Skip to main content
SpringerLink
Log in

Uteroplacental Ischemia Is Associated with Increased PAPP-A2

  • Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Residence at high altitude (> 2500 m) has been associated with an increased frequency of preeclampsia. Pappalysin-2 (PAPP-A2) is an insulin-like growth factor binding protein-5 (IGFBP-5) protease that is elevated in preeclampsia, and up-regulated by hypoxia in placental explants. The relationships between PAPP-A2, altitude, and indices of uteroplacental ischemia are unknown. We aimed to evaluate the association of altitude, preeclampsia, and uterine artery flow or vascular resistance with PAPP-A2 levels. PAPP-A2, uterine artery diameter, volumetric blood flow, and pulsatility indices were measured longitudinally in normotensive Andean women residing at low or high altitudes in Bolivia and in a separate Andean high-altitude cohort with or without preeclampsia. PAPP-A2 levels increased with advancing gestation, with the rise tending to be greater at high compared to low altitude, and higher in early-onset preeclamptic compared to normotensive women at high altitude. Uterine artery blood flow was markedly lower and pulsatility index higher in early-onset preeclamptic normotensive women compared to normotensive women. PAPP-A2 was unrelated to uterine artery pulsatility index in normotensive women but positively correlated in the early-onset preeclampsia cases. We concluded that PAPP-A2 is elevated at high altitude and especially in cases of early-onset preeclampsia with Doppler indices of uteroplacental ischemia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Jensen GM, Moore LG. The effect of high altitude and other risk factors on birthweight: independent or interactive effects? Am J Public Health. 1997;87(6):1003–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Lichty JA, Ting RY, Bruns PD, Dyar E. Studies of babies born at high altitudes. I. Relation of altitude to birth weight. AMA J Dis Child. 1957;93(6):666–9.

    Article  CAS  PubMed  Google Scholar 

  3. Zamudio S, Postigo L, Illsley NP, et al. Maternal oxygen delivery is not related to altitude- and ancestry-associated differences in human fetal growth. J Physiol. 2007;582(Pt 2):883–95. https://doi.org/10.1113/jphysiol.2007.130708[published Online First: Epub Date]|.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Julian CG, Wilson MJ, Lopez M, et al. Augmented uterine artery blood flow and oxygen delivery protect Andeans from altitude-associated reductions in fetal growth. Am J Phys Regul Integr Comp Phys. 2009;296(5):R1564–75. https://doi.org/10.1152/ajpregu.90945.2008[published Online First: Epub Date]|.

    Article  CAS  Google Scholar 

  5. Moore LG, Young D, McCullough RE, Droma T, Zamudio S. Tibetan protection from intrauterine growth restriction (IUGR) and reproductive loss at high altitude. Am J Hum Biol. 2001;13(5):635–44. https://doi.org/10.1002/ajhb.1102 [published Online First: Epub Date]|.

    Article  CAS  PubMed  Google Scholar 

  6. Julian CG, Vargas E, Armaza JF, Wilson MJ, Niermeyer S, Moore LG. High-altitude ancestry protects against hypoxia-associated reductions in fetal growth. Arch Dis Child Fetal Neonatal Ed. 2007;92(5):F372–7. https://doi.org/10.1136/adc.2006.109579 [published Online First: Epub Date]|.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Soria R, Julian CG, Vargas E, Moore LG, Giussani DA. Graduated effects of high-altitude hypoxia and highland ancestry on birth size. Pediatr Res. 2013;74(6):633–8. https://doi.org/10.1038/pr.2013.150 [published Online First: Epub Date]|.

    Article  PubMed  Google Scholar 

  8. Lopez-Mendez MA, Martinez-Gaytan V, Cortes-Flores R, et al. Doppler ultrasound evaluation in preeclampsia. BMC Res Notes. 2013;6:477. https://doi.org/10.1186/1756-0500-6-477 [published Online First: Epub Date]|.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Duley L. The global impact of pre-eclampsia and eclampsia. Semin Perinatol. 2009;33(3):130–7. https://doi.org/10.1053/j.semperi.2009.02.010 [published Online First: Epub Date]|.

    Article  PubMed  Google Scholar 

  10. Uzan J, Carbonnel M, Piconne O, Asmar R, Ayoubi JM. Pre-eclampsia: pathophysiology, diagnosis, and management. Vasc Health Risk Manag. 2011;7:467–74. https://doi.org/10.2147/VHRM.S20181 [published Online First: Epub Date]|.

    Article  PubMed  PubMed Central  Google Scholar 

  11. ACOG. Hypertension in pregnancy. Report of the American college of obstetricians and gynecologists' task force on hypertension in pregnancy. Obstet Gynecol. 2013;122(5):1122–31. https://doi.org/10.1097/01.AOG.0000437382.03963.88 [published Online First: Epub Date]|.

    Article  Google Scholar 

  12. Keyes LE, Armaza JF, Niermeyer S, Vargas E, Young DA, Moore LG. Intrauterine growth restriction, preeclampsia, and intrauterine mortality at high altitude in Bolivia. Pediatr Res. 2003;54(1):20–5. https://doi.org/10.1203/01.PDR.0000069846.64389.DC [published Online First: Epub Date]|.

    Article  PubMed  Google Scholar 

  13. Palmer SK, Moore LG, Young D, Cregger B, Berman JC, Zamudio S. Altered blood pressure course during normal pregnancy and increased preeclampsia at high altitude (3100 meters) in Colorado. Am J Obstet Gynecol. 1999;180(5):1161–8 [published Online First: Epub Date]|.

    Article  CAS  PubMed  Google Scholar 

  14. Miller S, Tudor C, Nyima, et al. Maternal and neonatal outcomes of hospital vaginal deliveries in Tibet. Int J Gynaecol Obstet. 2007;98(3):217–21. https://doi.org/10.1016/j.ijgo.2007.03.033 [published Online First: Epub Date]|.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Nishizawa H, Pryor-Koishi K, Kato T, Kowa H, Kurahashi H, Udagawa Y. Microarray analysis of differentially expressed fetal genes in placental tissue derived from early and late onset severe pre-eclampsia. Placenta. 2007;28(5–6):487–97. https://doi.org/10.1016/j.placenta.2006.05.010 [published Online First: Epub Date]|.

    Article  CAS  PubMed  Google Scholar 

  16. Winn VD, Gormley M, Paquet AC, et al. Severe preeclampsia-related changes in gene expression at the maternal-fetal interface include sialic acid-binding immunoglobulin-like lectin-6 and pappalysin-2. Endocrinology. 2009;150(1):452–62. https://doi.org/10.1210/en.2008-0990 [published Online First: Epub Date]|.

    Article  CAS  PubMed  Google Scholar 

  17. Varkonyi T, Nagy B, Fule T, et al. Microarray profiling reveals that placental transcriptomes of early-onset HELLP syndrome and preeclampsia are similar. Placenta. 2011;32(Suppl):S21–9. https://doi.org/10.1016/j.placenta.2010.04.014 [published Online First: Epub Date]|.

    Article  CAS  PubMed  Google Scholar 

  18. Nishizawa H, Pryor-Koishi K, Suzuki M, et al. Increased levels of pregnancy-associated plasma protein-A2 in the serum of pre-eclamptic patients. Mol Hum Reprod. 2008;14(10):595–602. https://doi.org/10.1093/molehr/gan054 [published Online First: Epub Date]|.

    Article  CAS  PubMed  Google Scholar 

  19. Rasanen J, Girsen A, Lu X, et al. Comprehensive maternal serum proteomic profiles of preclinical and clinical preeclampsia. J Proteome Res. 2010;9(8):4274–81. https://doi.org/10.1021/pr100198m [published Online First: Epub Date]|.

    Article  CAS  PubMed  Google Scholar 

  20. Irwin JC, Suen LF, Martina NA, Mark SP, Giudice LC. Role of the IGF system in trophoblast invasion and pre-eclampsia. Hum Reprod. 1999;14(Suppl 2):90–6.

    Article  CAS  PubMed  Google Scholar 

  21. Nayak NR, Giudice LC. Comparative biology of the IGF system in endometrium, decidua, and placenta, and clinical implications for foetal growth and implantation disorders. Placenta. 2003;24(4):281–96.

    Article  CAS  PubMed  Google Scholar 

  22. Giudice LC, Martina NA, Crystal RA, Tazuke S, Druzin M. Insulin-like growth factor binding protein-1 at the maternal-fetal interface and insulin-like growth factor-I, insulin-like growth factor-II, and insulin-like growth factor binding protein-1 in the circulation of women with severe preeclampsia. Am J Obstet Gynecol. 1997;176(4):751–7 discussion 57-8.

    Article  CAS  PubMed  Google Scholar 

  23. Gratton RJ, Asano H, Han VK. The regional expression of insulin-like growth factor II (IGF-II) and insulin-like growth factor binding protein-1 (IGFBP-1) in the placentae of women with pre-eclampsia. Placenta. 2002;23(4):303–10. https://doi.org/10.1053/plac.2001.0780 [published Online First: Epub Date]|.

    Article  CAS  PubMed  Google Scholar 

  24. Kramer AW, Lamale-Smith LM, Winn VD. Differential expression of human placental PAPP-A2 over gestation and in preeclampsia. Placenta. 2016;37:19–25. https://doi.org/10.1016/j.placenta.2015.11.004 [published Online First: Epub Date]|.

    Article  CAS  PubMed  Google Scholar 

  25. Macintire K, Tuohey L, Ye L, et al. PAPPA2 is increased in severe early onset pre-eclampsia and upregulated with hypoxia. Reprod Fertil Dev. 2014;26(2):351–7. https://doi.org/10.1071/RD12384 [published Online First: Epub Date]|.

    Article  CAS  PubMed  Google Scholar 

  26. Wagner PK, Otomo A, Christians JK. Regulation of pregnancy-associated plasma protein A2 (PAPPA2) in a human placental trophoblast cell line (BeWo). Reprod Biol Endocrinol. 2011;9:48. https://doi.org/10.1186/1477-7827-9-48 [published Online First: Epub Date]|.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Browne VA, Toledo-Jaldin L, Davila RD, et al. High-end arteriolar resistance limits uterine artery blood flow and restricts fetal growth in preeclampsia and gestational hypertension at high altitude. Am J Phys Regul Integr Comp Phys. 2011;300(5):R1221–9. https://doi.org/10.1152/ajpregu.91046.2008 [published Online First: Epub Date]|.

    Article  CAS  Google Scholar 

  28. Wilson MJ, Lopez M, Vargas M, et al. Greater uterine artery blood flow during pregnancy in multigenerational (Andean) than shorter-term (European) high-altitude residents. Am J Phys Regul Integr Comp Phys. 2007;293(3):R1313–24. https://doi.org/10.1152/ajpregu.00806.2006 [published Online First: Epub Date]|.

    Article  CAS  Google Scholar 

  29. Williams R, Creasy R, Cunningham G, Hawes W, Norris FD, Tashiro M. Fetal growth and perinatal viability in California. Obstet Gynecol. 1982;58(5):624–32.

    Google Scholar 

  30. Kloverpris S, Gaidamauskas E, Rasmussen LC, et al. A robust immunoassay for pregnancy-associated plasma protein-A2 based on analysis of circulating antigen: establishment of normal ranges in pregnancy. Mol Hum Reprod. 2013;19(11):756–63. https://doi.org/10.1093/molehr/gat047 [published Online First: Epub Date]|.

    Article  CAS  PubMed  Google Scholar 

  31. Chen X, Chen K, Feng Y, et al. The potential role of pregnancy-associated plasma protein-A2 in angiogenesis and development of preeclampsia. Hypertens Res. 2019. https://doi.org/10.1038/s41440-019-0224-8 [published Online First: Epub Date]|.

  32. Crosley EJ, Dunk CE, Beristain AG, Christians JK. IGFBP-4 and -5 are expressed in first-trimester villi and differentially regulate the migration of HTR-8/SVneo cells. Reprod Biol Endocrinol. 2014;12:123. https://doi.org/10.1186/1477-7827-12-123 [published Online First: Epub Date]|.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Winship AL, Koga K, Menkhorst E, et al. Interleukin-11 alters placentation and causes preeclampsia features in mice. Proc Natl Acad Sci U S A. 2015;112(52):15928–33. https://doi.org/10.1073/pnas.1515076112 [published Online First: Epub Date].

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Crosley EJ, Durland U, Seethram K, MacRae S, Gruslin A, Christians JK. First-trimester levels of pregnancy associated plasma protein A2 ( PAPP-A2) in the maternal circulation are elevated in pregnancies that subsequently develop preeclampsia. Reprod Sci. 2014;21(6):754–60. https://doi.org/10.1177/1933719113512532 [published Online First: Epub Date]|.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. WHO. Maternal mortality. Data by WHO region. Secondary Maternal mortality. Data by WHO region. http://apps.who.int/gho/data/view.main.1370?lang=en.2016.

Download references

Acknowledgments

This study would not have been possible without the assistance of personnel at the Hospital Boliviano Holandés, Clinica CEMES, Clinica Siranni, and the many other hospitals or clinics in La Paz/El Alto, Bolivia where patients were recruited. We also thank the Instituto Boliviano de Biología de Altura for their help with the collection and processing of blood samples and the University Colorado School of Medicine Global Health program for student assistance in collecting the birth record data.

Funding

Grant support for the collection of samples was provided by NIH HL HL079647 and HL079647-S1. Support for the PAPP-A2 analyses was provided by NIH WRHR K12 HD001271, R01 HD60723–01, NIH Building Interdisciplinary Research Careers Women’s Health grant HD057022–07, and NIH/NCATS Colorado CTSA Grant UL1 TR001082.

Author information

Authors and Affiliations

  1. Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California San Diego, San Diego, CA, USA

    Leah M. Lamale-Smith

  2. Department of Obstetrics and Gynecology, University of Colorado Denver, Aurora, CO, USA

    Diane L. Gumina, Anita W. Kramer & Lorna G. Moore

  3. Department of Emergency Medicine, University of Colorado Denver, Aurora, CO, USA

    Vaughn A. Browne

  4. Hospital Materno-Infantil, La Paz, Bolivia

    Lilian Toledo-Jaldin

  5. Department of Medicine, University of Colorado, Denver, Aurora, CO, USA

    Colleen G. Julian

  6. Department of Obstetrics and Gynecology, Stanford University, Stanford, CA, USA

    Virginia D. Winn

Authors
  1. Leah M. Lamale-Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Diane L. Gumina
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anita W. Kramer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vaughn A. Browne
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lilian Toledo-Jaldin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Colleen G. Julian
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Virginia D. Winn
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lorna G. Moore
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Leah M. Lamale-Smith.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Virginia D. WINN and Lorna G. MOORE are co-senior author.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lamale-Smith, L.M., Gumina, D.L., Kramer, A.W. et al. Uteroplacental Ischemia Is Associated with Increased PAPP-A2. Reprod. Sci. 27, 529–536 (2020). https://doi.org/10.1007/s43032-019-00050-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43032-019-00050-3

Keywords

Search

Navigation