Diabetes mellitus during pregnancy and increased risk of schizophrenia in offspring: a review of the evidence and putative mechanisms.
OBJECTIVE
To identify converging themes from the neurodevelopmental hypothesis of schizophrenia and the pathophysiology of diabetic pregnancy and to examine mechanisms by which diabetes mellitus in a pregnant mother may increase the risk of schizophrenia in offspring.


METHODS
We reviewed relevant publications on clinical, epidemiologic and animal studies of diabetic pregnancy and the neurodevelopmental aspects of schizophrenia.


RESULTS
Epidemiologic studies have shown that the offspring of mothers who experienced diabetes mellitus during their pregnancies are 7 times more likely to develop schizophrenia, compared with those who were not exposed to diabetic pregnancy. Maternal hyperglycemia during pregnancy could predispose to schizophrenia in adult life through at least 3 prenatal mechanisms: hypoxia, oxidative stress and increased inflammation. Hyperglycemia increases oxidative stress, alters lipid metabolism, affects mitochondrial structure, causes derangements in neural cell processes and neuronal architecture and results in premature specialization before neural tube closure. The molecular mechanisms underlying these processes include the generation of excess oxyradicals and lipid peroxide intermediates as well as reductions in levels of polyunsaturated fatty acids that are known to cause increased dopaminergic and lowered gamma-aminobutyric acidergic activity. The combination of hyperglycemia and hypoxia in pregnancy also leads to altered immune function including increased tumour necrosis factor-alpha, C-reactive protein and upregulation of other proinflammatory cytokines. Finally, maternal hyperglycemia could have a lasting impact on fetal cellular physiology, resulting in increased vulnerability to stress and predisposition to schizophrenia via a mechanism known as programming. These prenatal events can also result in obstetric complications such as fetal growth abnormalities and increased susceptibility to prenatal infection, all of which are associated with a spectrum of neurodevelopmental anomalies and an enhanced risk of schizophrenia.


CONCLUSIONS
On the basis of the evidence presented and taking into consideration the projected increases in the rates of diabetes mellitus among younger women of child-bearing potential, it is imperative that the neurodevelopmental sequelae of diabetic pregnancy in general, and the increased risk for schizophrenia in particular, receive further study.
Van Lieshout
Ryan J
RJ
Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada.
Voruganti
Lakshmi P
LP
D002648:Child; D016241:Child of Impaired Parents / Q000706:statistics & numerical data*; D016640:Diabetes, Gestational / Q000453:epidemiology* / Q000503:physiopathology*; D005260:Female; D006801:Humans; D011247:Pregnancy; D011248:Pregnancy Complications / Q000453:epidemiology; D012559:Schizophrenia / Q000453:epidemiology*
Toxicol Lett. 2003 Apr 11;140-141:171-81
12676464
Schizophr Res. 2001 Oct 1;52(1-2):1-19
11595387
Annu Rev Med. 2007;58:49-61
16903799
J Clin Endocrinol Metab. 2004 Nov;89(11):5627-33
15531521
Neuron. 2006 Oct 5;52(1):139-53
17015232
Diabetes Metab Res Rev. 2006 Mar-Apr;22(2):131-8
16170833
Circulation. 2002 Oct 15;106(16):2067-72
12379575
Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15729-34
12438650
Minn Med. 2006 Mar;89(3):44-7
16669433
Am J Psychiatry. 2002 Jul;159(7):1080-92
12091183
Brain Dev. 1986;8(3):269-73
2945494
Arch Gen Psychiatry. 1987 Jul;44(7):660-9
3606332
Brain Res Dev Brain Res. 1998 Aug 8;109(2):201-9
9729385
Int J Dev Neurosci. 1995 Jun-Jul;13(3-4):201-12
7572276
Diabet Med. 2005 Jul;22(7):914-20
15975108
Ginekol Pol. 2001 Dec;72(12A):1255-8
11883260
J Pediatr. 1992 Jul;121(1):109-14
1625067
Semin Pediatr Neurol. 2006 Sep;13(3):158-65
17101454
J Endocrinol Invest. 2005 Oct;28(9):779-86
16370555
Eur J Clin Invest. 2003 Apr;33(4):352-8
12662167
Mol Psychiatry. 2004 Jul;9(7):684-97, 643
15098003
Int J Biochem Cell Biol. 2006;38(5-6):894-903
16118061
Diabetologia. 2004 Jan;47(1):75-81
14634727
Horm Metab Res. 2001 Apr;33(4):227-31
11383927
Science. 2005 Jan 21;307(5708):375-9
15662002
J Pediatr. 1988 Aug;113(2):345-53
3397799
Free Radic Biol Med. 1989;6(5):485-92
2744581
Science. 1992 Aug 28;257(5074):1220-4
1355616
J Neurochem. 1988 Feb;50(2):565-71
2447244
Mol Psychiatry. 1999 Mar;4(2):145-54
10208446
Neurosci Behav Physiol. 1999 Mar-Apr;29(2):217-21
10432512
Schizophr Res. 1996 Mar;19(1):1-17
9147491
Schizophr Res. 1997 Aug 29;26(2-3):227-33
9323355
Curr Opin Clin Nutr Metab Care. 2006 Jul;9(4):388-94
16778567
Am J Epidemiol. 2003 Aug 15;158(4):291-300
12915493
Am J Obstet Gynecol. 1998 Aug;179(2):476-80
9731856
Diabetes Care. 1995 Nov;18(11):1446-51
8722068
Am J Reprod Immunol. 2001 Aug;46(2):161-8
11506081
Anat Rec. 1995 Feb;241(2):255-67
7710141
Schizophr Res. 2003 Nov 1;64(1):25-34
14511798
Schizophr Res. 1997 Apr 11;24(3):365-7
9134598
Psychiatr Clin North Am. 2005 Sep;28(3):613-33, 626
16122570
J Soc Gynecol Investig. 1994 Jan-Mar;1(1):3-13
9419739
Am J Pathol. 1986 Dec;125(3):620-4
2432794
Indian J Exp Biol. 1991 Dec;29(12):1095-100
1816091
Eur Arch Psychiatry Clin Neurosci. 1997;247(4):228-33
9332905
J Psychiatr Res. 1999 Nov-Dec;33(6):513-21
10628528
Neuropsychopharmacology. 2004 Jul;29(7):1221-9
15085088
Schizophr Res. 2002 Oct 1;57(2-3):247-58
12223256
Schizophr Bull. 2006 Jan;32(1):3-8
16306181
Schizophr Res. 2000 Mar 16;42(1):7-17
10706981
Pediatr Res. 2001 Jun;49(6):735-41
11385130
Placenta. 2006 Feb-Mar;27(2-3):327-32
16338477
J Neurosci. 2003 Jan 1;23(1):297-302
12514227
J Autoimmun. 2006 Sep;27(2):71-80
16997531
Eur Psychiatry. 2005 Dec;20 Suppl 4:S335-9
16459247
Teratology. 1985 Dec;32(3):363-73
4082067
Am J Psychiatry. 1998 Mar;155(3):355-64
9501745
Genomics. 1995 Sep 1;29(1):217-24
8530074
Int J Biochem Cell Biol. 2006;38(5-6):794-803
16442834
Diabet Med. 2002 Apr;19(4):322-6
11943005
Psychiatry Res. 1999 Oct 11;87(2-3):129-36
10579546
Obstet Gynecol Clin North Am. 2004 Dec;31(4):907-33, xi-xii
15550342
Brain Res Bull. 2001 Jul 15;55(5):597-610
11576756
Early Pregnancy. 2001 Jan;5(1):57-8
11753515
Schizophr Bull. 2000;26(2):275-86
10885630
Int J Dev Neurosci. 1997 Oct;15(6):711-6
9402221
Am J Psychiatry. 2004 May;161(5):889-95
15121655
Schizophr Bull. 1999;25(3):413-23
10478777
Neuropsychopharmacology. 2002 Feb;26(2):204-15
11790516
Dev Psychobiol. 2005 Mar;46(2):141-53
15732057
Science. 2003 Oct 31;302(5646):822-6
14593167
BMJ. 1991 Oct 26;303(6809):1019-22
1954451
Clin Obstet Gynecol. 1997 Dec;40(4):771-86
9429792
Schizophr Res. 1994 Oct;13(3):217-26
7841134
Diabetes. 1991 Dec;40 Suppl 2:197-201
1748259
Biol Psychiatry. 2001 Nov 15;50(10):743-9
11720692
J Pediatr Endocrinol Metab. 2001;14 Suppl 1:681-9
11393563
Cell Mol Neurobiol. 2002 Feb;22(1):25-33
12064515
Ann Med. 2003;35(2):86-93
12795338
Obstet Gynecol Clin North Am. 1996 Mar;23(1):29-45
8684783
Psychol Bull. 1986 Jul;100(1):43-66
2874579
Biol Psychiatry. 1991 Oct 15;30(8):795-805
1751622
J Natl Med Assoc. 1986 Oct;78(10):963-8
3783750
Schizophr Res. 1998 Jun 22;32(1):9-15
9690329
Br J Psychiatry. 1982 Apr;140:416-20
7093620
Pediatrics. 1990 Jan;85(1):1-9
2404255
J Pediatr. 2003 Nov;143(5):625-9
14615734
J Neurochem. 1995 Dec;65(6):2652-62
7595563
Drug Saf. 1998 Mar;18(3):209-20
9530539
Indian J Exp Biol. 2000 Mar;38(3):231-6
10927864
Trends Neurosci. 1997 Aug;20(8):357-65
9246730
J Neurosci. 2003 Apr 15;23(8):3308-15
12716938
Schizophr Bull. 1984;10(3):430-59
6382590
Am J Psychiatry. 1993 Sep;150(9):1408-10
8102512
Can Fam Physician. 2005 May;51:688-95
15934273
Diabetes Care. 2003 Jan;26 Suppl 1:S5-20
12502614
Ann Allergy Asthma Immunol. 2000 Jan;84(1):37-42
10674563
Arch Gen Psychiatry. 2003 May;60(5):443-56
12742865
J Clin Invest. 1984 Jul;74(1):279-86
6429196
Lancet. 1994 Nov 19;344(8934):1398-402
7968076
Mol Psychiatry. 2006 Jan;11(1):47-55
16189509
Am J Clin Nutr. 1991 Sep;54(3):438-63
1908631
Semin Perinatol. 2002 Jun;26(3):232-6
12099314
J Nutr. 1992 Mar;122(3 Suppl):631-5
1542023
Horm Metab Res. 2005 Jul;37(7):450-4
16034719
Pediatr Res. 2004 Jun;55(6):1034-41
15155871
JAMA. 2005 Aug 3;294(5):557-62
16077049
Schizophr Res. 2001 Jul 1;50(3):169-75
11439237
Arch Gen Psychiatry. 2003 Jul;60(7):709-17
12860775
Am J Clin Nutr. 1989 Sep;50(3 Suppl):618-25; discussion 625-9
2570524
J Pediatr. 1993 Jan;122(1):115-9
8419598
Pediatr Neurol. 2004 Apr;30(4):227-35
15087099
Schizophr Res. 1999 May 4;37(1):97-106
10227112
Brain Behav Immun. 2001 Dec;15(4):411-20
11782107
Biol Psychiatry. 1991 Aug 15;30(4):357-62
1912126
Am J Clin Nutr. 2005 Dec;82(6):1162-8
16332647
Am J Obstet Gynecol. 1994 Apr;170(4):1036-46; discussion 1046-7
8166187
Lancet. 1989 Mar 4;1(8636):495
2563862
Acta Paediatr. 1997 Sep;86(9):969-74
9343277
Mol Psychiatry. 2005 Jan;10(1):40-68; image 5
15263907
Arch Gen Psychiatry. 2002 May;59(5):449-56
11982449
Arch Gen Psychiatry. 1996 Jan;53(1):25-31
8540774
Brain Res. 1994 Apr 18;643(1-2):40-9
7518332
Am J Physiol Regul Integr Comp Physiol. 2007 Jan;292(1):R308-15
16973935
Neurochem Int. 1997 Apr-May;30(4-5):375-83
9106251
Pediatr Endocrinol Rev. 2005 Dec;3(2):104-13
16361984
Dev Neurosci. 1992;14(1):1-10
1350976
Biol Neonate. 2004;85(4):237-42
14718755
Diabetologia. 1993 Mar;36(3):225-8
8462770
J Pediatr. 2000 Dec;137(6):777-84
11113833
J Biol Chem. 1961 Jul;236:2043-9
13761407
Soc Psychiatry Psychiatr Epidemiol. 1998 Aug;33(8):373-9
9708024
Exp Biol Med (Maywood). 2003 Feb;228(2):152-9
12563021
Brain Res. 1986 Feb 5;364(2):377-81
3947975
Biol Neonate. 2001;79(3-4):224-7
11275656
Behav Brain Res. 2006 Jun 30;170(2):224-32
16569441
CNS Drugs. 2001;15(4):287-310
11463134
Lipids. 2000 Aug;35(8):927-31
10984116
Diabet Med. 2000 Mar;17(3):171-80
10784220
Behav Brain Res. 2006 Aug 10;171(2):261-70
16713640
Schizophr Res. 2000 Sep 1;44(3):165-75
10962218
J Pediatr. 2002 Feb;140(2):165-70
11865266
Arch Dis Child Fetal Neonatal Ed. 1998 Sep;79(2):F94-9
9828733