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Jorgen Pedersen: The pregnant diabetic and her newborn, 1977

Fetal Hypoxia in Diabetic Pregnancy Kari Teramo, M.D. Department of Obstetrics and Gynecology, University Central Hospital, Helsinki, Finland. Jorgen Pedersen: The pregnant diabetic and her newborn, 1977.

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Jorgen Pedersen: The pregnant diabetic and her newborn, 1977

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  1. Fetal Hypoxia in Diabetic Pregnancy Kari Teramo, M.D.Department of Obstetrics and Gynecology, University Central Hospital, Helsinki, Finland

  2. Jorgen Pedersen: The pregnant diabetic and her newborn, 1977

  3. Frequency (%) of fetal and neonatal complications in Type 1 diabetic pregnancies and in the general population in Sweden 1991 - 2003------------------------------------------------------------------------------------------Outcome variable Type 1 DM Controls Adjusted OR (95% CI)------------------------------------------------------------------------------------------Singleton births 5.089 1.260.207Stillbirth 1.5 0.3 3.34 (2.46 – 4.55)Neonatal mortality 0.51 0.18 3.05 (1.68 – 5.55)Perinatal mortality 2.0 0.48 3.29 (2.50 – 4.33)LGA (≥ 2.0 SD) 31.0 3.6 11.40 (10.6 – 12.4) SGA (≤ -2.0 SD) 2.3 2.5 0.71 (0.55 – 0.91)Apgar <7 at 5 min. 3.1 1.1 2.60 (2.14 – 3.17) Erb’s palsy 2.1 0.25 6.69 (4.81 – 9.31) RDS 1.0 0.2 4.65 (2.20 – 9.84) ------------------------------------------------------------------------------------------ Persson et al. Diabetes Care 2009

  4. Perinatal mortality in Type 1 diabetic pregnancies Gabbe and Graves 2003

  5. Perinatal mortality in pregestational diabetic pregnancies Helsinki UCH 1951 - 2008------------------------------------------------------------Newborn Newborns/ Fetal Neonat. PMinfantsyear deaths deaths %--------------------------------------------------------------------1951-60 162 16 30 15 28.5 (3.2)*1959-68 231 23 25 23 20.8 (2.3)*1970-71 52 26 3 4 13.5 (1.7)*1975-80 279 47 3 3 2.2 (1.3)*1988-92 340 68 5 3 2.4 (0.8)*1993-97 362 72 5 4 2.5 (0.7)*1998-2002 330 66 4 1 1.5 (0.6)*2003-08 561 94 8 1 1.6 (0.5)* ------------------------------------------------------------------------------------------------*Annual mean in Finland

  6. Incidence of Type 1 diabetes among children under 15 years of age in Finland 1953 – 2003 Tuomilehto et al. 2005 Vuosi

  7. Perinatal deaths in pregestational diabetic pregnancies Helsinki UCH 1988 - 2008-----------------------------------------------------------------------------------------No. White’s Gestation Birth weight Fetal/ Comment class (weeks + d) g z-score Neonat.-----------------------------------------------------------------------------------------1. B 23 + 5 575 .. F PROM2. C 25 + 1 370 -5.0 F Mult.MF3. C 25 + 1 500 -4.4 N RDS4. B T2 25 + 2 725 -2.8 N RDS5. B 26 + 0 440 -4.5 F Preeclampsia6. D 26 + 1 650 -2.8 F IVF, twin B7. C 26 + 3 830 -1.5 F Unexplained8. F 26 + 4 785 -2.1 N RDS9. R 27 + 2 1160 -0.4 F Pl.abruption10. C 27 + 4 400 -5.3 F Pl.abruption11. D 28 + 4 705 -3.8 N RDS12. D 29 + 2 1195 -1.3 F Plac. infarcts13. F 30 + 1 810 -3.9 N RDS14. F 30 + 1 1900 +1.7 N Severe MF -------------------------------------------------------------------------------------------------

  8. Perinatal deaths in pregestational diabetic pregnanciesHelsinki UCH, 1988 - 2008 (cont.)-----------------------------------------------------------------------------------------No. White’s Gestation Birth weight Fetal/ Comment class (weeks + d) g z-score Neonat.-----------------------------------------------------------------------------------------15. B 31 + 1 1380 -1.6 F Cord compl.16. D 31 + 2 1255 -2.4 F Pl. abruption17. C 31 + 5 2160 +1.3 F Mat. ketoacid.18. B 33 + 6 1350 -3.4 F Plac. infarcts19. B 34 + 4 2310 -0.9 F Unexpl.Twin B20. D 35 + 4 4100 +3.4 N Sev. dystocia21. D 35 + 5 3150 +0.7 F Cord compl.22. C 36 + 0 4030 +2.9 F Unexplained23. B 36 + 1 2250 -1.8 F Pl. abruption24. R 36 + 3 4630 +4.5 F Unexplained25 B T2 36 + 4 5600 +6.4 F Unexplained26. C 36 + 6 2990 -0.5 F Unexplained27. B T2 37 + 3 6500 +7.8 F Unexplained28. C 37 + 5 3650 +0.7 F Fetal thrombosis29. D 38 + 1 3415 +0.2 F Unexplained30. C 38 + 4 4300 +1.8 F Shoulder dystocia31. D 39 + 2 5000 +3.0 N Heart MF-----------------------------------------------------------------------------------------------------------

  9. Distribution of relative birth weight in IDDM pregnancies with (N=28) or without (N=1465) a perinatal death---------------------------------------------------------------BW z-score Perinatal death(SD-units) No Yes---------------------------------------------------------------< -2.0 3.2 % 43.5 %* -2.0 - +2.0 64.1 % 37.8 %> +2.0 32.7 % 21.7 %---------------------------------------------------------------*p < 0.0001

  10. Last maternal HbA1c before delivery in IDDM pregnancies with (N=28) or without (N=1465) a perinatal death---------------------------------------------------------------Perinatal death No Yes ---------------------------------------------------------------Median 6.8 % 7.6 % p=0.00595 % CI 5.3 - 9.0 5.4 - 12.0Number 1465 28---------------------------------------------------------------

  11. Perinatal mortality in pregestational diabetic pregnancies ---------------------------------------------------------------1. Is increased especially among diabetics with poor glycemic control in the 3rd trimester 2. Over 40% occur before 30 weeks of pregnancy and many of these are growth restricted3. ”Unexplained” fetal deaths after 35 weeks are most likely caused by chronic fetal hypoxia, and hence may be preventable---------------------------------------------------------------

  12. Fetal och neonatal deaths between 32 och 40 pregnancy weeks in Type 1 diabetic pregnancies Hagbard 1956

  13. Stillbirth rate in diabetic and non-diabetic pregnancies according to birth weight in the United States 1995-97 Mondestin et al. AJOG 2002 100 % 10 % 1 % Diabetic 0.1 % Non-diabetic 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 g 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 g Birth weight

  14. Clinical evidence of chronic fetal hypoxia in Type 1 diabetic pregnancies---------------------------------------------------------------1. Increased frequency (12-25%) of abnormal fetal heart rate changes2. Increased frequency of acidosis at birth3. Fetal erytropoietin (EPO) levels are increased 4. Iron stores of fetal tissues are totally depleted in stillbirths5. Fetal deaths are 4-6 times more common than in the background population ---------------------------------------------------------------

  15. Fetal factors causing fetal hypoxia in diabetic pregnancies--------------------------------------------------------------------------1. Fetal oxygen consumption increases during fetal hyperglycemia and hyperinsulinemia2. The fetal oxyhemoglobin dissociation curve is shifted to the right, which tends to decrease placental oxygen transfer3. Fetal polycythemia → increased blood viscosity and reduced capillary blood flow in fetal tissues4. Hypertrophic cardiomyopathy → decreased cardiac output5.Decreased intervillousblood flow (”placental insufficiency”), mainly in diabetic pregnancies complicated by preeclampsia and/or nephropathy

  16. Fetal hyperinsulinemia at constant glucose concentration in chronically catheterized fetal sheep results------------------------------------------------------------------------------------------ in an 83% increase in fetal glucose utilization rate- in a 73% increase in glucose oxidation rate- in a 13% increase in oxygen consumption rate -----------------------------------------------------------------------------------------Hay et al. Quart J Exp Physiol 1986

  17. Osmotic minipump for continuous insulin release placed in the thigh of a fetal Rhesus monkey Susa et al: Diabetes 1979

  18. Chronic hyperinsulinemia without maternal hyperglycemia results in fetal overgrowth in the Rhesus monkey Susa and Schwartz: Diabetes 1985

  19. Umbilical arterial glucose (p<0.03), insulin (p<0.001) and erythropoietin (p<0.001) levels in control (open squares) and hyperinsulinemic (closed triangles) Rhesus fetuses Widness et al. JCI 1981

  20. Arterial oxygen content decreases with increasing fetal insulin concentration in the fetal sheep Milley et al. Am J Obstet Gynecol 1984

  21. Amniotic fluid insulin levels correlate with cord plasma EPO levels at birth in Type 1 diabetic pregnanciesWidness et al. Diabetologia 1990

  22. Negative correlation between fetal arterial O2 content and fetal plasma EPO-concentration in hyperglycemic fetal sheep Philipps et al. Proc Soc Exp Biol Med 1982

  23. Negative correlation between UA pO2 at birth and AF EPO levels in Type 1 diabetic pregnancies (N=152) Teramo et al. Diabetologia 2004 Am EPO (mU/ml) r= -0.62, p<0.0001 Umbilical artery pO2 (mmHg)

  24. Experimental and clinical studies indicate that both maternal hyperglycemia and fetal hyperinsulinemia can independently cause fetal hypoxemia Maternal hyperglycemia Fetal hyperglycemia Fetal hyperinsulinemia Fetal hypoxemia Experimental: Carson eyt al. 1980 Widness et al. 1981 Philipps et al. 1982 Milley et al. 1984 Hay et al. 1986 Human studies: Widness et al. 1981 Widness et al. 1990 Salvesen et al. 1993 Teramo et al. 2004

  25. The fetus adapts to chronic hypoxia ---------------------------------------------------------------1. By redistributing its cardiac output in order to maintain adequate blood supply to the brain, heart and adrenals 2. By increasing EPO synthesis → increasederythropoiesis → increased oxygen carrying capacity (slow process)3. By activating the transcription factor HIF- 1α → regulates tissue oxygenation locally (rapid process)---------------------------------------------------------------

  26. Regulation of EPO and VEGF gene expression by HIF (hypoxia inducable factor): Hypoxia Normoxia PHD and FIH enzymes inactive PHD and FIH enzymes active Hydroxylation Stable HIF-1 alfa HIF-1 alfa - OH Ubiquitylation Proteolysis VEGF and Inactive HIF-1 alfa EPO gene expression ++ Active HIF-1 alfa

  27. FETAL ERYTHROPOIETIN (EPO)---------------------------------------------------------------1. Regulates fetal erythropoiesis 2. Does not cross the placenta (molecular weight 34 kDa)3. EPO is not stored, hence plasma levels reflect rate of synthesis and elimination 4. EPO synthesis occures at least in the yolk sac, liver, kidneys, placenta and brain5. Has also protective properties in the brain (neurones, astrocytes) and in other tissues (retina, heart)---------------------------------------------------------------

  28. Correlation between UV plasma and amniotic fluid EPO levels in IDDM and HT pregnancies HT: r = 0.85, p<0.0001, N = 62 IDDM: r = 0.86, p<0.0001, N = 44 HT IDDM

  29. Correlation between simultaneously obtained AF and fetal plasma EPO levels at different AF EPO concentrations in HT and IDDM pregnancies Low: r= 0.45, p=0.0004 Intermediate: r= -0.09 High: r= 0.73, p=0.00003 High Low Intermed.

  30. Negative correlation between UA pH and AF EPO levels in pregnancies complicated by hypertension Teramo et al. JPM 2004 AF EPO (mU/ml) r = -0.61, p<0.0001, N=64 Umbilical artery pH

  31. Amniotic fluid EPO levels increase exponentially in hypoxic fetuses (panel C) in HT pregnanciesTeramo et al. JPM 2004

  32. Exponentially increasing AF EPO levels in Type 1 diabetic pregnancies. The cross (+) is the AF EPO level one day after the fetus died. Teramo et al. Diabetologia 2004

  33. A 26-year old White’s class C diabetic. AF EPO level increased exponentially. Emergency C/S because of late decelerations. Apgar scores 6/8, birth weight 4485 g (+3.7 SD-units).

  34. Fetal and neonatal complications are more common in Type 1 diabetics with high AF EPO level (>60.0 mU/mL, N=21) than in diabetics with normal AF EPO level (<14.0 mU/mL, N=76) Teramo et al. 2004---------------------------------------------------------------Complication OR 95 % CI p---------------------------------------------------------------Macrosomia 5.4 1.9-15.3 0.0006(BW z-score>2.0 SD)Hypoglycemia 11.3 3.8-33.7 <0.0001Cardiomyopathy 12.5 2.6-59.3 0.0001Hyperbilirubin. 5.9 1.9-18.4 0.0008NICU admission 3.4 1.1-10.8 0.037---------------------------------------------------------------

  35. Positive correlation between mean maternal HbA1c during the last month before delivery and cord plasma EPO levels in Type 1 diabetic pregnancies (r = 0.57, p<0.0001, N = 44) Widness et al. Diabetologia 1990

  36. Positive correlation between last maternal HbA1c and AF EPO levels in Type 1 diabetic pregnancies (N=155)Teramo et al. Diabetologia 2004 Am EPO (mU/ml) r = 0.43, p<0.0001 Hemoglobin A1c (%)

  37. In conclusion, in Type 1 diabetic pregnancies---------------------------------------------------------------1. Chronic intrauterine hypoxia (AF EPO >60.0 mU/ml) occurred in 14% 2. Increased AF EPO levels are associated with increased fetal and neonatal morbidity3. It is possible to identify antenatally cases with high risk of intrauterine hypoxia and neonatal complications by measuring the AF EPO level---------------------------------------------------------------

  38. Why does the fetus increase its EPO level in the plasma and in the amniotic fluid?

  39. Experimental studies show that during hypoxia both endogenous and exogenous EPO has neuroprotective properties in the brain ---------------------------------------------------------------Sakanaka M et al. In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc Natl Acad Sci 1998;95:4635-40Siren AL et al. Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc Natl Acad Sci 2001; 98: 4004-9Chong ZZ et al. Hematopoietic factor erythropoietin fosters neuroprotection through novel signal transduction cascades. J Cerebr Blood Flow Metabol 2002; 22: 503-14Siren AL et al. Global brain atrophy after unilateral parietal lesion and its prevention by erythropoietin. Brain 2006;129:480-9--------------------------------------------------------------------------

  40. swelling,

  41. Clinical studies suggest that exogenous EPO has neuroprotective properties in the brain against hypoxia ---------------------------------------------------------------Ehrenreich H et al. Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med 2002; 8: 495-505Bierer R et al. Erythropoietin concentrations and neurodevelopmental outcome in preterm infants. Pediatrics 2006; 118: e635-4640 --------------------------------------------------------------------------

  42. Protection of neurones during hypoxia-------------------------------------------------------------------------- Hypoxia/ischemiaCytokines/growth factorsHIF-1αEPOVEGFNeuronesEndothelial cells Neuroprotection, Angiogenesis, proliferation, neurotrophic effect, decreasing apoptosis decreasing apoptosis-----------------------------------------------------------------------------------------Marti H: J Exp Biol 2004

  43. EPO concentration in fetal spinal fluid after iv. injection of EPO (5000 IU/kg) in fetal sheep (Juul et al. Biol Neonate 2004)

  44. Umbilical vein to artery concentration ratio of EPO as a function of pO2 in fetal sheep Davis et al. AJOG 2003

  45. The placenta secrets 15 x more EPO than the kidneys during severe hypoxia in the fetal sheep --------------------------------------------------------------Mean secretion of EPO: From the placenta 1.100 000 mU/h From the kidneys 67 400 mU/h------------------------------------------------------------- Davis et al. AJOG 2003

  46. Negative correlation between UV/UA EPO concentration ratio and UA pO2 r = -0.48 p = 0.033 n = 20 UV/UA EPO concentration ratio Umbilical artery pO2 (kPa)

  47. Speculation:---------------------------------------------------------------1. The fetus regulates its erythropoiesis by small changes in EPO synthesis in the liver and the kidneys 2. In severe hypoxia the placenta starts to produce large amounts of EPO in order to protect the fetal brain (and other organs)---------------------------------------------------------------

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