Skip to main content

Advertisement

Log in

Twin gestation and the burden of adult cardio-renal disease

  • Educational Review
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

The rate of twin births has increased by nearly 80% in recent decades largely due to advanced reproductive technologies. Twins are often born preterm and/or growth restricted which are independently associated with impaired renal and vascular development. Many preterm and twin infants are surviving into adulthood, albeit with an increased burden of chronic health conditions. Twinning as a research tool offers the unique opportunity to investigate the impact of genetics versus the environment on clinical outcomes. This educational review will focus on delineating our current understanding of the renal and cardiovascular development and long-term outcomes among twin born individuals. Specifically, existing literature regarding how twins differ in kidney size and function as well as vascular stiffness and hypertension profiles from singletons will be discussed. The unique situation of twin–twin transfusion syndrome which is associated with distinct short- and long-term cardio-renal disease will be highlighted. Ultimately, the ability to stratify risk of future cardio-renal disease at birth for infants born preterm and/or growth restricted, including twins, is important to guide clinical follow up. In addition, this early risk stratification could direct research efforts to better understand the mechanisms driving impaired organogenesis and allow for discovery of therapeutic interventions aimed at modifying disease progression and improving longevity in the most vulnerable infant subgroups.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Martin J, Hamilton BE, Osterman MJK (2018) Births: final data for 2017. Natl Vital Stat Rep 67:1–50

    Google Scholar 

  2. 2018 AGUDoHaHS (2016) Assisted Reproductive Technology National Summary Report. Centers for Disease Control and Prevention, American Society for Reproductive Medicine, Society for Assisted Reproductive Technology

  3. DeFreitas M, Katsoufis CK, Abitbol CL (2016) Cardio-renal consequences of low birth weight and preterm birth. Prog Pediatr Cardiol 41:83–88

    Google Scholar 

  4. Luyckx VA, Bertram JF, Brenner BM, Fall C, Hoy WE, Ozanne SE, Vikse BE (2013) Effect of fetal and child health on kidney development and long-term risk of hypertension and kidney disease. Lancet 382:273–283

    Google Scholar 

  5. Barker DJ (1990) The fetal and infant origins of adult disease. BMJ 301:1111

    CAS  Google Scholar 

  6. Skogen JC, Overland S (2012) The fetal origins of adult disease: a narrative review of the epidemiological literature. JRSM Short Rep 3:59

    Google Scholar 

  7. Crump C, Sundquist K, Sundquist J, Winkleby MA (2011) Gestational age at birth and mortality in young adulthood. Jama 306:1233–1240

    CAS  Google Scholar 

  8. Phillips DI, Davies MJ, Robinson JS (2001) Fetal growth and the fetal origins hypothesis in twins—problems and perspectives. Twin Res 4:327–331

    CAS  Google Scholar 

  9. Oberg S, Cnattingius S, Sandin S, Lichtenstein P, Morley R, Iliadou AN (2012) Twinship influence on morbidity and mortality across the lifespan. Int J Epidemiol 41:1002–1009

    Google Scholar 

  10. Hjelmborg J, Larsen P, Kaprio J, McGue M, Scheike T, Hougaard P, Christensen K (2019) Lifespans of twins: does zygosity matter? Genes (Basel) 10

  11. Stern E, Cohen N, Odom E, Stroustrup A, Gupta S, Saltzman DH, Rebarber A, Fox NS (2018) Long-term outcomes of twins based on gestational age at delivery. J Matern Fetal Neonatal Med 31:3102–3107

    CAS  Google Scholar 

  12. Townsend R, Khalil A (2018) Fetal growth restriction in twins. Best Pract Res Clin Obstet Gynaecol 49:79–88

    CAS  Google Scholar 

  13. Lambert NC (2016) How twin studies help to understand inflammatory joint disease. Joint Bone Spine 83:637–643

    Google Scholar 

  14. Bamberg C, Hecher K (2019) Update on twin-to-twin transfusion syndrome. Best Pract Res Clin Obstet Gynaecol

  15. Burton GJ, Jauniaux E (2018) Pathophysiology of placental-derived fetal growth restriction. Am J Obstet Gynecol 218:S745–s761

    CAS  Google Scholar 

  16. Godfrey KM (2002) The role of the placenta in fetal programming—a review. Placenta 23 Suppl A:S20-27

  17. Salafia CM, Maas E (2005) The twin placenta: framework for gross analysis in fetal origins of adult disease initiatives. Paediatr Perinat Epidemiol 19(Suppl 1):23–31

    Google Scholar 

  18. Geelhoed JJ, Verburg BO, Nauta J, Lequin M, Hofman A, Moll HA, Witteman JC, van der Heijden AJ, Steegers EA, Jaddoe VW (2009) Tracking and determinants of kidney size from fetal life until the age of 2 years: the generation R study. Am J Kidney Dis 53:248–258

    Google Scholar 

  19. Davis EF, Lazdam M, Lewandowski AJ, Worton SA, Kelly B, Kenworthy Y, Adwani S, Wilkinson AR, McCormick K, Sargent I, Redman C, Leeson P (2012) Cardiovascular risk factors in children and young adults born to preeclamptic pregnancies: a systematic review. Pediatrics 129:e1552–e1561

    Google Scholar 

  20. DeFreitas MJ, Mathur D, Seeherunvong W, Cano T, Katsoufis CP, Duara S, Yasin S, Zilleruelo G, Rodriguez MM, Abitbol CL (2017) Umbilical artery histomorphometry: a link between the intrauterine environment and kidney development. J Dev Orig Health Dis 8:349–356

    CAS  Google Scholar 

  21. Hubinont C, Lewi L, Bernard P, Marbaix E, Debieve F, Jauniaux E (2015) Anomalies of the placenta and umbilical cord in twin gestations. Am J Obstet Gynecol 213:S91–s102

    Google Scholar 

  22. Blanco MV, Vega HR, Giuliano R, Grana DR, Azzato F, Lerman J, Milei J (2011) Histomorphometry of umbilical cord blood vessels in preeclampsia. J Clin Hypertens (Greenwich) 13:30–34

    Google Scholar 

  23. Chaddha V, Viero S, Huppertz B, Kingdom J (2004) Developmental biology of the placenta and the origins of placental insufficiency. Semin Fetal Neonatal Med 9:357–369

    Google Scholar 

  24. Groene SG, Todtenhaupt P, van Zwet EW, van Pel M, Berkhout RJM, Haak MC, Roest AAW, Lopriore E, van Klink JMM, Heijmans BT (2019) TwinLIFE: the twin longitudinal investigation of FEtal discordance. Twin Res Hum Genet:1–6

  25. Zandi-Nejad K, Luyckx VA, Brenner BM (2006) Adult hypertension and kidney disease: the role of fetal programming. Hypertension 47:502–508

    CAS  Google Scholar 

  26. South AM, Shaltout HA, Washburn LK, Hendricks AS, Diz DI, Chappell MC (2019) Fetal programming and the angiotensin-(1–7) axis: a review of the experimental and clinical data. Clin Sci (Lond) 133:55–74

    CAS  Google Scholar 

  27. Shaltout HA, Figueroa JP, Rose JC, Diz DI, Chappell MC (2009) Alterations in circulatory and renal angiotensin-converting enzyme and angiotensin-converting enzyme 2 in fetal programmed hypertension. Hypertension 53:404–408

    CAS  Google Scholar 

  28. South AM, Nixon PA, Chappell MC, Diz DI, Russell GB, Snively BM, Shaltout HA, Rose JC, O'Shea TM, Washburn LK (2017) Antenatal corticosteroids and the renin–angiotensin–aldosterone system in adolescents born preterm. Pediatr Res 81:88–93

    Google Scholar 

  29. Abitbol CL, DeFreitas MJ, Strauss J (2016) Assessment of kidney function in preterm infants: lifelong implications. Pediatr Nephrol 31:2213–2222

    Google Scholar 

  30. Rodriguez MM, Gomez AH, Abitbol CL, Chandar JJ, Duara S, Zilleruelo GE (2004) Histomorphometric analysis of postnatal glomerulogenesis in extremely preterm infants. Pediatr Dev Pathol 7:17–25

    Google Scholar 

  31. Luyckx VA, Shukha K, Brenner BM (2011) Low nephron number and its clinical consequences. Rambam Maimonides Med J 2:e0061

    Google Scholar 

  32. Mitchell EK, Louey S, Cock ML, Harding R, Black MJ (2004) Nephron endowment and filtration surface area in the kidney after growth restriction of fetal sheep. Pediatr Res 55:769–773

    Google Scholar 

  33. Mahieu-Caputo D, Dommergues M, Delezoide AL, Lacoste M, Cai Y, Narcy F, Jolly D, Gonzales M, Dumez Y, Gubler MC (2000) Twin-to-twin transfusion syndrome. Role of the fetal renin–angiotensin system. Am J Pathol 156:629–636

    CAS  Google Scholar 

  34. Galea P, Barigye O, Wee L, Jain V, Sullivan M, Fisk NM (2008) The placenta contributes to activation of the renin angiotensin system in twin–twin transfusion syndrome. Placenta 29:734–742

    CAS  Google Scholar 

  35. Barr M Jr, Sedman AB, Heidelberger KP (1998) Renal tubular dysgenesis in twins. Pediatr Nephrol 12:408–413

    Google Scholar 

  36. Tarnoki DL, Tarnoki AD, Littvay L, Bata P, Berczi V, Garami Z, Karlinger K (2013) Genetic and environmental variance of renal parenchymal thickness: a twin study. Croat Med J 54:550–554

    Google Scholar 

  37. Giapros V, Drougia A, Hotoura E, Argyropoulou M, Papadopoulou F, Andronikou S (2010) Kidney growth in twin children born small for gestational age. Nephrol Dial Transplant 25:3548–3554

    Google Scholar 

  38. Drougia A, Giapros V, Hotoura E, Papadopoulou F, Argyropoulou M, Andronikou S (2009) The effects of gestational age and growth restriction on compensatory kidney growth. Nephrol Dial Transplant 24:142–148

    Google Scholar 

  39. Gielen M, Pinto-Sietsma SJ, Zeegers MP, Loos RJ, Fagard R, de Leeuw PW, Beunen G, Derom C, Vlietinck R (2005) Birth weight and creatinine clearance in young adult twins: influence of genetic, prenatal, and maternal factors. J Am Soc Nephrol 16:2471–2476

    Google Scholar 

  40. Poulter NR, Chang CL, MacGregor AJ, Snieder H, Spector TD (1999) Association between birth weight and adult blood pressure in twins: historical cohort study. BMJ 319:1330–1333

    CAS  Google Scholar 

  41. RG IJ, Stehouwer CD, Boomsma DI (2000) Evidence for genetic factors explaining the birth weight-blood pressure relation. Analysis in twins. Hypertension 36:1008–1012

    Google Scholar 

  42. Dwyer T, Blizzard L, Morley R, Ponsonby AL (1999) Within pair association between birth weight and blood pressure at age 8 in twins from a cohort study. Bmj 319:1325–1329

    CAS  Google Scholar 

  43. Loos RJ, Fagard R, Beunen G, Derom C, Vlietinck R (2001) Birth weight and blood pressure in young adults: a prospective twin study. Circulation 104:1633–1638

    CAS  Google Scholar 

  44. Andraweera PH, Lassi ZS (2019) Cardiovascular risk factors in offspring of preeclamptic pregnancies—systematic review and meta-analysis. J Pediatr 208:104–113.e106

    Google Scholar 

  45. Weiner E, Feldstein O, Schreiber L, Grinstein E, Barber E, Dekalo A, Bar J, Kovo M (2018) Placental component and pregnancy outcome in singleton versus twin pregnancies complicated by preeclampsia. Fetal Diagn Ther 44:142–148

    Google Scholar 

  46. Connolly KA, Factor SH, Getrajdman CS, Bigelow CA, Weintraub AS, Stone JL (2016) Maternal clinical disease characteristics and maternal and neonatal outcomes in twin and singleton pregnancies with severe preeclampsia. Eur J Obstet Gynecol Reprod Biol 201:36–41

    Google Scholar 

  47. Martyn CN, Greenwald SE (1997) Impaired synthesis of elastin in walls of aorta and large conduit arteries during early development as an initiating event in pathogenesis of systemic hypertension. Lancet 350:953–955

    CAS  Google Scholar 

  48. Burkhardt T, Matter CM, Lohmann C, Cai H, Luscher TF, Zisch AH, Beinder E (2009) Decreased umbilical artery compliance and IGF-I plasma levels in infants with intrauterine growth restriction—implications for fetal programming of hypertension. Placenta 30:136–141

    CAS  Google Scholar 

  49. Medda E, Fagnani C, Schillaci G, Tarnoki AD, Tarnoki DL, Baracchini C, Meneghetti G, Fanelli F, Alaeddin A, Pucci G, Alviti S, Cotichini R, Brescianini S, Boatta E, Lucatelli P, Nistico L, Penna L, Salemi M, Toccaceli V, Zini C, Garami Z, Stazi MA (2014) Heritability of arterial stiffness and carotid intima–media thickness: an Italian twin study. Nutr Metab Cardiovasc Dis 24:511–517

    CAS  Google Scholar 

  50. Society for Maternal-Fetal M, Simpson LL (2013) Twin–twin transfusion syndrome. Am J Obstet Gynecol 208:3–18

    Google Scholar 

  51. Cincotta RB, Gray PH, Phythian G, Rogers YM, Chan FY (2000) Long term outcome of twin–twin transfusion syndrome. Arch Dis Child Fetal Neonatal Ed 83:F171–F176

    CAS  Google Scholar 

  52. Jetton JG, Boohaker LJ, Sethi SK, Wazir S, Rohatgi S, Soranno DE, Chishti AS, Woroniecki R, Mammen C, Swanson JR, Sridhar S, Wong CS, Kupferman JC, Griffin RL, Askenazi DJ, Neonatal Kidney C (2017) Incidence and outcomes of neonatal acute kidney injury (AWAKEN): a multicentre, multinational, observational cohort study. Lancet Child Adolesc Health 1:184–194

    Google Scholar 

  53. Christensen AM, Daouk GH, Norling LL, Catlin EA, Ingelfinger JR (1999) Postnatal transient renal insufficiency in the feto-fetal transfusion syndrome. Pediatr Nephrol 13:117–120

    CAS  Google Scholar 

  54. De Paepe ME, Stopa E, Huang C, Hansen K, Luks FI (2003) Renal tubular apoptosis in twin-to-twin transfusion syndrome. Pediatr Dev Pathol 6:215–225

    Google Scholar 

  55. Melhem NZ, Ledermann S, Rees L (2019) Chronic kidney disease following twin-to-twin transfusion syndrome—long-term outcomes. Pediatr Nephrol 34:883–888

    Google Scholar 

  56. Verbeek L, Joemmanbaks FA, Quak JME, Sukhai RN, Middeldorp JM, Oepkes D, Lopriore E (2017) Renal function in neonates with twin–twin transfusion syndrome treated with or without fetoscopic laser surgery. Eur J Pediatr 176:1209–1215

    CAS  Google Scholar 

  57. Beck M, Graf C, Ellenrieder B, Bokenkamp A, Huber A, Hecher K, Bartmann P (2005) Long-term outcome of kidney function after twin–twin transfusion syndrome treated by intrauterine laser coagulation. Pediatr Nephrol 20:1657–1659

    CAS  Google Scholar 

  58. Mahieu-Caputo D, Meulemans A, Martinovic J, Gubler MC, Delezoide AL, Muller F, Madelenat P, Fisk NM, Dommergues M (2005) Paradoxic activation of the renin–angiotensin system in twin–twin transfusion syndrome: an explanation for cardiovascular disturbances in the recipient. Pediatr Res 58:685–688

    Google Scholar 

  59. Kilby MD, Platt C, Whittle MJ, Oxley J, Lindop GB (2001) Renin gene expression in fetal kidneys of pregnancies complicated by twin–twin transfusion syndrome. Pediatr Dev Pathol 4:175–179

    CAS  Google Scholar 

  60. Corvol P, Schutz S, Gasc JM (1998) Early expression of all components of the renin–angiotensin system in human development. Adv Nephrol Necker Hosp 28:195–212

    CAS  Google Scholar 

  61. Guilherme R, Patrier S, Gubler MC, Lemercier D, Guimiot F, Dommergues M (2009) Very early twin-to-twin transfusion syndrome and discordant activation of the renin–angiotensin system. Placenta 30:731–734

    CAS  Google Scholar 

  62. Gubler MC (2014) Renal tubular dysgenesis. Pediatr Nephrol 29:51–59

    Google Scholar 

  63. Gardiner HM, Taylor MJ, Karatza A, Vanderheyden T, Huber A, Greenwald SE, Fisk NM, Hecher K (2003) Twin–twin transfusion syndrome: the influence of intrauterine laser photocoagulation on arterial distensibility in childhood. Circulation 107:1906–1911

    Google Scholar 

  64. Cheung YF, Taylor MJ, Fisk NM, Redington AN, Gardiner HM (2000) Fetal origins of reduced arterial distensibility in the donor twin in twin–twin transfusion syndrome. Lancet 355:1157–1158

    CAS  Google Scholar 

  65. Gardiner HM, Barlas A, Matsui H, Diemert A, Taylor MJ, Preece J, Gordon F, Greenwald SE, Hecher K (2012) Vascular programming in twins: the effects of chorionicity and fetal therapy for twin-to-twin transfusion syndrome. J Dev Orig Health Dis 3:182–189

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Marissa J. DeFreitas.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Additional information

Answers 1. d; 2. d; 3. d; 4. c; 5. c

Publisher’s note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

DeFreitas, M.J., Abitbol, C.L. Twin gestation and the burden of adult cardio-renal disease. Pediatr Nephrol 35, 2241–2251 (2020). https://doi.org/10.1007/s00467-019-04418-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-019-04418-0

Keywords

Navigation