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Vascular complications in diabetic pregnancy
Thrombosis Research 127 Suppl. 3 (2011) S53–S55
Contents lists available at ScienceDirect
Thrombosis Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / t h r o m r e s
Vascular complications in diabetic pregnancy R. Kaaja* Obstetric physician, Professor in Medicine, Turku University/ Satakunta Central Hospital, Finland
article info
abstract
Keywords: Type 1 and 2 diabetes Pregnancy Microangiopathy Macroangiopathy Vascular complications
Until now, vascular complications in diabetic pregnancy are mainly related to hyperglycemia caused by type 1 diabetes (Type 1 DM). Progression of diabetic retinopathy (DR) occurs at least temporarily during pregnancy and postpartum. There is a short-term increase in the level of retinopathy during pregnancy that persisted into the first year postpartum. Nephropathy is associated with increased risk of preeclampsia, nephrotic syndrome, preterm delivery, fetal growth restriction, and perinatal mortality [1]. Presence of retinopathy increases also risk of preeclampsia and also poor glycemic control. The pregnancy itself (first or subsequent) is not a long-term risk factor for developing microalbuminuria, any retinopathy, proliferative retinopathy, or neuropathy. The prevalence of type 2 diabetes (Type 2 DM) is rising leading to similar or even worse pregnancy outcome than in T1 DM. Micro- and macroangiopathic complications still rather rare in the mother will also become more prevalent with increasing age, obesity and more severe forms of Type 2 DM. Good glycemic control, normotension, lack of nephropathy as well as lack of pre-proliferative/proliferative changes of diabetic retinopathy and lack of signs of macroangiopathies are good prognostic factors as regards the progression of vascular complications during pregnancy. Women with diabetes should be evaluated before pregnancy for microangiopathies, treated and followed closely during pregnancy by obstetrician, internist/diabetologue, cardiologist and ophthalmologist and nephrologist. © 2011 Elsevier Ltd. All rights reserved.
Introduction Type 1 DM complicates approximately 0.3–0.5% of all pregnancies and both are associated with an increased risk of adverse outcome to the mother and fetus [1]. The high prevalence of obesity and sedentary lifestyle in the population, compounded by later child bearing, has led to an increase in the prevalence of Type 2 DM pre-dating pregnancy. In some centers, pregnant women with Type 2 DM now outnumber those with type 1 DM [2]. Determining the risks of maternal type 1 and type 2 DM in pregnancy requires a full assessement of maternal vascular diasease, including examination for microangiopathies (nephropathy and retinopathy) mainly for type 1 DM and macroangiopathies (for example coronary artery disease) mainly for type 2 DM. It could be expected that pregnancy as a state of hypervolemia, hypercoagulability, insulin resistance and “milieu of growth” could induce worsening of diabetic retinopathy and nephropathy. The clinical picture is, however, less alarming especially in long-term. Although there is controversy as to whether type 2 DM is associated with worse outcomes than type 1 DM in pregnancy, modern reports clearly acknowledge the seriousness of this condition [2]. This short review * Correspondence: Risto Kaaja, MD. Department of Obstetrics and Gynecology, Helsinki University Hospital, Haartmaninkatu 2, Helsinki FIN-00290, Finland. Tel.: +358 9 471 72850; fax: +358 9 471 72812. E-mail address: risto.kaaja@hus.fi (R. Kaaja). 0049-3848 /$ – see front matter © 2011 Elsevier Ltd. All rights reserved.
will focus on the short- and long-term effectct of pregnancy on diabetes microangiopathies and vice-versa. Progression of diabetic retinopathy during pregnancy Progression of diabetic retinopathy (DR) occurs at least temporarily during pregnancy and postpartum. The pathogenetic mechanisms of DR progression during pregnancy are not fully understood. Several factors related to metabolic changes (hyperglycaemia), diabetes itself (duration of diabetes before conception, baseline status of DR), pregnancy physiology (hypervolaemia and hypercoagulation, impaired retinal autoregulation) and pregnancy complications (preeclampsia) seem to play important roles in the progression of DR during pregnancy. One of the largest prospective studies to assess the effect of pregnancy on the development and progression of diabetic retinopathy [3] showed that in both intensive and conventional treatment groups, there was a short-term increase in the level of retinopathy during pregnancy that persisted into the first year postpartum; the conventional group was somewhat more affected by pregnancy than the intensive group. A minor effect of rapid improvement of glycemic control on worsening of retinopathy confirmed earlier findings [4]. Good glycemic control, normotension, lack of nephropathy as well as lack of preproliferative/proliferative changes of DR are good prognostic factors as regards the progression of DR during pregnancy [5]. Women with type 1 diabetes must be followed closely by an experienced retina
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R. Kaaja / Thrombosis Research 127 (2011) S53–S55
specialist during pregnancy. This adverse effect of pregnancy on retinal status persists into the first year postpartum, and increased retinal surveillance by a retina specialist should be continued during the first year. Fortunately, the effect of pregnancy is relatively transient; most changes revert to prepregnancy levels after a year or more [3]. Progression of diabetic nephropathy during pregnancy Nephropathy complicates 5% to 10% of pregnancies in women who have diabetes mellitus and is associated with increased risk of preeclampsia, nephrotic syndrome, preterm delivery, fetal growth restriction, and perinatal mortality [1]. The degree of renal impairment and proteinuria in early pregnancy predict pregnancy complications in women with diabetic nephropathy. The risk for pre-eclaampsia increases with severity of proteinuria: diabetic women with microalbuminuria (dU-albumin 30–300 mg) and macroalbuminuria (dU-albumin >300 mg) have preeclampsia in 42% and 64% of the cases [6]. Suboptimal control of hypertension in early pregnancy, which can be directly treated, has not been evaluat as ed a predictor of adverse perinatal outcome. Maximizing blood pressure and diabetes control before pregnancy may improve perinatal outcome in women with diabetic nephropathy [7]. Diabetic microangiopathy and pregnancy outcome Although women with prevalent vascular disease are often older and had a longer duration of diabetes the maternal vascular disease significantly and adversely affects pregnancy outcome. As mentioned above diabetic nephropathy is the most significant risk factor for pre-eclampsia [6]. In a recent study [1] it was noted that the presence of retinopathy alone was independently associated with an increased risk of pre-eclampsia, particularly as retinopathy is almost universal beyond 20 years of diabetes. Macrosomia is the expected outcome in babies born to women with uncomplicated type 1 DM. In contrast, in women with vascular disease, the the babies have more often problems related to intrauterine growth retardation (IUGR) most often associated to preeclampsia. This suggests that maternal diabetes and vascular disease provide an even poorer intrauterine environment: a double hit that restricts macrosomia to falsely ’normalize’ growth. This reinforces the need for frequent assessment of fetal well-being. Pre-eclampsia has been, beside vascular disease, significantly and positively associated with HbA1c values in the second and third trimester [1]. Pre-eclampsia on the other hand could affect the progression of diabetic nephropathy but interestingly not pregnancy-induced hypertension [8]. Type 2 diabetes is a growing concern, with the number of new cases increasing and occurring at a younger age due to obesity. Type 2 DM is often perceived as a benign form of diabetes, but this is not the case when one examines pregnancy outcomes [9]. Rates of perinatal mortality (25/1000) and congenital malformation (99/1000) are significantly greater than those in background populations and at least as poor as those in type 1 diabetes. The rates of hypertension, pre-eclampsia and postpartum haemorrhage are greater than the general maternity population, as is the rate of operative delivery [10]. Long-term effects of pregnancy on diabetic micro- and macroangiopathies Some older studies, where blood pressure was less well controlled, pregnancy accelerated renal insufficiency in patients with preexisting renal impairment. Recent studies with a follow-up up to 16-years and intensive hypertensive treatment found no adverse long-term impact of pregnancy on kidney function and survival. The EURODIAB Prospective Complications Study involved a large
European-wide cohort of individuals with Type 1 DM with standardized measures of both risk factors and outcomes [11]. At baseline, parous women had a lower prevalence of retinopathy and a similar prevalence of microalbuminuria when compared with nulliparous women. However glycaemic control was better in the parous women. The authors examined prospectively the relationship between pregnancy and the incidence or progression of microvascular complications over a mean follow-up period of 7.3 years. The study confirmed earlier studies [3,12] that pregnancy itself (first or subsequent) was not a risk factor for developing microalbuminuria, any retinopathy, proliferative retinopathy, or neuropathy, several years post-partum. These findings have practical implications for counselling young women in planning their pregnancies. However, in current practice, women having experienced a worsening of their retinopathy during pregnancy are often counselled not to have another pregnancy [11]. Endothelial dysfunction, an early marker of macrovascular disease, is present in pregnancies complicated by type 2 DM, glucose intolerance and gestational diabetes. This alteration seems to be directly related to glycemic levels but also to dyslipidemia and hypertension, which can precede the type 2 DM [13]. Interestingly hypertensive pregnancy disorders are strongly associated with subsequent type 2 diabetes mellitus and hypertension, the latter independent of subsequent type 2 diabetes mellitus. The severity, parity, and recurrence of these hypertensive pregnancy disorders increase the risk of subsequent cardiovascular events [14]. A history of gestational diabetes (GDM) significantly increases the risk of developing type 2 diabetes, an independent risk factor for cardiovascular disease (CVD). Nondiabetic women with prior GDM have evidence of subclinical inflammation, hypoadiponectinemia, and early vascular dysfunction; this population may be at increased risk of developing CVD [15]. Conclusions Determining the risks of maternal type 1 and 2 DM in pregnancy requires a full assessment of maternal vascular disease, including examination for nephropathy, retinopathy, dyslipidemia and hypertension. The presence of one or more of these factors should prompt a cautious appraisal of the risks of pregnancy. The level of glycemic control achieved during pregnancy seems to modify this risk downward. Younger women with fewer vascular complications and good glycaemic control are, unsurprisingly, less likely to suffer an adverse outcome during pregnancy. Type 2 DM is often perceived as a benign form of diabetes, but rates of perinatal mortality and congenital malformation are significantly greater than those in background populations and at least as poor as those in type 1 DM. Fortunately until now clinical macrovascular complications are still rare. Conflict of Interest Statement There are no conflicts of interest. References [1] Howarth C, Gazis A, James D. Associations of Type 1 diabetes mellitus, maternal vascular disease and complications of pregnancy. Diabet Med 2007;24:1229–34. [2] McIntyre HD, Thomae MK, Wong SF, Idris N, Callaway LK. Pregnancy in type 2 diabetes mellitus – problems & promises. Curr Diabetes Rev 2009;3:190–200. [3] The Diabetes Control and Complications Trial Research Group. Effect of pregnancy on microvascular complications in the Diabetes Control and Complications Trial. Diabetes Care 2000;23:1084–91. [4] Laatikainen L, Teramo K, Hieta-Heikurainen H, Koivisto V, Pelkonen R. A controlled study on the influence of continuous subcutaneous insulin infusion treatment on diabetic retinopathy during pregnancy. Acta Med Scand 1987;221(4):367–76. [5] Kaaja R, Loukovaara S. Progression of retinopathy in type 1 diabetic women during pregnancy. Curr Diabetes Rev 2007;3:85–93.
R. Kaaja / Thrombosis Research 127 (2011) S53–S55 [6] Ekbom P, Damm P, Feldt-Rasmussen B, Molvig J, Mathiesen ER. Pregnancy outcome in type 1 diabetic women with microalbuminuria. Diabetes Care 2001;24:1739–44. [7] Nielsen LR, Damm P, Mathiesen ER.Improved pregnancy outcome in type 1 diabetic women with microalbuminuria or diabetic nephropathy: effect of intensified antihypertensive therapy? Diabetes Care 2009;32(1):38–44. [8] Gordin D, Hiilesmaa V, Fagerudd J, Ronnback ¨ M, Forsblom C, Kaaja R, et al.; FinnDiane Study Group. Pre-eclampsia, but not pregnancy-induced hypertension is a risk factor for diabetic retinopathy in type 1 diabetic women. Diabetologia 2007;50:516–22. [9] Clausen TD, Mathiesen E, Ekbom P, Hellmuth E, Mandrup-Poulsen T, Damm P. Poor pregnancy outcome in women with type 2 diabetes. Diabetes Care 2005; 28:323–8. [10] Dunne F. Type 2 diabetes and pregnancy. Semin Fetal Neonatal Med 2005;10: 333–9. [11] Verier-Mine ´ O, Chaturvedi N, Webb D, Fuller JH and The EURODIAB Prospective
[12] [13]
[14]
[15]
S55
Complications Study Group. Is pregnancy a risk factor for microvascular complications? The EURODIAB Prospective Complications Study. Diabet Med 2005;22:1503–9. Kaaja R, Sjoberg ¨ L, Hellsted T, Immonen I, Sane T, Teramo K. Long-term effects of pregnancy on diabetic complications. Diabet Med 1996;13:165–9. Paradisi G, Biaggi A, Ferrazzani S, De Carolis S, Caruso A. Abnormal carbohydrate metabolism during pregnancy : association with endothelial dysfunction. Diabetes Care 2002;25(3):560–4. Lykke JA, Langhoff-Roos J, Sibai BM, Funai EF, Triche EW, Paidas MJ. Hypertensive pregnancy disorders and subsequent cardiovascular morbidity and type 2 diabetes mellitus in the mother. Hypertension 2009 Jun;53(6): 944–51. Heitritter SM, Solomon CG, Mitchell GF, Skali-Ounis N, Seely EW. Subclinical inflammation and vascular dysfunction in women with previous gestational diabetes mellitus. J Clin Endocrinol Metab 2005 Jul;90(7):3983–8.
Contents lists available at ScienceDirect
Thrombosis Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / t h r o m r e s
Vascular complications in diabetic pregnancy R. Kaaja* Obstetric physician, Professor in Medicine, Turku University/ Satakunta Central Hospital, Finland
article info
abstract
Keywords: Type 1 and 2 diabetes Pregnancy Microangiopathy Macroangiopathy Vascular complications
Until now, vascular complications in diabetic pregnancy are mainly related to hyperglycemia caused by type 1 diabetes (Type 1 DM). Progression of diabetic retinopathy (DR) occurs at least temporarily during pregnancy and postpartum. There is a short-term increase in the level of retinopathy during pregnancy that persisted into the first year postpartum. Nephropathy is associated with increased risk of preeclampsia, nephrotic syndrome, preterm delivery, fetal growth restriction, and perinatal mortality [1]. Presence of retinopathy increases also risk of preeclampsia and also poor glycemic control. The pregnancy itself (first or subsequent) is not a long-term risk factor for developing microalbuminuria, any retinopathy, proliferative retinopathy, or neuropathy. The prevalence of type 2 diabetes (Type 2 DM) is rising leading to similar or even worse pregnancy outcome than in T1 DM. Micro- and macroangiopathic complications still rather rare in the mother will also become more prevalent with increasing age, obesity and more severe forms of Type 2 DM. Good glycemic control, normotension, lack of nephropathy as well as lack of pre-proliferative/proliferative changes of diabetic retinopathy and lack of signs of macroangiopathies are good prognostic factors as regards the progression of vascular complications during pregnancy. Women with diabetes should be evaluated before pregnancy for microangiopathies, treated and followed closely during pregnancy by obstetrician, internist/diabetologue, cardiologist and ophthalmologist and nephrologist. © 2011 Elsevier Ltd. All rights reserved.
Introduction Type 1 DM complicates approximately 0.3–0.5% of all pregnancies and both are associated with an increased risk of adverse outcome to the mother and fetus [1]. The high prevalence of obesity and sedentary lifestyle in the population, compounded by later child bearing, has led to an increase in the prevalence of Type 2 DM pre-dating pregnancy. In some centers, pregnant women with Type 2 DM now outnumber those with type 1 DM [2]. Determining the risks of maternal type 1 and type 2 DM in pregnancy requires a full assessement of maternal vascular diasease, including examination for microangiopathies (nephropathy and retinopathy) mainly for type 1 DM and macroangiopathies (for example coronary artery disease) mainly for type 2 DM. It could be expected that pregnancy as a state of hypervolemia, hypercoagulability, insulin resistance and “milieu of growth” could induce worsening of diabetic retinopathy and nephropathy. The clinical picture is, however, less alarming especially in long-term. Although there is controversy as to whether type 2 DM is associated with worse outcomes than type 1 DM in pregnancy, modern reports clearly acknowledge the seriousness of this condition [2]. This short review * Correspondence: Risto Kaaja, MD. Department of Obstetrics and Gynecology, Helsinki University Hospital, Haartmaninkatu 2, Helsinki FIN-00290, Finland. Tel.: +358 9 471 72850; fax: +358 9 471 72812. E-mail address: risto.kaaja@hus.fi (R. Kaaja). 0049-3848 /$ – see front matter © 2011 Elsevier Ltd. All rights reserved.
will focus on the short- and long-term effectct of pregnancy on diabetes microangiopathies and vice-versa. Progression of diabetic retinopathy during pregnancy Progression of diabetic retinopathy (DR) occurs at least temporarily during pregnancy and postpartum. The pathogenetic mechanisms of DR progression during pregnancy are not fully understood. Several factors related to metabolic changes (hyperglycaemia), diabetes itself (duration of diabetes before conception, baseline status of DR), pregnancy physiology (hypervolaemia and hypercoagulation, impaired retinal autoregulation) and pregnancy complications (preeclampsia) seem to play important roles in the progression of DR during pregnancy. One of the largest prospective studies to assess the effect of pregnancy on the development and progression of diabetic retinopathy [3] showed that in both intensive and conventional treatment groups, there was a short-term increase in the level of retinopathy during pregnancy that persisted into the first year postpartum; the conventional group was somewhat more affected by pregnancy than the intensive group. A minor effect of rapid improvement of glycemic control on worsening of retinopathy confirmed earlier findings [4]. Good glycemic control, normotension, lack of nephropathy as well as lack of preproliferative/proliferative changes of DR are good prognostic factors as regards the progression of DR during pregnancy [5]. Women with type 1 diabetes must be followed closely by an experienced retina
S54
R. Kaaja / Thrombosis Research 127 (2011) S53–S55
specialist during pregnancy. This adverse effect of pregnancy on retinal status persists into the first year postpartum, and increased retinal surveillance by a retina specialist should be continued during the first year. Fortunately, the effect of pregnancy is relatively transient; most changes revert to prepregnancy levels after a year or more [3]. Progression of diabetic nephropathy during pregnancy Nephropathy complicates 5% to 10% of pregnancies in women who have diabetes mellitus and is associated with increased risk of preeclampsia, nephrotic syndrome, preterm delivery, fetal growth restriction, and perinatal mortality [1]. The degree of renal impairment and proteinuria in early pregnancy predict pregnancy complications in women with diabetic nephropathy. The risk for pre-eclaampsia increases with severity of proteinuria: diabetic women with microalbuminuria (dU-albumin 30–300 mg) and macroalbuminuria (dU-albumin >300 mg) have preeclampsia in 42% and 64% of the cases [6]. Suboptimal control of hypertension in early pregnancy, which can be directly treated, has not been evaluat as ed a predictor of adverse perinatal outcome. Maximizing blood pressure and diabetes control before pregnancy may improve perinatal outcome in women with diabetic nephropathy [7]. Diabetic microangiopathy and pregnancy outcome Although women with prevalent vascular disease are often older and had a longer duration of diabetes the maternal vascular disease significantly and adversely affects pregnancy outcome. As mentioned above diabetic nephropathy is the most significant risk factor for pre-eclampsia [6]. In a recent study [1] it was noted that the presence of retinopathy alone was independently associated with an increased risk of pre-eclampsia, particularly as retinopathy is almost universal beyond 20 years of diabetes. Macrosomia is the expected outcome in babies born to women with uncomplicated type 1 DM. In contrast, in women with vascular disease, the the babies have more often problems related to intrauterine growth retardation (IUGR) most often associated to preeclampsia. This suggests that maternal diabetes and vascular disease provide an even poorer intrauterine environment: a double hit that restricts macrosomia to falsely ’normalize’ growth. This reinforces the need for frequent assessment of fetal well-being. Pre-eclampsia has been, beside vascular disease, significantly and positively associated with HbA1c values in the second and third trimester [1]. Pre-eclampsia on the other hand could affect the progression of diabetic nephropathy but interestingly not pregnancy-induced hypertension [8]. Type 2 diabetes is a growing concern, with the number of new cases increasing and occurring at a younger age due to obesity. Type 2 DM is often perceived as a benign form of diabetes, but this is not the case when one examines pregnancy outcomes [9]. Rates of perinatal mortality (25/1000) and congenital malformation (99/1000) are significantly greater than those in background populations and at least as poor as those in type 1 diabetes. The rates of hypertension, pre-eclampsia and postpartum haemorrhage are greater than the general maternity population, as is the rate of operative delivery [10]. Long-term effects of pregnancy on diabetic micro- and macroangiopathies Some older studies, where blood pressure was less well controlled, pregnancy accelerated renal insufficiency in patients with preexisting renal impairment. Recent studies with a follow-up up to 16-years and intensive hypertensive treatment found no adverse long-term impact of pregnancy on kidney function and survival. The EURODIAB Prospective Complications Study involved a large
European-wide cohort of individuals with Type 1 DM with standardized measures of both risk factors and outcomes [11]. At baseline, parous women had a lower prevalence of retinopathy and a similar prevalence of microalbuminuria when compared with nulliparous women. However glycaemic control was better in the parous women. The authors examined prospectively the relationship between pregnancy and the incidence or progression of microvascular complications over a mean follow-up period of 7.3 years. The study confirmed earlier studies [3,12] that pregnancy itself (first or subsequent) was not a risk factor for developing microalbuminuria, any retinopathy, proliferative retinopathy, or neuropathy, several years post-partum. These findings have practical implications for counselling young women in planning their pregnancies. However, in current practice, women having experienced a worsening of their retinopathy during pregnancy are often counselled not to have another pregnancy [11]. Endothelial dysfunction, an early marker of macrovascular disease, is present in pregnancies complicated by type 2 DM, glucose intolerance and gestational diabetes. This alteration seems to be directly related to glycemic levels but also to dyslipidemia and hypertension, which can precede the type 2 DM [13]. Interestingly hypertensive pregnancy disorders are strongly associated with subsequent type 2 diabetes mellitus and hypertension, the latter independent of subsequent type 2 diabetes mellitus. The severity, parity, and recurrence of these hypertensive pregnancy disorders increase the risk of subsequent cardiovascular events [14]. A history of gestational diabetes (GDM) significantly increases the risk of developing type 2 diabetes, an independent risk factor for cardiovascular disease (CVD). Nondiabetic women with prior GDM have evidence of subclinical inflammation, hypoadiponectinemia, and early vascular dysfunction; this population may be at increased risk of developing CVD [15]. Conclusions Determining the risks of maternal type 1 and 2 DM in pregnancy requires a full assessment of maternal vascular disease, including examination for nephropathy, retinopathy, dyslipidemia and hypertension. The presence of one or more of these factors should prompt a cautious appraisal of the risks of pregnancy. The level of glycemic control achieved during pregnancy seems to modify this risk downward. Younger women with fewer vascular complications and good glycaemic control are, unsurprisingly, less likely to suffer an adverse outcome during pregnancy. Type 2 DM is often perceived as a benign form of diabetes, but rates of perinatal mortality and congenital malformation are significantly greater than those in background populations and at least as poor as those in type 1 DM. Fortunately until now clinical macrovascular complications are still rare. Conflict of Interest Statement There are no conflicts of interest. References [1] Howarth C, Gazis A, James D. Associations of Type 1 diabetes mellitus, maternal vascular disease and complications of pregnancy. Diabet Med 2007;24:1229–34. [2] McIntyre HD, Thomae MK, Wong SF, Idris N, Callaway LK. Pregnancy in type 2 diabetes mellitus – problems & promises. Curr Diabetes Rev 2009;3:190–200. [3] The Diabetes Control and Complications Trial Research Group. Effect of pregnancy on microvascular complications in the Diabetes Control and Complications Trial. Diabetes Care 2000;23:1084–91. [4] Laatikainen L, Teramo K, Hieta-Heikurainen H, Koivisto V, Pelkonen R. A controlled study on the influence of continuous subcutaneous insulin infusion treatment on diabetic retinopathy during pregnancy. Acta Med Scand 1987;221(4):367–76. [5] Kaaja R, Loukovaara S. Progression of retinopathy in type 1 diabetic women during pregnancy. Curr Diabetes Rev 2007;3:85–93.
R. Kaaja / Thrombosis Research 127 (2011) S53–S55 [6] Ekbom P, Damm P, Feldt-Rasmussen B, Molvig J, Mathiesen ER. Pregnancy outcome in type 1 diabetic women with microalbuminuria. Diabetes Care 2001;24:1739–44. [7] Nielsen LR, Damm P, Mathiesen ER.Improved pregnancy outcome in type 1 diabetic women with microalbuminuria or diabetic nephropathy: effect of intensified antihypertensive therapy? Diabetes Care 2009;32(1):38–44. [8] Gordin D, Hiilesmaa V, Fagerudd J, Ronnback ¨ M, Forsblom C, Kaaja R, et al.; FinnDiane Study Group. Pre-eclampsia, but not pregnancy-induced hypertension is a risk factor for diabetic retinopathy in type 1 diabetic women. Diabetologia 2007;50:516–22. [9] Clausen TD, Mathiesen E, Ekbom P, Hellmuth E, Mandrup-Poulsen T, Damm P. Poor pregnancy outcome in women with type 2 diabetes. Diabetes Care 2005; 28:323–8. [10] Dunne F. Type 2 diabetes and pregnancy. Semin Fetal Neonatal Med 2005;10: 333–9. [11] Verier-Mine ´ O, Chaturvedi N, Webb D, Fuller JH and The EURODIAB Prospective
[12] [13]
[14]
[15]
S55
Complications Study Group. Is pregnancy a risk factor for microvascular complications? The EURODIAB Prospective Complications Study. Diabet Med 2005;22:1503–9. Kaaja R, Sjoberg ¨ L, Hellsted T, Immonen I, Sane T, Teramo K. Long-term effects of pregnancy on diabetic complications. Diabet Med 1996;13:165–9. Paradisi G, Biaggi A, Ferrazzani S, De Carolis S, Caruso A. Abnormal carbohydrate metabolism during pregnancy : association with endothelial dysfunction. Diabetes Care 2002;25(3):560–4. Lykke JA, Langhoff-Roos J, Sibai BM, Funai EF, Triche EW, Paidas MJ. Hypertensive pregnancy disorders and subsequent cardiovascular morbidity and type 2 diabetes mellitus in the mother. Hypertension 2009 Jun;53(6): 944–51. Heitritter SM, Solomon CG, Mitchell GF, Skali-Ounis N, Seely EW. Subclinical inflammation and vascular dysfunction in women with previous gestational diabetes mellitus. J Clin Endocrinol Metab 2005 Jul;90(7):3983–8.