Novel Biochemical Markers of Glycemia to Predict Pregnancy Outcomes in Women With Type 1 Diabetes

OBJECTIVEThe optimal method of monitoring glycemia in pregnant women with type 1 diabetes remains controversial. This study aimed to assess the predictive performance of HbA_1c, continuous glucose monitoring (CGM) metrics, and alternative biochemical markers of glycemia to predict obstetric and neonatal outcomes.RESEARCH DESIGN AND METHODSOne hundred fifty-seven women from the Continuous Glucose Monitoring in Women With Type 1 Diabetes in Pregnancy Trial (CONCEPTT) were included in this prespecified secondary analysis. HbA_1c, CGM data, and alternative biochemical markers (glycated CD59, 1,5-anhydroglucitol, fructosamine, glycated albumin) were compared at ∼12, 24, and 34 weeks’ gestation using logistic regression and receiver operating characteristic (ROC) curves to predict pregnancy complications (preeclampsia, preterm delivery, large for gestational age, neonatal hypoglycemia, admission to neonatal intensive care unit).RESULTSHbA_1c, CGM metrics, and alternative laboratory markers were all significantly associated with obstetric and neonatal outcomes at 24 weeks’ gestation. More outcomes were associated with CGM metrics during the first trimester and with laboratory markers (area under the ROC curve generally <0.7) during the third trimester. Time in range (TIR) (63–140 mg/dL [3.5–7.8 mmol/L]) and time above range (TAR) (>140 mg/dL [>7.8 mmol/L]) were the most consistently predictive CGM metrics. HbA_1c was also a consistent predictor of suboptimal pregnancy outcomes. Some alternative laboratory markers showed promise, but overall, they had lower predictive ability than HbA_1c.CONCLUSIONSHbA_1c is still an important biomarker for obstetric and neonatal outcomes in type 1 diabetes pregnancy. Alternative biochemical markers of glycemia and other CGM metrics did not substantially increase the prediction of pregnancy outcomes compared with widely available HbA_1c and increasingly available CGM metrics (TIR and TAR).     

Pregnancy Outcomes in Youth With Type 2 Diabetes: The TODAY Study Experience

OBJECTIVE

We evaluated pregnancy outcomes, maternal and fetal/neonatal, during the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study.

RESEARCH DESIGN AND METHODS

The TODAY study was a randomized controlled trial comparing three treatment options for youth with type 2 diabetes. Informed consent included the requirement for contraception, including abstinence; this was reinforced at each visit. Following informed consent, self-reported data related to the mother’s prenatal care and delivery and the infant’s health were retrospectively collected. When permitted, maternal medical records and infant birth records were reviewed.

RESULTS

Of the 452 enrolled female participants, 46 (10.2%) had 63 pregnancies. Despite continued emphasis on adequate contraception, only 4.8% of the pregnant participants reported using contraception prior to pregnancy. The mean age at first pregnancy was 18.4 years; the mean diabetes duration was 3.17 years. Seven pregnancies were electively terminated; three pregnancies had no data reported. Of the remaining 53 pregnancies, 5 (9.4%) resulted in early pregnancy loss, and 7 (13%) resulted in loss with inadequate pregnancy duration data. Two pregnancies ended in stillbirth, at 27 and 37 weeks, and 39 ended with a live-born infant. Of the live-born infants, six (15.4%) were preterm and eight (20.5%) had a major congenital anomaly.

CONCLUSIONS

Despite diabetes-specific information recommending birth control and the avoidance of pregnancy, 10% of the study participants became pregnant. Pregnancies in youth with type 2 diabetes may be especially prone to result in congenital anomalies. Reasons for the high rate of congenital anomalies are uncertain, but may include poor metabolic control and extreme obesity.     

Maternal Efficacy and Safety Outcomes in a Randomized, Controlled Trial Comparing Insulin Detemir With NPH Insulin in 310 Pregnant Women With Type 1 Diabetes

OBJECTIVE This randomized, controlled noninferiority trial aimed to compare the efficacy and safety of insulin detemir (IDet) versus neutral protamine Hagedorn (NPH) (both with prandial insulin aspart) in pregnant women with type 1 diabetes. RESEARCH DESIGN AND METHODS Patients were randomized and exposed to IDet or NPH up to 12 months before pregnancy or at 8-12 weeks gestation. The primary analysis aimed to demonstrate noninferiority of IDet to NPH with respect to A1C at 36 gestational weeks (GWs) (margin of 0.4%). The data were analyzed using linear regression, taking several baseline factors and covariates into account. RESULTS A total of 310 type 1 diabetic women were randomized and exposed to IDet (n = 152) or NPH (n = 158) up to 12 months before pregnancy (48%) or during pregnancy at 8-12 weeks (52%). The estimated A1C at 36 GWs was 6.27% for IDet and 6.33% for NPH in the full analysis set (FAS). IDet was declared noninferior to NPH (FAS, -0.06% [95% CI -0.21 to 0.08]; per protocol, -0.15% [-0.34 to 0.04]). Fasting plasma glucose (FPG) was significantly lower with IDet versus NPH at both 24 GWs (96.8 vs. 113.8 mg/dL, P = 0.012) and 36 GWs (85.7 vs. 97.4 mg/dL, P = 0.017). Major and minor hypoglycemia rates during pregnancy were similar between groups. CONCLUSIONS Treatment with IDet resulted in lower FPG and noninferior A1C in late pregnancy compared with NPH insulin. Rates of hypoglycemia were comparable.     

Association of Type 1 Diabetes With Month of Birth Among U.S. Youth: The SEARCH for Diabetes in Youth Study

OBJECTIVE

Seasonal environment at birth may influence diabetes incidence in later life. We sought evidence for this effect in a large sample of diabetic youth residing in the U.S.

RESEARCH DESIGN AND METHODS

We compared the distribution of birth months within the SEARCH for Diabetes in Youth Study (SEARCH study) with the monthly distributions in U.S. births tabulated by race for years 1982–2005. SEARCH study participants (9,737 youth with type 1 diabetes and 1,749 with type 2 diabetes) were identified by six collaborating U.S. centers.

RESULTS

Among type 1 diabetic youth, the percentage of observed to expected births differed across the months (P = 0.0092; decreased in October–February and increased in March–July). Their smoothed birth-month estimates demonstrated a deficit in November–February births and an excess in April–July births (smoothed May versus January relative risk [RR] = 1.06 [95% CI 1.02–1.11]). Stratifications by sex or by three racial groups showed similar patterns relating type 1 diabetes to month of birth. Stratification by geographic regions showed a peak-to-nadir RR of 1.10 [1.04–1.16] in study regions from the northern latitudes (Colorado, western Washington State, and southern Ohio) but no birth-month effect (P > 0.9) in study regions from more southern locations. Among type 2 diabetic youth, associations with birth month were inconclusive.

CONCLUSIONS

Spring births were associated with increased likelihood of type 1 diabetes but possibly not in all U.S. regions. Causal mechanisms may involve factors dependent on geographic latitude such as solar irradiance, but it is unknown whether they influence prenatal or early postnatal development.Diabetes has been found by some investigators to be least common among youth who were born in the fall and/or most common among youth born in the spring. Similar reports have come from several regions of Europe (1–4), from New Zealand (where spring occurs in September–November) (5), and from Israeli Jews (6). This pattern was not demonstrated, however, by some studies elsewhere in Europe (3), in East Asia (7,8), or in Cuba (9). The sole previous publication from the U.S. that tested the birth month and diabetes relationship was restricted to 604 African American diabetic youth who lived in Chicago (10). This report showed that the standardized birth ratio for all participants was reduced for births in October but that this finding was statistically significant only for youth diagnosed with diabetes at 15–17 years of age (versus younger ages) or for youth classified as probably having type 2 diabetes.Motivated by our interest in the developmental origins of diabetes, we have examined the distribution of birth months in a population-based U.S. sample of youth with diabetes. The calendar date of birth may serve as a useful marker for environmental exposures during the prenatal and early postnatal periods. The date of birth is known precisely for nearly every individual in modern societies, its normative distributions are empirically available wherever births have been widely registered, and it can be categorized in conventional calendar units such as season, month, or week. Knowing the date of birth can also provide a reasonable estimate of the date of conception or of any other developmental “time window.” Thus, critical developmental periods can be associated ecologically with variations in environmental phenomena such as solar exposure, climate, microbial burden, culture, or maternal nutrition. These associations, however, may not be the same in all geographic regions.     

Sulfonylurea Use and Incident Cardiovascular Disease Among Patients With Type 2 Diabetes: Prospective Cohort Study Among Women

OBJECTIVE

Evidence is inconsistent for the association between sulfonylurea use and risk of cardiovascular disease among patients with diabetes. We aimed to prospectively evaluate this association using the Nurses’ Health Study (NHS), a well-established cohort of U.S. women with long-term follow-up.

RESEARCH DESIGN AND METHODS

We followed 4,902 women (mean age 68 years) with diabetes (mean duration 11 years), but without cardiovascular disease at baseline. The use of sulfonylureas and other medications was self-reported at baseline and during the follow-up period of up to 10 years. Cox proportional hazards regression models were used to estimate the relative risk (RR) and 95% CI for the association between the sulfonylurea use and incident cardiovascular disease while accounting for potential confounders, including age, diabetes duration, diabetes-related complications, other antihyperglycemic medications, BMI, lifestyle factors, family history of cardiovascular diseases, and present chronic conditions. We also applied the propensity score stratification method to address the possibility of residual confounding.

RESULTS

We identified 339 incident cases of cardiovascular disease, including 191 cases of coronary heart disease (CHD) and 148 cases of stroke. A longer duration of sulfonylurea use was significantly associated with a higher risk of CHD (P for trend = 0.002); the RRs for CHD were 1.24 (95% CI 0.85–1.81) for patients who used sulfonylurea therapy for 1–5 years, 1.51 (0.94–2.42) for 6–10 years, and 2.15 (1.31–3.54) for >10 years, compared with nonusers. Compared with users of metformin monotherapy, the RR for CHD was 3.27 (1.31–8.17) for those who were treated with the combination of metformin and sulfonylurea. The analysis using propensity score stratification yielded similar results. We did not observe a significant association between sulfonylurea therapy and stroke risk.

CONCLUSIONS

Long-term use of sulfonylureas was associated with a significantly higher risk of developing CHD among women with diabetes.     

The Role of Nurses in Comprehensive Care Management of Pregnant Women With Drug Addiction

Drug addiction during pregnancy is a complex health and social issue that requires an interdisciplinary health care team providing nonjudgmental, comprehensive care. Critical challenges include onset of and attendance at prenatal care, potential obstetric complications, transition to extrauterine life and potential neonatal abstinence syndrome for the neonate, newborn feeding issues, postpartum depression and risk of relapse for women.     

Microalbuminuria, Preeclampsia, and Preterm Delivery in Pregnant Women With Type 1 Diabetes: Results from a nationwide Danish study

OBJECTIVE

To study the association between microalbuminuria and development of preeclampsia and preterm delivery in pregnant women with type 1 diabetes.

RESEARCH DESIGN AND METHODS

This was a population-based prospective study in 846 normoalbuminuric or microalbuminuric women with type 1 diabetes without antihypertensive treatment in early pregnancy. Data were collected prospectively by one to three caregivers in each center and reported to a central registry.

RESULTS

The prevalence of microalbuminuria in the first trimester was 10%, median diabetes duration was 11 years, and third-trimester A1C was 6.6%. The frequencies of preeclampsia and preterm delivery before 34 weeks in the microalbuminuric group were 40 and 13%, both significantly higher than those in the normoalbuminuric group (12 and 6%, respectively, P < 0.001). After adjustments for possible confounders, significant predictors for development of preeclampsia were microalbuminuria (odds ratio 4.0 [95% CI]), nulliparity (3.1 [1.9–5.1]), and third-trimester A1C (1.3 [1.1–1.5] per 1% increase). Delivery before 34 weeks was associated with early microalbuminuria in univariate analyses, but in multivariate analyses A1C was the only significant predictor of this outcome. Preeclampsia was associated with a threefold higher risk of delivery before 34 weeks.

CONCLUSIONS

The presence of microalbuminuria in early pregnancy is associated with a fourfold increased risk of developing preeclampsia. A1C values during pregnancy are highly predictive of both preeclampsia and preterm delivery. Future research with antihypertensive treatment in normotensive, microalbuminuric pregnant women to prevent preeclampsia is proposed.Women with type 1 diabetes and their offspring are at increased risk of development of preeclampsia and preterm delivery (1). It is well documented that the presence of diabetic nephropathy is associated with a very high risk of gestational hypertension, preeclampsia, and preterm delivery. The forerunner of diabetic nephropathy is characterized by urinary albumin excretion between 30 and 300 mg/24 h, so-called microalbuminuria (2,3). Whether the presence of microalbuminuria in early pregnancy is also associated with development of preeclampsia has only been investigated in relatively small selected samples (4–9), and some of these include women with type 1, type 2, and gestational diabetes mellitus. In one center a prevalence of preeclampsia of 40% in 26 women with type 1 diabetes and microalbuminuria has been described (9). Others could not find an association between slightly elevated protein excretion early in pregnancy and development of preeclampsia (10).In Denmark, clinical data on >1,200 pregnancies in women with type 1 diabetes were collected prospectively during 7 years. The current report focuses on the relationship between microalbuminuria present at the first pregnancy visit and the risk of preeclampsia and preterm delivery in patients without preexisting use of antihypertensive medication and/or diabetic nephropathy.     

Peri-Conceptional A1C and Risk of Serious Adverse Pregnancy Outcome in 933 Women With Type 1 Diabetes

OBJECTIVE

To study the association between peri-conceptional A1C and serious adverse pregnancy outcome (congenital malformations and perinatal mortality).

RESEARCH DESIGN AND METHODS

Prospective data were collected in 933 singleton pregnancies complicated by type 1 diabetes.

RESULTS

The risk of serious adverse outcome at different A1C levels was compared with the background population. The risk was significantly higher when peri-conceptional A1C exceeded 6.9%, and the risk tended to increase gradually with increasing A1C. Women with A1C exceeding 10.4% had a very high risk of 16%. Congenital malformation rate increased significantly at A1C above 10.4%, whereas perinatal mortality was increased even at A1C below 6.9%.

CONCLUSIONS

These results support recent guidelines of preconceptional A1C levels <7% in women with type 1 diabetes.Recently, guidelines for management of pregnancy in women with pregestational diabetes have recommended pregestational A1C values <7.0% (1,2) and <6.1% (3). Previous studies have reported information of early A1C including 116–691 pregnancies (4–10). We aimed to study whether there is a threshold value for peri-conceptional A1C in women with type 1 diabetes below which the risk of serious adverse pregnancy outcome (congenital malformation and perinatal mortality) is not increased.     

Comprehensive Care and Pregnancy: The Unmet Care Needs of Pregnant Women with a History of Rape

This paper proposes a framework for assessing the unmet needs of rape survivors during pregnancy based on the Sexual Assault Nurse Examiner (SANE) practice level theory and an empirical exploration of rape survivors’ health status in pregnancy via a secondary analysis. Our findings indicate that there may be unmet needs in pregnancy related to all five post-assault comprehensive care components: (1) physical care, (2) pregnancy prevention, (3) sexually transmitted infection screening, (4) psychological care, and (5) legal care. Rape history and its current impact on the survivor predicted somatic disorders, substance use, unwanted pregnancy, infections, posttraumatic stress disorder, and recent abuse.     

Maternal Family History of Diabetes Is Associated With a Reduced Risk of Cardiovascular Disease in Women With Type 2 Diabetes: The Fremantle Diabetes Study

OBJECTIVE

To investigate whether parental family history of diabetes influences cardiovascular outcomes in type 2 diabetes.

RESEARCH DESIGN AND METHODS

We studied 1,294 type 2 diabetic patients (mean age 64.1 years, 51.2% female) recruited to a community-based cohort study from 1993 to 1996 and followed until mid-2006. A data linkage system assessed all-cause and cardiac mortality, incident myocardial infarction, and stroke. Cox proportional hazards modeling was used to determine the influence of maternal or paternal family history on these outcomes.

RESULTS

A maternal family history of diabetes was reported by 20.4% of the cohort, 8.3% reported paternal family history, and 2.0% reported both parents affected. Maternal and paternal family history was associated with earlier age of diabetes onset, and maternal family history was associated with worse glycemic control. For all patients, maternal family history was significantly associated with reduced risk of all-cause mortality and cardiac mortality. When analyzed by sex, maternal family history had no effect on male patients, whereas female patients with diabetic mothers had significantly reduced hazard ratios for death from all causes (0.63 [95% CI 0.41–0.96]; P = 0.033), for death from cardiac causes (0.32 [0.14–0.72]; P = 0.006), and for first myocardial infarction (0.45 [0.26–0.76]; P = 0.003). Paternal family history status was not associated with these outcomes.

CONCLUSIONS

A maternal family history of diabetes confers relative protection against cardiovascular disease in female patients but not in male patients with type 2 diabetes. Paternal family history is associated with risks equivalent to those without a family history of diabetes. Some of the clinical heterogeneity of type 2 diabetes is related to maternal transmission effects with differential impact on male and female patients.The complex etiology of type 2 diabetes involves both genetic components and environmental exposures. In type 2 diabetes, there is a well documented association between a family history of the disease and its development (1,2). Maternal and paternal family histories of diabetes are both associated with an earlier age of onset (2–4), and this effect is more marked when multiple family members are affected (5). In addition, intrauterine exposure to diabetes increases the risk of diabetes in offspring (6), which may help explain the reported excess maternal transmission (7,8).Patients with familial diabetes have relatively poor glycemic control, but few other clinical differences have been reported (4,5,9,10). An early age of onset and poor glycemic control would both be expected to have a negative impact on the development of chronic complications, but no such longitudinal data have been published. In the present study, we examined relationships among parental diabetes and important clinical outcomes in type 2 diabetes, including incident coronary heart disease (CHD) and all-cause and cardiac mortality in a large community-based sample of patients with type 2 diabetes. We hypothesized that familial diabetes would indicate worse clinical outcomes. We investigated potential relationships in male and female patients separately, given the known differences in CHD incidence between men and women with diabetes (11).     

Diabetic Nephropathy and Microalbuminuria in Pregnant Women With Type 1 and Type 2 Diabetes: Prevalence,antihypertensive strategy,and pregnancy outcome

OBJECTIVE

To evaluate the prevalence of diabetic nephropathy and microalbuminuria in pregnant women with type 2 diabetes in comparison with type 1 diabetes and to describe pregnancy outcomes in these women following the same antihypertensive protocol.

RESEARCH DESIGN AND METHODS

Among 220 women with type 2 diabetes and 445 women with type 1 diabetes giving birth from 2007–2012, 41 women had diabetic nephropathy (albumin-creatinine ratio ≥300 mg/g) or microalbuminuria (albumin-creatinine ratio 30–299 mg/g) in early pregnancy. Antihypertensive therapy was initiated if blood pressure ≥135/85 mmHg or albumin-creatinine ratio ≥300 mg/g.

RESULTS

The prevalence of diabetic nephropathy was 2.3% (5 of 220) in women with type 2 diabetes and 2.5% (11 of 445) in women with type 1 diabetes (P = 1.00). The figures for microalbuminuria were 4.5 (10 of 220) vs. 3.4% (15 of 445) (P = 0.39). Baseline glycemic control was comparable between women with type 2 diabetes (n = 15) and type 1 diabetes (n = 26). Blood pressure at baseline was median 128 (range 100–164)/81 (68–91) vs. 132 (100–176)/80 (63–100) mmHg (not significant) and antihypertensive therapy in type 2 versus type 1 diabetes was used in 0 and 62%, respectively, at baseline, increasing to 33 and 96%, respectively, in late pregnancy. Pregnancy outcome was comparable regardless type of diabetes; gestational age at delivery: 259 days (221–276) vs. 257 (184–271) (P = 0.19); birth weight 3,304 g (1,278–3,914) vs. 2,850 (370–4,180) (P = 0.67).

CONCLUSIONS

The prevalence of diabetic nephropathy and microalbuminuria in early pregnancy was similar in type 2 and type 1 diabetes. Antihypertensive therapy was used more frequently in type 1 diabetes. Pregnancy outcome was comparable regardless type of diabetes.Youth onset of type 2 diabetes continues to increase worldwide (1), and pregnancy in women with type 2 diabetes is a substantial clinical problem (2). Cross-sectional studies show a higher prevalence of albuminuria in young adults with type 2 diabetes compared with type 1 diabetes (3–5). Subjects with youth-onset type 2 diabetes have a fourfold increased risk of end-stage kidney disease compared with youth with type 1 diabetes (6). Literature focusing on kidney involvement in pregnant women with diabetes is scarce (7–11). To our knowledge, no studies using strict diagnostic criteria have described the prevalence of diabetic nephropathy and microalbuminuria in early pregnancy in women with type 2 diabetes. Likewise, recommendations for an antihypertensive strategy during these pregnancies is missing.In pregnant women with type 1 diabetes, nephropathy is associated with poor pregnancy outcome in terms of increased rates of preeclampsia and preterm delivery (11–13). In these women, intrauterine growth restriction (11) occurs almost twice as often as in the general population (13), and in the late 1990s, preterm delivery before 34 weeks occurred in ∼30% (13). In women with type 1 diabetes and microalbuminuria, preterm delivery and preeclampsia are also frequent and serious complications (11,13,14).In nonpregnant subjects with diabetes, inhibition of the renin angiotensin system is a cornerstone in the treatment of microalbuminuria and diabetic nephropathy (15–19). However, during pregnancy, antihypertensive therapy is often not indicated until sustained blood pressure elevations >150 mmHg systolic or 100 mmHg diastolic are documented (20), owing to concerns for reduced placental circulation, which may cause fetal hypoxia and intrauterine growth restriction (21).In Copenhagen, we recommend blood pressure levels <135/85 mmHg and urinary albumin-creatinine ratio <300 mg/g during pregnancy in women with diabetes and diabetic nephropathy or microalbuminuria (14,22), regardless of the type of diabetes. Using this strategy, observational studies have shown that early initiation of intensive antihypertensive therapy during pregnancy leads to a reduced prevalence of preterm delivery in women with type 1 diabetes and diabetic nephropathy or microalbuminuria (14,22). Brown and Garovic (23) also recommend a lower threshold for antihypertensive treatment in pregnant women with diabetes and kidney involvement compared with nondiabetic pregnant women.However, it has not been evaluated whether women with type 2 diabetes benefit from intensive antihypertensive therapy to the same degree as women with type 1 diabetes during pregnancy.In this study, we evaluated the prevalence of diabetic nephropathy and microalbuminuria as well as pregnancy outcome in a recent cohort of pregnant women with type 2 or type 1 diabetes treated according to the same protocol for intensive antihypertensive treatment during pregnancy.     

Driving Mishaps Among Individuals With Type 1 Diabetes: A prospective study

OBJECTIVE

Hypoglycemia-related neuroglycopenia disrupts cognitive-motor functioning, which can impact driving safety. Retrospective studies suggest that drivers with type 1 diabetes experience more collisions and citations than their nondiabetic spouses. We present the first prospective data documenting the occurrence of apparent neuroglycopenia-related driving performance impairments.

RESEARCH DESIGN AND METHODS

We completed the initial screening of 452 drivers from three geographically diverse centers who then reported monthly occurrences of driving “mishaps,” including collisions, citations, losing control, automatic driving, someone else taking over driving, and moderate or severe hypoglycemia while driving.

RESULTS

Over 12 months, 52% of the drivers reported at least one hypoglycemia-related driving mishap and 5% reported six or more. These mishaps were related to mileage driven, history of severe hypoglycemia, and use of insulin pump therapy.

CONCLUSIONS

Many individuals with type 1 diabetes report hypoglycemia-related driving events. Clinicians should explore the recent experiences with hypoglycemia while driving and the risk of future events.Hypoglycemia is the major barrier to type 1 diabetes intensive insulin therapy (1), in part because of its disruptions on cognitive-motor functioning (2). One practical implication is its adverse effect on vehicular driving performance, resulting in collisions and citations (3,4). These potential disruptive effects are made further problematic because some individuals with diabetes decide to drive when they know that their blood glucose is low (5).Retrospective studies (6) have documented that individuals with type 1 diabetes compared with those with type 2 diabetes have more collisions and citations. The current study presents the first prospective data documenting the occurrence of different types of hypoglycemia-related driving mishaps.     

Reduced Heart Rate Variability Among Youth With Type 1 Diabetes: The SEARCH CVD study

OBJECTIVE

This study compared heart rate variability (HRV) parameters in youth with and without type 1 diabetes and explored potential contributors of altered HRV.

RESEARCH DESIGN AND METHODS

HRV parameters were measured among 354 youth with type 1 diabetes (mean age 18.8 years, diabetes duration 9.8 years, and mean A1C 8.9%) and 176 youth without diabetes (mean age 19.2 years) participating in the SEARCH CVD study. Multiple linear regression was used to assess the relationship between diabetes status and HRV parameters, adjusting for covariates.

RESULTS

Compared with control subjects, youth with type 1 diabetes had reduced overall HRV (10.09 ms lower SD of NN intervals [SDNN]) and markers of parasympathetic loss (13.5 ms reduced root mean square successive difference of NN intervals [RMSSD] and 5.2 normalized units (n.u.) reduced high frequency [HF] power) with sympathetic override (5.2 n.u. increased low frequency [LF] power), independent of demographic, anthropometric, and traditional cardiovascular risk factors. Older age, female sex, higher LDL cholesterol and triglyceride levels, and presence of microalbuminuria were independently associated with lower HRV but did not account for the observed differences between youth with and without diabetes. Youth with type 1 diabetes and A1C levels ≥7.5% had significantly worse HRV parameters than control subjects; however, in youth with optimal glycemic control (A1C <7.5%), HRV parameters did not differ significantly from control subjects.

CONCLUSIONS

Youth with type 1 diabetes have signs of early cardiac autonomic neuropathy: reduced overall HRV and parasympathetic loss with sympathetic override. The main driver of these subclinical abnormalities appears to be hyperglycemia.Cardiac autonomic neuropathy (CAN) is one of the most overlooked chronic complications of diabetes, progressing silently over time before it becomes clinically apparent (1). Since individuals with diabetes and CAN have a 3.4 times higher risk of mortality than those without CAN, early identification may mitigate the increased risk (2). Reduced heart rate variability (HRV) is the earliest subclinical marker of CAN and has been shown to increase the risk of arrhythmia, sudden death, and silent myocardial ischemia in adults (1). Subclinical CAN has been detected within a year of diagnosis in individuals with type 2 diabetes and within 2 years in individuals with type 1 diabetes (3). Several epidemiological studies have documented the prevalence and correlates of CAN in adults with diabetes (1,4–6). The European Epidemiology and Prevention of Diabetes (EURODIAB) study reported 36% CAN prevalence among nearly 3,000 adults with type 1 diabetes (4). However, data regarding the presence and correlates of subclinical CAN among contemporary youth and young adults with type 1 diabetes are sparse (7–10). On one hand, these individuals with type 1 diabetes have a younger age at onset and thus a longer duration of hyperglycemia (11); on the other hand, they are benefiting from more sophisticated insulin regimens and improved glucose monitoring than persons with type 1 diabetes diagnosed in earlier years (12). To address this gap, we explored the presence of subclinical markers of CAN among youth with and without type 1 diabetes and assessed the demographic, anthropometric, and metabolic risk factors associated with these markers in the SEARCH Cardiovascular Disease Study (SEARCH CVD).     

Increase in Prevalence of Diabetic Ketoacidosis at Diagnosis Among Youth With Type 1 Diabetes: The SEARCH for Diabetes in Youth Study

OBJECTIVEWe previously reported a high (˜30%) but stable prevalence of diabetic ketoacidosis (DKA) at youth-onset diagnosis of type 1 diabetes (2002 and 2010). Given the changing demographics of youth-onset type 1 diabetes, we sought to evaluate temporal trends in the prevalence of DKA at diagnosis of type 1 diabetes from 2010 to 2016 among youth <20 years of age and evaluate whether any change observed was associated with changes in sociodemographic distribution of those recently diagnosed.RESEARCH DESIGN AND METHODSWe calculated prevalence of DKA within 1 month of type 1 diabetes diagnosis by year and evaluated trends over time (2010–2016) (n = 7,612 incident diabetes cases; mean [SD] age 10.1 [4.5] at diagnosis). To assess whether trends observed were attributable to the changing distribution of sociodemographic factors among youth with incident type 1 diabetes, we estimated an adjusted relative risk (RR) of DKA in relation to calendar year, adjusting for age, sex, race/ethnicity, income, education, health insurance status, language, season of diagnosis, and SEARCH for Diabetes in Youth Study site.RESULTSDKA prevalence increased from 35.3% (95% CI 32.2, 38.4) in 2010 to 40.6% (95% CI 37.8, 43.4) in 2016 (P_trend = 0.01). Adjustment for sociodemographic factors did not substantively change the observed trends. We observed a 2% annual increase in prevalence of DKA at or near diagnosis of type 1 diabetes (crude RR 1.02 [95% CI 1.01, 1.04] and adjusted RR 1.02 [95% CI 1.01, 1.04]; P = 0.01 for both).CONCLUSIONSPrevalence of DKA at or near type 1 diabetes diagnosis has increased from 2010 to 2016, following the high but stable prevalence observed from 2002 to 2010. This increase does not seem to be attributable to the changes in distribution of sociodemographic factors over time.     

妊娠期糖尿病孕妇血糖管理决策困境的质性研究

目的 了解妊娠期糖尿病孕妇在血糖管理过程中面临的决策困境,为促进孕妇良好的血糖管理决策提供支持.方法 采用目的抽样方法,选取2020年9-12月上海市4所医疗机构就诊的28名妊娠期糖尿病孕妇进行半结构式个人深度访谈.采用内容分析法分析资料并提炼主题.结果 妊娠期糖尿病孕妇在血糖管理过程中主要有三大决策困境,包括:信息来...     

The Role of Angiogenic and Antiangiogenic Factors in the Second Trimester in the Prediction of Preeclampsia in Pregnant Women With Type 1 Diabetes

OBJECTIVE

To assess the association between circulating angiogenic and antiangiogenic factors in the second trimester and risk of preeclampsia in women with type 1 diabetes.

RESEARCH DESIGN AND METHODS

Maternal plasma concentrations of placental growth factor (PlGF), soluble fms-like tyrosine kinase 1 (sFlt-1), and soluble endoglin (sEng) were available at 26 weeks of gestation in 540 women with type 1 diabetes enrolled in the Diabetes and Preeclampsia Intervention Trial.

RESULTS

Preeclampsia developed in 17% of pregnancies (n = 94). At 26 weeks of gestation, women in whom preeclampsia developed later had significantly lower PlGF (median [interquartile range]: 231 pg/mL [120–423] vs. 365 pg/mL [237–582]; P < 0.001), higher sFlt-1 (1,522 pg/mL [1,108–3,393] vs. 1,193 pg/mL [844–1,630] P < 0.001), and higher sEng (6.2 ng/mL [4.9–7.9] vs. 5.1 ng/mL[(4.3–6.2]; P < 0.001) compared with women who did not have preeclampsia. In addition, the ratio of PlGF to sEng was significantly lower (40 [17–71] vs. 71 [44–114]; P < 0.001) and the ratio of sFlt-1 to PlGF was significantly higher (6.3 [3.4–15.7] vs. 3.1 [1.8–5.8]; P < 0.001) in women who later developed preeclampsia. The addition of the ratio of PlGF to sEng or the ratio of sFlt-1 to PlGF to a logistic model containing established risk factors (area under the curve [AUC], 0.813) significantly improved the predictive value (AUC, 0.850 and 0.846, respectively; P < 0.01) and significantly improved reclassification according to the integrated discrimination improvement index (IDI) (IDI scores 0.086 and 0.065, respectively; P < 0.001).

CONCLUSIONS

These data suggest that angiogenic and antiangiogenic factors measured during the second trimester are predictive of preeclampsia in women with type 1 diabetes. The addition of the ratio of PlGF to sEng or the ratio of sFlt-1 to PlGF to established clinical risk factors significantly improves the prediction of preeclampsia in women with type 1 diabetes.Preeclampsia is characterized by the development of hypertension and new-onset proteinuria during the second half of pregnancy (1,2), leading to increased maternal morbidity and mortality (3). Women with type 1 diabetes are at increased risk for development of preeclampsia during pregnancy, with rates being two-times to four-times higher than that of the background maternity population (4,5). Small advances have come from preventive measures, such as low-dose aspirin in women at high risk (6); however, delivery remains the only effective intervention, and preeclampsia is responsible for up to 15% of preterm births and a consequent increase in infant mortality and morbidity (7).Although the etiology of preeclampsia remains unclear, abnormal placental vascular remodeling and placental ischemia, together with maternal endothelial dysfunction, hemodynamic changes, and renal pathology, contribute to its pathogenesis (8). In addition, over the past decade accumulating evidence has suggested that an imbalance between angiogenic factors, such as placental growth factor (PlGF), and antiangiogenic factors, such as soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng), plays a key role in the pathogenesis of preeclampsia (8,9). In women at low risk (10–13) and women at high risk (14,15), concentrations of angiogenic and antiangiogenic factors are significantly different between women who later develop preeclampsia (lower PlGF, higher sFlt-1, and higher sEng levels) compared with women who do not.Few studies have specifically focused on circulating angiogenic factors and risk of preeclampsia in women with diabetes, and the results have been conflicting. In a small study, higher sFlt-1 and lower PlGF were reported at the time of delivery in women with diabetes who developed preeclampsia (16). In a longitudinal prospective cohort of pregnant women with diabetes, Yu et al. (17) reported increased sFlt-1 and reduced PlGF in the early third trimester as potential predictors of preeclampsia in women with type 1 diabetes, but they did not show any difference in sEng levels in women with preeclampsia compared with women without preeclampsia. By contrast, Powers et al. (18) reported only increased sEng in the second trimester in women with pregestational diabetes who developed preeclampsia.The aim of this study, which was significantly larger than the previous studies highlighted, was to assess the association between circulating angiogenic (PlGF) and antiangiogenic (sFlt-1 and sEng) factors and the risk of preeclampsia in women with type 1 diabetes. A further aim was to evaluate the added predictive ability and clinical usefulness of angiogenic factors and established risk factors for preeclampsia risk prediction in women with type 1 diabetes.