Fetal factors causing fetal hypoxia in diabetic pregnancies

49 slides
10.16 MB
783 views

Similar Presentations

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 1991 - 2003 ------------------------------------------------------------------------------------------ Outcome variable Type 1 DM Controls Adjusted OR (95% CI) ------------------------------------------------------------------------------------------ Singleton births 5.089 1.260.207 Stillbirth 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. PM infants year 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 PROM 2. C 25 + 1 370 -5.0 F Mult.MF 3. C 25 + 1 500 -4.4 N RDS 4. B T2 25 + 2 725 -2.8 N RDS 5. B 26 + 0 440 -4.5 F Preeclampsia 6. D 26 + 1 650 -2.8 F IVF, twin B 7. C 26 + 3 830 -1.5 F Unexplained 8. F 26 + 4 785 -2.1 N RDS 9. R 27 + 2 1160 -0.4 F Pl.abruption 10. C 27 + 4 400 -5.3 F Pl.abruption 11. D 28 + 4 705 -3.8 N RDS 12. D 29 + 2 1195 -1.3 F Plac. infarcts 13. F 30 + 1 810 -3.9 N RDS 14. F 30 + 1 1900 +1.7 N Severe MF -------------------------------------------------------------------------------------------------

8

Perinatal deaths in pregestational diabetic pregnancies Helsinki 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. abruption 17. C 31 + 5 2160 +1.3 F Mat. ketoacid. 18. B 33 + 6 1350 -3.4 F Plac. infarcts 19. B 34 + 4 2310 -0.9 F Unexpl.Twin B 20. D 35 + 4 4100 +3.4 N Sev. dystocia 21. D 35 + 5 3150 +0.7 F Cord compl. 22. C 36 + 0 4030 +2.9 F Unexplained 23. B 36 + 1 2250 -1.8 F Pl. abruption 24. R 36 + 3 4630 +4.5 F Unexplained 25 B T2 36 + 4 5600 +6.4 F Unexplained 26. C 36 + 6 2990 -0.5 F Unexplained 27. B T2 37 + 3 6500 +7.8 F Unexplained 28. C 37 + 5 3650 +0.7 F Fetal thrombosis 29. D 38 + 1 3415 +0.2 F Unexplained 30. C 38 + 4 4300 +1.8 F Shoulder dystocia 31. 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=0.005 95 % CI 5.3 - 9.0 5.4 - 12.0 Number 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 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 1995-97 Mondestin et al. AJOG 2002 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 g 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 g 100 %10 %1 %0.1 %DiabeticNon-diabeticBirth weight

14

Clinical evidence of chronic fetal hypoxia in Type 1 diabetic pregnancies ---------------------------------------------------------------1. 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 -------------------------------------------------------------------------- 1. 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 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 2004Am EPO (mU/ml) Umbilical artery pO2 (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 hypoxemiaMaternal hyperglycemiaFetal hyperglycemiaFetal hyperinsulinemia 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 → increased erythropoiesis → 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): NormoxiaHypoxiaHydroxylationHIF-1 alfa - OH Inactive HIF-1 alfaUbiquitylation ProteolysisPHD and FIH enzymes activePHD and FIH enzymes inactive Stable HIF-1 alfaActive HIF-1 alfa EPO gene expression ++VEGF and

Browse More Presentations

Last Updated: 8th March 2018

Recommended PPTs