1. Kady, S. M. & Gardosi, J. Perinatal mortality and fetal growth restriction. Best Pract. Res. Clin. Obstet. Gynaecol. 18, 397–410 (2004).
2. Hutcheon, J. A., Lisonkova, S. & Joseph, K. S. Epidemiology of pre-eclampsia and the other hypertensive disorders of pregnancy. Best Pract. Res. Clin. Obstet. Gynaecol. 25, 391–403 (2011).
3. Sibley, C. P. Treating the dysfunctional placenta. J. Endocrinol. 234, R81–R97 (2017).
4. Kaufmann, P., Black, S. & Huppertz, B. Endovascular trophoblast invasion: Implications for the pathogenesis of intrauterine growth retardation and preeclampsia. Biol. Reprod. 69, 1–7 (2003).
5. Redman, C. W. & Sargent, I. L. Latest advances in understanding preeclampsia. Science 308, 1592–1594 (2005).
6. Villar, J. et al. Preeclampsia, gestational hypertension and intrauterine growth restriction, related or independent conditions?. Am. J. Obstet. Gynecol. 194, 921–931 (2006).
7. Nwabuobi, C. et al. hCG: Biological functions and clinical applications. Int. J. Mol. Sci. 18, 2037 (2017).
8. Braunstein, G. D., Rasor, J., Adler, D., Danzer, H. & Wade, M. E. Serum human chorionic gonadotropin levels throughout normal pregnancy. Am. J. Obstet. Gynecol. 126, 678–681 (1976).
9. Sharma, V., Sharma, P. & Firdous, N. Beta hCG in mid trimester as a predictor of pregnancy induced hypertension. Int. J. Sci. Res. 5, 303–305 (2016).
10. Choudhury, K. M., Das, M., Ghosh, S., Bhattacharya, D. & Ghosh, T. K. Value of serum β-hCG in pathogenesis of pre-eclampsia. J. Clin. Gynecol. Obstet. 1, 71–75 (2012).
11. Boonpiam, R. et al. Quad test for fetal aneuploidy screening as a predictor of small-for-gestational age fetuses: A population-based study. BMC Pregnancy Childbirth. 20, 621 (2020).
12. Fitzgerald, B. et al. Villous trophoblast abnormalities in extremely preterm deliveries with elevated second trimester maternal serum hCG or inhibin-A. Placenta 32, 339–345 (2011).
13. Önderoǧlu, L. S. & Kabukçu, A. Elevated second trimester human chorionic gonadotropin level associated with adverse pregnancy outcome. Int. J. Gynecol. Obstet. 56, 245–249 (1997).
14. Chandra, S. et al. Unexplained elevated maternal serum α-fetoprotein and/or human chorionic gonadotropin and the risk of adverse outcomes. Am. J. Obstet. Gynecol. 189, 775–781 (2003).
15. Odibo, A. O., Sehdev, H. M., Stamilio, D. M. & Macones, G. A. Evaluating the thresholds of abnormal second trimester multiple marker screening tests associated with intra-uterine growth restriction. Am. J. Perinatol. 23, 363–367 (2006).
16. Martinez, F., Olvera-Sanchez, S., Esparza-Perusquia, M., Gomez-Chang, E. & Flores-Herrera, O. Multiple functions of syncytiotrophoblast mitochondria. Steroids 103, 11–22 (2015).
17. Holland, O. et al. Review: Placental mitochondrial function and structure in gestational disorders. Placenta 54, 2–9 (2017).
18. Muta, T., Kang, D., Kitajima, S., Fujiwara, T. & Hamasaki, N. p32 Protein, a splicing factor 2-associated protein, is localized in mitochondrial matrix and is functionally important in maintaining oxidative phosphorylation. J. Biol. Chem. 272, 24363–24370 (1997).
19. Kim, K. B. et al. Cell-surface receptor for complement component C1q (gC1qR) is a key regulator for lamellipodia formation and cancer metastasis. J. Biol. Chem. 286, 23093–23101 (2011).
20. Gotoh, K. et al. Mitochondrial p32/C1qbp is a critical regulator of dendritic cell metabolism and maturation. Cell Rep. 25, 1800– 1815 (2018).
21. Matos, P. et al. A role for the mitochondrial-associated protein p32 in regulation of trophoblast proliferation. Mol. Hum. Reprod. 20, 745–755 (2014).
22. Zsengellér, Z. K. et al. Trophoblast mitochondrial function is impaired in preeclampsia and correlates negatively with the expression of soluble fms-like tyrosine kinase 1. Pregnancy Hypertens. 6, 313–319 (2016).
23. Zhou, X. et al. Impaired mitochondrial fusion, autophagy, biogenesis and dysregulated lipid metabolism is associated with preeclampsia. Exp. Cell Res. 359, 195–204 (2017).
24. Maynard, S. E. et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J. Clin. Invest. 111, 649–658 (2003).
25. Bodnar, R. J., Yates, C. C. & Wells, A. IP-10 blocks vascular endothelial growth factor-induced endothelial cell motility and tube formation via inhibition of calpain. Circ. Res. 98, 617–625 (2006).
26. Maisonpierre, P. C. et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277, 55–60 (1997).
27. Gupta, A. K., Hasler, P., Holzgreve, W., Gebhardt, S. & Hahn, S. Induction of neutrophil extracellular DNA lattices by placental microparticles and IL-8 and their presence in preeclampsia. Hum. Immunol. 66, 1146–1154 (2005).
28. Otun, H. A. et al. Efect of tumour necrosis factor-α in combination with interferon-γ on frst trimester extravillous trophoblast invasion. J. Reprod. Immunol. 88, 1–11 (2011).
29. Xu, B., Nakhla, S., Makris, A. & Hennessy, A. TNF-α inhibits trophoblast integration into endothelial cellular networks. Placenta 32, 241–246 (2011).
30. Bauer, S. et al. Tumor necrosis factor-α inhibits trophoblast migration through elevation of plasminogen activator inhibitor-1 in frst-trimester villous explant cultures. J. Clin. Endocrinol. Metab. 89, 812–822 (2004).
31. Leinonen, E. et al. Maternal serum angiopoietin-1 and -2 and tie-2 in early pregnancy ending in preeclampsia or intrauterine growth retardation. J. Clin. Endocrinol. Metab. 95, 126–133 (2010).
32. Szarka, A., Rigó, J. Jr., Lázár, L., Beko, G. & Molvarec, A. Circulating cytokines, chemokines and adhesion molecules in normal pregnancy and preeclampsia determined by multiplex suspension array. BMC Immunol. 11, 59 (2010).
33. Raghupathy, R., Al-Azemi, M. & Azizieh, F. Intrauterine growth restriction: cytokine profles of trophoblast antigen-stimulated maternal lymphocytes. Clin. Dev. Immunol. 2012, 734865 (2012).
34. Zhou, C. C. et al. Autoantibody from women with preeclampsia induces soluble fms-like tyrosine kinase-1 production via angiotensin type 1 receptor and calcineurin/nuclear factor of activated T-cells signaling. Hypertension 51, 1010–1019 (2008).
35. Tal, R. et al. Efects of hypoxia-inducible factor-1α overexpression in pregnant mice: Possible implications for preeclampsia and intrauterine growth restriction. Am. J. Pathol. 177, 2950–2962 (2010).
36. Montero, R. et al. GDF-15 is elevated in children with mitochondrial diseases and is induced by mitochondrial dysfunction. PLoS ONE 11, e0148709 (2016).
37. Casarini, L. et al. LH and hCG action on the same receptor results in quantitatively and qualitatively diferent intracellular signalling. PLoS ONE 7, e46682 (2012).
38. Choi, J. & Smitz, J. Luteinizing hormone and human chorionic gonadotropin: Origins of diference. Mol. Cell Endocrinol. 383, 203–213 (2014).
39. McAllister, J. M., Legro, R. S., Modi, B. P. & Strauss, J. F. 3rd. Functional genomics of PCOS: From GWAS to molecular mechanisms. Trends Endocrinol. Metab. 26, 118–124 (2015).
40. Kang, I., Chu, C. T. & Kaufman, B. A. Te mitochondrial transcription factor TFAM in neurodegeneration: Emerging evidence and mechanisms. FEBS Lett. 592, 793–811 (2018).
41. Hu, X. Q. & Zhang, L. Hypoxia and mitochondrial dysfunction in pregnancy complications. Antioxidants. 10, 405 (2021).
42. Lin, L. H. et al. Multiple pregnancies with complete mole and coexisting normal fetus in North and South America: A retrospective multicenter cohort and literature review. Gynecol. Oncol. 145, 88–95 (2017).
43. Paré, E. et al. Clinical risk factors for preeclampsia in the 21st century. Obstet. Gynecol. 124, 763–770 (2014).
44. Kaur, G., Jain, V., Mehta, S. & Himani, S. Prediction of PIH by maternal serum beta hCG levels in the second trimester (13–20 weeks) of pregnancy. J. Obstet. Gynecol. India. 62, 32–34 (2012).
45. Strohmer, H. et al. Hypoxia downregulates continuous and interleukin-1-induced expression of human chorionic gonadotropin in choriocarcinoma cells. Placenta 18, 597–604 (1997).
46. Esterman, A., Finlay, T. H. & Dancis, J. Te efect of hypoxia on term trophoblast: Hormone synthesis and release. Placenta 17, 217–222 (1996).
47. Alsat, E. et al. Hypoxia impairs cell fusion and diferentiation process in human cytotrophoblast, in vitro. J. Cell Physiol. 168, 346–353 (1996).
48. Shao, R. et al. Increase of SUMO-1 expression in response to hypoxia: Direct interaction with HIF-1alpha in adult mouse brain and heart in vivo. FEBS Lett. 569, 293–300 (2004).
49. Bae, S. et al. Sumoylation increases HIF-1alpha stability and its transcriptional activity. Biochem. Biophys. Res. Commun. 324, 394–400 (2004).
50. Isoe, T. et al. High glucose activates HIF-1-mediated signal transduction in glomerular mesangial cells through a carbohydrate response element binding protein. Kidney Int. 78, 48–59 (2010).
51. Watson, A. L., Skepper, J. N., Jauniaux, E. & Burton, G. J. Susceptibility of human placental syncytiotrophoblastic mitochondria to oxygen-mediated damage in relation to gestational age. J. Clin. Endocrinol. Metab. 83, 1697–1705 (1998).
52. Watson, A. L., Skepper, J. N., Jauniaux, E. & Burton, G. J. Changes in concentration, localization and activity of catalase within the human placenta during early gestation. Placenta 19, 27–34 (1998).
53. Watson, A. L., Palmer, M. E., Jauniaux, E. & Burton, G. J. Variations in expression of copper/zinc superoxide dismutase in villous trophoblast of the human placenta with gestational age. Placenta 18, 295–299 (1997).
54. Mitani, M. et al. Clinical features of fetal growth restriction complicated later by preeclampsia. J. Obstet. Gynaecol. Res. 35, 882–887 (2009).
55. Korevaar, T. I. M. et al. Reference ranges and determinants of total hCG levels during pregnancy: Te Generation R Study. Eur. J. Epidemiol. 30, 1057–1066 (2015).
56. Meurs, M. V. et al. Bench-to-bedside review: Angiopoietin signalling in critical illness—a future target?. Crit. Care. 13, 207 (2009).1. Kady, S. M. & Gardosi, J. Perinatal mortality and fetal growth restriction. Best Pract. Res. Clin. Obstet. Gynaecol. 18, 397–410 (2004).
2. Hutcheon, J. A., Lisonkova, S. & Joseph, K. S. Epidemiology of pre-eclampsia and the other hypertensive disorders of pregnancy. Best Pract. Res. Clin. Obstet. Gynaecol. 25, 391–403 (2011).
3. Sibley, C. P. Treating the dysfunctional placenta. J. Endocrinol. 234, R81–R97 (2017).
4. Kaufmann, P., Black, S. & Huppertz, B. Endovascular trophoblast invasion: Implications for the pathogenesis of intrauterine growth retardation and preeclampsia. Biol. Reprod. 69, 1–7 (2003).
5. Redman, C. W. & Sargent, I. L. Latest advances in understanding preeclampsia. Science 308, 1592–1594 (2005).
6. Villar, J. et al. Preeclampsia, gestational hypertension and intrauterine growth restriction, related or independent conditions?. Am. J. Obstet. Gynecol. 194, 921–931 (2006).
7. Nwabuobi, C. et al. hCG: Biological functions and clinical applications. Int. J. Mol. Sci. 18, 2037 (2017).
8. Braunstein, G. D., Rasor, J., Adler, D., Danzer, H. & Wade, M. E. Serum human chorionic gonadotropin levels throughout normal pregnancy. Am. J. Obstet. Gynecol. 126, 678–681 (1976).
9. Sharma, V., Sharma, P. & Firdous, N. Beta hCG in mid trimester as a predictor of pregnancy induced hypertension. Int. J. Sci. Res. 5, 303–305 (2016).
10. Choudhury, K. M., Das, M., Ghosh, S., Bhattacharya, D. & Ghosh, T. K. Value of serum β-hCG in pathogenesis of pre-eclampsia. J. Clin. Gynecol. Obstet. 1, 71–75 (2012).
11. Boonpiam, R. et al. Quad test for fetal aneuploidy screening as a predictor of small-for-gestational age fetuses: A population-based study. BMC Pregnancy Childbirth. 20, 621 (2020).
12. Fitzgerald, B. et al. Villous trophoblast abnormalities in extremely preterm deliveries with elevated second trimester maternal serum hCG or inhibin-A. Placenta 32, 339–345 (2011).
13. Önderoǧlu, L. S. & Kabukçu, A. Elevated second trimester human chorionic gonadotropin level associated with adverse pregnancy outcome. Int. J. Gynecol. Obstet. 56, 245–249 (1997).
14. Chandra, S. et al. Unexplained elevated maternal serum α-fetoprotein and/or human chorionic gonadotropin and the risk of adverse outcomes. Am. J. Obstet. Gynecol. 189, 775–781 (2003).
15. Odibo, A. O., Sehdev, H. M., Stamilio, D. M. & Macones, G. A. Evaluating the thresholds of abnormal second trimester multiple marker screening tests associated with intra-uterine growth restriction. Am. J. Perinatol. 23, 363–367 (2006).
16. Martinez, F., Olvera-Sanchez, S., Esparza-Perusquia, M., Gomez-Chang, E. & Flores-Herrera, O. Multiple functions of syncytiotrophoblast mitochondria. Steroids 103, 11–22 (2015).
17. Holland, O. et al. Review: Placental mitochondrial function and structure in gestational disorders. Placenta 54, 2–9 (2017).
18. Muta, T., Kang, D., Kitajima, S., Fujiwara, T. & Hamasaki, N. p32 Protein, a splicing factor 2-associated protein, is localized in mitochondrial matrix and is functionally important in maintaining oxidative phosphorylation. J. Biol. Chem. 272, 24363–24370 (1997).
19. Kim, K. B. et al. Cell-surface receptor for complement component C1q (gC1qR) is a key regulator for lamellipodia formation and cancer metastasis. J. Biol. Chem. 286, 23093–23101 (2011).
20. Gotoh, K. et al. Mitochondrial p32/C1qbp is a critical regulator of dendritic cell metabolism and maturation. Cell Rep. 25, 1800– 1815 (2018).
21. Matos, P. et al. A role for the mitochondrial-associated protein p32 in regulation of trophoblast proliferation. Mol. Hum. Reprod. 20, 745–755 (2014).
22. Zsengellér, Z. K. et al. Trophoblast mitochondrial function is impaired in preeclampsia and correlates negatively with the expression of soluble fms-like tyrosine kinase 1. Pregnancy Hypertens. 6, 313–319 (2016).
23. Zhou, X. et al. Impaired mitochondrial fusion, autophagy, biogenesis and dysregulated lipid metabolism is associated with preeclampsia. Exp. Cell Res. 359, 195–204 (2017).
24. Maynard, S. E. et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J. Clin. Invest. 111, 649–658 (2003).
25. Bodnar, R. J., Yates, C. C. & Wells, A. IP-10 blocks vascular endothelial growth factor-induced endothelial cell motility and tube formation via inhibition of calpain. Circ. Res. 98, 617–625 (2006).
26. Maisonpierre, P. C. et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277, 55–60 (1997).
27. Gupta, A. K., Hasler, P., Holzgreve, W., Gebhardt, S. & Hahn, S. Induction of neutrophil extracellular DNA lattices by placental microparticles and IL-8 and their presence in preeclampsia. Hum. Immunol. 66, 1146–1154 (2005).
28. Otun, H. A. et al. Efect of tumour necrosis factor-α in combination with interferon-γ on frst trimester extravillous trophoblast invasion. J. Reprod. Immunol. 88, 1–11 (2011).
29. Xu, B., Nakhla, S., Makris, A. & Hennessy, A. TNF-α inhibits trophoblast integration into endothelial cellular networks. Placenta 32, 241–246 (2011).
30. Bauer, S. et al. Tumor necrosis factor-α inhibits trophoblast migration through elevation of plasminogen activator inhibitor-1 in frst-trimester villous explant cultures. J. Clin. Endocrinol. Metab. 89, 812–822 (2004).
31. Leinonen, E. et al. Maternal serum angiopoietin-1 and -2 and tie-2 in early pregnancy ending in preeclampsia or intrauterine growth retardation. J. Clin. Endocrinol. Metab. 95, 126–133 (2010).
32. Szarka, A., Rigó, J. Jr., Lázár, L., Beko, G. & Molvarec, A. Circulating cytokines, chemokines and adhesion molecules in normal pregnancy and preeclampsia determined by multiplex suspension array. BMC Immunol. 11, 59 (2010).
33. Raghupathy, R., Al-Azemi, M. & Azizieh, F. Intrauterine growth restriction: cytokine profles of trophoblast antigen-stimulated maternal lymphocytes. Clin. Dev. Immunol. 2012, 734865 (2012).
34. Zhou, C. C. et al. Autoantibody from women with preeclampsia induces soluble fms-like tyrosine kinase-1 production via angiotensin type 1 receptor and calcineurin/nuclear factor of activated T-cells signaling. Hypertension 51, 1010–1019 (2008).
35. Tal, R. et al. Efects of hypoxia-inducible factor-1α overexpression in pregnant mice: Possible implications for preeclampsia and intrauterine growth restriction. Am. J. Pathol. 177, 2950–2962 (2010).
36. Montero, R. et al. GDF-15 is elevated in children with mitochondrial diseases and is induced by mitochondrial dysfunction. PLoS ONE 11, e0148709 (2016).
37. Casarini, L. et al. LH and hCG action on the same receptor results in quantitatively and qualitatively diferent intracellular signalling. PLoS ONE 7, e46682 (2012).
38. Choi, J. & Smitz, J. Luteinizing hormone and human chorionic gonadotropin: Origins of diference. Mol. Cell Endocrinol. 383, 203–213 (2014).
39. McAllister, J. M., Legro, R. S., Modi, B. P. & Strauss, J. F. 3rd. Functional genomics of PCOS: From GWAS to molecular mechanisms. Trends Endocrinol. Metab. 26, 118–124 (2015).
40. Kang, I., Chu, C. T. & Kaufman, B. A. Te mitochondrial transcription factor TFAM in neurodegeneration: Emerging evidence and mechanisms. FEBS Lett. 592, 793–811 (2018).
41. Hu, X. Q. & Zhang, L. Hypoxia and mitochondrial dysfunction in pregnancy complications. Antioxidants. 10, 405 (2021).
42. Lin, L. H. et al. Multiple pregnancies with complete mole and coexisting normal fetus in North and South America: A retrospective multicenter cohort and literature review. Gynecol. Oncol. 145, 88–95 (2017).
43. Paré, E. et al. Clinical risk factors for preeclampsia in the 21st century. Obstet. Gynecol. 124, 763–770 (2014).
44. Kaur, G., Jain, V., Mehta, S. & Himani, S. Prediction of PIH by maternal serum beta hCG levels in the second trimester (13–20 weeks) of pregnancy. J. Obstet. Gynecol. India. 62, 32–34 (2012).
45. Strohmer, H. et al. Hypoxia downregulates continuous and interleukin-1-induced expression of human chorionic gonadotropin in choriocarcinoma cells. Placenta 18, 597–604 (1997).
46. Esterman, A., Finlay, T. H. & Dancis, J. Te efect of hypoxia on term trophoblast: Hormone synthesis and release. Placenta 17, 217–222 (1996).
47. Alsat, E. et al. Hypoxia impairs cell fusion and diferentiation process in human cytotrophoblast, in vitro. J. Cell Physiol. 168, 346–353 (1996).
48. Shao, R. et al. Increase of SUMO-1 expression in response to hypoxia: Direct interaction with HIF-1alpha in adult mouse brain and heart in vivo. FEBS Lett. 569, 293–300 (2004).
49. Bae, S. et al. Sumoylation increases HIF-1alpha stability and its transcriptional activity. Biochem. Biophys. Res. Commun. 324, 394–400 (2004).
50. Isoe, T. et al. High glucose activates HIF-1-mediated signal transduction in glomerular mesangial cells through a carbohydrate response element binding protein. Kidney Int. 78, 48–59 (2010).
51. Watson, A. L., Skepper, J. N., Jauniaux, E. & Burton, G. J. Susceptibility of human placental syncytiotrophoblastic mitochondria to oxygen-mediated damage in relation to gestational age. J. Clin. Endocrinol. Metab. 83, 1697–1705 (1998).
52. Watson, A. L., Skepper, J. N., Jauniaux, E. & Burton, G. J. Changes in concentration, localization and activity of catalase within the human placenta during early gestation. Placenta 19, 27–34 (1998).
53. Watson, A. L., Palmer, M. E., Jauniaux, E. & Burton, G. J. Variations in expression of copper/zinc superoxide dismutase in villous trophoblast of the human placenta with gestational age. Placenta 18, 295–299 (1997).
54. Mitani, M. et al. Clinical features of fetal growth restriction complicated later by preeclampsia. J. Obstet. Gynaecol. Res. 35, 882–887 (2009).
55. Korevaar, T. I. M. et al. Reference ranges and determinants of total hCG levels during pregnancy: Te Generation R Study. Eur. J. Epidemiol. 30, 1057–1066 (2015).
56. Meurs, M. V. et al. Bench-to-bedside review: Angiopoietin signalling in critical illness—a future target?. Crit. Care. 13, 207 (2009).
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