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

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Presentation on theme: "Fetal Hypoxia in Diabetic Pregnancy Kari Teramo, M.D. Department of Obstetrics and Gynecology, University Central Hospital, Helsinki, Finland."— Presentation transcript:

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 Outcome variable Type 1 DM Controls Adjusted OR (95% CI) Singleton births Stillbirth (2.46 – 4.55) Neonatal mortality (1.68 – 5.55) Perinatal mortality (2.50 – 4.33) LGA (≥ 2.0 SD) (10.6 – 12.4) SGA (≤ -2.0 SD) (0.55 – 0.91) Apgar <7 at 5 min (2.14 – 3.17) Erb’s palsy (4.81 – 9.31) RDS (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 Newborn Newborns/ Fetal Neonat. PM infants year deaths deaths % (3.2)* (2.3)* (1.7)* (1.3)* (0.8)* (0.7)* (0.6)* (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 Vuosi

7 Perinatal deaths in pregestational diabetic pregnancies Helsinki UCH No. White’s Gestation Birth weight Fetal/ Comment class (weeks + d) g z-score Neonat B F PROM 2. C F Mult.MF 3. C N RDS 4. B T N RDS 5.B F Preeclampsia 6.D F IVF, twin B 7.C F Unexplained 8.F N RDS 9.R F Pl.abruption 10.C F Pl.abruption 11.D N RDS 12.D F Plac. infarcts 13.F N RDS 14.F N Severe MF

8 Perinatal deaths in pregestational diabetic pregnancies Helsinki UCH, (cont.) No. White’s Gestation Birth weight Fetal/ Comment class (weeks + d) g z-score Neonat B F Cord compl. 16.D F Pl. abruption 17.C F Mat. ketoacid. 18.B F Plac. infarcts 19.B F Unexpl.Twin B 20.D N Sev. dystocia 21.D F Cord compl. 22.C F Unexplained 23.B F Pl. abruption 24.R F Unexplained 25B T F Unexplained 26.C F Unexplained 27.B T F Unexplained 28.C F Fetal thrombosis 29.D F Unexplained 30.C F Shoulder dystocia 31.D 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 % 21.7 % *p <

10 Last maternal HbA 1c 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= % CI Number

11 Perinatal mortality in pregestational diabetic pregnancies 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 restricted 3. ”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 Mondestin et al. AJOG g 100 % 10 % 1 % 0.1 % Diabetic Non-diabetic Birth weight

14 Clinical evidence of chronic fetal hypoxia in Type 1 diabetic pregnancies Increased frequency (12-25%) of abnormal fetal heart rate changes 2. Increased frequency of acidosis at birth 3. Fetal erytropoietin (EPO) levels are increased 4. Iron stores of fetal tissues are totally depleted in stillbirths 5. Fetal deaths are 4-6 times more common than in the background population

15 Fetal factors causing fetal hypoxia in diabetic pregnancies Fetal oxygen consumption increases during fetal hyperglycemia and hyperinsulinemia 2. The fetal oxyhemoglobin dissociation curve is shifted to the right, which tends to decrease placental oxygen transfer 3. Fetal polycythemia → increased blood viscosity and reduced capillary blood flow in fetal tissues 4. Hypertrophic cardiomyopathy → decreased cardiac output 5. Decreased intervillous blood 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 pregnancies Widness et al. Diabetologia 1990

22 Negative correlation between fetal arterial O 2 content and fetal plasma EPO-concentration in hyperglycemic fetal sheep Philipps et al. Proc Soc Exp Biol Med 1982

23 Negative correlation between UA pO 2 at birth and AF EPO levels in Type 1 diabetic pregnancies (N=152) Teramo et al. Diabetologia 2004 Am EPO (mU/ml) Umbilical artery pO 2 (mmHg) r= -0.62, p<0.0001

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

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

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

27 FETAL ERYTHROPOIETIN (EPO) 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 brain 5. Has also protective properties in the brain (neurones, astrocytes) and in other tissues (retina, heart)

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

30 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= Intermediate: r= High: r= 0.73, p= High Low Intermed.

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

32 Amniotic fluid EPO levels increase exponentially in hypoxic fetuses (panel C) in HT pregnancies Teramo et al. JPM 2004

33 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

34 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).

35 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 ( 2.0 SD) Hypoglycemia < Cardiomyopathy Hyperbilirubin NICU admission

36 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

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

38 In conclusion, in Type 1 diabetic pregnancies Chronic intrauterine hypoxia (AF EPO >60.0 mU/ml) occurred in 14% 2. Increased AF EPO levels are associated with increased fetal and neonatal morbidity 3. It is possible to identify antenatally cases with high risk of intrauterine hypoxia and neonatal complications by measuring the AF EPO level

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

41 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: Siren AL et al. Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc Natl Acad Sci 2001; 98: Chong ZZ et al. Hematopoietic factor erythropoietin fosters neuroprotection through novel signal transduction cascades. J Cerebr Blood Flow Metabol 2002; 22: Siren AL et al. Global brain atrophy after unilateral parietal lesion and its prevention by erythropoietin. Brain 2006;129:

42 swelling,

43 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: Bierer R et al. Erythropoietin concentrations and neurodevelopmental outcome in preterm infants. Pediatrics 2006; 118: e

44 Protection of neurones during hypoxia Hypoxia/ischemiaCytokines/growth factors HIF-1 α EPO VEGF Neurones Endothelial cells Neuroprotection, Angiogenesis, proliferation, neurotrophic effect,decreasing apoptosis decreasing apoptosis Marti H: J Exp Biol 2004

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

46 Umbilical vein to artery concentration ratio of EPO as a function of pO 2 in fetal sheep Davis et al. AJOG 2003

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

48 UV/UA EPO concentration ratio Negative correlation between UV/UA EPO concentration ratio and UA pO2 Umbilical artery pO2 (kPa) r = p = n = 20

49 Speculation: 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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