Int Ophthalmol DOI 10.1007/s10792-014-9906-z
Diabetic retinopathy and pregnancy Nicola Pescosolido • Orazio Campagna Andrea Barbato
Received: 27 December 2013 / Accepted: 16 January 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract Diabetes mellitus and pregnancy have reciprocal influences between them, therefore diabetes mellitus may complicate the course of pregnancy as well as pregnancy can worsen the performance of diabetes especially at the fundus oculi. Several factors seem to play a role in retinal neovascularization. Actually it’s not possible to understand the mechanisms underlying this progression. Moreover chronic hyperglycemia leads to several events such as: the activation of aldose reductase metabolic pathway, the activation of the diacylglycerol-protein kinase C, the non-enzymatic glycation of proteins with formation of advanced glycation endproducts and the increase of hexosamines pathway. Although every structure of the eye can be affected by diabetes, retinal tissue, with all its vessels, is particularly susceptible. Pregnancy may promote the onset of diabetic retinopathy, in about 10 % of cases, as well as contribute to its worsening
N. Pescosolido Department of Cardiovascular, Respiratory, Nephrology, Geriatric and Anesthesiology Science, ‘‘Sapienza’’ University of Rome, viale del Policlinico 155, 00161 Rome, Italy O. Campagna A. Barbato (&) Department of Sense Organs, Centre of Ocular Electrophysiology, ‘‘Sapienza’’ University of Rome, viale del Policlinico 155, 00161 Rome, Italy e-mail: [email protected]
when already present. The proliferative retinopathy must always be treated; treatment should be earlier in pregnant women compared to non-pregnant women. Pregnancy can also cause macular edema; it spontaneously regresses during the postpartum and therefore does not require immediate treatment. In summary, collaboration between the various specialists is primary to ensure the best outcomes for both mother’s health and sight, and fetus’ health. Keywords Diabetes mellitus Diabetic retinopathy Hyperglycemia Pregnancy Oxidative stress
Introduction Diabetes mellitus is defined by WHO as a chronic disease, which occurs when the pancreas does not produce enough insulin, or when the body cannot effectively use the insulin it produces [1–4]. This leads to an increased concentration of glucose in the blood (hyperglycaemia) (Table 1). Diabetes mellitus affects 2–5 % of the European population. According to the current classification can be divided into different forms: type-1 diabetes mellitus (previously known as insulin-dependent or childhood-onset diabetes), characterized by the destruction of pancreatic beta cells, representing approximately 10 % of cases, while type2 diabetes mellitus (formerly called non-insulindependent or adult-onset diabetes), characterized by
a relative peripheric resistance or insufficient production of insulin, regards the remaining 90 % of patients; another type of diabetes is the so called gestational one, defined as any degree of glucose intolerance whose onset occurs in pregnancy and finally several rare forms of diabetes mellitus genetically determined [1–4]. Generally the chronic complications of diabetes mellitus appear after many years of disease and are essentially of vascular type [1, 2]. They differ in microangiopathic and macroangiopathic complications. The first ones are due to alterations that occur in small blood vessels, the latter concern the larger vessels. The cause of vascular damage is to be found in chronic hyperglycemia, but nevertheless, the progression of such damage is also regulated by other factors such as hypertension, dyslipidemia, obesity, cigarette smoking [1–4]. Chronic hyperglycemia leads to several events such as: the activation of aldose reductase metabolic pathway, the activation of the diacylglycerol-protein kinase C, the non-enzymatic glycation of proteins with formation of advanced glycation endproducts and the increase of hexosamines pathway [1–5]. Although every structure of the eye can be affected by diabetes, retinal tissue, with all its vessels, is particularly susceptible. Recent estimates show that at least 30 % of the diabetic population is affected by retinopathy. Diabetic retinopathy (DR), in fact, Table 1 Diagnostic classification of diabetes mellitus (DM)
constitutes the main cause of blindness in industrialized countries among those of working age and represents the most severe complications of type1diabetes mellitus (40 %) and type-2 (20 %) [1–3]. Vascular cells (pericytes and endothelial cells), the macroglia (astrocytes and Mu¨ller cells), neurons (photoreceptors, bipolar cells, amacrine and ganglion cells) and microglia (macrophages) are mainly involved. The outcome of the cellular changes will result in different degrees of DR [1–3] (Table 2). Regarding the vascular damage, hyperglycemia determines the loss of the endothelial glycocalyx. This causes the loss of the regulation of coagulation and inflammation, that protect the retinal circulation, leaving exposed the lumen endothelial accession of leukocytes that initiate the inflammatory process. This determines a state of chronic inflammation that changes vascular permeability (edema, hypoxia) and increases the risk of bleeding and thrombosis [1–5]. This review has been conducted to evaluate the mechanisms of pregnancy-induced changes on the development and/or progression of DR.
Diabetes mellitus and oxidative stress Several pathogenetic mechanisms reflect a single unifying process induced by hyperglycemia which consists in the overproduction of superoxide by the 2 h after glucose mmol/l (mg/dl)
Fasting glycemia mmol/l (mg/dl)
Altered fasting glycemia
C7.8 (C140) C11.1 (C200)
\7.0 (\126) C7.0 (C126)
Altered tolerance to glucose Diabetes mellitus
Table 2 Classification of diabetic retinopathy (DR). Intraretinal microvascular anomalies (IRMA) Stage
Microaneurisms, retinal hemorrhages, hard exudates, and isolated soft nodules.
Numerous retinal hemorrhages, soft nodules, IRMA, venous irregularities, and venous loop.
Optic disk and retina neovessels, pre-retinal hemorrhages, and fibrous-glial membranes.
Advanced diabetic ophthalmopathy
Retinal detachment due to traction or laceration, rubeosis iridis, and neovascular glaucoma.
mitochondrial transport chain which determines an increase of the production of reactive oxygen species (ROS) [6, 7]. The mitochondrial production of superoxide induced by hyperglycemia inhibits glyceraldehyde 3-phosphate dehydrogenase and activates the four mentioned above metabolic pathways. In addition, ROS increase the permeability of the mitochondrial membranes, even at the retinal level, through an up-regulation of type 2 metalloproteases, thus altering the membrane potential and causing a release of cytochrome c and the activation of the apoptosis cascade. [5–8]. Physiologically, in our body, there are antioxidant systems able to buffer the presence of ROS. When the excessive production of ROS exceeds the intracellular availability of these systems a condition called oxidative stress is established [7–9]. Oxygen metabolism is essential to sustain aerobic life, cellular homeostasis is responsible for maintain the appropriate balance between the formation and elimination of ROS [3–7]. Oxidative stress, a direct result of the excessive production of ROS, has an important role in the genesis of many diseases, including diabetes and its complications [6–10]. Diabetes mellitus leads to an important stress against the capillary endothelium by changing vascular permeability (edema, hypoxia) and increases the risk of bleeding and thrombosis. Hypoxia is the main stimulus to the physiological and pathological neovascularization. When the cells of a tissue appear to have a perfusion and oxygenation lower than required is generated overexpression of neoangiogenic factors against those antiangiogenic that result in formation of new vessels [8, 11, 12]. All this occurs also in diabetes, where, the hypoxic stimulus does not stop with the formation of new vessels, which are immature and fragile, so it induces a vicious circle deleterious to visual function that results in proliferative DR and blindness [4, 7, 11]. Among the main factors that regulate angiogenesis there is certainly the vascular endothelial growth factor (VEGF). An important role about it is also that of some hormones such as prolactin (PRL), the hormone placental lactogen (HPL) and growth hormone (GH). All these hormones share a pro-angiogenic effect. Their effect over time, however, is self-regulated through proteolytic processing of these hormones in a family of proteins have recently been discovered and have potent anti-angiogenic: the vasoinhibins.
Pregnancy Pregnancy and childbirth are central moments of woman’s life. Changes that occur during pregnancy are due to the effects of specific hormones. These changes allow the mother to feed the fetus, prepare her body for childbirth, to develop mammary glands and accumulate reserves of fat tissue to provide the necessary calories for milk production during puerperium. Also the psychological state is influenced by hormones that interact with other external factors. Progesterone is a hormone synthesized by ovaries and adrenal glands. It’s secreted by the ovary in women in small quantities in the first half of the menstrual cycle; after ovulation, during the second phase of the cycle, called luteal or progestinic phase, the corpus luteum produces high quantities of it. From that moment the progesterone exercises its main action allowing the creation of the right conditions for the fecundation of the ovum and its implantation in the uterine lining (endometrium), events that mark the beginning of pregnancy. Finally, during pregnancy, progesterone is produced in large quantities by placenta. PRL is produced and secreted by cells of adenohypophysis called lattotrophe. PRL is the only pituitary hormone that suffers a constant inhibitory tone from the hypothalamus. Dopamine is the main factor that inhibits the secretion of PRL. During pregnancy there is an increase of PRL production, which can be explained by the action of estrogen, which promote lattotrophe cell hyperplasia and the increase of PRL gene expression. HPL is a hormone produced by the embryo and fetus from syncytiotrophoblast and thus spread in the maternal circulation. The hormone affects the metabolism of the maternal organism: insulin sensitivity decreases and thus increases the levels of glucose in the mother’s blood and decreases its use, with the purpose of ensuring the fetal nutrition. Chronic hypoglycemia leads to an increase of the hormone. HPL induces lipolysis with release of free fatty acids. It is detectable in the blood and urine of women from the sixth week of pregnancy and during this period increases progressively after which its levels decay very quickly after childbirth. Angiogenesis is an important event that is activated in pregnancy. During embryonic vasculogenesis blood
vessels are formed ‘‘de novo’’ from the endothelial precursors (angioblasts), which assemble into a primary capillary plexus. This primitive vascular network later differentiates and new vessels extend and branch out from pre-existing capillaries . Vascular system in the adult is normally quiescent, and the endothelial cells are among the most durable. The point where these normal physiological processes differ from pathological angiogenesis is finely regulated in the balance of pro-and anti-angiogenic factors. During physiological angiogenesis, new vessels mature quickly and become stable. In contrast pathological vascularization takes on different characteristics: they are irregularly shaped, dilated, tortuous and may have no extremities. The network that is formed is often structurally weak and may lead to bleeding. All these abnormalities are the result of unbalanced expression of angiogenic factors . Hypoxia in body tissues and therefore also in the retina, is the main stimulus to neovascularization. The transcriptional complex hypoxia-inducible factor (HIF-1) plays an essential role in cellular and systemic oxygen concentrations. HIF-1 induces the transcription of multiple genes including VEGF, erythropoietin, nitric oxide synthase. HIF-1 undergoes conformational changes in response to oxygen concentrations, which allow to induce the expression of genes responsive to hypoxia . Angiogenesis can be inhibited at every level of the growth cycle of endothelial cells. The activation of quiescent vessels by angiogenic factors such as VEGF, can be blocked by neutralizing antibodies or by molecules that affect the activation signal (inhibition of I level). The degradation of the extracellular matrix by activated endothelial cells can be prevented in order to suppress capillaries growth (inhibition level II). The proliferation of endothelial cells can be inhibited by agents that lock signaling systems by stopping the cycle of cell division (inhibition of III level) or agents which prevent the differentiation of endothelial cells into tubular functional structures (inhibition of IV level). Finally, endothelial cells can be forced to apoptosis (inhibition of V level). There are about a dozen of endogenous proteins that can inhibit angiogenesis. Among all these molecules angiostatin, endostatin and thrombospondin-1 seem to play a prominent role.
A fine balance between the concentration of proteins with inhibitory activity and activators of angiogenesis, such as VEGF and basic fibroblast growth factor (bFGF), determines the possibility of neovascularization [14–17]. Angiogenesis is therefore largely regulated by the balance that exists between the various angiogenic factors, such as VEGF and endogenous inhibitors of angiogenesis, most of which is not synthesized by endothelial cells [18–21]. Until recently, in fact, no release of mediators with inhibitory to angiogenesis function was known to be offered by the endothelium itself [22–24]. Currently, we are aware of the existence of a new inhibitor of angiogenesis, the vasohibin, whose production by the endothelial cells is selectively induced by pro-angiogenic substances such as VEGF. It seems that vasohibin operates its intrinsic and highly specific inhibition on activated endothelial cells that are engaged in the process of angiogenesis only during the latter stages of the process of angiogenesis and acts in order to limit any excessive proliferation. Furthermore, it seems that it has no action on migration of smooth muscle cells or fibroblasts. Unlike other inhibitors of angiogenesis, such as thrombospondin, that can be secondarily induced by other substances, even pharmacological, the synthesis of vasohibin by endothelial cells is induced by angiogenic factors such as VEGF and acts on some endothelial cell functions essential for the phenomenon of neo-vascularization [25–27]. Gene coding for this specific protein, if transferred into cancer cells, is observed to cause block of cell proliferation in vivo only, not in vitro, suggesting a specific role in the angiogenic process: therefore it seems that the vasohibin is secreted by endothelial cells and that carries its action only on the same cell that produce it [28–30]. Pregnancy is associated with pathophysiological changes not only at systemic level but also in the eye; often these are only transient, but more rarely they become permanent. The effects of pregnancy can be divided into physiological, pathological or modifications of pre-existing conditions. Changes of corneal thickness and curvature, corneal sensitivity, the composition of the tear film, reduction of the intraocular pressure, refractive and accommodative errors, can be considered as physiological [31, 32]. Central serous chorioretinopathy, vascular disorders, increased risk of retinal
detachment, are the main pathological changes. Among the changes, for the worse, of pre-existing conditions are to be mentioned Graves’ disease, retinitis pigmentosa, optic neuritis and doubtless DR [33, 34].
Diabetes mellitus in pregnancy Diabetes and abnormal glucose metabolism in pregnancy may be pre-existing pregnancy (diabetes type 1, 2, impaired glucose tolerance), or appear in pregnancy (gestational diabetes, impaired glucose tolerance during pregnancy). The treatment of diabetes in pregnancy must be intensive in order to achieve glycemic values close to ‘‘normoglycemia’’ . The presence of diabetes mellitus affects pregnancy outcomes (congenital malformations, fetal mortality and morbidity) and also pregnancy can adversely affect the development of microvascular complications (DR and diabetic nephropathy). In 10 % of the cases, pregnancy is able to induce DR not existing before conception; during pregnancy may appear retinal lesions (microaneurysms, micro-haemorrhages, etc.) that most often regress spontaneously in the postpartum. The presence of nonproliferative retinopathy at the beginning of gestation, rarely involves the progression to the proliferative form. In patients with proliferative forms at the moment of conception, the risk of progression to more severe forms is very high. In such patients should therefore be performed laser therapy early in gestation or at the onset of proliferative lesions. Risk factors that contribute to the progression of retinopathy in pregnancy are: duration of diabetes, not fine metabolic control before and during pregnancy, rapid normalization of blood glucose levels, degree of retinopathy at the beginning of pregnancy, hypertension, diabetic nephropathy, low physical activity, cigarette smoking [36–40].
Discussion Despite recent findings, there is still lack of guidelines suggesting the necessity to take both screening and timely treatment measures in order to face DR in pregnancy. In 1982 Larinkari et al.  have studied the correlation between metabolic control, serum levels of
some hormones and DR during pregnancy. The levels of progesterone and HPL, especially during the second and third trimester of pregnancy, were increased in diabetic women compared with those who had a normal pregnancy. There were no significant differences in the values of estradiol; instead were significantly lower concentrations of serum PRL compared with controls . Some Finnish studies conducted in 2004 and 2005 by Loukovaara et al. [42–44] have analyzed the association between DR, angiopoietic factors, vasoactive mediators and markers of inflammation. Two groups were observed: patients with diabetes mellitus and non-affected patients, during pregnancy and postpartum. Circulating levels of angiopoietic factors were found to be similar (angiopoietin I, A-VEGF, soluble receptor of VEGF) if not lower (angiopoietin II) between the two groups of patients. The progression of retinopathy does not seem to be connected with the hematopoietic factors. The levels of atrial natriuretic peptide and plasma renin activity were significantly lower in diabetic women than in non-affected, were not highlighted substantial differences between plasmatic levels of angiotensin II (AngII), aldosterone, adrenomedullin, brain natriuretic peptide, C natriuretic peptide between the two groups. The decrease of the activity of the renin-angiotensin-aldosterone system may therefore contribute to the determination of more dynamic of blood flow within the vessels and thus to the progression of DR during pregnancy, but there are still no clear associations. Subsequently, in another study, were analyzed plasma levels of C-reactive protein (CRP), interleukin-6 and vascular cell adhesion molecule-1. Among the patients with diabetes mellitus and non-affected were not observed substantial differences of these inflammatory markers, except for patients with diabetes mellitus with poor glycemic control that showed levels of CRP higher than in the group of control. Loukovaara et al.  studied also the correlation between the speed of macular capillary blood flow and DR in women during pregnancy and postpartum. It was shown that blood flow was greater in pregnant patients with diabetes mellitus compared to healthy pregnant women. It is also observed that the flow velocity was correlated in a way directly proportional to the degree of retinopathy . Recently he showed great scientific interest to the study of plasmatic concentrations of vitamin D during
pregnancy. It was observed that reduced or insufficient blood levels of vitamin D are associated with index of impaired glucose homeostasis and a higher risk of developing gestational diabetes. It may need to inquire what should be the optimal levels of vitamin D during pregnancy and eventually suggest a supplement of it in order to prevent gestational diabetes [46, 47]. In 2006 Shen et al.  have analyzed the activity of a protein recently identified: the vasohibin. In a model of retinal neovascularization was seen that the vasohibin is over-expressed in vascular endothelial cells by VEGF and bFGF. It inhibits the migration and proliferation of endothelial cells and thus promotes the suppression of angiogenesis. It has been experienced that in the ischemic retina the increased expression of VEGF mRNA was is followed by the increase of vasohibin and blocking the increase of VEGF mRNA with the administration of siRNA (short interfering RNA) was observed has shown a significant decrease of vasoibina mRNA. The decreased expression of mRNA vasohibin in the ischemic retina, has no significant effect on the levels of VEGF mRNA and VEGF receptor-1 mRNA, but leads to a significant increase in the elevation of VEGF receptor-2 mRNA levels. These data support the theory that vasohibin would act with a negative feedback mechanism on retinal neovascularization and suggest that suppression of VEGF receptor-2 may play a role in this activity. Recent studies conducted by Triebel et al. [49, 50] in 2011 showed that the pituitary PRL is proteolytically cleaved into vasoinhibins, a class of proteins with potent vasoconstrictor activity, inhibiting vascular permeability and with antiangiogenic action that can protect eyes from the deleterious effects of diabetes. The levels of circulating PRL and vasoinhibins were related to the progression of DR during pregnancy; particular value is given to hyperprolactinemia during pregnancy and post-partum. Analyze and act on these factors could positively change the progression of retinopathy, and should therefore be considered these hormones as a major target for future therapeutic interventions. Even Wakusawa et al.  in 2011 have studied the expression and the effects of the levels of vasohibin-1 during the development of choroidal neovascularization (CNV) experimentally induced. The CNV was induced by laser photocoagulation. The vasohibin-1 was injected into the vitreous and the activity and the
size of CNV was evaluated by fluorescein angiography. The intravitreal injection of vasohibin-1 was effective in suppressing neoangiogenesis. In one study, Helen et al.  (2011) have followed over time four young pregnant women with diabetes mellitus type I and proliferative retinopathy. These four cases have shown that poor glycemic control, concomitant diabetic nephropathy, arterial hypertension were all negative prognostic factors about the outcome of pregnancy both for mother and fetus’ health. In all cases, however, there was advanced DR and poor visual acuity. The adverse outcomes for mothers were abortion for the first one, pre-eclampsia and preterm birth for the second one, renal failure requiring dialysis for the third one; adverse outcomes for the fetus were neonatal death for one and premature birth for another. In each case panretinic laser treatment was effective in stopping the progression of retinopathy. Experimental studies have suggested that insulinlike growth factor-I (IGF-I) has a proangiogenetic effect on retinal vasculature. On the other hand, IGF binding proteins (IGFBPs), especially IGF binding protein-3 (IGFBP-3), is known to counteract such effects , not only by binding free IGF-I but also by an independent direct proapoptotic counterproliferative effect on human retinal endothelial cells . Almost all of the circulating IGF binding protein-1 (IGFBP-1) in nonpregnant adults is highly phosphorylated, but the phosphorylation of IGFBP-1 is altered during pregnancy. Moreover the results of Loukovaara et al.  (2005) showed that mean serum levels of IGF-1 and IGFBP-3 in diabetic women are lower than in nondiabetic controls during pregnancy and/or postpartum. Because there was no clear connection between the IGF system and progression of DR during pregnancy and the authors stated it is unlikely that these substances mediate the tendency of DR to progress during pregnancy.
Treatment Pregnancy may promote the onset of DR (in about 10 % of cases) as well as contribute to its worsening when already present . The proliferative retinopathy must always be treated; treatment should be earlier in pregnant women compared to non-pregnant women. Pregnancy can also cause macular edema; it
spontaneously regresses during the postpartum and therefore does not require immediate treatment [57–59]. As confirmed by Sheth  in 2008 it is necessary to identify and treat any sign of DR as well as possibly optimize glycemic control prior to pregnancy or otherwise during the third trimester. Since 1982 Dibble et al.  were proposed to study the best therapeutic strategies for pre-proliferative and proliferative DR. In 4 patients with proliferative retinopathy laser treatment performed during pregnancy had proved effective in stopping the progression of the disease, only in one patient of 6, laser photocoagulation performed prior to pregnancy had not proved to be effective.
Conclusions Currently there is still no clear evidence about the possibility of predicting the progression of DR during and after pregnancy. Recognizing symptoms and signs, as well as understanding the right therapeutic approach, are essential for proper control of diabetic patients, especially during two moments of their lives so critical like pregnancy and postpartum. On the other hand, DR is considered as a negative prognostic factor for mother and fetus’ health during and after pregnancy. The utilization of drugs, although topical, should be careful during pregnancy considering the lack of accurate studies about it. During pregnancy, differentiating physiological modifications from pathological ones is an issue of primary importance. A close collaboration between specialists ophthalmologist, diabetologist and gynecologist in order to establish a careful case by case assessment is therefore a goal for the eye health of the mother and fetus. Acknowledgments Conflict of interest no conflict of interest.
The authors declare
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