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February 13, 1991, Vol 265, No. 6 >
ARTICLE | February 13, 1991

Preconception Care of Diabetes: Title and subTitle BreakGlycemic Control Prevents Congenital Anomalies FREE

John L. Kitzmiller, MD; Laurence A. Gavin, MD; Gary D. Gin, MD, MPH; Lois Jovanovic-Peterson, MD; Elliott K. Main, MD; William D. Zigrang, MD
[+] Author Affiliations

Reprint requests to Department of Obstetrics, Gynecology, and Reproductive Services, University of California School of Medicine, Room M-1489, San Francisco, CA 94143 (Dr Kitzmiller).


JAMA. 1991;265(6):731-736. doi:10.1001/jama.1991.03460060063025
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References

To test the value of intensive management of diabetes before and during early pregnancy, 84 women recruited prior to conception were compared with 110 women who were already pregnant referred at 6 to 30 weeks' gestation. All underwent daily measurement of fasting and postprandial capillary blood glucose levels. Mean blood gluose levels during embryogenesis and organogenesis were within 3.3 to 7.8 mmol/L in 50% of preconception subjects and exceeded 10 mmol/L in 6.5%. One major congenital anomaly occurred in 84 infants (1.2%) of women treated before conception compared with 12 anomalies in 110 infants (10.9%) of mothers in the postconception group. Transient symptomatic hypoglycemia occurred during embryogenesis in 60% of women in the preconception group, with a median frequency of 2.7 episodes per week, but was not associated with excess malformations. We conclude that education and intensive management for glycemic control of diabetic women before and during early pregnancy will prevent excess rates of congenital anomalies in their infants.

(JAMA. 1991;265:731-736)

REFERENCES

1 +
Kitzmiller JL, Cloherty JP, Younger MD, et al.  Diabetic pregnancy and perinatal morbidity . Am J Obstet Gynecol. 1978;;131:560-580.
2 +
Gabbe SG.  Congenital malformations in infants of diabetic mothers . Obstet Gynecol Surv. 1977;; 32:125-131.
3 +
Cousins L.  Congenital anomalies among infants of diabetic mothers: etiology, prevention, diagnosis . Am J Obstet Gynecol. 1983;;147:333-338.
4 +
Mills JL, Baker L, Goldman AS.  Malformations in infants of diabetic mothers occur before the seventh gestational week: implications for treatment . Diabetes . 1979;;28:292-293.
5 +
Pedersen J. The Pregnant Diabetic and Her Newborn . 2nd ed. Baltimore, Md: Williams & Wilkins; 1977;.
6 +
Karlsson K, Kjellmer I.  The outcome of diabetic pregnancies in relation to the mother's blood sugar level . Am J Obstet Gynecol. 1972;;112:213-220.
7 +
Leslie RDG, Pyke DA, John PN, White JM.  Haemoglobin A1 in diabetic pregnancy . Lancet . 1978;;2:958-959.
8 +
Miller E, Hare JW, Cloherty JP, et al.  Elevated maternal hemoglobin A1c in early pregnancy and major congenital anomalies in infants of diabetic mothers . N Engl J Med. 1981;;304:1331-1334.
9 +
Ylinen K, Aula P, Stenman U-H, et al.  Risk of minor and major fetal malformations in diabetes with high haemoglobin A1c values in early pregnancy . BMJ . 1984;;289:345-346.
10 +
Key TC, Guiffrida R, Moore TR.  Predictive value of early pregnancy glycohemoglobin in the insulin treated diabetic patient . Am J Obstet Gynecol. 1987;;156:1096-1100.
11 +
Miodovnik M, Mimouni F, Dignam PS.  Major malformations in infants of IDDM women: vasculopathy and early first-trimester poor glycemic control . Diabetes Care . 1988;;11:713-718.
12 +
Greene MF, Hare JW, Cloherty JP, et al.  Firsttrimester hemoglobin A1 and risk of major malformation and spontaneous abortion in diabetic pregnancy . Teratology . 1989;;39:225-231.
13 +
Mills JL, Knopp RH, Simpson JL, et al.  Lack of relation of increased malformation rates in infants of diabetic mothers to glycemic control during organogenesis . N Engl J Med. 1988;;318:671-676.
14 +
Hare JW, White P.  Gestational diabetes and the White classification . Diabetes Care . 1980;;3: 294-295.
15 +
Piaquadio K, Hollingsworth D, Murphy H.  Fetal malformation following first trimester use of oral hypoglycemic agents . Diabetes . 1990;;39( (suppl 1) ):123A.
16 +
Kitzmiller JL, Gavin LA, Gin GD, et al.  Managing diabetes and pregnancy . Curr Probl Obstet Gynecol Fertil. 1988;;11:107-167.
17 +
Kitzmiller JL, Younger DM, Hare J, et al.  Continuous subcutaneous infusion therapy during early pregnancy . Obstet Gynecol. 1985;;66:1177-1182.
18 +
Sosenko JM, Kitzmiller JL, Fluckiger R, Loos SWH, Younger D, Gabbay KH.  Umbilical cord glycosylated hemoglobin in infants of diabetic mothers: relationships to neonatal hypoglycemic, macrosomia, and cord serum C-peptide . Diabetes Care. 1982;;5:566-570.
19 +
Fuhrmann K, Reiher H, Semmler K, et al.  Prevention of congenital malformations in infants of insulin-dependent diabetic mothers . Diabetes Care. 1983;;6:219-223.
20 +
Goldman JA, Dicker D, Feldberg D, et al.  Pregnancy outcome in patients with insulin-dependent diabetes mellitus with preconceptional diabetic control: a comparative study . Am J Obstet Gynecol. 1986;;155:293-297.
21 +
Damm P, Mølsted-Pedersen L.  Significant decrease in congenital malformations in newborn infants of an unselected population of diabetic women . Am J Obstet Gynecol. 1989;;161:1163-1167.
22 +
Mills JL, Simpson JL, Driscoll SG, et al.  Incidence of spontaneous abortion among normal women and insulin-dependent diabetic women whose pregnancies were identified within 21 days of conception . N Engl J Med. 1988;;319:1617-1623.
23 +
Crockroft DL, Coppola PT.  Teratogenic effects of excess glucose on head-fold rat embryos in culture . Teratology . 1977;;16:141-146.
24 +
Sadler TW.  Effects of maternal diabetes on early embryogenesis, II: hyperglycemia-induced exencephaly . Teratology . 1980;;21:349-356.
25 +
Eriksson UJ. Importance of genetic predisposition and maternal environment for the occurrence of congenital malformation in offspring of diabetic rats. Teratology. 1988;;37:365-374.
26 +
Freinkel N, Cockroft DL, Lewis NJ, et al.  Fuelmediated teratogenesis during early organogenesis: the effects of increased concentrations of glucose, ketones, or somatomedin inhibitor during rat embryo culture . Am J Clin Nutr. 1986;;44:986-995.
27 +
Goldman AS, Baker L, Piddington R, et al.  Hyperglycemia-induced teratogenesis is mediated by a functional deficiency of arachidonic acid . Proc Natl Acad Sci U S A . 1985;;82:8227-8231.
28 +
Pinter E, Reece EA, Leranth C, et al.  Arachidonic acid prevents hyperglycemia associated yolk sac damage and embryopathy . Am J Obstet Gynecol. 1986;;155:691-702.
29 +
Hod M, Star S, Passonneau JV, et al.  Effect of hyperglycemia on sorbitol and myo-inositol content of cultured rat conceptus: failure of aldose reductase inhibitors to modify myo-inositol depletion and dysmorphogenesis . Biochem Biophys Res Comm. 1986;;140:974-980.
30 +
Sussman I, Matschinsky FM.  Diabetes affects sorbitol and myo-inositol levels of neuroectodermal tissue during embryogenesis in rat . Diabetes . 1988;;37:974-981.
31 +
Horton WE Jr, Sadler TW.  Effects of maternal diabetes on early embryogenesis: alterations in morphogenesis produced by the ketone body, β-hydroxybutyrate . Diabetes . 1983;;32:610-616.
32 +
Hunter ES III, Sadler TW, Wynn RE.  A potential mechanism of DL-β-hydroxybutyrate-induced malformations in mouse embryos . Am J Physiol. 1987;;253:E72-E80.
33 +
Sadler TW, Hunter ES III, Wynn RE, Phillips LS.  Evidence of multifactorial origin of diabetesinduced embryopathies . Diabetes . 1989;;38:70-74.
34 +
Freinkel N, Lewis NJ, Akazawa S, et al.  The honeybee syndrome: implications of the teratogenicity of mannose in rat-embryo . N Engl J Med. 1984;;310:223-230.
35 +
Buchanan TA, Schemmer JK, Freinkel N.  Embryotoxic effects of brief maternal insulin-hypoglycemia during organogenesis in the rat . J Clin Invest. 1986;;78:643-649.
36 +
Akazawa M, Akazawa S, Hashimoto M, et al.  Effects of brief exposure to insulin-induced hypoglycemic serum during organogenesis in rat embryo culture . Diabetes . 1989;;38:1573-1578.
37 +
Buchanan TA, Sipos GF.  Lack of teratogenic effect of brief maternal insulin-induced hypoglycemia in rats during late neurulation . Diabetes . 1989;;38:1063-1066.
38 +
Steel JM, Johnstone FD, Hepburn DA, Smith AF.  Can pregnancy care of diabetic women reduce the risk of abnormal babies? BMJ . 1990;;301:1070-1074.

Figures

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Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
Kitzmiller JL, Cloherty JP, Younger MD, et al.  Diabetic pregnancy and perinatal morbidity . Am J Obstet Gynecol. 1978;;131:560-580.
2 +
Gabbe SG.  Congenital malformations in infants of diabetic mothers . Obstet Gynecol Surv. 1977;; 32:125-131.
3 +
Cousins L.  Congenital anomalies among infants of diabetic mothers: etiology, prevention, diagnosis . Am J Obstet Gynecol. 1983;;147:333-338.
4 +
Mills JL, Baker L, Goldman AS.  Malformations in infants of diabetic mothers occur before the seventh gestational week: implications for treatment . Diabetes . 1979;;28:292-293.
5 +
Pedersen J. The Pregnant Diabetic and Her Newborn . 2nd ed. Baltimore, Md: Williams & Wilkins; 1977;.
6 +
Karlsson K, Kjellmer I.  The outcome of diabetic pregnancies in relation to the mother's blood sugar level . Am J Obstet Gynecol. 1972;;112:213-220.
7 +
Leslie RDG, Pyke DA, John PN, White JM.  Haemoglobin A1 in diabetic pregnancy . Lancet . 1978;;2:958-959.
8 +
Miller E, Hare JW, Cloherty JP, et al.  Elevated maternal hemoglobin A1c in early pregnancy and major congenital anomalies in infants of diabetic mothers . N Engl J Med. 1981;;304:1331-1334.
9 +
Ylinen K, Aula P, Stenman U-H, et al.  Risk of minor and major fetal malformations in diabetes with high haemoglobin A1c values in early pregnancy . BMJ . 1984;;289:345-346.
10 +
Key TC, Guiffrida R, Moore TR.  Predictive value of early pregnancy glycohemoglobin in the insulin treated diabetic patient . Am J Obstet Gynecol. 1987;;156:1096-1100.
11 +
Miodovnik M, Mimouni F, Dignam PS.  Major malformations in infants of IDDM women: vasculopathy and early first-trimester poor glycemic control . Diabetes Care . 1988;;11:713-718.
12 +
Greene MF, Hare JW, Cloherty JP, et al.  Firsttrimester hemoglobin A1 and risk of major malformation and spontaneous abortion in diabetic pregnancy . Teratology . 1989;;39:225-231.
13 +
Mills JL, Knopp RH, Simpson JL, et al.  Lack of relation of increased malformation rates in infants of diabetic mothers to glycemic control during organogenesis . N Engl J Med. 1988;;318:671-676.
14 +
Hare JW, White P.  Gestational diabetes and the White classification . Diabetes Care . 1980;;3: 294-295.
15 +
Piaquadio K, Hollingsworth D, Murphy H.  Fetal malformation following first trimester use of oral hypoglycemic agents . Diabetes . 1990;;39( (suppl 1) ):123A.
16 +
Kitzmiller JL, Gavin LA, Gin GD, et al.  Managing diabetes and pregnancy . Curr Probl Obstet Gynecol Fertil. 1988;;11:107-167.
17 +
Kitzmiller JL, Younger DM, Hare J, et al.  Continuous subcutaneous infusion therapy during early pregnancy . Obstet Gynecol. 1985;;66:1177-1182.
18 +
Sosenko JM, Kitzmiller JL, Fluckiger R, Loos SWH, Younger D, Gabbay KH.  Umbilical cord glycosylated hemoglobin in infants of diabetic mothers: relationships to neonatal hypoglycemic, macrosomia, and cord serum C-peptide . Diabetes Care. 1982;;5:566-570.
19 +
Fuhrmann K, Reiher H, Semmler K, et al.  Prevention of congenital malformations in infants of insulin-dependent diabetic mothers . Diabetes Care. 1983;;6:219-223.
20 +
Goldman JA, Dicker D, Feldberg D, et al.  Pregnancy outcome in patients with insulin-dependent diabetes mellitus with preconceptional diabetic control: a comparative study . Am J Obstet Gynecol. 1986;;155:293-297.
21 +
Damm P, Mølsted-Pedersen L.  Significant decrease in congenital malformations in newborn infants of an unselected population of diabetic women . Am J Obstet Gynecol. 1989;;161:1163-1167.
22 +
Mills JL, Simpson JL, Driscoll SG, et al.  Incidence of spontaneous abortion among normal women and insulin-dependent diabetic women whose pregnancies were identified within 21 days of conception . N Engl J Med. 1988;;319:1617-1623.
23 +
Crockroft DL, Coppola PT.  Teratogenic effects of excess glucose on head-fold rat embryos in culture . Teratology . 1977;;16:141-146.
24 +
Sadler TW.  Effects of maternal diabetes on early embryogenesis, II: hyperglycemia-induced exencephaly . Teratology . 1980;;21:349-356.
25 +
Eriksson UJ. Importance of genetic predisposition and maternal environment for the occurrence of congenital malformation in offspring of diabetic rats. Teratology. 1988;;37:365-374.
26 +
Freinkel N, Cockroft DL, Lewis NJ, et al.  Fuelmediated teratogenesis during early organogenesis: the effects of increased concentrations of glucose, ketones, or somatomedin inhibitor during rat embryo culture . Am J Clin Nutr. 1986;;44:986-995.
27 +
Goldman AS, Baker L, Piddington R, et al.  Hyperglycemia-induced teratogenesis is mediated by a functional deficiency of arachidonic acid . Proc Natl Acad Sci U S A . 1985;;82:8227-8231.
28 +
Pinter E, Reece EA, Leranth C, et al.  Arachidonic acid prevents hyperglycemia associated yolk sac damage and embryopathy . Am J Obstet Gynecol. 1986;;155:691-702.
29 +
Hod M, Star S, Passonneau JV, et al.  Effect of hyperglycemia on sorbitol and myo-inositol content of cultured rat conceptus: failure of aldose reductase inhibitors to modify myo-inositol depletion and dysmorphogenesis . Biochem Biophys Res Comm. 1986;;140:974-980.
30 +
Sussman I, Matschinsky FM.  Diabetes affects sorbitol and myo-inositol levels of neuroectodermal tissue during embryogenesis in rat . Diabetes . 1988;;37:974-981.
31 +
Horton WE Jr, Sadler TW.  Effects of maternal diabetes on early embryogenesis: alterations in morphogenesis produced by the ketone body, β-hydroxybutyrate . Diabetes . 1983;;32:610-616.
32 +
Hunter ES III, Sadler TW, Wynn RE.  A potential mechanism of DL-β-hydroxybutyrate-induced malformations in mouse embryos . Am J Physiol. 1987;;253:E72-E80.
33 +
Sadler TW, Hunter ES III, Wynn RE, Phillips LS.  Evidence of multifactorial origin of diabetesinduced embryopathies . Diabetes . 1989;;38:70-74.
34 +
Freinkel N, Lewis NJ, Akazawa S, et al.  The honeybee syndrome: implications of the teratogenicity of mannose in rat-embryo . N Engl J Med. 1984;;310:223-230.
35 +
Buchanan TA, Schemmer JK, Freinkel N.  Embryotoxic effects of brief maternal insulin-hypoglycemia during organogenesis in the rat . J Clin Invest. 1986;;78:643-649.
36 +
Akazawa M, Akazawa S, Hashimoto M, et al.  Effects of brief exposure to insulin-induced hypoglycemic serum during organogenesis in rat embryo culture . Diabetes . 1989;;38:1573-1578.
37 +
Buchanan TA, Sipos GF.  Lack of teratogenic effect of brief maternal insulin-induced hypoglycemia in rats during late neurulation . Diabetes . 1989;;38:1063-1066.
38 +
Steel JM, Johnstone FD, Hepburn DA, Smith AF.  Can pregnancy care of diabetic women reduce the risk of abnormal babies? BMJ . 1990;;301:1070-1074.

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