Preventing Preterm Birth, Intrauterine Growth Retardation (IUGR) and Preeclampsia by the Normalisation of Placentation

  • György Siklósi


As we have demonstrated in the previous chapters, the outcome of pregnancy is essentially determined by the folliculo-luteal function (FLF) – the level of follicular oestradiol and then luteal progesterone – which defines the conditions for placentation. Insufficient FLF and the consequent inadequate placentation, which is known as ischaemic placental disease, underlie preterm birth, intrauterine growth retardation (IUGR) and preeclampsia. Because of the extraordinary importance of this issue, we investigated how the normalisation of FLF prior to conception can influence the prevalence of these three obstetric complications.

During the treatment of unexplained infertility, successful birth occurred in 606 cases with physiological FLF (average luteal progesterone >23 ng/ml). The rates of preterm birth, IUGR, newborn weight <2500 g and preeclampsia decreased by an order of magnitude in singular births (0.7 %, 0.7 %, 1.0 % and 0 %, respectively) compared to both the Hungarian population (9.5 %, 10.1 %, 9.3 % and 3.0 %, respectively) and the untreated control group (30.2 %, 30.2 %, 35.7 % and 5.6 %, respectively). Besides the less frequent occurrence of preterm and growth-retarded newborns, their characteristics were also significantly (p < 0.001) better compared to the national average: except for one case, every preterm birth were late preterm deliveries after the 34th week, with newborn weights >2200 g, and every newborn with IUGR was born after the 37th week with a weight of >2000 g.

Multiple pregnancies conceived four times more often with physiological FLF (6.3 %) than the national average (1.6 %), while the occurrence of preterm births was significantly (p < 0.001) lower with physiological FLF than the national average, 23.7 and 47.1 %, similar to that of IUGR, 18.4 and 47.7 %.

Through the normalisation of FLF before conception, the incidence of these three obstetrical complications can be reduced from 21.8 to 1.4 % with singular births and from 22.6 to 2.9 % including all births. In addition, newborn characteristics are also significantly improved compared to spontaneously conceived pregnancies.


Preterm Birth Trophoblast Cell Adverse Pregnancy Outcome HELLP Syndrome Spiral Artery 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Abdalla HI, Billett A, Kan AK, Baig S, Wren M, Korea L, Studd JW. Obstetric outcome in 232 ovum donation pregnancies. Br J Obstet Gynaecol. 1998;105(3):332–7.CrossRefPubMedGoogle Scholar
  2. Ananth CV, Friedman AM. Ischemic placental disease and risks of perinatal mortality and morbidity and neurodevelopmental outcomes. Semin Perinatol. 2014;38(3):151–8.CrossRefPubMedGoogle Scholar
  3. Ananth CV. Ischemic placental disease: a unifying concept for preeclampsia, intrauterine growth restriction and placental abruption. Semin Perinatol. 2014;38(3):131–2.CrossRefPubMedGoogle Scholar
  4. ASRM 2012 – The clinical relevance of luteal phase deficiency: a committeb opinion. The Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2012a;98:1112–7.Google Scholar
  5. Asvold BO, Vatten LJ, Romundstad PR, Jenum PA, Karumanchi SA, Eskild A. Angiogenic factors in maternal circulation and the risk of severe fetal growth restriction. Am J Epidemiol. 2011;173(6):630–9.CrossRefPubMedGoogle Scholar
  6. Asvold BO, Vatten LJ, Tanbo TG, Eskild A. Concentrations of human chorionic gonadotrophin in very early pregnancy and subsequent pre-eclampsia: a cohort study. Hum Reprod. 2014;29(6):1153–60.CrossRefPubMedGoogle Scholar
  7. Bamfo JE, Odibo AO. Diagnosis and management of fetal growth restriction. J Pregnancy. 2011;2011:640–715.CrossRefGoogle Scholar
  8. Barker DJ. Birth weight and hypertension. Hypertension. 2006;48:357–8.CrossRefPubMedGoogle Scholar
  9. Barnhart KT, Sammel MD, Rinaudo PF, Zhou L, Hummel AC, Guo W. Symptomatic patients with an early viable intrauterine pregnancy: HCG curves redefined. Obstet Gynecol. 2004;104:50–5.CrossRefPubMedGoogle Scholar
  10. Baschat AA. Neurodevelopment following fetal growth restriction and its relationship with antepartum parameters of placental dysfunction. Ultrasound Obstet Gynecol. 2011;37:501–14.CrossRefPubMedGoogle Scholar
  11. Berkő P. A new method for the classification of neonates based on maturity and somatic development. [Article in Hungarian]. Orv Hetil. 1992;133(9):529–32.PubMedGoogle Scholar
  12. Berkő P, Joubert K. The effect of intrauterine development and nutritional status on perinatal mortality. J Matern Fetal Neonatal Med. 2009;22(7):552–9.CrossRefPubMedGoogle Scholar
  13. Berkő P, Joubert K. IUGR and its obstetrical management (Az intrauterin növekedési retardáció és annak szülészeti ellátása.).[Article in Hungarian]. Magyar Nőorvosok Lapja, 2015:78(2), 18–28. (In press)Google Scholar
  14. Blencowe H, Cousens S, Oestergaard MZ, Chou D, Moller AB, Narwal R, Adler A, Vera Garcia C, Rohde S, Say L, Lawn JE. 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):2162–72.CrossRefPubMedGoogle Scholar
  15. Brosens I, Pijnenborg R, Vercruysse L, Romero R. The “Great Obstetrical Syndromes” are associated with disorders of deep placentation. Am J Obstet Gynecol. 2011;204:193–201.CrossRefPubMedGoogle Scholar
  16. Bukowski R, Smith GC, Malone FD, Ball RH, Nyberg DA, Comstock CH, Hankins GD, Berkowitz RL, Gross SJ, Dugoff L, Craigo SD, Timor-Tritsch IE, Carr SR, Wolfe HM, D’Alton ME, FASTER Research Consortium. Fetal growth in early pregnancy and risk of delivering low birth weight infant: prospective cohort study. BMJ. 2007;334(7598):836.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Conrad KP, Baker VL. Corpus luteal contribution to maternal pregnancy physiology and outcomes in assisted reproductive technologies. Am J Physiol Regul Integr Comp Physiol. 2013; 304(2):R69–72. Google Scholar
  18. Conrad KP, Shroff SG. Effects of relaxin on arterial dilation, remodeling, and mechanical properties. Curr Hypertens Rep. 2011;13:409–20.CrossRefPubMedGoogle Scholar
  19. Conrad KP. Emerging role of relaxin in the maternal adaptations to normal pregnancy: implications for preeclampsia. Semin Nephrol. 2011a;31(1):15–32.CrossRefPubMedPubMedCentralGoogle Scholar
  20. Conrad KP. Maternal vasodilation in pregnancy: the emerging role of relaxin. Am J Physiol Regul Integr Comp Physiol. 2011b;301(2):R267–75.CrossRefPubMedPubMedCentralGoogle Scholar
  21. Cosmi E, Fanelli T, Visentin S, Trevisanuto D, Zanardo V. Consequences in infants that were intrauterine growth restricted. J Pregnancy. 2011;2011:364381.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Dickey RP, Holtkamp DE. Development, pharmacology and clinical experience with clomiphene citrate. Hum Reprod Update. 1996;62:483–506.CrossRefGoogle Scholar
  23. George EM, Granger JP. Endothelin: key mediator of hypertension in preeclampsia. Am J Hypertens. 2011;24(9):964–9.CrossRefPubMedPubMedCentralGoogle Scholar
  24. Gluckman PD, Hanson MA, Cooper C, Thornburg KL. Effect of in utero and early-life conditions on adult health and disease. N Engl J Med. 2008;359(1):61–73.CrossRefPubMedPubMedCentralGoogle Scholar
  25. Goldsmith LT, Weiss G. Relaxin in human pregnancy. Ann N Y Acad Sci. 2009;1160:130–5.CrossRefPubMedGoogle Scholar
  26. Hafner E, Metzenbauer M, Höfinger D, Munkel M, Gassner R, Schuchter K, Dillinger-Paller B, Philipp K. Placental growth from the first to the second trimester of pregnancy in SGA-foetuses and pre-eclamptic pregnancies compared to normal foetuses. Placenta. 2003;24:336–42.CrossRefPubMedGoogle Scholar
  27. Jauniaux E, Burton GJ. Pathophysiology of histological changes in early pregnancy loss. Placenta. 2005;26:114–23.CrossRefPubMedGoogle Scholar
  28. Kiprono LV, Wallace K, Moseley J, Martin Jr J, Lamarca B. Progesterone blunts vascular endothelial cell secretion of endothelin-1 in response to placental ischemia. Am J Obstet Gynecol. 2013;209:44.e1–6.CrossRefGoogle Scholar
  29. Kristiansson P, Svärdsudd K, von Schoultz B, Wramsby H. Supraphysiological serum relaxin concentration during pregnancy achieved by in-vitro fertilization is strongly correlated to the number of growing follicles in the treatment cycle. Hum Reprod. 1996;11(9):2036–40.CrossRefPubMedGoogle Scholar
  30. Kristiansson P, Wang JX. Reproductive hormones and blood pressure during pregnancy. Hum Reprod. 2001;16:13–17.Google Scholar
  31. Larsen B, Hwang J. Progesterone interactions with the cervix: translational implications for term and preterm birth. Infect Dis Obstet Gynecol. 2011;35:32–97.Google Scholar
  32. Leslie K, Thilaganathan B, Papageorghiou A. Early prediction and prevention of preeclampsia. Best Pract Res Clin Obstet Gynaecol. 2011;25(3):343–54.CrossRefPubMedGoogle Scholar
  33. Mook-Kanamori DO, Steegers EA, Eilers PH, Raat H, Hofman A, Jaddoe VW. Risk factors and outcomes associated with first-trimester fetal growth restriction. JAMA. 2010;303(6):527–34.CrossRefPubMedGoogle Scholar
  34. Muglia LJ, Katz M. The enigma of spontaneous preterm birth. N Engl J Med. 2010;362(6):529–35.CrossRefPubMedGoogle Scholar
  35. Naljayan MV, Karumanchi SA. New developments in the pathogenesis of preeclampsia. Adv Chronic Kidney Dis. 2013;20(3):265–70.CrossRefPubMedPubMedCentralGoogle Scholar
  36. Roberts CL, Ford JB, Algert CS, Antonsen S, Chalmers J, Cnattingius S, Gokhale M, Kotelchuck M, Melve KK, Langridge A, Morris C, Morris JM, Nassar N, Norman JE, Norrie J, Sørensen HT, Walker R, Weir CJ. Population-based trends in pregnancy hypertension and pre-eclampsia: an international comparative study. BMJ Open. 2011;24:1.Google Scholar
  37. Seely EW, Ecker J. Clinical practice. Chronic hypertension in pregnancy. N Engl J Med. 2011;365:439–46.CrossRefPubMedGoogle Scholar
  38. Smith GC, Smith MF, McNay MB, Fleming JE. First-trimester growth and the risk of low birth weight. N Engl J Med. 1998,339(25):1817–22.Google Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • György Siklósi
    • 1
  1. 1.Semmelweis University Second Department of Obstetrics and GynecologyBudapestHungary

Personalised recommendations