Complications and screening in children and adolescents with type 1 diabetes mellitus

INTRODUCTION — Type 1 diabetes mellitus (T1DM), one of the most common chronic diseases in childhood, is caused by insulin deficiency resulting from the destruction of insulin-producing pancreatic beta cells. (See "Pathogenesis of type 1 diabetes mellitus".)

In children and adolescents with T1DM, the most common complications include hypoglycemia, hyperglycemia, diabetic ketoacidosis (DKA), and psychiatric disorders. The pathogenesis of long-term sequelae (including retinopathy, nephropathy, neuropathy, and cardiovascular disease) begins in childhood, although clinical manifestations of these complications are uncommon before adulthood. Vascular complications and mortality during adulthood are discussed in a separate topic review. (See "Glycemic control and vascular complications in type 1 diabetes mellitus".)

The chronic complications of T1DM that occur in childhood will be presented here. Other issues related to the management of T1DM in children are discussed separately:

●(See "Epidemiology, presentation, and diagnosis of type 1 diabetes mellitus in children and adolescents".)

●(See "Overview of the management of type 1 diabetes mellitus in children and adolescents".)

●(See "Hypoglycemia in children and adolescents with type 1 diabetes mellitus".)

●(See "Diabetic ketoacidosis in children: Clinical features and diagnosis".)

●(See "Diabetic ketoacidosis in children: Treatment and complications".)

ACUTE GLYCEMIC COMPLICATIONS

Hypoglycemia — Hypoglycemia is the most common acute complication of T1DM in childhood. Severe and recurrent hypoglycemia can lead to acute and permanent neurologic complications. The symptoms, risk factors, treatment and complications of hypoglycemia in children and adolescents with T1DM are discussed in a separate topic review. (See "Hypoglycemia in children and adolescents with type 1 diabetes mellitus".)

Hyperglycemia and diabetic ketoacidosis — Diabetic ketoacidosis (DKA) is a common and potentially life-threatening complication of T1DM. It can be present at the initial presentation of T1DM or can occur in a patient with known diabetes. It is caused by inadequate insulin levels, leading to hyperglycemia and lipid breakdown, with production and accumulation of ketoacids. Frequent blood glucose testing or continuous glucose monitoring helps avoid this complication. The presentation, clinical features, diagnosis, and treatment of DKA are discussed separately. (See 'Mortality' below and "Epidemiology, presentation, and diagnosis of type 1 diabetes mellitus in children and adolescents" and "Diabetic ketoacidosis in children: Clinical features and diagnosis" and "Diabetic ketoacidosis in children: Treatment and complications".)

GROWTH — Height and weight should be monitored carefully at least twice a year and plotted on growth curves so that deviations can be detected early and therapy appropriately adjusted. Most children with T1DM grow normally. However, poor glycemic control can result in poor linear growth, poor weight gain, and/or delayed skeletal and pubertal development. Excessive calorie intake and/or high insulin doses may promote excessive weight gain. If obesity develops, this can lead to insulin resistance, which further complicates diabetes management. (See "Nutritional considerations in type 1 diabetes mellitus", section on 'Weight gain with intensive therapy'.)

Children with poorly controlled T1DM may develop Mauriac syndrome, which is characterized by growth attenuation, delayed puberty, hepatomegaly with abnormal glycogen storage and steatosis, and Cushingoid features. Mauriac syndrome is rare in the modern era of insulin therapy but is occasionally reported [1-4]. The mechanisms are not well understood but may involve hypercortisolemia induced by episodes of hyperglycemia and ketosis [5]. One report suggested that undiagnosed mild glycogen storage disease could lead to this picture in poorly controlled T1DM [6]. Catch-up growth generally occurs if diabetic control is restored. However, individuals who are quickly restored to euglycemia may have a paradoxical worsening of retinopathy and should be followed closely [7].

AUTOIMMUNE DISEASES — Children and adolescents with T1DM are at increased risk for developing other autoimmune diseases, most commonly autoimmune thyroiditis and celiac disease. The American Diabetes Association (ADA) and International Society for Pediatric and Adolescent Diabetes (ISPAD) recommend that children with T1DM should be screened for these diseases [8,9]. (See "Associated autoimmune diseases in children and adolescents with type 1 diabetes mellitus" and "Diagnosis of celiac disease in children".)

PSYCHIATRIC DISORDERS — The negative psychologic impact of the diagnosis of diabetes on children and adolescents has been well established and is primarily manifested as depression [10-15]. Other psychiatric morbidity includes a higher prevalence of anxiety disorders, eating disorders, substance misuse, and personality disorders [16]. The overall risk is highest five or more years after onset of diabetes.

Depression — Depression is more prevalent in children and adolescents with diabetes than those without diabetes [10]. The highest rate of depression occurs in the first year after diagnosis and in adolescents [10,11]. Adolescent girls are at greater risk than adolescent boys for recurrent episodes of depression [12]. Furthermore, insulin-dependent diabetes was a risk factor for attempted suicide in a study using a Danish registry [17].

Depression in patients with diabetes impacts adherence to diabetes care [18], and is associated with worse glycemic control and diabetic complications [13,14]. As an example, in a study of 2672 adolescents with diabetes, most of whom had T1DM, the overall prevalence of depression was 22.6 percent and was moderate to severe in 8.6 percent [14]. Depression was associated with higher glycated hemoglobin (A1C) levels and increased frequency of emergency department visits.

Accordingly, comprehensive management of diabetes that addresses the psychological impact of diabetes in children and adolescents can improve glycemic control and reduce the frequency of hospitalizations even in the high-risk adolescent. As examples, in two controlled studies, structured psychoeducational support significantly improved glycemic control and reduced hospital admission rate in adolescents who had previously been poorly controlled [19,20]. Similarly, in a systematic review of 543 children and adolescents with T1DM, psychological therapy significantly improved A1C levels [21]. Psychological intervention included counseling, cognitive behavior therapy, family systems therapy, and psychodynamic therapy.

Because depression occurs commonly in adolescents with diabetes and psychological intervention can improve care, an assessment for depression should be performed at least annually for all children and adolescents, as recommended by the American Diabetes Association (ADA) [8]. This is especially important for children and adolescents who are not adhering to the diabetes management regimen. Those with symptoms of depression or a positive depression screening should be further evaluated by a skilled mental health worker and intervention initiated, if appropriate. Clinical guidelines from the International Society for Pediatric and Adolescent Diabetes (ISPAD) support an intensive approach to such diagnosis and management [22].

Eating disorders — Adolescent girls with T1DM are more likely to develop an eating disorder compared with girls without diabetes [22-27]. Screening for eating disorders (eg, using the Diabetes Eating Problems Survey-Revised [DEPS-R]) is recommended for all patients, beginning between 10 and 12 years of age [8,28]. Eating disorders may manifest as weight control practices such as fasting, self-induced vomiting (bulimia), and diuretic abuse, as well as the purposeful omission of insulin for weight loss (sometimes referred to as "diabulimia") [29]. As an example, a Norwegian study of adolescents with T1DM found that 28 percent of females and 9 percent of males had abnormal scores on the DEPS-R survey and nearly one-third reported restricting their insulin dose after overeating [27].

Patients with T1DM and eating disorders have poorer metabolic control, require more frequent hospitalization, and are more likely to develop microvascular complications compared with those without eating disorders [30-34]. They also have an increased mortality rate compared with patients with only diabetes or only an eating disorder [35]. (See "Nutritional considerations in type 1 diabetes mellitus".)

VASCULAR COMPLICATIONS — In adults and adolescents, conclusive randomized trials have established that poor glycemic control is causally associated with long-term vascular sequelae of T1DM, including nephropathy, retinopathy, neuropathy, and cardiovascular disease. Recommended monitoring approaches and schedule are outlined in the table (table 1). (See "Glycemic control and vascular complications in type 1 diabetes mellitus".)

Although these vascular complications typically become clinically apparent in adulthood, their pathogenesis begins at disease onset. Cardiovascular risk factors (hypertension, dyslipidemia) increase with advancing age and have been reported to be more common among ethnic minority youth [36]. It is unclear whether these differences across minority groups are attributable to social, cultural, and economic factors or other unknown factors. Subclinical findings of vascular disease can be detected in a significant number of children and adolescents with diabetes. For example, increased vascular stiffness is seen in children with T1DM compared with healthy controls [37]. Small artery elasticity peaks earlier and declines faster in those at risk for vascular complications [38]. Lower small vessel elasticity and higher pulse pressure are associated with a higher risk of microvascular complications in adult life. Similarly, a close association has been reported between daytime and nighttime blood pressure (BP) regulation and these complications [39]. The risk of vascular disease depends on the duration of diabetes, genetic susceptibility, pubertal status, sex, degree of glycemic control, and other lifestyle factors (eg, smoking, diet, and exercise) [40]. Exercise has a protective effect, in that it is associated with decreased early markers of atherosclerosis in children with T1DM [41].

Pathogenesis — The mechanism by which poor glycemic control predisposes to vascular disease is incompletely understood. Proposed mechanisms include accumulation of advanced glycation end products and sorbitol, combined with end-organ responses that include activation of cytokines and protein kinase C. (See "Glycemic control and vascular complications in type 1 diabetes mellitus".)

Discussions of the specific pathogenesis of each of the complications are found separately:

●(See "Diabetic kidney disease: Pathogenesis and epidemiology", section on 'Pathogenesis'.)

●(See "Diabetic retinopathy: Pathogenesis".)

●(See "Pathogenesis of diabetic polyneuropathy".)

Nephropathy — The earliest sign of diabetic nephropathy is moderately increased albuminuria (formerly known as microalbuminuria), defined as persistent albumin excretion between 30 and 300 mg/day (20 to 200 microgram/minute). If not treated successfully, moderately increased albuminuria may progress to overt proteinuria (formerly known as macroalbuminuria), defined as persistent albumin excretion >300 mg/day (>200 microgram/minute).

Rates of diabetic nephropathy have decreased during the past decades in several populations, coinciding with improved glycemic control [42-44]. Nonetheless, albuminuria develops in a substantial proportion of individuals with T1DM and is associated with longer duration of diabetes and poor glycemic control [45-52]. As an example, in a large population-based study, the cumulative prevalence of moderately increased albuminuria was 26 percent after 10 years of diabetes and 51 percent after 19 years of diabetes [50]. Glycemic control, as measured by mean glycated hemoglobin (A1C) concentration, was a strong predictor of the risk for albuminuria. However, the risk of developing albuminuria by age 20 was approximately 15 percent, even in patients with mean A1C levels <8.5 percent. Overt proteinuria eventually developed in 14 percent of the subjects, at a mean age of 18.5 years. In a separate study with long-term follow-up, 88 percent of patients had developed moderately increased albuminuria (microalbuminuria), and 72 percent had developed overt proteinuria (macroalbuminuria), by 50 years of T1DM duration, and 60 percent had progressed to end-stage kidney disease [53].

Screening for albuminuria permits detection and treatment at a time when therapy can reverse, retard, or prevent further progression of renal disease (see 'Screening' below). With treatment, moderately increased albuminuria can be reversed and further progression of renal disease halted. As nephropathy progresses to overt proteinuria, irreversible damage occurs and there is an increased risk of end-stage renal failure. The prognosis of diabetic nephropathy has dramatically improved with better glycemic control, more aggressive antihypertensive therapy, and the use of angiotensin-converting enzyme (ACE) inhibitors. (See "Moderately increased albuminuria (microalbuminuria) in type 1 diabetes mellitus" and "Treatment of diabetic kidney disease".)

Smoking considerably increases the risk of progression of microalbuminuria to overt nephropathy [54]. In addition, hypertension and cardiovascular autonomic dysfunction are associated with an increased risk and severity of nephropathy [55]. Studies conflict as to whether earlier age of onset of diabetes affects the rate of progression to diabetic nephropathy [44,50,56,57]. (See 'Hypertension' below.)

Screening — We recommend annual screening for albuminuria beginning at 10 years of age (or at onset of puberty if earlier), once the child has had diabetes for five years [8,58]. More frequent testing should be performed if the albumin:creatinine ratio is increasing. Annual screening is most conveniently done on a random urine sample in which the albumin:creatinine ratio is measured. Abnormal results (>30 mg albumin/g creatinine [>3.4 mg/mmol]) should be confirmed with a second random sample because transient elevations in urinary albumin excretion are common in pediatric patients, particularly in association with exercise or fever. Other possible confounders include menstrual bleeding, urinary tract infection, or marked hyperglycemia [59]. Orthostatic albuminuria can also occur in some individuals and should be ruled out with a first morning urine sample (see "Orthostatic (postural) proteinuria").

If the albumin:creatinine ratio is persistently elevated, moderately increased albuminuria is likely; in this case, some experts suggest confirmation of albuminuria with a twelve-hour overnight or 24-hour urine sample. However, in general, an elevated albumin:creatinine ratio on two occasions, which is not a result of orthostatic albuminuria, should be sufficient to trigger treatment with an ACE inhibitor. Annual assessment of renal function by measuring serum creatinine and computing creatinine clearance is also recommended. (See "Moderately increased albuminuria (microalbuminuria) in type 1 diabetes mellitus", section on 'Detection'.)

Treatment — If persistent albuminuria is confirmed, non-diabetes-related causes of renal diseases including orthostatic proteinuria should be excluded. (See "Evaluation of proteinuria in children".)

Treatment of albuminuria associated with diabetes is summarized below. A more complete discussion is presented separately. (See "Moderately increased albuminuria (microalbuminuria) in type 1 diabetes mellitus", section on 'Treatment'.)

●Pharmacotherapy – Treat the nephropathy with an ACE inhibitor (eg, enalapril or lisinopril), regardless of whether hypertension is present. Titrate the dose as tolerated to normalize albumin excretion. We usually start enalapril or lisinopril at a dose of 5 mg daily [60], and refer the patient to Nephrology if microalbuminuria persists after 3 to 12 months of use of ACE inhibitors.

Because of potential teratogenic effects, appropriate counseling should be given before an ACE inhibitor is prescribed to reproductive-aged females; these drugs should be avoided if young women are heterosexually active and not using reliable contraception. Otherwise, these drugs have been used effectively and safely in children, and are effective in reversing albuminuria and overt nephropathy [8,58]. Angiotensin receptor blockers (ARBs) may be used if the patient cannot tolerate ACE inhibitors or if targeted BP goals are not reached (ARBs also require appropriate reproductive counseling due to potential teratogenicity).

ACE inhibitors and ARBs are not useful for primary prevention of nephropathy in patients who are normotensive and normoalbuminuric. (See "Moderately increased albuminuria (microalbuminuria) in type 1 diabetes mellitus", section on 'ACE inhibitors or ARBs'.)

●Management of related comorbidities

•Hypertension – If hypertension is present despite maximal doses of ACE inhibitors or ARBs, treat aggressively to normalize BP. (See 'Hypertension' below.)

•Hyperglycemia – Review glycemic control and implement measures for improvement. (See "Insulin therapy for children and adolescents with type 1 diabetes mellitus", section on 'Target for hemoglobin A1c'.)

•Dyslipidemia – If there is elevation of serum lipids, treat to improve lipid profile. (See 'Cardiovascular disease' below.)

•Smoking – Counsel patients regarding health risks of smoking, specifically that smoking markedly increases the risk of nephropathy as well as other vascular complications [40]. For patients who smoke, offer support and referral for cessation interventions. Also discourage use of e-cigarettes (vaping nicotine) due to concerns that it may promote nicotine dependence and other adverse health effects [8]. In addition, nicotine itself may be important in the propagation of long-term vascular complications of type 1 diabetes [61]. (See "Prevention of smoking and vaping initiation in children and adolescents" and "Management of smoking and vaping cessation in adolescents".)

Hypertension — Adolescents with diabetes generally have higher systolic BP (SBP) and diastolic BP (DBP) than healthy adolescents. Two studies that utilized 24-hour ambulatory BP monitoring reported increased SBP and DBP in children with diabetes compared with their nondiabetic siblings [62,63]. Risk factors for hypertension include ethnicity (minority groups), obesity, and poor glycemic control [64]. Elevations in BP are associated with subsequent development of moderately increased albuminuria [63], and patients with albuminuria had higher BPs than those without albuminuria.

Screening — Screening for hypertension should be performed at each routine visit for diabetes management (at least every three months), and more often in patients with abnormal results [58].

The American Diabetes Association (ADA) Standards of Medical Care for Diabetes uses the following definitions [8]:

●Elevated BP:

•Children <13 years – SBP or DBP ≥90 to 95^th percentile for age, sex, and height

•Adolescents ≥13 years – SBP 120 to 129 mmHg with DBP <80 mmHg

●Hypertension:

•Children <13 years – SBP or DBP ≥95^th percentile for age, sex, and height

•Adolescents ≥13 years – SBP ≥130 mmHg or DBP ≥80 mmHg

This definition of hypertension consolidates stages 1 and 2 of hypertension as defined by the American Academy of Pediatrics and American Heart Association [65].

Age- and height-specific BP percentiles may be determined from a table for girls (table 2) or for boys (table 3). For equivocal cases, ambulatory blood pressure monitoring may be helpful [8]. If hypertension is detected, the patient should undergo a basic clinical evaluation to confirm that this is primary hypertension rather than due to renal disease or other secondary cause. (See "Evaluation of hypertension in children and adolescents".)

Treatment — Nonpharmacologic intervention, such as diet and exercise, should be initiated for all children with BPs in the "elevated BP" (prehypertensive) range.

Pharmacologic treatment using an ACE inhibitor should be started for children with [8,65]:

●Hypertension – ie, BP persistently ≥95^th percentile for children 1 to 13 years or >130/80 mmHg in children 13 years and older.

●Elevated BP unresponsive to nonpharmacologic intervention – ie, BP 90^th to 95^th percentile for children 1 to 13 years or SBP >120 to 130 mmHg in children 13 years and older, despite three to six months of nonpharmacologic intervention. We advise pharmacologic treatment for this group because of the established associations between hypertension and subsequent development of complications in patients with diabetes. This is a somewhat more stringent treatment plan than recommended by the ADA guidelines but approximates the ISPAD guidelines [59]. (See "Nonemergent treatment of hypertension in children and adolescents", section on 'Who should be treated'.)

Before initiating treatment, all females should be given appropriate reproductive counseling because these drugs can be teratogenic.

Lisinopril and enalapril are ACE inhibitors that have been shown to be effective and safe in children, and have been shown to protect against the development of progressive nephropathy [66]. Therapy should be targeted to decrease BP values below the 90^th percentile, and <130/80 for adolescents ≥13 years old [65]. Other hypertensive agents, including angiotensin receptor blockers (ARBs), can be used if the patient cannot tolerate ACE inhibitors or if targeted BP goals are not reached. (See "Nonemergent treatment of hypertension in children and adolescents".)

Retinopathy — The risk for diabetic retinopathy is closely associated with longer duration of diabetes and poorer glycemic control, as demonstrated by studies in adults. Observational data from children confirm these same relationships [46,47,51,67-73]. As an example, in a large study of 441 children (median age of 15.5 years and median duration of diabetes 6.3 years), mild nonproliferative retinopathy was present in 16 percent [69]. Among those with retinopathy, the median duration of diabetes at the time of detection of retinal changes was 16.6 years. Patients with poorer glycemic control developed retinopathy more rapidly than those with good glycemic control: the median disease duration prior to detection of retinopathy was 15.5 years for patients with A1C values ≥7.5 percent, as compared with 18.3 years for those with A1C values <7.5 percent.

Other risk factors associated with retinopathy include hypertension, hyperlipidemia, smoking, and genetic susceptibility [40,70,71,74-76]. Persistent albuminuria is a risk factor for impaired color vision, which can precede retinopathy [77]. A low insulin-like growth factor-1 (IGF-1) level (which is associated with poor metabolic control) predicts progression of retinopathy, independent of age, sex, glycemic control, and diabetes duration [78].

The following is a brief summary of the retinal changes seen in patients with T1DM. A more complete description is presented separately. (See "Diabetic retinopathy: Classification and clinical features".)

●Background retinopathy describes the earliest retinal changes, including dilated retinal venules, microaneurysms, and capillary leakage (picture 1). Loss of visual acuity can occur if these changes are near the macula.

●Preproliferative retinopathy is the second stage of retinopathy with retinal microinfarcts visible as small flame-shaped blot hemorrhages proximal to the occlusion (picture 2) and "cotton wool" or "soft exudates" distal to the occlusion (picture 3).

●Proliferative retinopathy is the most severe form. It includes retinal ischemia, proliferation of new retinal blood vessels (picture 4), further hemorrhage, scarring resulting from contraction of fibrovascular proliferation, and retinal detachment.

If retinopathy is present in children and adolescents with T1DM, it is usually in the background or preproliferative stage.

Screening — To screen for retinopathy, we recommend a dilated ophthalmologic examination or retinal photography for children ≥11 years of age (or at onset of puberty if earlier) if the youth has had diabetes for three to five years, consistent with recommendations from the ADA and similar to those from ISPAD [8,58,59]. This examination generally should be repeated every two years; less frequent examinations may be acceptable if recommended by the child's eye care professional based on risk factor assessment, including an A1C of <8 percent. Note that a funduscopic examination without dilation of the pupils is not sufficient to screen for diabetic retinopathy.

Screening is mandated in order to detect early retinal changes, which may be reversible. Screening also identifies patients with more advanced disease that may be amenable to laser therapy, which, if applied in a timely manner, may prevent further progression of disease and vision loss. (See "Diabetic retinopathy: Screening".)

Neural retinal changes, including reduced macular and peripapillary retinal nerve fiber layer thickness (assessed using spectral domain optical coherence tomography), may precede clinically detectable retinal vasculopathy, and may serve in the future as an early indicator of retinopathy [79]. Also, specific changes in retinal vascular geometry, such as thinner and more tortuous vessels, may predict which patients are at a higher risk of developing diabetes complications [80].

Treatment — The following is a brief summary of the treatment of retinopathy in patients with T1DM. A more complete discussion is presented separately. (See "Diabetic retinopathy: Prevention and treatment".)

●Strict glycemic control can prevent, retard, or delay the onset of retinopathy. Background retinopathy can be reversed with better glycemic control, although initial worsening may occur.

●In patients with more advanced disease, laser therapy, if applied in a timely manner, may prevent progression of disease and visual loss, as may treatment with anti-vascular endothelial growth factor (anti-VEGF) therapy for macular edema.

●If hypertension is present, ACE inhibitors should be started because they retard progression of retinopathy, similar to their effect on diabetic nephropathy.

Neuropathy

●Screening – To screen for diabetic polyneuropathy, we recommend testing for vibration (using a 128 Hz tuning fork) and pressure sensation (using a 10 g monofilament) and proprioception at least annually in children 10 years or older (or at the onset of puberty, whichever is earlier), beginning five years after the diagnosis of diabetes [8] (see "Screening for diabetic polyneuropathy", section on 'Who should be screened?'). A comprehensive foot evaluation should also include assessment of symptoms of neuropathic pain, inspection of the foot, assessment of dorsalis pedis and posterior tibialis pulses, and assessment of patellar and ankle reflexes. In addition, patients should be screened for signs and symptoms of diabetic autonomic neuropathy, which include resting tachycardia, exercise intolerance, constipation, and symptoms of gastroparesis (nausea, vomiting, and early satiety). (See 'Miscellaneous' below.)

●Clinical manifestations – Although symptomatic diabetic neuropathy is uncommon in children and adolescents with T1DM, subclinical impairment of neurologic function has been reported in up to 68 percent of pediatric patients [47,81-86]. In children, both peripheral and autonomic neurologic systems can be affected. (See "Epidemiology and classification of diabetic neuropathy".)

•Peripheral polyneuropathy – Impaired peripheral nerve functions include nerve conduction and sensory perception [83-85,87,88]. The earliest evidence of peripheral neuropathy is distal sensory loss (distal symmetric sensorimotor polyneuropathy) affecting the "gloves and stockings" distribution, best tested with a 10 g monofilament. Nerve conduction studies, however, demonstrate a higher prevalence of subclinical motor rather than sensory neuropathy [83].

•Autonomic neuropathy – Impaired autonomic functions include abnormal heart rate variability and postural BP control, pupillary adaptation to darkness, and vibratory threshold [47,81,82,89,90]. Puberty is a critical time for the development of diabetic cardiac autonomic dysfunction [87,89]. (See "Diabetic autonomic neuropathy".)

●Risk factors – Similar to other microvascular complications, the risk of diabetic neuropathy increases with poor glycemic control and longer duration of disease [68,81,84,89,91]. The risk of neuropathy was also reported to be higher in patients taking insulin via multiple daily injections (MDI) compared with those on insulin pump therapy, which may reflect poorer glycemic control in those on MDI [92]. Improved glycemic control improves nerve function in diabetic patients. (See "Pathogenesis of diabetic polyneuropathy" and "Management of diabetic neuropathy".)

Cardiovascular disease — Cardiovascular disease is a major cause of morbidity and mortality in adults with T1DM. As an example, a study conducted in the United Kingdom during the 1990s documented a fourfold increase in risk for major cardiovascular disease in adult men with diabetes, and an eightfold increase in adult women, as compared with healthy individuals [93]. Although clinically apparent disease is rare during childhood, abnormalities in cardiac function and serum lipid profiles suggest that the disease process begins early in the course of diabetes. (See "Prevalence of and risk factors for coronary heart disease in patients with diabetes mellitus" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

Children with T1DM have reduced left ventricular size and decreased stroke volume even in the absence of hypertension or nephropathy, thought to represent a metabolically induced cardiomyopathy [94]. Decreased myocardial contractility has been reported in children with longstanding and poorly controlled diabetes, and subclinical alterations in cardiac function can be identified even earlier [95].

Dyslipidemia, atherosclerotic changes, and vascular stiffness are more common in children with diabetes than in healthy children and are associated with poor glycemic control, as illustrated by the following studies [96-98]:

●An observational study compared lipid profiles of 682 children with T1DM with those of healthy children in the general population [96]. Total cholesterol >200 mg/dL (5.2 mmol/L) was more common in children with diabetes compared with the general population (15.4 versus 11.2 percent), and abnormal total cholesterol or high-density lipoprotein (HDL) were seen more frequently in children with diabetes (18.6 versus 16.3 percent). A1C levels were significantly related to total cholesterol and non-HDL levels.

●Children and adolescents with T1DM are more likely to develop early atherosclerotic changes compared with controls, as indicated by increased carotid intima-media thickness and arterial stiffness [41,99,100]. These effects are partly mediated by low-density lipoprotein cholesterol (LDL), obesity and insulin resistance.

●Children with T1DM are at risk for cardiac autonomic dysfunction, and central adiposity and obesity further increase this risk, after controlling for A1C [101].

Screening for dyslipidemia — Screening should be provided to patients with T1DM as it can detect hyperlipidemia, which can be improved by better glycemic control and dietary changes. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

We agree with the following ADA guidelines for screening for hyperlipidemia in children with T1DM [8,102]:

●Obtain a lipid profile at diagnosis, after glycemic control is well established and ideally in the fasting state. Perform the initial screen at age ≥2 years.

●If the profile is within the accepted risk levels (LDL <100 mg/dL), initiate serial testing at 9 to 11 years of age and repeat every three years. Borderline or abnormal values should be repeated for confirmation in the fasting state. If lipids are abnormal, annual monitoring is recommended. If the initial screen is normal but the child's diabetes is in poor control (eg, A1C >9 percent), we suggest screening annually.

Treatment of hyperlipidemia — Appropriate therapy of dyslipidemia begins with diet, exercise, and improvement in glycemic control.

●Goal lipid levels for children with diabetes are similar to established guidelines for all children [103] but are somewhat more stringent in recognition of their increased cardiovascular risk. The ADA recommends the following lipid goals for children with diabetes [102]:

•LDL <100 mg/dL

•HDL >35 mg/dL

•Triglycerides <150 mg/dL

●Nonpharmacologic intervention – If LDL is >130 mg/dL, the initial step is to limit dietary fat according to the American Heart Association's "step 2" diet (dietary cholesterol less than 200 mg/day, fats <25 to 30 percent of total calories, saturated fat <7 percent of total calories, and avoidance of trans fats) [8,103]. In addition, blood glucose and weight control should be optimized and exercise recommendations provided. Fasting lipid profiles should be performed after three months and six months of intervention to determine trends in glycemic control and lipid concentrations [102].

●Pharmacologic therapy – Subsequent intervention is based primarily on LDL levels, as outlined below. Factors that prompt use of medication for children in this category include other cardiovascular risk factors (other lipid parameters, smoking status, BP, and family history of early cardiovascular disease), as well as assessment of whether nonpharmacologic options have been optimized.

Pharmacologic treatment with lipid-lowering agents is recommended for children with diabetes over 10 years of age if LDL exceeds the following levels despite dietary and other lifestyle changes [8,102]:

•LDL ≥160 mg/dL (4.1 mmol/L)

•LDL between 130 and 159 (3.4 to 4.1 mmol/L) if one or more other cardiovascular risk factors are present (including obesity, tobacco use, or a family history of early cardiovascular disease)

Statins (HMG-CoA reductase inhibitors) are generally recommended as first-line therapy [8]. The goal of pharmacologic therapy is an LDL <100 mg/dL (<2.6 mmol/L). An expert panel has published recommendations to guide decisions regarding treatment of lipid abnormalities in children and adolescents [103]. The use of statins in early pregnancy may be associated with risks to the fetus, so prevention of unplanned pregnancy is important for adolescent girls who are taking these drugs [104]. (See "Dyslipidemia in children and adolescents: Management" and "Statins: Actions, side effects, and administration", section on 'Risks in pregnancy and breastfeeding'.)

Despite a higher prevalence of hypertension and hyperlipidemia in children with T1DM than in controls without T1DM, pharmacotherapy is often underutilized for treatment of these cardiovascular risk factors [105].

MISCELLANEOUS — Other complications in pediatric patients with T1DM include:

●Gastroparesis – Postprandial antral hypomotility and delayed gastric emptying occur in 30 to 50 percent of individuals with longstanding T1DM; conversely, gastric emptying is accelerated in some individuals [106-111]. The gastric dysmotility is often but not consistently associated with nausea, vomiting, chronic abdominal pain, and constipation following meals, and can result in poor glycemic control and early satiety. Thus, adolescents with poor glycemic control and decreased caloric intake or other significant gastrointestinal symptoms should be evaluated for delayed gastric emptying, which is typically performed with scintigraphy (gastric emptying scan). Metoclopramide helps improve gastroparesis. (See "Diabetic autonomic neuropathy of the gastrointestinal tract", section on 'Gastroparesis'.)

●Necrobiosis lipoidica – This inflammatory skin condition associated with diabetes mellitus can be seen in 1 to 2 percent of children with diabetes and is more common in those with poorer glycemic control. Asymptomatic skin lesions usually occur on the shin as oval or irregularly shaped, indurated plaques with central atrophy and yellow pigmentation (picture 5). Patients with this condition have an increased risk for diabetic retinopathy and nephropathy [112].

●Joint mobility – Limited joint mobility, primarily affecting the hands and feet, occurred in the past in 9 to 50 percent of patients >10 years of age with T1DM and duration of diabetes that is >5 years [89,113]. Higher glycated hemoglobin (A1C) increases the risk of restricted joint mobility [114]. In severe cases, the skin has a thick and waxy appearance. Restricted joint mobility is detected when the patient cannot flatten the fingers on a flat surface or cannot completely appose their hands when asked to press both hands together in a praying position. Limited joint mobility is associated with other complications associated with poor glycemic control (ie, retinopathy and nephropathy). Because of improvements in diabetes control in most resource-abundant countries, this complication is uncommon today [115].

●Menstrual irregularities – In postmenarchal females, 19 percent will have menstrual irregularities, which increase in frequency with poor control and are most prevalent when A1C exceeds 10 percent. Menstrual cycles become more regular with better glycemic control [116].

●Paronychia – Adolescents with T1DM have a high prevalence of paronychia as compared with nondiabetic adolescents [117]. The risk of paronychia increases with duration of diabetes and is associated with impaired vibration sensation. It is associated with other complications associated with poor glycemic control (ie, retinopathy and nephropathy).

●Calcium, vitamin D, and bone changes – Patients with diabetes who have persistent microalbuminuria have lower levels of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and osteocalcin compared with children with diabetes who are normoalbuminuric [118]. Increased calcium losses in urine have been demonstrated, which improve with use of angiotensin-converting enzyme (ACE) inhibitors [119]. A lower rate of bone mineral accrual and decreased bone mineral content has been demonstrated in children and adolescents with T1DM compared with healthy children [120,121]. Decreased bone turnover and increased fracture rate has been reported [122].

MORTALITY — Diabetic ketoacidosis (DKA) is the primary cause of death in children and adolescents with T1DM. This was illustrated in a retrospective review of all deaths in the city of Chicago among children, adolescents, and young adults with T1DM [123]. Among 30 deaths, 20 were attributed to DKA or coincided with the diagnosis of diabetes. Five deaths were attributed to renal disease, and one to hypoglycemia. Similarly, in a series describing 83 deaths attributed to diabetes among children and adolescents in England, over 80 percent of the deaths were related to hyperglycemia or DKA, and most of the deaths that occurred in hospitals were attributed to cerebral edema [124]. Of note, 41 percent of the patients died at home or were moribund on arrival at the hospital, suggesting a need for closer supervision of this population. Hypoglycemia is identified as a cause of death in 5 to 10 percent of patients. (See "Diabetic ketoacidosis in children: Treatment and complications", section on 'Complications and mortality'.)

Mortality in children and adolescents with diabetes varies substantially with race in the United States. In the Chicago-based study cited above, deaths were disproportionately increased in non-Hispanic Black and Hispanic patients when compared with the ethnic distribution in the city of Chicago [123]. This may reflect socioeconomic disparities as well as institutional racism leading to differences in access to or implementation of comprehensive diabetes care. Similarly, a report from the Centers for Disease Control and Prevention found that mortality rates were more than twice as high among Black youths as compared with White youths [125]; this report included individuals with type 2 diabetes.

In adults with T1DM, important causes of mortality include vascular complications (such as cardiovascular disease) as well as DKA and hypoglycemia. An overview of these issues in adults is discussed in a separate topic review. (See "Glycemic control and vascular complications in type 1 diabetes mellitus".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lipid disorders and atherosclerosis in children" and "Society guideline links: Diabetes mellitus in children".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Type 1 diabetes (The Basics)" and "Patient education: My child has diabetes: How will we manage? (The Basics)" and "Patient education: Managing blood sugar in children with diabetes (The Basics)" and "Patient education: Carb counting for children with diabetes (The Basics)" and "Patient education: Managing diabetes in school (The Basics)" and "Patient education: Giving your child insulin (The Basics)" and "Patient education: Checking your child's blood sugar level (The Basics)" and "Patient education: Should I switch to an insulin pump? (The Basics)")

●Beyond the basics topics (see "Patient education: Type 1 diabetes: Overview (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Overview – Prevention, monitoring, and management of complications is a critical component of care for patients with type 1 diabetes mellitus (T1DM). Recommended monitoring approaches and schedules are outlined in the table (table 1).

Hypoglycemia and diabetic ketoacidosis are discussed in detail in separate topic reviews. (See "Hypoglycemia in children and adolescents with type 1 diabetes mellitus" and "Diabetic ketoacidosis in children: Clinical features and diagnosis" and "Diabetic ketoacidosis in children: Treatment and complications".)

●Growth – Most children with T1DM maintain normal growth and development, but those with poor glycemic control sometimes have growth failure and delayed puberty. In other patients, excessive caloric intake and/or excessive insulin doses may promote excessive weight gain. (See 'Growth' above.)

●Depression and eating disorders – Depression and eating disorders are common complications in adolescents with diabetes and are associated with poor glycemic control and an increased frequency of hospitalization.

All children with T1DM should be assessed for depression at least annually. This assessment is especially important for children 10 years and older and for those who are not adhering to the diabetes management regimen. Youth should also be screened for eating disorders, beginning between 10 and 12 years of age. (See 'Depression' above and 'Eating disorders' above.)

●Screening for vascular complications – For all children and adolescents with T1DM, routine screening includes the following; our suggested screening schedule is outlined in the table (table 1):

•Nephropathy – Screening consists of measuring the albumin:creatinine ratio in a random urine specimen. Moderately elevated albuminuria is the earliest stage of diabetic nephropathy and is reversible with appropriate therapy. (See 'Nephropathy' above.)

•Hypertension – Blood pressure should be measured at each routine visit for diabetes management (at least every three months) and more often in patients with abnormal results. Hypertension is defined as systolic blood pressure (SBP) or diastolic BP (DBP) ≥95^th percentile for children 1 to 13 years of age and ≥130/80 for adolescents 13 years and older on at least three occasions.

Hypertension in children with T1DM should be treated with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). (See 'Hypertension' above.)

•Retinopathy – Screening consists of a dilated ophthalmologic examination. The early stages of diabetic retinopathy can be reversed with appropriate therapy. (See 'Retinopathy' above.)

•Neuropathy – Screening consists of a foot examination and testing for vibration and pressure.

•Lipids – Screening consists of a lipid panel (random or fasting). The frequency of screening depends on the child's age and initial results; if glycemic control is very poor, more frequent screening may be necessary. (See 'Screening for dyslipidemia' above.)

•Smoking – During each routine health care visit, ask about smoking and use of electronic cigarettes (e-cigarettes [eg, vaping nicotine]), counsel youth about the adverse health effects of smoking and vaping (particularly diabetic vascular complications), and offer support and referral for smoking and vaping cessation. (See 'Treatment' above.)

●Autoimmune disease – Patients with T1DM are at increased risk for autoimmune thyroid disease and celiac disease. Details about these disorders and screening procedures are discussed separately. (See "Associated autoimmune diseases in children and adolescents with type 1 diabetes mellitus".)