Predisposing Factors to Abnormal First Trimester Placentation and the Impact on Fetal Outcomes

Abstract

Normal placentation during the first trimester sets the stage for the rest of pregnancy and involves a finely orchestrated cellular and molecular interplay of maternal and fetal tissues. The resulting intrauterine environment plays an important role in fetal programming and the future health of the fetus, and is impacted by multiple genetic and epigenetic factors. Abnormalities in placentation and spiral artery invasion can lead to ischemia, placental disease, and adverse obstetrical outcomes including preeclampsia, intrauterine growth restriction, and placental abruption. Although first trimester placentation is affected by multiple factors, preconception environmental influences such as mode of conception, including assisted reproductive technologies which result in fertilization in vitro and intrauterine influences due to sex differences, are emerging as potential significant factors impacting first trimester placentation.

Keywords

first trimester placentation - abnormal placentation - trophoblast - assisted reproductive technology - IVF - NIFT - sex differences

• References

• 1 Roberts CT. IFPA Award in Placentology Lecture: complicated interactions between genes and the environment in placentation, pregnancy outcome and long term health. Placenta 2010; 31 (Suppl): S47-S53
• 2 O'Tierney-Ginn PF, Lash GE. Beyond pregnancy: modulation of trophoblast invasion and its consequences for fetal growth and long-term children's health. J Reprod Immunol 2014; 104–105: 37-42
• 3 Redman CW, Sargent IL. Latest advances in understanding preeclampsia. Science 2005; 308 (5728) 1592-1594
• 4 Pijnenborg R, Vercruysse L, Hanssens M. The uterine spiral arteries in human pregnancy: facts and controversies. Placenta 2006; 27 (9–10) 939-958
• 5 Khong TY, De Wolf F, Robertson WB, Brosens I. Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants. Br J Obstet Gynaecol 1986; 93 (10) 1049-1059
• 6 Kim YM, Bujold E, Chaiworapongsa T , et al. Failure of physiologic transformation of the spiral arteries in patients with preterm labor and intact membranes. Am J Obstet Gynecol 2003; 189 (4) 1063-1069
• 7 La Sala GB, Ardizzoni A, Capodanno F , et al. Protein microarrays on midtrimester amniotic fluids: a novel approach for the diagnosis of early intrauterine inflammation related to preterm delivery. Int J Immunopathol Pharmacol 2012; 25 (4) 1029-1040
• 8 Shimonovitz S, Hurwitz A, Dushnik M, Anteby E, Geva-Eldar T, Yagel S. Developmental regulation of the expression of 72 and 92 kd type IV collagenases in human trophoblasts: a possible mechanism for control of trophoblast invasion. Am J Obstet Gynecol 1994; 171 (3) 832-838
• 9 Chakraborty C, Gleeson LM, McKinnon T, Lala PK. Regulation of human trophoblast migration and invasiveness. Can J Physiol Pharmacol 2002; 80 (2) 116-124
• 10 Lash GE, Otun HA, Innes BA, Bulmer JN, Searle RF, Robson SC. Low oxygen concentrations inhibit trophoblast cell invasion from early gestation placental explants via alterations in levels of the urokinase plasminogen activator system. Biol Reprod 2006; 74 (2) 403-409
• 11 Genbacev O, Joslin R, Damsky CH, Polliotti BM, Fisher SJ. Hypoxia alters early gestation human cytotrophoblast differentiation/invasion in vitro and models the placental defects that occur in preeclampsia. J Clin Invest 1996; 97 (2) 540-550
• 12 Burton GJ, Woods AW, Jauniaux E, Kingdom JC. Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy. Placenta 2009; 30 (6) 473-482
• 13 Andraweera PH, Dekker GA, Roberts CT. The vascular endothelial growth factor family in adverse pregnancy outcomes. Hum Reprod Update 2012; 18 (4) 436-457
• 14 Helske S, Vuorela P, Carpén O, Hornig C, Weich H, Halmesmäki E. Expression of vascular endothelial growth factor receptors 1, 2 and 3 in placentas from normal and complicated pregnancies. Mol Hum Reprod 2001; 7 (2) 205-210
• 15 Nevo O, Lee DK, Caniggia I. Attenuation of VEGFR-2 expression by sFlt-1 and low oxygen in human placenta. PLoS ONE 2013; 8 (11) e81176
• 16 Orendi K, Kivity V, Sammar M , et al. Placental and trophoblastic in vitro models to study preventive and therapeutic agents for preeclampsia. Placenta 2011; 32 (Suppl): S49-S54
• 17 Graham CH, Hawley TS, Hawley RG , et al. Establishment and characterization of first trimester human trophoblast cells with extended lifespan. Exp Cell Res 1993; 206 (2) 204-211
• 18 Straszewski-Chavez SL, Abrahams VM, Alvero AB , et al. The isolation and characterization of a novel telomerase immortalized first trimester trophoblast cell line, Swan 71. Placenta 2009; 30 (11) 939-948
• 19 Barker DJ, Eriksson JG, Forsén T, Osmond C. Fetal origins of adult disease: strength of effects and biological basis. Int J Epidemiol 2002; 31 (6) 1235-1239
• 20 Barker DJ. Adult consequences of fetal growth restriction. Clin Obstet Gynecol 2006; 49 (2) 270-283
• 21 Barker DJ, Lampl M, Roseboom T, Winder N. Resource allocation in utero and health in later life. Placenta 2012; 33 (Suppl. 02) e30-e34
• 22 Rinaudo P, Wang E. Fetal programming and metabolic syndrome. Annu Rev Physiol 2012; 74: 107-130
• 23 Calkins K, Devaskar SU. Fetal origins of adult disease. Curr Probl Pediatr Adolesc Health Care 2011; 41 (6) 158-176
• 24 Kajantie E, Eriksson JG, Osmond C, Thornburg K, Barker DJ. Pre-eclampsia is associated with increased risk of stroke in the adult offspring: the Helsinki birth cohort study. Stroke 2009; 40 (4) 1176-1180
• 25 Kajantie E, Osmond C, Barker DJ, Forsén T, Phillips DI, Eriksson JG. Size at birth as a predictor of mortality in adulthood: a follow-up of 350 000 person-years. Int J Epidemiol 2005; 34 (3) 655-663
• 26 Fowden AL, Coan PM, Angiolini E, Burton GJ, Constancia M. Imprinted genes and the epigenetic regulation of placental phenotype. Prog Biophys Mol Biol 2011; 106 (1) 281-288
• 27 Haig D. Altercation of generations: genetic conflicts of pregnancy. Am J Reprod Immunol 1996; 35 (3) 226-232
• 28 Petry CJ, Ong KK, Dunger DB. Does the fetal genotype affect maternal physiology during pregnancy?. Trends Mol Med 2007; 13 (10) 414-421
• 29 Reik W, Constância M, Fowden A , et al. Regulation of supply and demand for maternal nutrients in mammals by imprinted genes. J Physiol 2003; 547 (Pt 1): 35-44
• 30 Bressan FF, De Bem TH, Perecin F , et al. Unearthing the roles of imprinted genes in the placenta. Placenta 2009; 30 (10) 823-834
• 31 Jaquet D, Swaminathan S, Alexander GR , et al. Significant paternal contribution to the risk of small for gestational age. BJOG 2005; 112 (2) 153-159
• 32 Zetterström K, Lindeberg S, Haglund B, Magnuson A, Hanson U. Being born small for gestational age increases the risk of severe pre-eclampsia. BJOG 2007; 114 (3) 319-324
• 33 Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. BMJ 2005; 330 (7491) 565
• 34 Lie RT, Rasmussen S, Brunborg H, Gjessing HK, Lie-Nielsen E, Irgens LM. Fetal and maternal contributions to risk of pre-eclampsia: population based study. BMJ 1998; 316 (7141) 1343-1347
• 35 Nelissen EC, van Montfoort AP, Dumoulin JC, Evers JL. Epigenetics and the placenta. Hum Reprod Update 2011; 17 (3) 397-417
• 36 Feinberg AP. Epigenetics at the epicenter of modern medicine. JAMA 2008; 299 (11) 1345-1350
• 37 Feinberg AP. Genome-scale approaches to the epigenetics of common human disease. Virchows Arch 2010; 456 (1) 13-21
• 38 Lister R, Pelizzola M, Dowen RH , et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 2009; 462 (7271) 315-322
• 39 Ferretti C, Bruni L, Dangles-Marie V, Pecking AP, Bellet D. Molecular circuits shared by placental and cancer cells, and their implications in the proliferative, invasive and migratory capacities of trophoblasts. Hum Reprod Update 2007; 13 (2) 121-141
• 40 Koslowski M, Sahin U, Mitnacht-Kraus R, Seitz G, Huber C, Türeci O. A placenta-specific gene ectopically activated in many human cancers is essentially involved in malignant cell processes. Cancer Res 2007; 67 (19) 9528-9534
• 41 Dokras A, Coffin J, Field L , et al. Epigenetic regulation of maspin expression in the human placenta. Mol Hum Reprod 2006; 12 (10) 611-617
• 42 Wong NC, Novakovic B, Weinrich B , et al. Methylation of the adenomatous polyposis coli (APC) gene in human placenta and hypermethylation in choriocarcinoma cells. Cancer Lett 2008; 268 (1) 56-62
• 43 Novakovic B, Rakyan V, Ng HK , et al. Specific tumour-associated methylation in normal human term placenta and first-trimester cytotrophoblasts. Mol Hum Reprod 2008; 14 (9) 547-554
• 44 Mayer W, Niveleau A, Walter J, Fundele R, Haaf T. Demethylation of the zygotic paternal genome. Nature 2000; 403 (6769) 501-502
• 45 Santos F, Hendrich B, Reik W, Dean W. Dynamic reprogramming of DNA methylation in the early mouse embryo. Dev Biol 2002; 241 (1) 172-182
• 46 Serman L, Vlahović M, Sijan M , et al. The impact of 5-azacytidine on placental weight, glycoprotein pattern and proliferating cell nuclear antigen expression in rat placenta. Placenta 2007; 28 (8–9) 803-811
• 47 Rahnama F, Shafiei F, Gluckman PD, Mitchell MD, Lobie PE. Epigenetic regulation of human trophoblastic cell migration and invasion. Endocrinology 2006; 147 (11) 5275-5283
• 48 Xu N, Chua AK, Jiang H, Liu NA, Goodarzi MO. Early embryonic androgen exposure induces transgenerational epigenetic and metabolic changes. Mol Endocrinol 2014; 28 (8) 1329-1336
• 49 Doherty AS, Mann MR, Tremblay KD, Bartolomei MS, Schultz RM. Differential effects of culture on imprinted H19 expression in the preimplantation mouse embryo. Biol Reprod 2000; 62 (6) 1526-1535
• 50 Song S, Ghosh J, Mainigi M , et al. DNA methylation differences between in vitro- and in vivo-conceived children are associated with ART procedures rather than infertility. Clin Epigenetics 2015; 7 (1) 41
• 51 Katari S, Turan N, Bibikova M , et al. DNA methylation and gene expression differences in children conceived in vitro or in vivo. Hum Mol Genet 2009; 18 (20) 3769-3778
• 52 Moore GE, Ishida M, Demetriou C , et al. The role and interaction of imprinted genes in human fetal growth. Philos Trans R Soc Lond B Biol Sci 2015; 370 (1663) 20140074
• 53 Frost JM, Moore GE. The importance of imprinting in the human placenta. PLoS Genet 2010; 6 (7) e1001015
• 54 Reik W, Dean W, Walter J. Epigenetic reprogramming in mammalian development. Science 2001; 293 (5532) 1089-1093
• 55 Hemberger M. Epigenetic landscape required for placental development. Cell Mol Life Sci 2007; 64 (18) 2422-2436
• 56 Apostolidou S, Abu-Amero S, O'Donoghue K , et al. Elevated placental expression of the imprinted PHLDA2 gene is associated with low birth weight. J Mol Med (Berl) 2007; 85 (4) 379-387
• 57 Pozharny Y, Lambertini L, Ma Y , et al. Genomic loss of imprinting in first-trimester human placenta. Am J Obstet Gynecol 2010; 202 (4) 391.e1-391.e8
• 58 Constância M, Hemberger M, Hughes J , et al. Placental-specific IGF-II is a major modulator of placental and fetal growth. Nature 2002; 417 (6892) 945-948
• 59 Parker SE, Werler MM. Epidemiology of ischemic placental disease: a focus on preterm gestations. Semin Perinatol 2014; 38 (3) 133-138
• 60 Brosens I, Pijnenborg R, Vercruysse L, Romero R. The “Great Obstetrical Syndromes” are associated with disorders of deep placentation. Am J Obstet Gynecol 2011; 204 (3) 193-201
• 61 Ananth CV, Vintzileos AM. Maternal-fetal conditions necessitating a medical intervention resulting in preterm birth. Am J Obstet Gynecol 2006; 195 (6) 1557-1563
• 62 Blencowe H, Cousens S, Oestergaard MZ , et al. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet 2012; 379 (9832) 2162-2172
• 63 Saigal S, Doyle LW. An overview of mortality and sequelae of preterm birth from infancy to adulthood. Lancet 2008; 371 (9608) 261-269
• 64 Lykke JA, Langhoff-Roos J, Sibai BM, Funai EF, Triche EW, Paidas MJ. Hypertensive pregnancy disorders and subsequent cardiovascular morbidity and type 2 diabetes mellitus in the mother. Hypertension 2009; 53 (6) 944-951
• 65 Lisonkova S, Joseph KS. Incidence of preeclampsia: risk factors and outcomes associated with early- versus late-onset disease. Am J Obstet Gynecol 2013; 209 (6) 544.e1-544.e12
• 66 Ness RB, Sibai BM. Shared and disparate components of the pathophysiologies of fetal growth restriction and preeclampsia. Am J Obstet Gynecol 2006; 195 (1) 40-49
• 67 Roberts JM, Taylor RN, Musci TJ, Rodgers GM, Hubel CA, McLaughlin MK. Preeclampsia: an endothelial cell disorder. Am J Obstet Gynecol 1989; 161 (5) 1200-1204
• 68 Dildy III GA, Belfort MA, Smulian JC. Preeclampsia recurrence and prevention. Semin Perinatol 2007; 31 (3) 135-141
• 69 Kajantie E, Thornburg KL, Eriksson JG, Osmond C, Barker DJ. In preeclampsia, the placenta grows slowly along its minor axis. Int J Dev Biol 2010; 54 (2–3) 469-473
• 70 Kovo M, Schreiber L, Ben-Haroush A, Wand S, Golan A, Bar J. Placental vascular lesion differences in pregnancy-induced hypertension and normotensive fetal growth restriction. Am J Obstet Gynecol 2010; 202 (6) 561.e1-561.e5
• 71 Levine RJ, Maynard SE, Qian C , et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 2004; 350 (7) 672-683
• 72 Lash GE, Taylor CM, Trew AJ , et al. Vascular endothelial growth factor and placental growth factor release in cultured trophoblast cells under different oxygen tensions. Growth Factors 2002; 20 (4) 189-196
• 73 Yong HE, Melton PE, Johnson MP , et al. Genome-wide transcriptome directed pathway analysis of maternal pre-eclampsia susceptibility genes. PLoS ONE 2015; 10 (5) e0128230
• 74 Copel JA, Bahtiyar MO. A practical approach to fetal growth restriction. Obstet Gynecol 2014; 123 (5) 1057-1069
• 75 Mayhew TM, Charnock-Jones DS, Kaufmann P. Aspects of human fetoplacental vasculogenesis and angiogenesis. III. Changes in complicated pregnancies. Placenta 2004; 25 (2–3) 127-139
• 76 Taylor RN, Grimwood J, Taylor RS, McMaster MT, Fisher SJ, North RA. Longitudinal serum concentrations of placental growth factor: evidence for abnormal placental angiogenesis in pathologic pregnancies. Am J Obstet Gynecol 2003; 188 (1) 177-182
• 77 Villar J, Carroli G, Wojdyla D , et al; World Health Organization Antenatal Care Trial Research Group. Preeclampsia, gestational hypertension and intrauterine growth restriction, related or independent conditions?. Am J Obstet Gynecol 2006; 194 (4) 921-931
• 78 Ananth CV, Peltier MR, Chavez MR, Kirby RS, Getahun D, Vintzileos AM. Recurrence of ischemic placental disease. Obstet Gynecol 2007; 110 (1) 128-133
• 79 Ananth CV. Ischemic placental disease: a unifying concept for preeclampsia, intrauterine growth restriction, and placental abruption. Semin Perinatol 2014; 38 (3) 131-132
• 80 Ananth CV, Williams MA. Placental abruption and placental weight - implications for fetal growth. Acta Obstet Gynecol Scand 2013; 92 (10) 1143-1150
• 81 Klemetti R, Gissler M, Sevón T, Koivurova S, Ritvanen A, Hemminki E. Children born after assisted fertilization have an increased rate of major congenital anomalies. Fertil Steril 2005; 84 (5) 1300-1307
• 82 Jackson RA, Gibson KA, Wu YW, Croughan MS. Perinatal outcomes in singletons following in vitro fertilization: a meta-analysis. Obstet Gynecol 2004; 103 (3) 551-563
• 83 Hansen M, Kurinczuk JJ, Bower C, Webb S. The risk of major birth defects after intracytoplasmic sperm injection and in vitro fertilization. N Engl J Med 2002; 346 (10) 725-730
• 84 Strömberg B, Dahlquist G, Ericson A, Finnström O, Köster M, Stjernqvist K. Neurological sequelae in children born after in-vitro fertilisation: a population-based study. Lancet 2002; 359 (9305) 461-465
• 85 Schieve LA, Meikle SF, Ferre C, Peterson HB, Jeng G, Wilcox LS. Low and very low birth weight in infants conceived with use of assisted reproductive technology. N Engl J Med 2002; 346 (10) 731-737
• 86 Verlaenen H, Cammu H, Derde MP, Amy JJ. Singleton pregnancy after in vitro fertilization: expectations and outcome. Obstet Gynecol 1995; 86 (6) 906-910
• 87 Hiura H, Okae H, Chiba H , et al. Imprinting methylation errors in ART. Reprod Med Biol 2014; 13 (4) 193-202
• 88 Lazaraviciute G, Kauser M, Bhattacharya S, Haggarty P, Bhattacharya S. A systematic review and meta-analysis of DNA methylation levels and imprinting disorders in children conceived by IVF/ICSI compared with children conceived spontaneously. Hum Reprod Update 2014; 20 (6) 840-852
• 89 Sunderam S, Kissin DM, Crawford SB, Folger SG, Jamieson DJ, Barfield WD ; Centers for Disease Control and Prevention (CDC). Assisted reproductive technology surveillance—United States, 2011. MMWR Surveill Summ 2014; 63 (10) 1-28
• 90 Romundstad LB, Romundstad PR, Sunde A , et al. Effects of technology or maternal factors on perinatal outcome after assisted fertilisation: a population-based cohort study. Lancet 2008; 372 (9640) 737-743
• 91 Delle Piane L, Lin W, Liu X , et al. Effect of the method of conception and embryo transfer procedure on mid-gestation placenta and fetal development in an IVF mouse model. Hum Reprod 2010; 25 (8) 2039-2046
• 92 Bloise E, Lin W, Liu X , et al. Impaired placental nutrient transport in mice generated by in vitro fertilization. Endocrinology 2012; 153 (7) 3457-3467
• 93 Feuer SK, Liu X, Donjacour A , et al. Use of a mouse in vitro fertilization model to understand the developmental origins of health and disease hypothesis. Endocrinology 2014; 155 (5) 1956-1969
• 94 Collier AC, Miyagi SJ, Yamauchi Y, Ward MA. Assisted reproduction technologies impair placental steroid metabolism. J Steroid Biochem Mol Biol 2009; 116 (1–2) 21-28
• 95 Paulson RJ, Boostanfar R, Saadat P , et al. Pregnancy in the sixth decade of life: obstetric outcomes in women of advanced reproductive age. JAMA 2002; 288 (18) 2320-2323
• 96 Sauer MV, Paulson RJ, Lobo RA. Oocyte donation to women of advanced reproductive age: pregnancy results and obstetrical outcomes in patients 45 years and older. Hum Reprod 1996; 11 (11) 2540-2543
• 97 Wiggins DA, Main E. Outcomes of pregnancies achieved by donor egg in vitro fertilization—a comparison with standard in vitro fertilization pregnancies. Am J Obstet Gynecol 2005; 192 (6) 2002-2006 , discussion 2006–2008
• 98 Kaser DJ, Melamed A, Bormann CL , et al. Cryopreserved embryo transfer is an independent risk factor for placenta accreta. Fertil Steril 2015; 103 (5) 1176-84.e2
• 99 Jackson S, Hong C, Wang ET, Alexander C, Gregory KD, Pisarska MD. Pregnancy outcomes in very advanced maternal age pregnancies: the impact of assisted reproductive technology. Fertil Steril 2015; 103 (1) 76-80
• 100 Conway DA, Liem J, Patel S, Fan KJ, Williams III J, Pisarska MD. The effect of infertility and assisted reproduction on first-trimester placental and fetal development. Fertil Steril 2011; 95 (5) 1801-1804
• 101 Conway DA, Patel SS, Liem J , et al. The risk of cytogenetic abnormalities in the late first trimester of pregnancies conceived through assisted reproduction. Fertil Steril 2011; 95 (2) 503-506
• 102 Huang A, Adusumalli J, Patel S, Liem J, Williams III J, Pisarska MD. Prevalence of chromosomal mosaicism in pregnancies from couples with infertility. Fertil Steril 2009; 91 (6) 2355-2360
• 103 Basso O, Baird DD. Infertility and preterm delivery, birthweight, and Caesarean section: a study within the Danish National Birth Cohort. Hum Reprod 2003; 18 (11) 2478-2484
• 104 Giritharan G, Talbi S, Donjacour A, Di Sebastiano F, Dobson AT, Rinaudo PF. Effect of in vitro fertilization on gene expression and development of mouse preimplantation embryos. Reproduction 2007; 134 (1) 63-72
• 105 Farhi J, Ben-Haroush A, Andrawus N , et al. High serum oestradiol concentrations in IVF cycles increase the risk of pregnancy complications related to abnormal placentation. Reprod Biomed Online 2010; 21 (3) 331-337
• 106 Kalra SK, Ratcliffe SJ, Coutifaris C, Molinaro T, Barnhart KT. Ovarian stimulation and low birth weight in newborns conceived through in vitro fertilization. Obstet Gynecol 2011; 118 (4) 863-871
• 107 Kent AL, Wright IM, Abdel-Latif ME ; New South Wales and Australian Capital Territory Neonatal Intensive Care Units Audit Group. Mortality and adverse neurologic outcomes are greater in preterm male infants. Pediatrics 2012; 129 (1) 124-131
• 108 Ingemarsson I. Gender aspects of preterm birth. BJOG 2003; 110 (Suppl. 20) 34-38
• 109 Bacak SJ, Baptiste-Roberts K, Amon E, Ireland B, Leet T. Risk factors for neonatal mortality among extremely-low-birth-weight infants. Am J Obstet Gynecol 2005; 192 (3) 862-867
• 110 Rankin J, Pearce MS, Bell R, Glinianaia SV, Parker L. Perinatal mortality rates: adjusting for risk factor profile is essential. Paediatr Perinat Epidemiol 2005; 19 (1) 56-58
• 111 Lauterbach MD, Raz S, Sander CJ. Neonatal hypoxic risk in preterm birth infants: the influence of sex and severity of respiratory distress on cognitive recovery. Neuropsychology 2001; 15 (3) 411-420
• 112 Stevenson DK, Verter J, Fanaroff AA , et al. Sex differences in outcomes of very low birthweight infants: the newborn male disadvantage. Arch Dis Child Fetal Neonatal Ed 2000; 83 (3) F182-F185
• 113 Clifton VL. Review: Sex and the human placenta: mediating differential strategies of fetal growth and survival. Placenta 2010; 31 (Suppl): S33-S39
• 114 Murji A, Proctor LK, Paterson AD, Chitayat D, Weksberg R, Kingdom J. Male sex bias in placental dysfunction. Am J Med Genet A 2012; 158A (4) 779-783
• 115 Sood R, Zehnder JL, Druzin ML, Brown PO. Gene expression patterns in human placenta. Proc Natl Acad Sci U S A 2006; 103 (14) 5478-5483
• 116 Gabory A, Roseboom TJ, Moore T, Moore LG, Junien C. Placental contribution to the origins of sexual dimorphism in health and diseases: sex chromosomes and epigenetics. Biol Sex Differ 2013; 4 (1) 5
• 117 Mittwoch U. Blastocysts prepare for the race to be male. Hum Reprod 1993; 8 (10) 1550-1555
• 118 Cuffe JS, Walton SL, Singh RR , et al. Mid- to late term hypoxia in the mouse alters placental morphology, glucocorticoid regulatory pathways and nutrient transporters in a sex-specific manner. J Physiol 2014; 592 (Pt 14): 3127-3141
• 119 Horie K, Takakura K, Fujiwara H, Suginami H, Liao S, Mori T. Immunohistochemical localization of androgen receptor in the human ovary throughout the menstrual cycle in relation to oestrogen and progesterone receptor expression. Hum Reprod 1992; 7 (2) 184-190
• 120 Ghidini A, Salafia CM. Gender differences of placental dysfunction in severe prematurity. BJOG 2005; 112 (2) 140-144