus, MC, Jaddoe, Vincent, Taylor, JA, Anderson, D, Zhao, SS, Smit, HA, Josey, MJ, Bradman, A, Baccarelli, AA, Bustamante, M, Haberg, SE, Pershagen, G, Hertz-Picciotto, I, Newschaffer, C, Corpeleijn, E, Bouchard, L, Lawlor, DA, Maguire, RL, Barcellos, LF, Smith, GD, Eskenazi, B, Karmaus, W, Marsit, CJ, Hivert, MF, Snieder, H, Fallin, MD, Melen, E, Munthe-Kaas, MC, Arshad, H, Wiemels, JL, Annesi-Maesano, I, Vrijheid, M, Oken, E, Holland, N, Murphy, SK, Sorensen, TIA, Koppelman, GH, Newnham, JP, Wilcox, AJ, Nystad, W, London, SJ, Felix, Janine, and Relton, CL

Published
2017

9. Genetic Basis for Gestation Length

Author

Pennell, CE, Warrington, NM, Mook-Kanamori, D, Lye, SJ, Newnham, JP, Palmer, LJ, Jaddoe, VWV, Freathy, RM, Jacobssen, B, Holloway, J, McCarthy, MI, Frayling, TM, Consortium, PGP, and Consortium, EGG

Published
2016

10. Association of genetic Loci with glucose levels in childhood and adolescence: a meta-analysis of over 6,000 children

Author

Barker, A, Sharp, SJ, Timpson, NJ, Bouatia-Naji, N, Warrington, NM, Kanoni, S, Beilin, LJ, Brage, S, Deloukas, P, Evans, DM, Grontved, A, Hassanali, N, Lawlor, DA, Lecoeur, C, Loos, RJ, Lye, SJ, McCarthy, MI, Mori, TA, Ndiaye, NC, Newnham, JP, Ntalla, I, Pennell, CE, St Pourcain, B, Prokopenko, I, Ring, SM, Sattar, N, Visvikis-Siest, S, Dedoussis, GV, Palmer, LJ, Froguel, P, Smith, GD, Ekelund, U, Wareham, NJ, and Langenberg, C

Subjects
Blood Glucose, Male, Adenylate Cyclase, HOMEOSTASIS, ENDOCRINOLOGY & METABOLISM, Adolescent, VARIANT, Polymorphism, Single Nucleotide, Humans, Child, Glucose Transporter Type 2, Homeodomain Proteins, Science & Technology, INSULIN SENSITIVITY, MTNR1B, Tumor Suppressor Proteins, Fasting, 11 Medical And Health Sciences, Protein-Serine-Threonine Kinases, POLYMORPHISM, Cryptochromes, FASTING PLASMA-GLUCOSE, TWINS, Genetic Loci, Glucose-6-Phosphatase, SECRETION, Female, TYPE-2 DIABETES RISK, Life Sciences & Biomedicine, RESISTANCE, Adenylyl Cyclases, Genome-Wide Association Study, Transcription Factors
Abstract

OBJECTIVE-To investigate whether associations of common genetic variants recently identified for fasting glucose or insulin levels in nondiabetic adults are detectable in healthy children and adolescents. RESEARCH DESIGN AND METHODS-A total of 16 single nucleotide polymorphisms (SNPs) associated with fasting glucose were genotyped in six studies of children and adolescents of European origin, including over 6,000 boys and girls aged 9-16 years. We performed meta-analyses to test associations of individual SNPs and a weighted risk score of the 16 loci with fasting glucose. RESULTS-Nine loci were associated with glucose levels in healthy children and adolescents, with four of these associations reported in previous studies and five reported here for the first time (GLIS3, PROX1, SLC2A2, ADCY5, and CRY2). Effect sizes were similar to those in adults, suggesting age-independent effects of these fasting glucose loci. Children and adolescents carrying glucose-raising alleles of G6PC2, MTNR1B, GCK, and GLIS3 also showed reduced p-cell function, as indicated by homeostasis model assessment of beta-cell function. Analysis using a weighted risk score showed an increase [beta (95% CI)] in fasting glucose level of 0.026 mrnol/L (0.021-0.031) for each unit increase in the score. CONCLUSIONS-Novel fasting glucose loci identified in genome-wide association studies of adults are associated with altered fasting glucose levels in healthy children and adolescents with effect sizes comparable to adults. In nondiabetic adults, fasting glucose changes little over time, and our results suggest that age-independent effects of fasting glucose loci contribute to long-term interindividual differences in glucose levels from childhood onwards. Diabetes 60:1805-1812, 2011

Published
2011
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11. A novel common variant in DCST2 is associated with length in early life and height in adulthood

Author

van der Valk RJ, Kreiner-Møller E, Kooijman MN, Guxens M, Stergiakouli E, Sääf A, Bradfield JP, Geller F, Hayes MG, Cousminer DL, Körner A, Thiering E, Curtin JA, Myhre R, Huikari V, Joro R, Kerkhof M, Warrington NM, Pitkänen N, Ntalla I, Horikoshi M, Veijola R, Freathy RM, Teo YY, Barton SJ, Evans DM, Kemp JP, St Pourcain B, Ring SM, Davey Smith G, Bergström A, Kull I, Hakonarson H, Mentch FD, Bisgaard H, Chawes B, Stokholm J, Waage J, Eriksen P, Sevelsted A, Melbye M, Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium, van Duijn CM, Medina-Gomez C, Hofman A, de Jongste JC, Taal HR, Uitterlinden AG, Genetic Investigation of ANthropometric Traits (GIANT) Consortium, Armstrong LL, Eriksson J, Palotie A, Bustamante M, Estivill X, Gonzalez JR, Llop S, Kiess W, Mahajan A, Flexeder C, Tiesler CM, Murray CS, Simpson A, Magnus P, Sengpiel V, Hartikainen AL, Keinanen-Kiukaanniemi S, Lewin A, Da Silva Couto Alves A, Blakemore AI, Buxton JL, Kaakinen M, Rodriguez A, Sebert S, Vaarasmaki M, Lakka T, Lindi V, Gehring U, Postma DS, Ang W, Newnham JP, Lyytikäinen LP, Pahkala K, Raitakari OT, Panoutsopoulou K, Zeggini E, Boomsma DI, Groen-Blokhuis M, Ilonen J, Franke L, Hirschhorn JN, Pers TH, Liang L, Huang J, Hocher B, Knip M, Saw SM, Holloway JW, Melén E, Grant SF, Feenstra B, Lowe WL, Widén E, Sergeyev E, Grallert H, Custovic A, Jacobsson B, Jarvelin MR, Atalay M, Koppelman GH, Pennell CE, Niinikoski H, Dedoussis GV, Mccarthy MI, Frayling TM, Sunyer J, Timpson NJ, Rivadeneira F, Bønnelykke K, Jaddoe VW, and Early Growth Genetics (EGG) Consortium

Subjects
Genetic variants, DCST2, Single nucleotide polymorphisms (SNPs), Skeletal growth, Adult height, Early growth
Abstract

Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; β = 0.046, SE = 0.008, P = 2.46 × 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10(-4)) and adult height (N = 127 513; P = 1.45 × 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height. R.M.F. is supported by a Sir Henry Wellcome Postdoctoral Fellowship (Wellcome Trust grant 085541/Z/08/Z). T.H.P. is supported by The Danish Council for Independent Research Medical Sciences (FSS) The Alfred Benzon Foundation. B.F. is supported by an Oak Foundation fellowship. M.M. is a Wellcome Trust Senior Investigator (Wellcome Trust grant 090532) and a NIHR Senior Investigator. T.M.F. is supported by the European Research Council grant: SZ-245 50371- GLUCOSEGENES-FP7-IDEAS-ERC. F.R. (VIDI 016.136.367) and V.W.V.J. (VIDI 016.136.361) received grants from the Netherlands Organization for Health Research and Development.

Published
2015

13. Prostaglandins and mechanisms of preterm birth

Author

Challis, John, Sloboda, Deborah, Alfaidy, Nadia, Lye, Steven, Gibb, William, Patel, Fal, Whittle, Wendy, Newnham, John, Sloboda, DM, Lye, SJ, Patel, FA, Whittle, WL, Newnham, JP, Biologie du Cancer et de l'Infection (BCI ), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
endocrine system, Embryology, medicine.medical_specialty, Hydrocortisone, Corticotropin-Releasing Hormone, Placenta, Prostaglandin, Biology, Uterine contraction, Uterine Contraction, 03 medical and health sciences, chemistry.chemical_compound, Fetus, Obstetric Labor, Premature, 0302 clinical medicine, Endocrinology, Glucocorticoid receptor, Pregnancy, Internal medicine, medicine, Animals, Humans, Prostaglandin E2, Glucocorticoids, reproductive and urinary physiology, 030304 developmental biology, 0303 health sciences, 030219 obstetrics & reproductive medicine, Infant, Newborn, Myometrium, Obstetrics and Gynecology, Trophoblast, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, Cell Biology, medicine.anatomical_structure, Reproductive Medicine, chemistry, Prostaglandin-Endoperoxide Synthases, embryonic structures, Prostaglandins, Female, medicine.symptom, medicine.drug
Abstract

International audience; Increased uterine contractility at term and preterm results first from activation and then stimulation of the myometrium. Activation can be provoked by mechanical stretch of the uterus, and by an endocrine pathway resulting from increased activity of the fetal hypothalamic-pituitary-adrenal axis. In sheep fetuses, increased cortisol output during pregnancy regulates expression of prostaglandin synthase type 2 (PGHS-2) in the placenta in an oestrogen-independent manner, resulting in increased concentrations of prostaglandin E2 (PGE2) in the fetal circulation. Later increases in maternal uterine expression of PGHS-2 require increases in oestrogen and lead to increased concentrations of PGF(2alpha) in the maternal circulation. Thus, regulation of PGHS-2 at term is differentially controlled in fetal (trophoblast) and maternal (uterine epithelium) tissue. This difference may reflect expression of glucocorticoid receptor but not oestrogen receptor (ER) in placental trophoblast cells. In women, cortisol also contributes to increased prostaglandin production in fetal tissues through upregulation of PGHS-2 (amnion and chorion) and downregulation of 15-OH prostaglandin dehydrogenase (PGDH; chorion trophoblasts). The effect of cortisol on expression of PGDH in the chorion reverses a tonic stimulatory effect of progesterone, potentially through a paracrine or autocrine action. In membranes, cortisol may be derived from cortisone through activity of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1, in addition to secretion from the maternal or fetal adrenal glands. In placenta, 11beta-HSD-2 oxidase activity predominates and expression of this enzyme is reduced with hypoxaemia and in placentae from pre-eclamptic pregnancies. In these circumstances, increased concentrations of maternal cortisol may cross into the fetal compartment, contributing to growth restriction and programming later life disease.

Published
2002

14. Early growth genetics C. New loci associated with birgh weight identify genetic links between intrauterine growth and adult height and metabolism

Author

Horikoshi, M, Yaghootkar, H, Mook, Dennis, Sovio, U, Taal, Rob, Hennig, BJ, Bradfield, JP, St Pourcain, B, Evans, DM, Charoen, P, Kaakinen, M, Cousminer, DL, Lehtimaki, T, Kreiner-Moller, E, Warrington, NM, Bustamante, M, Feenstra, B, Berry, DJ, Thiering, E, Pfab, T, Barton, SJ, Shields, BM, Kerkhof, M, Leeuwen, Elisa, Fulford, AJ, Kutalik, Z, Zhao, JH, den Hoed, M, Mahajan, A, Lindi, V, Goh, LK, Hottenga, JJ (Jouke Jan), Wu, Fenny, Raitakari, OT, Harder, M, Meirhaeghe, A, Ntalla, I, Salem, RM, Jameson, KA, Zhou, K, Monies, D, Lagou, V, Kirin, M, Heikkinen, J, Adair, LS, Alkuraya, FS, Al-Odaib, A, Amouyel, P, Andersson, EAS, Bennett, AJ, Blakemore, AIF, Buxton, JL, Dallongeville, J, Das, Suman, de Geus, EJC, Estivill, X, Flexeder, C, Froguel, P, Geller, F, Godfrey, KM, Gottrand, F, Groves, CJ, Hansen, T, Hirschhorn, JN, Hofman, Bert, Hollegaard, MV, Hougaard, DM, Hypponen, E, Inskip, H, Isaacs, Aaron, Jorgensen, T, Kanaka-Gentenbein, C, Kemp, JP, Kiess, W, Kipelainen, TO, Klopp, N, Knight, BA, Kuzawa, CW, McMahon, G, Newnham, JP, Niinikoski, H, Oostra, Ben, Pedersen, L, Postma, DS, Ring, SM, Rivadeneira, Fernando, Robertson, NR, Sebert, S, Simell, O, Slowinski, T, Tiesler, CMT, Tonjes, A, Vaag, A, Viikari, JS, Vink, JM, Vissing, NH, Wareham, NJ, Willemsen, G, Witte, DR, Zhang, H, Zhao, J, Wilson, JF, Stumvoll, M, Prentice, AM, Meyer, BF, Pearson, ER, Boreham, CA, Cooper, C, Gilman, MW, Dedoussis, GV, Moreno, LA, Pedersen, O, Saarinen, M, Mohlke, KL, Boomsma, DI, Saw, SM, Lakka, TA, Korner, A, Loos, RJ, Ong, KK, Vollenweider, P, Duijn, Cornelia, Koppelman, GH, Hattersley, AT, Holloway, JW, Hocher, B, Heinrich, J, Power, C, Melbye, M, Guxens Junyent, Monica, Pennell, CE, Bonnelykke, K, Bisgaard, H, Eriksson, JG, Widen, E, Hakonarson, H, Uitterlinden, André, Pouta, A, Lawlor, DA, Smith, GD, Frayling, TM, McCarthy, M, Grant, SFA, Jaddoe, Vincent, Jarvelin, MR, Timpson, NJ, Prokopenko, I, Freathy, RM, Erasmus MC other, Epidemiology, Medical Microbiology & Infectious Diseases, Clinical Genetics, Internal Medicine, and Hematology

Published
2013

15. Effects of Intra-Amniotic Lipopolysaccharide and Maternal Betamethasone on Brain Inflammation in Fetal Sheep

Author

Kuypers, E, Jellema, RK, Ophelders, DRMG, Dudink, J, Nikiforou, M, Wolfs, TGAM, Nitsos, I, Pillow, JJ, Polglasem, GR, Kemp, MW, Saito, M, Newnham, JP, Jobe, AH, Kallapur, SG, Kramer, BW, Kuypers, E, Jellema, RK, Ophelders, DRMG, Dudink, J, Nikiforou, M, Wolfs, TGAM, Nitsos, I, Pillow, JJ, Polglasem, GR, Kemp, MW, Saito, M, Newnham, JP, Jobe, AH, Kallapur, SG, and Kramer, BW

Published
2013

16. Lifecourse Childhood Adiposity Trajectories Associated With Adolescent Insulin Resistance

Author

Huang, R-C, de Klerk, NH, Smith, A, Kendall, GE, Landau, LI, Mori, TA, Newnham, JP, Stanley, FJ, Oddy, WH, Hands, B, Beilin, LJ, Huang, R-C, de Klerk, NH, Smith, A, Kendall, GE, Landau, LI, Mori, TA, Newnham, JP, Stanley, FJ, Oddy, WH, Hands, B, and Beilin, LJ

Abstract

OBJECTIVE: In light of the obesity epidemic, we aimed to characterize novel childhood adiposity trajectories from birth to age 14 years and to determine their relation to adolescent insulin resistance. RESEARCH DESIGN AND METHODS: A total of 1,197 Australian children with cardiovascular/metabolic profiling at age 14 years were studied serially from birth to age 14 years. Semiparametric mixture modeling was applied to anthropometric data over eight time points to generate adiposity trajectories of z scores (weight-for-height and BMI). Fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR) were compared at age 14 years between adiposity trajectories. RESULTS: Seven adiposity trajectories were identified. Three (two rising and one chronic high adiposity) trajectories comprised 32% of the population and were associated with significantly higher fasting insulin and HOMA-IR compared with a reference trajectory group (with longitudinal adiposity z scores of approximately zero). There was a significant sex by trajectory group interaction (P < 0.001). Girls within a rising trajectory from low to moderate adiposity did not show increased insulin resistance. Maternal obesity, excessive weight gain during pregnancy, and gestational diabetes were more prevalent in the chronic high adiposity trajectory. CONCLUSIONS: A range of childhood adiposity trajectories exist. The greatest insulin resistance at age 14 years is seen in those with increasing trajectories regardless of birth weight and in high birth weight infants whose adiposity remains high. Public health professionals should urgently target both excessive weight gain in early childhood across all birth weights and maternal obesity and excessive weight gain during pregnancy.

Published
2011

29. Treatment of periodontal disease during pregnancy: a randomized controlled trial.

Author

Newnham JP, Newnham IA, Ball CM, Wright M, Pennell CE, Swain J, Doherty DA, Newnham, John P, Newnham, Ian A, Ball, Colleen M, Wright, Michelle, Pennell, Craig E, Swain, Jonathan, and Doherty, Dorota A

Abstract

Objective: To investigate whether treating periodontal disease prevents preterm birth and other major complications of pregnancy.Methods: This single-center trial was conducted across six obstetric sites in metropolitan Perth, Western Australia. Pregnant women identified by history to be at risk (n=3,737) were examined for periodontal disease. Approximately 1,000 women with periodontal disease were allocated at random to receive periodontal treatment commencing around 20 weeks of gestation (n=542) or 6 weeks after the pregnancy was completed (controls; n=540). The treatment included mechanical removal of oral biofilms together with oral hygiene instruction and motivation at a minimum of three weekly visits, with further visits if required.Results: There were no differences between the control and treatment groups in preterm birth (9.3% compared with 9.7%, odds ratio [OR] 1.05, 95% confidence interval [CI 0.7-1.58], P=.81), birth weight (3,450 compared with 3,410 g, P=.12), preeclampsia (4.1% compared with 3.4%, OR 0.82, 95% CI 0.44-1.56, P=.55), or other obstetric endpoints. There were four unexplained stillbirths in the control group and no pregnancy losses in the treated group (P=.12). Measures of fetal and neonatal well-being were similar in the two groups, including abnormalities in fetal heart rate recordings (P=.26), umbilical artery flow studies (P=.96), and umbilical artery blood gas values (P=.37). The periodontal treatment was highly successful in improving health of the gums (P<.01).Conclusion: The evidence provided by the present study does not support the hypothesis that treatment of periodontal disease during pregnancy in this population prevents preterm birth, fetal growth restriction, or preeclampsia. Periodontal treatment was not hazardous to the women or their pregnancies.Clinical Trial Registration: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00133926.Level Of Evidence: I. [ABSTRACT FROM AUTHOR]

Published
2009
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31. IL-1 mediates pulmonary and systemic inflammatory responses to chorioamnionitis induced by lipopolysaccharide.

Author

Kallapur SG, Nitsos I, Moss TJ, Polglase GR, Pillow JJ, Cheah FC, Kramer BW, Newnham JP, Ikegami M, Jobe AH, Kallapur, Suhas G, Nitsos, Ilias, Moss, Timothy J M, Polglase, Graeme R, Pillow, J Jane, Cheah, Fook-Choe, Kramer, Boris W, Newnham, John P, Ikegami, Machiko, and Jobe, Alan H

Abstract

Rationale: Chorioamnionitis frequently associates with preterm delivery and increased amniotic fluid IL-1, and causes fetal lung and systemic inflammation. However, chorioamnionitis is also associated with a paradoxical reduction in the incidence of surfactant deficiency-related respiratory distress syndrome in preterm infants.Objectives: To identify the role of IL-1 signaling in the mediation of pulmonary and systemic inflammation and lung maturation in a fetal sheep model of lipopolysaccharide (LPS) induced chorioamnionitis.Methods: After confirming the efficacy of recombinant human IL-1 receptor antagonist (rhIL-1ra), fetal sheep were exposed to intraamniotic (IA) injections of Escherichia coli LPS with or without prior IA injections of rhIL-1ra. Preterm lambs were delivered at 82% of term gestation.Measurements and Main Results: rhIL-1ra decreased IA LPS-induced lung inflammation assessed by decreased lung neutrophil and monocyte influx, inducible nitric oxide synthase expression, lung IL-6 and IL-1beta mRNA expression, and airway myeloperoxidase concentrations. rhIL-1ra inhibited IA LPS-induced fetal systemic inflammation assessed by decreased plasma IL-8, protein carbonyls, blood neutrophilia, and the expression of serum amyloid A3 mRNA in the liver. rhIL-1ra also partially blocked the lung maturational effects of IA LPS. Therefore blockade of IL-1 signaling in the amniotic compartment inhibited fetal lung and systemic inflammation and lung maturation in response to LPS-induced chorioamnionitis.Conclusions: IL-1 plays a central role in the pathogenesis of chorioamnionitis-induced fetal inflammatory responses. [ABSTRACT FROM AUTHOR]

Published
2009
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35. Repeated maternal glucocorticoid administration and the developing liver in fetal sheep

Author

Sloboda, DM, Newnham, JP, and Challis

Abstract

Prenatal glucocorticoid exposure has been associated with a reduction in birth weight and postnatal alterations in glucose homeostasis and hypothalamic-pituitary-adrenal (HPA) axis function. The mechanisms underlying these responses are unknown, although changes in fetal hepatic development may play an important role. The fetal liver produces key regulators of fuel metabolism and of the developing HPA axis that are altered by glucocorticoids. The local availability of glucocorticoids is regulated, in part, by corticosteroid-binding protein (CBG), glucocorticoid receptors (GR) and by the enzyme 11beta-hydroxysteroid dehydrogenase (11betaHSD), but the effects of maternal glucocorticoid administration on the expression of these genes in the fetal liver are unknown. 11betaHSD1 is the predominant form of this enzyme present in the liver and is responsible for the conversion of cortisone to cortisol. To determine if prenatal glucocorticoid exposure alters fetal hepatic regulation of CBG, 11betaHSD1 and GRs, we treated pregnant ewes with betamethasone (0.5 mg/kg) intramuscularly at 104, 111 and 118 days of gestation (term 150 days). Animals were killed at 125 or 146 days of gestation. Maternal betamethasone administration did not alter mean cord plasma glucose but significantly decreased cord plasma insulin levels (P<0.05) at 125 days of gestation. At 146 days of gestation, cord plasma glucose levels were significantly increased without alterations in insulin levels following maternal betamethasone treatment (P<0.05). Maternal betamethasone administration resulted in a significant increase in fetal hepatic 11betaHSD1 mRNA and protein levels at 125 days of gestation (P<0.05). CBG mRNA levels were significantly elevated over control at 125 days although levels of CBG protein were not significantly different. GR protein levels were not statistically different at either 125 or 146 days of gestation following glucocorticoid administration. These data suggest that prenatal betamethasone exposure in the ovine fetus results in alterations in cord glucose and insulin levels as well as alterations in hepatic 11betaHSD1 mRNA and protein expression. These changes in 11betaHSD1 increase the potential to generate local cortisol from circulating cortisone. We speculate that this could affect expression of glucocorticoid-dependent hepatic enzymes involved with the regulation of glucose production and HPA responsiveness.

Published
2002
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36. The effect of prenatal betamethasone administration on postnatal ovine hypothalamic-pituitary-adrenal function

Author

Sloboda, DM, Moss, TJ, Gurrin, LC, Newnham, JP, and Challis

Abstract

Prenatal exposure to glucocorticoids is associated with alterations in fetal growth and endocrine function. However, few studies have examined the effects of clinically relevant doses of glucocorticoids on postnatal hypothalamic-pituitary-adrenal (HPA) function. To determine the effects of maternal or fetal betamethasone administration (0.5 mg/kg maternal or estimated fetal weight) on postnatal HPA function at 6 months and 1 year postnatal age, pregnant ewes were randomized into the following treatment groups: no treatment (n=6); maternal saline (n=6); single maternal betamethasone (M1) (n=6); repeated maternal betamethasone (M4) (n=6); fetal saline (n=5); single fetal betamethasone (n=6) and repeated fetal betamethasone (F4) (n=6). Single injections were given at 104 days of gestation and repeated injections at 104, 111, 118 and 125 days. Lambs were born spontaneously and the ACTH and cortisol responses to i.v. corticotropin-releasing hormone (CRH) (0.5 microg/kg) plus arginine vasopressin (AVP) (0.1 microg/kg) were measured at 6 months and 1 year postnatally. At 6 months postnatal age, neither maternal nor fetal prenatal betamethasone administration altered significantly the ACTH and cortisol responses to CRH+AVP. However, in animals at 1 year postnatal age, a previous single injection of betamethasone to the mother (M1) resulted in significantly elevated basal and stimulated cortisol levels (P<0.05), without significant change in the ACTH response. In contrast, betamethasone administration to the fetus resulted in significantly attenuated ACTH responses to CRH+AVP at 1 year compared with control animals (P<0.05), but these were not associated with any significant changes in basal or stimulated cortisol levels. All control animals exhibited a significant increase in peak ACTH responses to CRH+AVP between 6 months and 1 year postnatal age (P<0.05). After prenatal betamethasone (F4, M4) the difference in peak ACTH response between animals at 6 months and 1 year postnatal age was abolished. We conclude that in sheep between 6 months and 1 year postnatal age, HPA function undergoes developmental changes that are influenced by prenatal glucocorticoid exposure. Furthermore, the effects of glucocorticoid on postnatal HPA responses may vary according to the time in gestation that the steroid was administered, and whether it was given directly into the fetal or maternal compartment.

Published
2002
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37. Effects of repeated maternal betamethasone administration on growth and hypothalamic-pituitary-adrenal function of the ovine fetus at term

Author

Sloboda, DM, Newnham, JP, and Challis

Abstract

Synthetic glucocorticoids have become an important clinical tool with which to advance fetal lung maturation in women at risk of early preterm birth, and this has succeeded in reducing neonatal mortality and morbidity from respiratory distress syndrome. Although previous studies have shown that glucocorticoids have deleterious consequences on fetal development, there is little information regarding the effects of clinically relevant repeated maternal doses of glucocorticoids on fetal growth and hypothalamic-pituitary-adrenal (HPA) function. We hypothesised that repeated prenatal exposure to increased concentrations of glucocorticoids would alter fetal growth and HPA axis development. Pregnant ewes were injected with betamethasone (0.5 mg/kg) or vehicle at 104, 111 and 118 days of gestation (term 150 days). Animals were sacrificed at 125 and 146 days of gestation, at which time fetal weights were recorded. Maternal and fetal blood samples were gathered and fetal tissue collected. Maternal oestradiol concentrations were significantly greater than those in controls at 125 days of gestation, but were not different at 146 days. Maternal plasma progesterone concentrations were similar between groups at both 125 and 146 days of gestation. Weight at birth was significantly reduced by 23% at 125 days and 19% at 146 days of gestation (P<0.05) after exposure to glucocorticoid. Cord plasma ACTH concentrations were not significantly different between groups at day 125, but were significantly increased in day 146 fetuses of ewes that had received betamethasone (P<0.05). Cord plasma cortisol concentrations followed the same trend, although differences were not statistically significant. Cord plasma corticosteroid binding capacity (CBC) was significantly increased at 125 days of gestation in fetuses of betamethasone-treated animals (P<0.05), but not at 146 days of gestation. To examine the mechanisms regulating the increase in cord plasma ACTH of 146-day fetuses, we used in situ hybridisation to determine the distribution and levels of mRNA encoding key pituitary and hypothalamic neuropeptides of the HPA axis. In pituitaries of 146-day fetuses, there were no significant differences in the regional pattern of distribution or amounts of pro-opiomelanocortin (POMC) mRNA between betamethasone-treated animals and controls, in either the pars intermedia or the inferior and superior regions of the pars distalis. Neither prohormone convertase (PC)-1 nor PC-2 mRNA levels in pituitaries of 146-day fetuses were significantly different between treatment groups. After maternal betamethasone, immunoreactive ACTH peptide content in the fetal pars distalis was not different but glucocorticoid receptor (GR) mRNA levels in the pars distalis were increased significantly (P<0.05). No significant difference in distribution pattern or concentrations of corticotrophin-releasing hormone (CRH) mRNA, GR mRNA, oxytocin mRNA and pre-proenkephalin mRNA were found in hypothalami from fetuses at 146 days of gestation after betamethasone treatment. We conclude that antenatal betamethasone given to pregnant sheep in a manner similar to that used in human obstetric practice results in reduced weight at birth at 125 and 146 days, and altered basal cord levels of plasma ACTH and corticosteroid binding capacity, but these changes are not reflective of changes in steady state concentrations of POMC and CRH mRNA in the fetal pituitary or hypothalamus.

Published
2000
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38. Fetal mortality from day 30 of pregnancy in Merino ewes offered different levels of nutrition

Author

Kelly, RW, Wilkins, JF, and Newnham, JP

Abstract

The effect of nutritional restriction during mid pregnancy on fetal mortality was examined in 3 experiments in which multiparous 3-6 year old Merino ewes were fed at maintenance (M) or 0.3M from about day 30 to 90 of pregnancy, followed by M or 2M for the remainder of gestation. Fetal wellbeing was determined by ultrasound examination at periodic intervals throughout pregnancy. Among 134 single borne fetuses, mortality was detected in only 3, between days 70-92 of pregnancy. There were no losses in 58 ewes bearing twins and fed at M. By comparison, 9 of 93 ewes bearing twins and fed at 0.3M lost 1 or both fetuses between days 30 and 95, and a further 3 of 66 remaining ewes had fetal losses between days 95 and 140. It was concluded that such losses in ewes bearing twins during periods of nutritional restriction may need to be considered when using scanning to predict the number of lambs born. Also it highlights the need to confirm the viability of each fetus during ultrasound examinations of multiple fetuses.

Published
1989
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39. Genome-wide associations for birth weight and correlations with adult disease

Author

Horikoshi, M, Beaumont, RN, Day, FR, Warrington, NM, Kooijman, MN, Fernandez-Tajes, J, Feenstra, B, Van Zuydam, NR, Gaulton, KJ, Grarup, N, Bradfield, JP, Strachan, DP, Li-Gao, R, Ahluwalia, TS, Kreiner, E, Rueedi, R, Lyytikäinen, L-P, Cousminer, DL, Wu, Y, Thiering, E, Wang, CA, Have, CT, Hottenga, J-J, Vilor-Tejedor, N, Joshi, PK, Boh, ETH, Ntalla, I, Pitkänen, N, Mahajan, A, Van Leeuwen, EM, Joro, R, Lagou, V, Nodzenski, M, Diver, LA, Zondervan, KT, Bustamante, M, Marques-Vidal, P, Mercader, JM, Bennett, AJ, Rahmioglu, N, Nyholt, DR, Ma, RCW, Tam, CHT, Tam, WH, CHARGE Consortium Hematology Working Group, Ganesh, SK, Van Rooij, FJA, Jones, SE, Loh, P-R, Ruth, KS, Tuke, MA, Tyrrell, J, Wood, AR, Yaghootkar, H, Scholtens, DM, Paternoster, L, Prokopenko, I, Kovacs, P, Atalay, M, Willems, SM, Panoutsopoulou, K, Wang, X, Carstensen, L, Geller, F, Schraut, KE, Murcia, M, Van Beijsterveldt, CEM, Willemsen, G, Appel, EVR, Fonvig, CE, Trier, C, Tiesler, CMT, Standl, M, Kutalik, Z, Bonàs-Guarch, S, Hougaard, DM, Sánchez, F, Torrents, D, Waage, J, Hollegaard, MV, De Haan, HG, Rosendaal, FR, Medina-Gomez, C, Ring, SM, Hemani, G, McMahon, G, Robertson, NR, Groves, CJ, Langenberg, C, Luan, J, Scott, RA, Zhao, JH, Mentch, FD, MacKenzie, SM, Reynolds, RM, Early Growth Genetics (EGG) Consortium, Lowe, WL, Tönjes, A, Stumvoll, M, Lindi, V, Lakka, TA, Van Duijn, CM, Kiess, W, Körner, A, Sørensen, TIA, Niinikoski, H, Pahkala, K, Raitakari, OT, Zeggini, E, Dedoussis, GV, Teo, Y-Y, Saw, S-M, Melbye, M, Campbell, H, Wilson, JF, Vrijheid, M, De Geus, EJCN, Boomsma, DI, Kadarmideen, HN, Holm, J-C, Hansen, T, Sebert, S, Hattersley, AT, Beilin, LJ, Newnham, JP, Pennell, CE, Heinrich, J, Adair, LS, Borja, JB, Mohlke, KL, Eriksson, JG, Widén, E, Kähönen, M, Viikari, JS, Lehtimäki, T, Vollenweider, P, Bønnelykke, K, Bisgaard, H, Mook-Kanamori, DO, Hofman, A, Rivadeneira, F, Uitterlinden, AG, Pisinger, C, Pedersen, O, Power, C, Hyppönen, E, Wareham, NJ, Hakonarson, H, Davies, E, Walker, BR, Jaddoe, VWV, Järvelin, M-R, Grant, SFA, Vaag, AA, Lawlor, DA, Frayling, TM, Smith, GD, Morris, AP, Ong, KK, Felix, JF, Timpson, NJ, Perry, JRB, Evans, DM, McCarthy, MI, and Freathy, RM

Subjects
quantitative trait, hypertension, intrauterine growth, genome-wide association studies, metabolic disorders, 3. Good health
Abstract

Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW ($\textit{P}$ < 5 × 10$^{-8}$). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure ($\textit{R}$ $_{g}$ = -0.22, $\textit{P}$ = 5.5 × 10$^{-13}$), T2D ($\textit{R}$ $_{g}$ = -0.27, $\textit{P}$ = 1.1 × 10$^{-6}$) and coronary artery disease ($\textit{R}$ $_{g}$ = -0.30, $\textit{P}$ = 6.5 × 10$^{-9}$). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions ($\textit{P}$ = 1.9 × 10$^{-4}$). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.

45. Perinatal mortality among term births: Informing decisions about singleton early term births in Western Australia.

Author

Berman YE, Newnham JP, Nathan EA, Doherty DA, Brown K, and Ward SV

Abstract

Background: To minimise the risk of perinatal mortality, clinicians and expectant mothers must understand the risks and benefits associated with continuing the pregnancy., Objectives: Report the gestation-specific risk of perinatal mortality at term., Methods: Population-based cohort study using linked health data to identify all singleton births at gestations 37-41 weeks, in Western Australia (WA) from 2009 to 2019. Lifetable analysis was used to combine the risk of each type of perinatal mortality and calculate the cumulative risk of perinatal mortality, termed the perinatal risk index (PRI). Rates of antepartum and intrapartum stillbirth and neonatal death, as well as the PRI, were examined for each gestational week at term by non-Aboriginal and Aboriginal ethnicity. For non-Aboriginal women, rates were also examined by time-period (pre- vs. post-WA Preterm Birth Prevention Initiative (the Initiative) rollout), primiparity, and obstetric risk., Results: There were 332,084 singleton term births, including 60 perinatal deaths to Aboriginal mothers (3.2 deaths per 1000 births to Aboriginal mothers) and 399 perinatal deaths to non-Aboriginal mothers (1.3 deaths per 1000 births to non-Aboriginal mothers). For non-Aboriginal women, the PRI was at its lowest (PRI 0.80, 95% CI 0.61, 1.00) at 39 weeks gestation. For Aboriginal women, it was at its lowest at 38 weeks (PRI 2.43, 95% CI 0.48, 4.39) with similar risk at 39 weeks (PRI 2.68, 95% CI 1.22, 4.14). The PRI increased steadily after 39 weeks gestation. The risk of perinatal mortality was higher among Aboriginal women. The gestation-specific perinatal mortality rates were similar by the time-period, primiparity and obstetric risk., Conclusions: The gestational ages at term associated with the lowest risk of perinatal mortality reinforce that the recommendation not to deliver before 39 weeks without medical indication is applicable to both Aboriginal and non-Aboriginal women giving birth in WA. There was no increase in the perinatal mortality rate associated with the introduction of the Initiative., (© 2024 The Author(s). Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd.)

Published
2024
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46. Routine transabdominal cervical length screening in mid-pregnancy for the prevention of preterm birth: Is it good enough to use as a screening test?

Author

Pedretti MK, Dickinson JE, Doherty DA, and Newnham JP

Abstract

Background: Preterm birth (PTB) is a major pregnancy complication. There is evidence that a short cervical length in mid-pregnancy may predict women at increased risk of PTB., Aims: To evaluate the utility of population-based, transabdominal cervical length (TACL) measurement screening in mid-pregnancy for PTB prediction in women., Materials and Methods: A transabdominal approach was initially performed, with a transvaginal (TVCL) approach offered when the TACL was <35 mm, could not be accurately measured, or the pregnancy had risk factors for PTB. TACL was compared to the directly related TVCL, when both were performed at the same assessment. Women with risk factors of PTB were included when they had both TACL and TVCL measurements performed at the same visit., Results: Data were provided for 9355 singleton pregnancies from 13 participating imaging centres. A transabdominal approach was used in 9006 (96.3%), including 682 (7.3%) TVCL combined with TACL. There were 349 (3.7%) women who had TVCL only. The median TACL was longer (40 mm) than the TVCL (38 mm). In 682 paired TACL and TVCL measurements, TACL <35 mm correctly identified 96.2% of pregnancies with TVCL <25 mm, compared with 65.4% of cases when using a TACL <30 mm. A TVCL <25 mm occurred in 59 (0.6%) women. A TACL <35 mm was associated with birth <37 weeks of gestation in 12.1% of women and birth <32 weeks of gestation in 3.9%., Conclusions: Universal TACL is a feasible option for population screening of cervical length in a low-risk population, progressing to TVCL if the TACL is <35 mm or the cervix cannot be transabdominally accurately measured., (© 2024 The Author(s). Australian and New Zealand Journal of Obstetrics and Gynaecology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Published
2024
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47. Ascertainment of Aboriginal and Torres Strait Islander status for assessment of perinatal health outcomes: Reported versus derived maternal ethnicity in Western Australian pregnancy data.

Author

Berman YE, Newnham JP, Ward SV, Brown K, and Doherty DA

Abstract

Background: Under-identification of Aboriginal and Torres Strait Islander (hereafter referred to as Aboriginal) people can result in inaccurate estimation of health outcomes. Data linkage has improved identification of Aboriginal people in administrative datasets., Aim: To compare three methods of ascertainment of Aboriginal status using only pregnancy data from the Western Australian Midwives Notification System (MNS), to the linked Indigenous Status Flag (ISF) derived by the Department of Health., Materials and Methods: This retrospective population-based cohort study utilised logistic regression to determine which demographic characteristics were associated with under-identification, and the effect of ascertainment method on perinatal adverse outcomes., Results: All methods identified a core group of 19 017 (83.0%) Aboriginal women and the ISF identified 2298 (10.0%) women who were not identified using any other method. Under-ascertainment was lowest when a woman's Aboriginal status was determined by ever being recorded as Aboriginal in the MNS data, and highest when taken as it had been recorded for the birth in question. Maternal age <20 years, smoking during pregnancy, pre-existing diabetes, a history of singleton preterm birth and being in the lowest 20% of Socio-Economic Indexes for Areas score were all associated with a higher chance of being identified by the methods using only the MNS. These methods were less likely to identify nulliparous women, and those with maternal age ≥35 years. The method of ascertainment of Aboriginality did not make a significant difference to the adjusted predicted marginal probabilities of adverse perinatal outcomes., Conclusion: Unlinked pregnancy data can be used for epidemiological research in Aboriginal obstetric populations., (© 2024 The Authors. Australian and New Zealand Journal of Obstetrics and Gynaecology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Published
2024
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48. A Reduction in Antenatal Steroid Dose Was Associated with Reduced Cardiac Dysfunction in a Sheep Model of Pregnancy.

Author

Kumagai Y, Kemp MW, Usuda H, Takahashi T, Takahashi Y, Hamada H, Schmidt AF, Hanita T, Watanabe S, Sato S, Ikeda H, Fee EL, Furfaro L, Newnham JP, Jobe AH, Yaegashi N, and Saito M

Subjects
Sheep, Female, Pregnancy, Animals, Fetal Organ Maturity, Adrenal Cortex Hormones, Steroids, Fetal Heart diagnostic imaging, Betamethasone, Heart Diseases drug therapy
Abstract

Despite widespread use, dosing regimens for antenatal corticosteroid (ACS) therapy are poorly unoptimized. ACS therapy exerts a programming effect on fetal development, which may be associated with an increased risk of cardiovascular disease. Having demonstrated that low-dose steroid therapy is an efficacious means of maturing the preterm lung, we hypothesized that a low-dose steroid exposure would exert fewer adverse functional and transcriptional changes on the fetal heart. We tested this hypothesis using low-dose steroid therapy (10 mg delivered to the ewe over 36 h via constant infusion) and compared cardiac effects with those of a higher dose treatment (30 mg delivered to the ewe over 24 h by intramuscular injection; simulating currently employed clinical ACS regimens). Fetal cardiac function was assessed by ultrasound on the day of ACS treatment initiation. Transcriptomic analyses were performed on fetal myocardial tissue. Relative to saline control, fetuses in the higher-dose clinical treatment group had significantly lower ratios between early diastolic ventricular filling and ventricular filling during atrial systole, and showed the differential expression of myocardial hypertrophy-associated transcripts including βMHC, GADD45γ, and PPARγ. The long-term implications of these changes remain unstudied. Irrespective, optimizing ACS dosing regimens to maximize respiratory benefit while minimizing adverse effects on key organ systems, such as the heart, offers a means of improving the acute and long-term outcomes associated with this important obstetric therapy., (© 2023. The Author(s).)

Published
2023
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49. Respiratory benefit in preterm lambs is progressively lost when the concentration of fetal plasma betamethasone is titrated below two nanograms per milliliter.

Author

Fee EL, Takahashi T, Takahashi Y, Carter SWD, Clarke MW, Milad MA, Usuda H, Ikeda H, Kumagai Y, Saito Y, Ireland DJ, Newnham JP, Saito M, Jobe AH, and Kemp MW

Abstract

Antenatal steroid therapy is the standard of care for women at imminent risk of preterm delivery. Current dosing regimens use suprapharmacological doses to achieve extended fetal steroid exposures. We aimed to determine the lowest fetal plasma betamethasone concentration sufficient to achieve functional preterm lung maturation. Ewes with single fetuses underwent surgery to install a fetal jugular catheter. Adopting a stepwise design, ewes were randomized to either a saline-only group (negative control group; n = 9) or one of four betamethasone treatment groups. Each betamethasone group fetus received a fetal intravenous infusion to target a constant plasma betamethasone level of either 1 ) 2 ng/mL (2 ng/mL positive control group, n = 9); 2 ) 1 ng/mL, (1 ng/mL group, n = 10); 3 ) 0.5 ng/mL (0.5 ng/mL group, n = 10); or 4 ) 0.25 ng/mL (0.25 ng/mL group, n = 10). Fetuses were infused for 48 h, delivered, and ventilated. The positive control group, negative control group, and mid-point 0.5 ng/mL group animals were tested first. An interim analysis informed the final betamethasone group tested. Positive control group animals had large, statistically significant improvements in respiratory function. Based on an interim analysis, the 1.0 ng/mL group was studied in favor of the 0.25 ng/mL group. Treatment efficacy was progressively lost at plasma betamethasone concentrations lower than 2 ng/mL. We demonstrated that the acute respiratory benefit conveyed by antenatal steroid exposure in the fetal sheep is progressively lost when constant fetal plasma betamethasone concentrations are reduced below a targeted value of 2 ng/mL. NEW & NOTEWORTHY Lung maturation benefits in preterm lambs were progressively lost when fetal plasma betamethasone concentrations fell below 2 ng/mL. The effective floor threshold for a robust, lung-maturing exposure likely lies between 1 and 2 ng betamethasone per milliliter of plasma. Hypothalamic pituitary adrenal axis signaling and immunocyte populations remained materially disrupted at subtherapeutic steroid concentrations. These data demonstrate the potential to improve antenatal steroid therapy using reduced dose regimens informed by glucocorticoid pharmacokinetics and pharmacodynamics.

Published
2023
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50. Fetal Growth Trajectories and Measures of Insulin Resistance in Young Adults.

Author

Yadav A, Beilin LJ, Huang RC, Newnham JP, White SW, and Mori TA

Subjects
Pregnancy, Female, Humans, Young Adult, Adult, Prospective Studies, Australia epidemiology, Fetal Development, Ultrasonography, Prenatal, Insulin Resistance
Abstract

Context: Events during gestation greatly influence the risk of cardiometabolic diseases including diabetes in offspring during later life., Objective: This study aimed to investigate relationships between serial ultrasound-derived fetal growth trajectories and markers of insulin resistance in young adults in the Raine Study, an Australian pregnancy cohort., Methods: Linear mixed modeling examined the relationship between fetal growth trajectory groups, constructed using serial ultrasound-based abdominal circumference (AC), femur length (FL), and head circumference (HC) from 1333 mother-fetal pairs, and offspring Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), as a marker of diabetes risk, at 20 (n = 414), 22 (n = 385), and 27 (n = 431) years. Analyses were adjusted for age, sex, ethnicity, socioeconomic status, adult lifestyle factors, and maternal factors during pregnancy., Results: The study identified 7 AC, 5 FL, and 5 HC growth trajectory groups. Compared to the average-stable (reference) group, a low-falling AC growth trajectory (26%; P = .005) and 2 low HC growth trajectories (20%; P = .006% and 8%; P = .021) were associated with higher adult HOMA-IR. Trajectories representing a high-stable FL and a rising HC were associated with 12% (P = .002) and 9% (P = .021) lower adult HOMA-IR, respectively, compared to the reference group., Conclusion: Restricted fetal HC and AC from early pregnancy are associated with higher relative insulin resistance in the offspring during adulthood. These data strengthen our understanding of the importance of the intrauterine environment and its effect on the risk of predisposition to adult diabetes and related metabolic disorders., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Published
2023
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