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Spontaneous premature birth as a target of genomic research

Abstract

Spontaneous preterm birth is a serious and common pregnancy complication associated with hormonal dysregulation, infection, inflammation, immunity, rupture of fetal membranes, stress, bleeding, and uterine distention. Heredity is 25–40% and mostly involves the maternal genome, with contribution of the fetal genome. Significant discoveries of candidate genes by genome-wide studies and confirmation in independent replicate populations serve as signposts for further research. The main task is to define the candidate genes, their roles, localization, regulation, and the associated pathways that influence the onset of human labor. Genomic research has identified some candidate genes that involve growth, differentiation, endocrine function, immunity, and other defense functions. For example, selenocysteine-specific elongation factor (EEFSEC) influences synthesis of selenoproteins. WNT4 regulates decidualization, while a heat-shock protein family A (HSP70) member 1 like, HSPAIL, influences expression of glucocorticoid receptor and WNT4. Programming of pregnancy duration starts before pregnancy and during placentation. Future goals are to understand the interactive regulation of the pathways in order to define the clocks that influence the risk of prematurity and the duration of pregnancy. Premature birth has a great impact on the duration and the quality of life. Intensification of focused research on causes, prediction and prevention of prematurity is justified.

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References

  1. 1.

    Blencowe, H. et al. Preterm birth-associated neurodevelopmental impairment estimates at regional and global levels for 2010. Pediatr. Res. 74(Suppl 1), 17–34 (2013).

  2. 2.

    Yoshida, S. et al. Setting research priorities to improve global newborn health and prevent stillbirths by 2025. J. Glob. Health 6, 010508 (2016).

  3. 3.

    Goldenberg, R. L., Culhane, J. F., Iams, J. D. & Romero, R. Epidemiology and causes of preterm birth. Lancet 371, 75–84 (2008).

  4. 4.

    Muglia, L. J. & Katz, M. The enigma of spontaneous preterm birth. N. Engl. J. Med. 362, 529–535 (2010).

  5. 5.

    Al Jishi, T. & Sergi, C. Current perspective of diethylstilbestrol (DES) exposure in mothers and offspring. Reprod. Toxicol. 71, 71–77 (2017).

  6. 6.

    Troisi, R., Hatch, E. E. & Titus, L. The diethylstilbestrol legacy: a powerful case against intervention in uncomplicated pregnancy. Pediatrics 138(Suppl 1), S42–S44 (2016).

  7. 7.

    Stewart, L. A. et al. Evaluating progestogens for prevention of preterm birth international collaborative (EPPPIC) individual participant data (IPD) meta-analysis: protocol. Syst. Rev. 6, 235 (2017).

  8. 8.

    Smid, M. C., Stringer, E. M. & Stringer, J. S. A worldwide epidemic: the problem and challenges of preterm birth in low- and middle-income countries. Am. J. Perinatol. 33, 276–289 (2016).

  9. 9.

    Lunde, A., Melve, K. K., Gjessing, H. K., Skjaerven, R. & Irgens, L. M. Genetic and environmental influences on birth weight, birth length, head circumference, and gestational age by use of population-based parent-offspring data. Am. J. Epidemiol. 165, 734–774 (2007).

  10. 10.

    Wilcox, A. J., Skjaerven, R. & Lie, R. T. Familial patterns of preterm delivery: maternal and fetal contributions. Am. J. Epidemiol. 167, 474–479 (2008).

  11. 11.

    Romero, R., Dey, S. K. & Fisher, S. J. Preterm labor: one syndrome, many causes. Science 345, 760–765 (2014).

  12. 12.

    Adams Waldorf, K. M. et al. Uterine overdistention induces preterm labor mediated by inflammation: observations in pregnant women and nonhuman primates. Am. J. Obstet. Gynecol. 213, 830.e1–830.e19 (2015).

  13. 13.

    Renthal, N. E., Williams, K. C. & Mendelson, C. R. MicroRNAs--mediators of myometrial contractility during pregnancy and labour. Nat. Rev. Endocrinol. 9, 391–401 (2013).

  14. 14.

    Hadley, C. B. 1, Main, D. M. & Gabbe, S. G. Risk factors for preterm premature rupture of the fetal membranes. Am. J. Perinatol. 7, 374–379 (1990).

  15. 15.

    Kim, C. J. et al. Chronic inflammation of the placenta: definition, classification, pathogenesis, and clinical significance. Am. J. Obstet. Gynecol. 213, S53–S69 (2015).

  16. 16.

    Bonney, E. A. Alternative theories: Pregnancy and immune tolerance. J. Reprod. Immunol. 123, 65–71 (2017).

  17. 17.

    Hillhouse, E. W. & Grammatopoulos, D. K. Role of stress peptides during human pregnancy and labour. Reproduction 124, 323–329 (2002).

  18. 18.

    Velez Edwards, D. R., Baird, D. D., Hasan, R., Savitz, D. A. & Hartmann, K. E. First-trimester bleeding characteristics associate with increased risk of preterm birth: data from a prospective pregnancy cohort. Hum. Reprod. 27, 54–60 (2012).

  19. 19.

    Schatz, F., Guzeloglu-Kayisli, O., Arlier, S., Kayisli, U. A. & Lockwood, C. J. The role of decidual cells in uterine hemostasis, menstruation, inflammation, adverse pregnancy outcomes and abnormal uterine bleeding. Hum. Reprod. Update 22, 497–515 (2016).

  20. 20.

    Morgan, T. K. Role of the placenta in preterm birth: a review. Am. J. Perinatol. 33, 258–266 (2016).

  21. 21.

    Mendelson, C. R., Montalbano, A. P. & Gao, L. Fetal-to-maternal signaling in the timing of birth. J. Steroid Biochem. Mol. Biol. 170, 19–27 (2017).

  22. 22.

    Hallman, M., Arjomaa, P., Mizumoto, M. & Akino, T. Surfactant proteins in the diagnosis of fetal lung maturity. I. Predictive accuracy of the 35 kD protein, the lecithin/sphingomyelin ratio, and phosphatidylglycerol. Am. J. Obstet. Gynecol. 158, 531–535 (1988).

  23. 23.

    Hallman, M. The surfactant system protects both fetus and newborn. Neonatology 103, 320–326 (2013).

  24. 24.

    Byrns, M. C. Regulation of progesterone signaling during pregnancy: implications for the use of progestins for the prevention of preterm birth. J. Steroid Biochem. Mol. Biol. 139, 173–181 (2014).

  25. 25.

    Mesiano, S. et al. Progesterone withdrawal and estrogen activation in human parturition are coordinated by progesterone receptor A expression in the myometrium. J. Clin. Endocrinol. Metab. 87, 2924–2930 (2002).

  26. 26.

    Patel, B. et al. Role of nuclear progesterone receptor isoforms in uterine pathophysiology. Hum. Reprod. Update 21, 155–173 (2015).

  27. 27.

    Petraglia, F., Imperatore, A. & Challis, J. R. Neuroendocrine mechanisms in pregnancy and parturition. Endocr. Rev. 31, 783–816 (2010).

  28. 28.

    Renthal N. E., et al. Molecular regulation of parturition: a myometrial perspective. Cold Spring Harb. Perspect. Med. 5, pii: a023069 (2015).

  29. 29.

    Menon, R., Bonney, E. A., Condon, J., Mesiano, S. & Taylor, R. N. Novel concepts on pregnancy clocks and alarms: redundancy and synergy in human parturition. Hum. Reprod. Update 22, 535–560 (2016).

  30. 30.

    Iams, J. D., Romero, R., Culhane, J. F. & Goldenberg, R. L. Primary, secondary, and tertiary interventions to reduce the morbidity and mortality of preterm birth. Lancet 371, 164–175 (2008).

  31. 31.

    Kenyon, S., Boulvain, M. & Neilson, J. P. Antibiotics for preterm rupture of membranes. Cochrane Database Syst. Rev. 12, CD001058 (2013).

  32. 32.

    Ruiz, L., Moles, L., Gueimonde, M. & Rodriguez, J. M. Perinatal microbiomes’ influence on preterm birth and preterms’ health: influencing factors and modulation strategies. J. Pediatr. Gastroenterol. Nutr. 63, e193–e203 (2016).

  33. 33.

    Haas, D. M., Caldwell, D. M., Kirkpatrick, P., McIntosh, J. J. & Welton, N. J. Tocolytic therapy for preterm delivery: systematic review and network meta-analysis. Brit. Med. J. 345, e6226 (2012).

  34. 34.

    Romero, R. et al. Vaginal progesterone decreases preterm birth and neonatal morbidity and mortality in women with a twin gestation and a short cervix: an updated meta‐analysis of individual patient data. Ultrasound Obstet. Gynecol. 49, 303–314 (2017).

  35. 35.

    Romero, R. et al. Vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in singleton gestations with a short cervix: meta-analysis of individual patient data. Am. J. Obstet. Gynecol. 218, 161–180 (2018).

  36. 36.

    Norman, J. E. et al. Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial. Lancet 387, 2106–2116 (2016).

  37. 37.

    Norman, J. E. et al. Does progesterone prophylaxis to prevent preterm labour improve outcome? A randomized double-blind placebo-controlled trial (OPPTIMUM). Health Technol. Assess. 22, 1–304 (2018).

  38. 38.

    Bezold, K. Y., Karjalainen, M. K., Hallman, M., Teramo, K. & Muglia, L. J. The genomics of preterm birth: from animal models to human studies. Genome Med. 5, 34 (2013).

  39. 39.

    York, T. P., Strauss, J. F. 3rd, Neale, M. C. & Eaves, L. J. Estimating fetal and maternal genetic contributions to premature birth from multiparous pregnancy histories of twins using MCMC and maximum-likelihood approaches. Twin Res Hum. Genet 12, 333–342 (2009).

  40. 40.

    Alleman, B. W. et al. No observed association for mitochondrial SNPs with preterm delivery and related outcomes. Pediatr. Res. 72, 539–544 (2012).

  41. 41.

    Manuck, T. A. et al. Absence of mitochondrial progesterone receptor polymorphisms in women with spontaneous preterm birth. Reprod. Sci. 17, 913–916 (2010).

  42. 42.

    Velez, D. R. et al. Mitochondrial DNA variant A4917G, smoking and spontaneous preterm birth. Mitochondrion 8, 130–135 (2008).

  43. 43.

    Zhang, G. et al. Genetic associations with gestational duration and spontaneous preterm birth. N. Engl. J. Med. 377, 1156–1167 (2017).

  44. 44.

    Rosenberg, N. A. et al. Genome-wide association studies in diverse populations. Nat. Rev. Genet. 11, 356–366 (2010).

  45. 45.

    Parets, S. E., Conneely, K. N., Kilaru, V., Menon, R. & Smith, A. K. DNA methylation provides insight into intergenerational risk for preterm birth in African Americans. Epigenetics 10, 784–792 (2015).

  46. 46.

    Palo, J. U., Ulmanen, I., Lukka, M., Ellonen, P. & Sajantila, A. Genetic markers and population history: Finland revisited. Eur. J. Hum. Genet. 17, 1336–1346 (2009).

  47. 47.

    Sheikh, I. A. et al. Spontaneous preterm birth and single nucleotide gene polymorphisms: a recent update. BMC Genom. 17(Suppl 9), 759 (2016).

  48. 48.

    Plunkett, J. & Muglia, L. J. Genetic contributions to preterm birth: implications from epidemiological and genetic association studies. Ann. Med. 40, 167–195 (2008).

  49. 49.

    Rood, K. M. & Buhimschi, C. S. Genetics, hormonal influences, and preterm birth. Semin. Perinatol. 41, 401–408 (2017).

  50. 50.

    Strauss, J. F. et al. Spontaneous preterm birth: advances toward the discovery of genetic predisposition. Am. J. Obstet. Gynecol. 218, 294–314 (2018).

  51. 51.

    Singh, A. J., Ramsey, S. A., Filtz, T. M. & Kioussi, C. Differential gene regulatory networks in development and disease. Cell. Mol. Life Sci. 75, 1013–1025 (2017).

  52. 52.

    Prince, A. L. et al. The placental membrane microbiome is altered among subjects with spontaneous preterm birth with and without chorioamnionitis. Am. J. Obstet. Gynecol. 214, 627.e16 (2016).

  53. 53.

    Nelson, D. B., Shin, H., Wu, J. & Dominguez-Bello, M. G. The gestational vaginal microbiome and spontaneous preterm birth among Nulliparous African American women. Am. J. Perinatol. 33, 887–893 (2016).

  54. 54.

    Dahl, C. et al. Gut microbiome of mothers delivering prematurely shows reduced diversity and lower relative abundance of Bifidobacterium and Streptococcus. PLoS ONE 12, e0184336 (2017).

  55. 55.

    Haataja, R. et al. Mapping a new spontaneous preterm birth susceptibility gene, IGF1R, using linkage, haplotype sharing, and association analysis. PLoS Genet. 7, e1001293 (2011).

  56. 56.

    Uzun, A., Dewan, A. T., Istrail, S. & Padbury, J. F. Pathway-based genetic analysis of preterm birth. Genomics 101, 163–170 (2013).

  57. 57.

    Rahkonen, L. et al. Elevated levels of decidual insulin-like growth factor binding protein-1 in cervical fluid in early and mid-pregnancy are associated with an increased risk of spontaneous preterm delivery. BJOG 117, 701–710 (2010).

  58. 58.

    Conde-Agudelo, A. & Romero, R. Cervical phosphorylated insulin-like growth factor binding protein-1 test for the prediction of preterm birth: a systematic review and meta-analysis. Am. J. Obstet. Gynecol. 214, 57–73 (2016).

  59. 59.

    Karjalainen, M. K. et al. A potential novel spontaneous preterm birth gene, AR, identified by linkage and association analysis of X chromosomal markers. PLoS ONE 7, e51378 (2012).

  60. 60.

    Bethin, K. E. et al. Microarray analysis of uterine gene expression in mouse and human pregnancy. Mol. Endocrinol. 17, 1454–1469 (2003).

  61. 61.

    Makieva, S., Saunders, P. T. & Norman, J. E. Androgens in pregnancy: roles in parturition. Hum. Reprod. Update 20, 542–559 (2014).

  62. 62.

    Karjalainen, M. K. et al. CXCR3 polymorphism and expression associate with spontaneous preterm birth. J. Immunol. 195, 2187–2198 (2015).

  63. 63.

    McElroy, J. J. et al. Maternal coding variants in complement receptor 1 and spontaneous idiopathic preterm birth. Hum. Genet. 132, 935–942 (2013).

  64. 64.

    Uzun, A. et al. Targeted sequencing and meta-analysis of preterm birth. PLoS ONE 11, e0155021 (2016).

  65. 65.

    Modi, B. P. et al. Rare mutations and potentially damaging missense variants in genes encoding fibrillar collagens and proteins involved in their production are candidates for risk for preterm premature rupture of membranes. PLoS ONE 12, e0174356 (2017).

  66. 66.

    Modi, B. P. et al. Mutations in fetal genes involved in innate immunity and host defense against microbes increase risk of preterm premature rupture of membranes (PPROM). Mol. Genet. Genom. Med. 5, 720–729 (2017).

  67. 67.

    Zhang, H. et al. A genome-wide association study of early spontaneous preterm delivery. Genet. Epidemiol. 39, 217–226 (2015).

  68. 68.

    Bacelis, J. et al. Literature-informed analysis of a genome-wide association study of gestational age in Norwegian women and children suggests involvement of inflammatory pathways. PLoS ONE 11, e0160335 (2016).

  69. 69.

    Rappoport, N. et al. A genome-wide association study identifies only two ancestry specific variants associated with spontaneous preterm birth. Sci. Rep. 8, 226 (2018).

  70. 70.

    Plunkett, J. et al. An evolutionary genomic approach to identify genes involved in human birth timing. PLoS Genet. 7, e1001365 (2011).

  71. 71.

    Haapalainen, A. M. et al. Expression of CPPED1 in human trophoblasts is associated with timing of term birth. J. Cell. Mol. Med. 22, 968–981 (2018).

  72. 72.

    Zhuo, D. X. et al. CSTP1, a novel protein phosphatase, blocks cell cycle, promotes cell apoptosis, and suppresses tumor growth of bladder cancer by directly dephosphorylating Akt at Ser473 site. PLoS ONE 8, e65679 (2013).

  73. 73.

    Diep, C. H. et al. Progesterone receptors induce FOXO1-dependent senescence in ovarian cancer cells. Cell Cycle 12, 1433–1449 (2013).

  74. 74.

    Beaumont, R. N. et al. Genome-wide association study of offspring birth weight in 86577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics. Hum. Mol. Genet. 27, 742–756 (2018).

  75. 75.

    GOPEC Consortium. Disentangling fetal and maternal susceptibility for pre-eclampsia: a British multicenter candidate-gene study. Am. J. Hum. Genet. 77, 127–131 (2005).

  76. 76.

    Kaukola, T. et al. Population cohort associating chorioamnionitis, cord inflammatory cytokines and neurologic outcome in very preterm, extremely low birth weight infants. Pediatr. Res. 59, 478–483 (2006).

  77. 77.

    Marsál, K. Intrauterine growth restriction. Curr. Opin. Obstet. Gynecol. 14, 127–135 (2002).

  78. 78.

    Zeitlin, J., Ancel, P. Y., Saurel-Cubizolles, M. J. & Papiernik, E. The relationship between intrauterine growth restriction and preterm delivery: an empirical approach using data from a European case-control study. Br. J. Obstet. Gynecol. 107, 750–758 (2000).

  79. 79.

    Burk, R. F. & Hill, K. E. Regulation of Selenium metabolism and transport. Annu. Rev. Nutr. 35, 109–134 (2015).

  80. 80.

    Li, M. et al. Loss of selenocysteine insertion sequence binding protein 2 suppresses the proliferation, migration/invasion and hormone secretion of human trophoblast cells via the PI3K/Akt and ERK signaling pathway. Placenta 55, 81–89 (2017).

  81. 81.

    McDermott, J. R. et al. Zinc- and bicarbonate-dependent ZIP8 trasporter mediates selenite uptake. Oncotarget 7, 35327–35340 (2016).

  82. 82.

    MacFarquhar, J. K. et al. Acute selenium toxicity associated with a dietary supplement. Arch. Intern. Med. 170, 256–261 (2010).

  83. 83.

    Zhou, H., Wang, T., Li, Q. & Li, D. Prevention of Keshan disease by selenium supplementation: a systematic review and meta-analysis. Biol. Trace Elem. Res. https://doi.org/10.1007/s12011-018-1302-5 (2018).

  84. 84.

    Schweizer, U. & Fradejas-Villar, N. Why 21? The significance of selenoproteins for human health revealed by inborn errors of metabolism. FASEB J. 30, 3669–3681 (2016).

  85. 85.

    Rayman, M. P., Wijnen, H., Vader, H., Kooistra, L. & Pop, V. Maternal selenium status during early gestation and risk for preterm birth. Can. Med. Assoc. J. 183, 549–555 (2011).

  86. 86.

    Hurst, R. et al. Soil-type influences human selenium status and underlies widespread selenium deficiency risks in Malawi. Sci. Rep. 3, 1425 (2013).

  87. 87.

    Olsen, P. et al. Epidemiology of preterm delivery in two birth cohorts with an interval of 20 years. Am. J. Epidemiol. 142, 1184–1193 (1995).

  88. 88.

    Knöfler, M. & Pollheimer, J. Human placental trophoblast invasion and differentiation: a particular focus on Wnt signaling. Front. Genet. 4, 190 (2013).

  89. 89.

    Huusko, J. M. et al. Whole exome sequencing reveals HSPA1L as a genetic risk factor for spontaneous preterm birth. PLoS Genet. 14, e1007394 (2018).

  90. 90.

    Zhang, G. et al. Assessing the causal relationship of maternal height on birth size and gestational age at birth: a mendelian randomization analysis. PLoS Med. 12, e1001865 (2015).

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Acknowledgements

Supported by the Jane and Aatos Erkko Foundation (M.H., M.R.), and the Sigrid Jusélius Foundation (M.H.).

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Correspondence to Mikko Hallman.

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